. 11:19. 3" 19.)} . 0. it... ‘ . " ”Elam; / .-~’ LIBRARY Michigan State University This is to certify that the dissertation entitled THE APPLICATIONS OF THE ANNULATIONS OF FISCHER CARBENE COMPLEXES presented by CHUNRUI WU has been accepted towards fulfillment of the requirements for the Doctoral degree in Chemistry J m b LW Major Professor’s Signature é/H/é'? Date MSU is an affirmative-action, equal-opportunity employer PLACE IN RETURN BOX to remove this checkout from your record. TO AVOID FINES return on or before date due. MAY BE RECALLED with earlier due date if requested. DAIEDUE DATEDUE DATEDUE 6/07 p:/ClRC/DateDue.indd-p.1 THE APPLICATIONS OF THE ANNULATIONS OF FISCHER CARBENE COMPLEXES VOLUME I By Chunrui Wu A DISSERTATION Submitted to Michigan State University In partial fulfillment of the requirements For the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 2007 ABSTRACT THE APPLICATION OF THE ANNULATIONS OF FISCHER CARBENE COMPLEXES By Chunrui Wu This dissertation covers the chromium Fischer carbene complexes in the annulation reactions in the following area: the chemoselectivity of different alkynes in the benzannulation reaction, the mechanism of the benzannulation reaction, and the applications of the benzannulation reaction toward the synthesis of natural products. A competition study in the benzannulation reaction of Fischer carbene complexes between different alkynes was examined. The temperature, solvent and the scope of alkynes were investigated. The chemoselectivity between the different alkynes was controlled by the steric interaction between the carbene complex and the alkyne. The solvent has small effect on the selectivity. A pseudo-symmetric intermediate was designed to generate in the reaction to probe the vinyl intermediate in the benzannulation reaction. The alkyne insertion step was proved to be irreversible. Electronic perturbation in the benzannulation was pursued by designing another pseudo-symmetric intermediate with two electronically differentiated arms. Between the two mechanisms demonstrated in this thesis, mechanism l with the initial formation of the n1,n3-carbene complexed intermediate is considered the more likely but the results of the present study could not rule out mechanism II which proposed the initial formation of the metallacyclobutene intermediate. results of the present study could not rule out mechanism II which proposed the initial formation of the metallacyclobutene intermediate. The tautomer-arrested annulation was strategically applied in the attempts to the synthesis of Richardianidin-1 to construct the BC ring moiety. Both intramolecular and intermolecular methods were attempted. The intramolecular annulation involves the tethering of the alkyne to the oxygen stabilizing substituent of the carbene carbon, and the outcome of the annulation was dependent on the nature of substituent on the alkyne. The study of the intermolecular approach was focus on the regioselectivity of the alkyne incorporation, and this annulation provided higher regioselectivity than the regular benzannulation. The cyclohexadienone annulation was successfully applied to the total synthesis of Phomactin BZ. Thebicyclic frame of Phomactin 82 could be generated in a single step by intramolecular cyclohexadienone annulation. Both diastereomers from the annulation could be converted to the natural product concisely by similar synthetic routes. An alternative pathway utilizing intermolecular cyclohexadienone annulation reaction and RCM as the key steps was also demonstrated. This intermolecular pathway provided the mutual bicyclic intermediates in high diastereoselectivity, and potentially could lead to the asymmetric synthesis of (+)-Phomactin 82 in the near future. ACKNOWLEDGEMENTS First and foremost, I would like to thank my advisor Dr. William Wulff for his endless patience, invaluable advice and encouragement during my graduate studies. Thanks him for providing me the great opportunity to work on the Fischer carbene complexes projects. Without his guidance, this thesis could not be possible. I would also like to thank my committee members, Dr. Babak Borhan, Dr. Gregory L. Baker and Dr. Aaron L Odom for their guidance in my research and reading my thesis. Special thanks go to Dr. Borhan for being my second reader and giving me valuable feedback for my thesis. Thanks my labmates for providing a friendly working environment. I would like to thank Dr. Jie Huang for the preliminary studies on the phomactin project. Many thanks to Dr. Yonghong Deng for her help in the first two years of my graduate studies. I am also grateful to Dr. Rui Huang for his assistant in the Mass spectra and elemental analysis. I am very grateful to my friends at Michigan State University, who make the boring graduate studies more colorful and easily. Finally, I would like to thank my mom, dad, my sister and my husband Feng for their love and support throughout my life. iv TABLE OF CONTENTS LIST OF SCHEMES ............................................................................................. ix LIST OF TABLES ................................................................................................ xiv LIST OF FIGURES ............................................................................................. xv ABBREVIATIONS ............................................................................................... xvi CHAPTER 1 Introduction and Background of Chromium Fischer Carbene Complexes ............ 1 1.1 Annulation reactions of Fischer carbene complexes with acetylenes ........ 4 1.1.1 Benzannulation ................................................................................. 4 1.1.2 Cyclohexadienone annulation ........................................................... 7 1.1.3 Tautomer-arrested annulation ........................................................... 8 1.1.4 Annulation reaction with B-amino substituted carbene complexes .. 10 1.1.5 Reaction of (LB-unsaturated Fischer carbene complex prepared in situ .................................................................................................. 13 1.2 Reaction of Fischer carbene complexes with alkenes ............................. 14 1.2.1 Cyclopropanation with simple alkenes ............................................ 14 1.2.2 Cyclopropanation with dienes ......................................................... 16 1.2.3 Metathesis ....................................................................................... 17 1.3 Reactions of Fischer carbene complexes involving metal-mediated transformation ......................................................................................... 18 1.3.1 Pd-catalyzed dimerizations ............................................................. 18 1.3.2 Rh-catalyzed annulations ................................................................ 20 1.3.3 Ni-mediated annulations .................................................................. 23 1.4 Photolysis of Fischer carbene complexes ................................................ 25 1.5 Summary ................................................................................................. 26 CHAPTER 2 A Competition Study in the Benzannulation Reaction of Fischer Chromium Carbene Complexes: Terminal vs. Internal Alkynes ........................................... 27 2.1 Background ............................................................................................. 27 2.2 Competition reaction between terminal and internal alkynes ................... 28 2.3 Competition reaction between different terminal alkynes and competition between different internal alkynes .......................................................... 36 2.4 Competition studies between terminal alkyne and 1—silyl protected terminal alkyne ........................................................................................ 38 2.5 Summary ................................................................................................. 39 V CHAPTER 3 Mechanistic Study on the Benzannulation Reaction: A Probe for Symmetrical Vinyl Carbene Complexed Inten'nediates ............................................................ 40 3.1 Introduction ............................................................................................. 40 3.2 Mechanistic studies with deuterium labeled pseudo-symmetric vinyl intermediate ............................................................................................ 43 3.2.1 Introduction ..................................................................................... 43 3.2.2 Preparation of carbene complexes and alkynes .............................. 46 3.2.3 Benzannulation Reaction with deuterium labeled substrates .......... 47 3.2.4 Discussion ....................................................................................... 49 3.3 Electronic perturbation of the benzannulation reaction ............................ 56 3.4 Summary ................................................................................................. 62 CHAPTER 4 Studies Toward Total Synthesis of Richardianidin-1 ........................................... 63 4.1 Background ............................................................................................. 63 4.1.1 Intramolecular Annulation of Fischer Carbene Complex ................. 63 4.1.2 Retrosynthetic analysis of Richardianidin-1 ..................................... 65 4.2 Intramolecular Approach .......................................................................... 66 4.2.1Intramolecular annulation of Fischer carbene complexes containing an acetal tether ................................................................................ 66 4.2.2lntramolecular annulation of Fischer carbene complexes containing a silicon tether ..................................................................................... 72 4.3 Intermolecular Approach ......................................................................... 74 4.4 Mechanistic considerations ..................................................................... 77 4.5 Summary ................................................................................................ 79 CHAPTER 5 Total Synthesis of Phomactin B2: the Application of an Intramolecular Cyclohexadienone Annulation of Fischer Carbene Complexes .......................... 81 5.1 Background on Phomactins ..................................................................... 81 5.1.1 Isolation and bioactivity of Phomactins ............................................ 81 5.1.2 Previous total syntheses of Phomactins .......................................... 82 5.1.3 Retrosynthetic analysis of Phomactins and previous work in our group ....................................................................................... 85 5.2 Synthesis of key intermediates 331 ......................................................... 88 5.2.1Synthesis of vinyl iodine 333 ............................................................ 88 5.2.2 Synthesis of carbene complexes ..................................................... 89 5.2.3 Modification of the carbene complex preparation ............................ 91 5.2.4 Thermolysis of carbene complexes 349 and 359 ............................ 95 5.3 Total synthesis of Phomactin 32 from the minor isomer 361 ................... 96 5.3.1 Synthesis of key intermediate 370 ................................................... 97 5.3.2 Synthesis of allylic alcohol ............................................................... 99 5.3.3 Epoxidation and end-game of the synthesis of Phomactin 82 ...... 102 5.4 Total synthesis of Phomactin 82 from major isomer 360 ....................... 106 5.4.1 Peterson olefination ....................................................................... 107 vi 5.4.2 Synthesis of allylic alcohols ........................................................... 110 5.4.3 Synthesis of Phomactin B2 from 390 ............................................ 112 5.5 Attempts to invert the stereocenter at C2 .............................................. 117 5.5.1 Conversion of stereocenter at CZ from B to a ............................... 117 5.5.2 Conversion of stereocenter at C2 from a to 8 ............................... 124 5.6 Summary ............................................................................................... 125 CHAPTER 6 Intermolecular Cyclohexadienone Annulation Approach to the Formal Total Synthesis of Phomactin B2 ............................................................................... 126 6.1 Background ........................................................................................... 126 6.1.1 Diastereoselective cyclohexadienone annulation .......................... 126 6.1.2 Retrosynthetic analysis of Phomactin B2 involving intermolecular cyclohexadienone annulation ........................................................ 128 6.2 Intermolecular cyclohexadienone annulation ......................................... 129 6.2.1 Preparation of carbene complex 329 and alkyne 431 ................... 129 6.2.2 Annulation of carbene complex 329 and alkyne 431 ..................... 131 6.2.3 Optimization of annulation reaction between 329 and 431s ......... 132 6.3 Ring-closing metathesis ......................................................................... 134 6.3.1 Ring-closing metathesis of 328 ..................................................... 134 6.3.2 Cleavage of the trityl group in 327 ................................................ 136 6.3.3 Ring-closing metathesis of 42% ................................................... 138 6.3.4 Ring-closing metathesis of 444 ..................................................... 139 6.3.5 Ring-closing metathesis of 429c-e ................................................ 140 6.3.6 Mini-conclusion ............................................................................. 141 6.4 Peterson olefination of 328 and 42% .................................................... 142 6.5 Summary ............................................................................................... 146 6.6 Future Work ........................................................................................... 147 CHAPTER 7 Preliminary Studies toward the Synthesis of Phomactins C and D ................... 149 7.1 Peterson olefination for the total synthesis of Phomactins C and D ...... 149 7.2 Simmon-Smith cyclopropanation ........................................................... 151 7.3 Reduction of Compounds 360 and 361 ................................................. 153 EXPERIMENTAL SECTION ............................................................................. 157 APPENDICES ................................................................................................... 326 REFERENCE .................................................................................................... 348 Vii LIST OF SCHEMES Scheme 1.1 Preparation of Fischer Carbene Complexes .................................... 2 Scheme 1.2 Brief Summary of Reactions of Fischer Carbene Complex .............. 4 Scheme 1.3 Benzannulation Reaction ................................................................. 5 Scheme 1.4 Regioselectivity of the Benzannulation Reaction ............................. 6 Scheme 1.5 Cyclohexadienone Annulation ......................................................... 8 Scheme 1.6 Tautomer-arrested Annulation ......................................................... 9 Scheme 1.7 Annulation Reaction of B-amino Fischer Carbene Complex with Internal Alkynes ........................................................................... 1 1 Scheme 1.8 Annulation Reaction of B—amino Fischer Carbene Complex with Terminal Alkynes ......................................................................... 12 Scheme 1. 9 Reaction of a ,B- -Unsaturated Fischer Carbene Complex Generated in situ ........................................................................................... 14 Scheme 1.10 Cyclopropanation of Fischer Carbene Complex .......................... 15 Scheme 1.11 Annulation of Fischer Carbene Complex with Dienes .................. 17 Scheme 1.12 Enyne Metathesis of Fischer Carbene Complex .......................... 18 Scheme 1.13 Pd Catalyzed Transmetallation .................................................... 20 Scheme 1.14 Rh Catalyzed Annulation of Fischer Carbene Complex with Alkynes ........................................................................................ 21 Scheme 1.15 Rh Catalyzed Annulation of Fischer Carbene Complex with Alkynes ll ..................................................................................... 22 Scheme 1.16 Rh Catalyzed Annulation of Fischer Carbene Complex with Allenzezs Scheme 1.17 Ni Catalyzed Reaction of Fischer Carbene Complex with Allenesza Scheme 1.18 Annulation of Fischer Carbene Complex Involving Ni° ................. 24 Scheme 1.19 Ni Catalyzed Cyclopropanation and Dimerization ........................ 25 viii Scheme 1.20 Photolysis of Fischer Carbene Complexes .................................. 26 Scheme 2.1 Benzannulation Reaction ............................................................... 27 Scheme 2.2 Benzannulation of Carbene Complexes with 1-Hexyne and 3- Hexyne .......................................................................................... 29 Scheme 2.3 Proposed Mechanistic Accounting of the Selectivity ...................... 32 Scheme 2.4 Competition Reactions with Different Terminal Alkynes or Internal Alkynes .......................................................................................... 37 Scheme 2.5 Competition Reaction between Terminal Alkyne and 1-Sinl Alkyne3 8 Scheme 3.1 Currently Accepted Mechanism for the Benzannulation Reaction (Mechanism I) ................................................................................ 41 Scheme 3.2 Mechanisms Involving nI-Intermediate (Mechanisms II and Ill) ..... 42 Scheme 3.3 Designed Intermediates 206 and 207 ............................................ 44 Scheme 3.4 Possible Product Distributions ....................................................... 45 Scheme 3.5 Syntheses of Carbene Complexes 178 and 178* .......................... 46 Scheme 3.6 Syntheses of Z- and E-Alkynes ...................................................... 47 Scheme 3.7 Detailed Mechanism for the Formation of 209 and 209* ................ 48 Scheme 3.8 Proposed Mechanism for Product Distributions ............................. 55 Scheme 3.9 Herndon’s Studies .......................................................................... 57 Scheme 3.10 Electronic Perturbation by MOMO-Substituent ............................ 57 Scheme 3.11 Preparation of MOM-Enyne 228 .................................................. 58 Scheme 3.12 Proposed Product Distribution ..................................................... 60 Scheme 3.13 Proposed Mechanism for Product Distribution from Z-Enynes ....61 Scheme 4.1 Intramolecular Benzannulation Reactions ...................................... 63 Scheme 4.2 Tautomer—arrested Type I Intramolecular Annulation ..................... 64 Scheme 4.3 Retrosynthetic Analysis of Richardianidin-1 ................................... 66 Scheme 4.4 Intramolecular Annulation Analysis ................................................ 67 Scheme 4.5 Syntheses and Thermolysis of Carbene Complexes 259 .............. 69 Scheme 4.6 Thermolysis of Carbene Complex 2599 ......................................... 71 Scheme 4.7 Preparation and Thermolysis of Carbene Complex 250 ................ 72 Scheme 4.8 Proposed Synthesis of 279 ............................................................ 73 Scheme 4.9 Synthesis of Carbene Complex Tethered with Silylether ............... 74 Scheme 4.10 Studies of the Regioselectivity in the lnterrnolecular Annulation ..76 Scheme 4.11 Annulation of Carbene Complex 46 and Alkyne 292 .................... 77 Scheme 4.12 Mechanism of Tautomer—arrested Annulation .............................. 79 Scheme 5.1 Yamada's Total Synthesis of Phomactin D .................................... 83 Scheme 5.2 Pattenden's Total Synthesis of Phomactin A ................................. 84 Scheme 5.3 Halcomb's Total Synthesis of (+)-Phomactin A .............................. 85 Scheme 5.4 Retrosynthesis of Phomactins (Intermolecular Version) ................ 86 Scheme 5.5 Retrosynthesis of Phomactins (Intramolecular Version) ................ 87 Scheme 5.6 Synthesis of Vinyl Iodine 333 from Geraniol (335) ......................... 89 Scheme 5.7 1,4—Asymmetric Induction in Intramolecular Cyclohexadienone Annulation ...................................................................................... 89 Scheme 5.8 Synthesis of Carbene Complex 349 ............................................... 91 Scheme 5.9 Preparation of Vinyl Iodide 353 ...................................................... 93 Scheme 5.10 Preparation of Carbene Complex with Protected Acetylene ........ 94 Scheme 5.11 Optimized Synthesis of Carbene Complexes ............................... 95 Scheme 5.12 Retrosynthesis of Phomactin B2 from 360 and 361 ..................... 97 Scheme 5.13 Peterson Olefination and Methylation .......................................... 99 Scheme 5.14 Synthesis of Allylic Alcohol ........................................................ 102 Scheme 5.15 Total Synthesis of Phomactin B2 ............................................... 104 Scheme 5.16 Mitsunobu Reaction of Compound 373b .................................... 106 Scheme 5.17 Peterson Olefination .................................................................. 110 Scheme 5.18 Acetylation of Compounds 391a and 391b ................................ 112 Scheme 5.19 Preparation of Allylic Alcohol 393b and 393a ............................ 113 Scheme 5.20 Mitsunobu Reaction of 393b and 394 ........................................ 114 Scheme 5.21 Synthesis of Phomactin B2 from 393b and 393a ....................... 115 Scheme 5.22 Epoxidation of Compound 370 ................................................... 116 Scheme 5.23 Epoxidation in Pattenden's Total Synthesis of Phomactin A ...... 117 Scheme 5.24 Mitsunobu Reaction of B-Alcohol 383 ........................................ 119 Scheme 5.25 Mechanistic Pathways for the Mitsunobu Reaction .................... 121 Scheme 5.26 Mitsunobu Reaction via Allylic Chloride ..................................... 121 Scheme 5.27 Reduction of Dione 417 ............................................................. 123 Scheme 5.28 Photolysis of 360 and 383 .......................................................... 124 Scheme 5.29 Conversion of Alcohol 404 into Dione 417 ................................. 124 Scheme 6.1 Possible Mechanism for the Diastereoselectivity ......................... 128 Scheme 6.2 Retrosynthesis of Phomactin 32 .................................................. 129 Scheme 6.3 Synthesis of Carbene Complex 329 ............................................. 130 Scheme 6.4 RCM in Pattenden’s Synthesis of Phomactin A ........................... 135 Scheme 6.5 RCM of 328 with Grubbs Generation l Catalyst ........................... 135 Scheme 6.6 RCM of 328 and 430a with Grubbs |l Generation Catalyst .......... 136 Scheme 6.7 Peterson Olefination of Compound 327 ....................................... 136 Scheme 6.8 RCM with Substrate 444 .............................................................. 139 xi Scheme 6.9 RCM of Compound 444 ............................................................... 140 Scheme 6.10 RCM of 429c-e .......................................................................... 141 Scheme 6.11 Peterson Olefination of 328 and 429b ....................................... 143 Scheme 6.12 Verification of Structure E452 and E-451 .................................. 145 Scheme 6.13 Methylation and RCM of Compound 448 ................................... 146 Scheme 6.14 Summary of Total Synthesis of Phomactin B2 ........................... 147 Scheme 6.15 Asymmetric Approach to Phomactin B2 ..................................... 148 Scheme 7.1 Proposed Total Synthesis Route for Phomactins C and D ........... 150 Scheme 7.2 Peterson Olefination of 360 and 361 ............................................ 151 Scheme 7.3 Proposed Simmon-Smith Reaction of 360 and 361 ..................... 151 Scheme 7.4 Simmon-Smith Reaction and Model Study .................................. 153 Scheme 7.5 Reduction by L-Selectride ............................................................ 154 Scheme 7.6 Methylation of Compound 480 ..................................................... 156 xii LIST OF TABLES Table 2.1 Temperature and Solvent Effects in the Reaction of Fischer Carbene Complexes with 1-Hexyne/3—Hexyne ..................................................... 30 Table 2.2 Competition Reactions with 1.5 Equivalents of Alkynes ..................... 34 Table 2.3 Competition Reaction of Carbene Complex 175-178 with 1-Hexyne and 3-Hexyne ........................................................................................... 35 Table 3.1 Benzannulation of Deuterated Carbene Complex with Enyne ........... 49 Table 3.2 Benzannulation of 178 with 228 and 227 with 208 ............................. 59 Table 4.1 Syntheses and Thermolysis of Carbene Complexes 259 ................... 69 Table 5.1 Model Study of Carbene Complex Synthesis ..................................... 93 Table 5.2 Cyclization of Carbene Complex ........................................................ 96 Table 5.3 Reduction of Ketone 370 .................................................................. 101 Table 5.4 13c NMR Chemical Shifts of Phomactin 32 and Compound 378a (CDaOD) .......................................................................................... 105 Table 5.5 Synthesis of Intermediate 391a and 391b ........................................ 111 Table 5.6 Cleavage of MOM-protected Group in 392b .................................... 112 Table 5.7 Mitsunobu Reaction with Silanols .................................................... 120 Table 6.1 Asymmetric Cyclohexandienone Annulation .................................... 127 Table 6.2 Preparation of Alkyne 431 ................................................................ 131 Table 6.3 Cyclohexadienone Annulation of 329 with 431 ................................ 132 Table 6.4 Optimization of Annulation Reaction of 329 with 4319 ..................... 133 Table 6.5 Cleavage of Trityl Group in Compound 327 ..................................... 137 Table 6.6 RCM of 429b with Catalysts 442 and 443 ........................................ 138 Table 6.7 RCM of Compound 448 and 449 ...................................................... 144 Table 7.1 1.2-Reduction of 360 ........................................................................ 155 xiii LIST OF FIGURES Figure 1.1 General Structure of Fischer Carbene Complexes ............................. 1 Figure 5.1 Structures of Some Natural Occurring Phomactins .......................... 81 Figure 5.2 X-ray structure of 370 ....................................................................... 99 Figure 5.3 X-ray structures of 383 and 361 ...................................................... 108 xiv Ac Acac Ar Bn Bz Calcd CAN DBU DCM DEAD DIBAL DIEPA DMAP DMF DMP DMPU El FAB FCC GC HMPA HRMS KHDMS LAH LHDMS MEM Mes ABBREVIATIONS acetyl acetyl acetonyl argon benzyl benzoyl calculated cerium ammonium nitrate 1 ,8-diazabicyclo[5.4.0]undec-7-ene dichloromethane diethyl azodicarboxylate diisobutylaluminum hydride diisoproylethyl amine 4—(dimethylamino) pyridine N, N-dimethylformaide Dess-martin periodinate 1, 3-dimethyl 3, 4, 5, 6-tetrahydro-2 (1H)- pyrimidinone electron ionization fast atom bombardment Fischer carbene complex gas chromatography Hexamethylphosphoramide high resolution mass spectrometry infrared spectroscopy potassium hexamethyldisilazide lithium aluminum hydride lithium hexamethyldisilazide 2-methoxyethoxymethyl 2,4,6—trimethylphenyl XV MOM MS NMR PAF PMB PNB Py RCM SEM TBAF TBDMS TBP Temp TES Tf TFA TFAA THF TIPS TMS toI Tr methoxymethyl mass Spectrometry nuclear magnetic resonance platelet activating factor 4-methoxybenzyl para-nitrobenzoic pyridine ring-closure metathesis room temperature 2-(Trimethylsilyl)ethoxymethyl tetrabutylammonium fluoride tert-butyl dimethyl silyl tert—butyl hydroperoxide temperature triethylsilyl trifluoromethanesulfonyl trifluoroacetic acid trifluoroacetic anhydride tetrahydrofuran triisopropylsilyl trimethylsilyl toluene triphenyl methyl (trityl) xvi CHAPTER 1 Introduction and Background of Chromium Fischer Carbene Complexes The Fischer carbene complex (Figure 1.1) was first discovered by Fischer and Maasbol in 1964.1 Structurally, a Fischer carbene complex (1) contains a metal center in a low oxidation state equipped with rc-acceptor ligands. The metal also binds itself to an electron-deficient carbene through a metal-carbon double bond, and the carbene carbon, in turn, bears a heteroatom, usually oxygen or nitrogen. Electronically the carbene carbon is considered electron-deficient, due to the electron-withdrawing nature of the metal center.2 The presence of the heteroatom is essential to balance the electron-deficient nature by delocalizing its lone pair electrons to the metal-carbon double bond. Among all Fischer carbene complexes, the a,[3-unsaturated chromium Fischer carbene complex (2) is arguably one of the most investigated and have been known to serve as versatile reagents for a variety of transformations.3 Figure 1.1 General Structure of Fischer Carbene Complexes X x (00301513 LnM= 1° = ( )5 :<—_—_< R6,R7=H,alkyl Lewis acid 5 R 9 1111 OR OR (OC)SCr + XH base (OC)sCr=<_—111: 1 Ph Me 45 : 1 Application of this benzannulation reaction as the key step in natural product total synthesis has also been reported. Recent examples include aflatoxin B2,13 arylglycines,14 landomycin A,15 and calphostins A16 Recent years have witnessed the application of new techniques to this benzannulation reaction, such as microwave-assisted conditions and solid- supported conditions.”18 Kerr and coworkers reported that microwave-assisted benzannulations can be completed in as short as 5 minutes in equal or better yield than the traditional thermolysis.17 The solid-supported annulation uses carbene complexes that are resin-bound via attachment to the heteroatom stabilizing substituent to afford resin-bound phenols, which can be cleaved off the resin by CAN workup to give free quinones.18 By virtue of phase separation, the solid-supported benzannulation reaction is much less sensitive to reaction conditions, including the solvent, and is much cleaner than traditional solution- phase reactions. These new applications obviously provide more efficient and rapid access to broad range of aromatic compounds, which in turn can be used in the synthesis of bioactive targets. 1.1.2 Cyclohexadienone annulation As mentioned previously, the mechanism of the benzannulation reaction involves the aromatization of intermediate 32 to afford a phenol (Scheme 1.3). Such an aromatization can only be achieved if at least one of the two substituents R2 or R3 in structure 32 is hydrogen. Consequently, in cases where neither R2 or R3 is hydrogen, this aromatization will not occur and the reaction will stop at the cyclohexadienone intermediate 32. This feature can be exploited when a 8,8-dialkyl substituted alkenyl chromium carbene complex is used as the substrate (Scheme 1.5). In this case, the presence of the two substituents at the B-position does not allow aromatization and therefore, cyclohexadienone 36 can be selectively generated after loss of the metal from complex 32.19 This specific annulation provides a unique approach to cyclohexadienones, which are common structural motifs and synthetic intermediates.20 Like the benzannulation reaction, the cyclohexadienone annulation can be highly regioselective with the preferred orientation of the larger group of the alkyne adjacent to the carbonyl. However, unlike the benzannulation reaction, the cyclohexadienone annulation creates a new chiral center. This unique feature of the cyclohexadienone annulation thus offers the promise of stereo control in these reactions, which in turn has prompted several different studies on how that can be affected.21 It has been found that intermolecular stereochemical control can be achieved by using an existing chiral center in the carbene complex to control the stereochemical outcome of this newly formed stereogenic center.19 Thus, annulation of Fischer carbene complex 37 bearing a chiral center provided annulated product 39 with good diastereoselectivity (Scheme 1.5). Scheme 1.5 Cyclohexadienone Annulation 20 20 (OC)5Cr RS _ ‘- 92 R3 a: H L R1 R2 R1 R3 R1 RS /0 Cr(CO)3 ,0 2° “ 32 36 CM 0 (OC)5Cr e Ri‘ R R °/o yield trans/01's 38 / —-———o-> Ph 58 95:5 1) THF. 45 C i n-Bu 78 90:10 2) air ‘ OMe TMS 75 92:8 37 39 1.1.3 Tautomer-arrested annulation The benzannulation reaction can give rise to phenol products when the a,B-unsaturated substituent is part of a double bond (Scheme 1.3) and part of an aromatic ring (Scheme 1.4). However, when the aromatic ring is 2,6- disubstituted, such as carbene complex 40, annulation will selectively give indenes as the major product (Scheme 1.6).22 Mechanistically, this type of annulation is similar to the benzannulation reaction in the early steps, leading to intermediate 44, where CO insertion does not occur. Cyclization of 44 followed by a 1,5-sigmatropic migration of the angular methyl group to restore the aromaticity generates indene 42 and the corresponding chromium tricarbonyl complex 43. As a special case of this indene forming reaction, tautomer-arrested annulation is observed for complexes where the 2,6-disubstituted aromatic ring is further equipped with a 4-hydroxy group. This hydroxy group can tautomerize to the corresponding ketone in the intermediate 48 (Scheme 1.6) and therefore interrupt the 1.5-migration of the methyl group.23 Thus, this tautomer-arrested annulation can afford hydrindenone products of the type-49. However, depending on the relative rate of tautomerization and 1,5-sigmatropic migration, annulation of 2,6—disubstituted 4-hydroxyphenyl chromium carbene complexes can give both hydrindenones and indenes depending on the nature of the alkyne. Thus, as shown in Scheme 1.6, 1-pentyne and 3-hexyne can react with carbene complex 46 to give exclusively tautomer-arrested hydrindenone product 49, whereas the TMS substituted acetylene give exclusively the indene product 50. Scheme 1.6 Tautomer-arrested Annulation (OC)5Cr Me Bu20, 100 °C, 2 h Me \ ° + pnepn : 0 Ph + | / Ph Me / Me 0‘ (OC)30r Me O\ 40 42 34% 43 18% Me Ph é Me / Ph ‘ 1, - ‘ t ' . \ 5 Sigma roplc \C P" Me OMe migration r Cr CO 44 (00),, 45 ( )3 R1 1 1 OMe R1 HO Me 0 Me R HO R Me (OC)50r Me Benzene / R2 2 2 + II ———~ \\ R + R Me 82 Me 0M9 OM OM Me ° Me e OH Cr(CO)3 46 47 48 49 50 R1 R2 Yield (49 + 50) (o/o) 49150 Et Et 75 100 :0 H Pr 9 100 :0 TMS i-Pr 51 0 : 100 1.1.4 Annulation reaction with B-amino substituted carbene complexes B-Amino alkenyl carbene complexes are another class of substrates that behave differently in the annulation reaction with alkynes due to the electron- donating feature of the N-substituent.3a These substrates do not afford the regular benzannulation products. Instead, they undergo a variety of different annulations, including formal [3 + 2], [2 + 2 + 1], [4 + 2] annulations, to afford cyclopentadienes, cyclopentanones, cyclopentapyrans among others. The course of the reaction depends upon the nature of the carbene complex and the alkyne as well upon the reaction conditions. In these cases, insertion of CO may not occur, and insertion of two molecules of alkyne may take place (Schemes 1.7 and 1.8). The reactivity of these B-amino alkenyl carbene complex can vary greatly and only small changes in the substrate structure and reaction conditions can cause a complete change in product formation. The exact reason for this sensitivity to substrate structure and reaction conditions remains elusive, but the electron-donating feature of the nitrogen is clearly an important factor. This electron-donating effect results in a more electron-rich chromium center which presumably leads to the different reactivity. For example, reaction of carbene complex 51 with internal alkyne 52 in pyridine follows a formal [3 + 2] annulation to generate amino cyclopentadiene 54 without the insertion of CO (Scheme 1.7).24 The absence of the CO insertion has been primarily attributed to the electron-donating effect of the nitrogen, resulting in a more electron-rich chromium center and a stronger Cr-CO bond. The use of coordinating solvents also suppresses the insertion of CO. The regioselectivity of 10 this annulation is the same as-other annulations, and results in the incorporation of the large group on the alkyne adjacent to the amino group. However, the same reaction run in THF did not give cyclopentadiene 54.25 Instead, a formal [2 + 2 + 1] annulation affords cyclopentenone 59. In this case, only the carbene carbon and the a carbon are incorporated into the 5-membered ring. Mechanistically, the annulation begins with insertion of the alkyne and then CO insertion occurs to afford the ketene intermediate 57. Due to the presence of the nitrogen, intermediate 57 has a strong dipole. Therefore, instead of the normal electrocyclic ring closure to give a phenol product, intermediate 57 undergoes enamine addition to the ketene to generate zwiterion 58. A 1,5- sigmatropic migration of hydrogen then generats 59 as a mixture of isomers. Scheme 1.7 Annulation Reaction of B-Amino Fischer Carbene Complex with Internal Alkynes 8‘ NMe 08 1 P ridine L‘ 2 R1 NMe2 (OC)5Cr R Y (OC)4Cr I n NMe2 80 0 RL oer RS RS OEI 51 52 53 54 6‘ " + 2 . 9 6* 0 NBn 0 DB 1 R THF 50' ~an 2 H 2 2 ~an _ + H W — _ R‘ R —. R ~an R2 R2 OE, R2 OEt R2 OEt 55 56 57 53 59 R1 = alkyl The reaction of terminal alkynes with amino-substituted carbene complexes is again different (Scheme 1.8). This reaction is dependent on the steric bulk of the R1 of carbene complex. Wlth small R1 groups, the annulation 11 takes place with the insertion of a single alkyne and without CO insertion to give cyclopentadiene products of the type-54 products in very low yield. But with bulky R1 groups, the annulation occurres with double alkyne insertion and a CO insertion to form cyclopentapyran 64 (Scheme 1.7).26 The proposed mechanism for the cyclopentapyran involves an intramolecular [4 + 2] hetero-Diels-Alder—type cycloaddition and an elimination of the amino group. The regioselectivity of the second alkyne insertion is not high and a mixture of regioisomers was obtained. Carbene complexes with a secondary amino substituent react in a totally different way.27 Thermolysis of carbene complex 65 with a terminal alkyne undergoes a [4 + 2] cycloaddition to give carbene complex 66. This complex has moderate stability due to the partial aromaticity of the ring, and the reaction stops at this point. Scheme 1.8 Annulation Reaction of B-Amino Fischer Carbene Complex with Terminal Alkynes DE! FR3 CE: .53 H 08 1 THF (OC)SCr=<-= -——> I I 24 n 29% Ph 70 71 Intramolecular reaction OMe Ph (OC)5Cr=< + ”I 75 71 OH 43°/c Ph 78 Ph Ph 72 73 74 o MeCN. 85 °c (OC)50r OMe M80 ph 36 h 76 77 1.2 Reaction of Fischer carbene complexes with alkenes 1.2.1 Cyclopropanation with simple alkenes Cyclopropanation of chromium Fischer carbene complexes with alkenes has been extensively investigated.30 The best alkene substrates are those substituted with either electron-releasing groups or electron-withdrawing groups.31 Electron-neutral alkenes are known to best react intramolecularly, although in rare cases intermolecular examples are known.32 For alkenes equipped with electron-releasing groups, such as ketene acetal 80, the reaction must be carried out under CO pressure. In the absence of CO, the alkene l4 metathesis product 82 is the major product (Scheme 1.10).33 The cyclopropanation reaction has good functional group tolerance, including esters, ethers and cyano groups. The reaction does not tolerate good leaving groups at the allylic positions. The diastereoselectivity of this cyclopropanation is generally not high. However, it can be improved if either the carbene carbon or the alkene is conjugate to a n-system. Barluenga and coworkers reported that the B-aryl alkenyl carbene complex 86 will react with simple alkenes, such as 1-hexene, to afford cyclopropane 88 in moderate to good yields and diastereoselectivities.32 The large substituent on the alkene preferentially incorporated into the cyclopropane trans to the alkenyl group from the carbene complex. Scheme 1.10 Cyclopropanation of Fischer Carbene Complex 2 0R1 on?- CO(500psi) Rio Ph OR (OC)5Cr=< + on2 (OC)5Cr=< 2 Ph 0R2 THF. 80 00 on? on 79 so 31 82 R1 R2 % Yield i-Pr E1 69 L-menthol Me 98 0/ . OMe I R R oYleld (OC)50r R 3° vem OMe - + =1 —' — COgMe 75 Ph 80 °C Ph COZNMeg 78 33 34 85 CN 89 OMe THF n-Bu,,. 3.0Me (ociscri + _/n-Bu H — _ '— moderate to ood 'elds and de A, 6510100°C H Ar 9 V' 86 87 86 15 1.2.2 Cyclopropanation with dienes Dienes can also react with chromium Fischer carbene complexes to give cyclopropanes. The reaction tends to occur at the less hindered or the more electron-rich double bond. Thus, the terminal alkene in diene 90 selectively reacts due to steric and electronics reasons, and the y,6-double bond in diene 92 selectively reacts due to electronic reasons.34 In certain cases, the cyclopropanation can be followed by other reactions in a domino process. For example, vinyl carbene complex 83 reacts with diene 24 to afford cyclopropane 94, which is set up for a subsequent [3,3]-sigmatropic rearrangement, eventually affording cycloheptadiene 95 with high diastereoselectivity.35 The reaction of diene 96 which has both an electron withdrawing and electron releasing substituent with carbene complex 83 goes through a different pathway.” It has been suggested that this reaction takes place via a hetero [4 + 2] cycloaddition between the electron-deficient chromadiene and the electron-rich terminal double bond of the siloxydiene. This cycloaddition is apparently endo- selective to give 97 and subsequent reductive elimination of the chromium fragment affords cyclopentene 98. 1.6 Scheme 1.11 Annulation of Fischer Carbene Complex with Dienes OTMS OMe vow; MeO>A<§/OMIe (OC’SC'=( > Ph OTMS Ph CO atm. 89 91 OMe RWX MeO F? \ X R X °/c Yield Cis/Trans (OC)SCr=< : WV Me COzMe 79 90:10 ph Ph‘ ’H Ph 002Me 36 100:0 89 93 OTBS / MeO OTBS OMe M . (OC)5Cr 24 0 e 49% Cls ’ —* 2% Trans 93 ph acetone, 56 °C, 4 h Ph OM e 95 OTBS OMe 96 (302MB 720/ TBSO,“ (OC)5CT _ > ————°——> OMe CHZC|CHZCL 80 °C, 18 h 83 Ph 98 1.2.3 Metathesis Metathesis reactions of chromium-carbene double bonds are rare. Mori reported that ring-closing enyne metathesis of enyne 102 with carbene complex 100 could afford metathesis product 103 in moderate yield.37 However, with the simplified enyne 99, reaction with same complex only provided the cyclopropane product 101. The difference in these two reactions is obviously the presence of the phenyl group. Insertion of the alkyne into the carbene complex gives the intermediates 104, which then undergoes [2 + 2] cycloaddition to give the chromacyclobutane intermediate 105. Metathesis would be expected to be more facile when R is phenyl than when R is hydrogen because this would involve an 17 extrusion of a more stabilized carbene complex 106. At the current stage, metathesis using chromium carbene complex is limited to a few examples and not yet general enough to be useful in synthesis. Scheme 1.12 Enyne Metathesis of Fischer Carbene Complex \ H OE! 1 70°C CH CN H Ph 1 J + (OC)5Cr=( ) ' 3 2 N Ph 0 Ts 2) HCI N o S 99 100 79“ 101 Ph Ph \ H OEI 070% CH CN #0 KL /I + (OC)SCr=< ' 3 t N ph N . 2) HCI l T5 69% T8 102 103 104 R OEt R Ph Ph | Cr OEt — 1oo \EfiCmOIS [ l/ — DB 99 or102 J8 , N N N R ' vph Ts - (OC)50r=J TS 104 105 106 107 I Hflyph N EtO Ts 108 1.3 Reactions of Fischer carbene complexes involving metal-mediated transformation 1.3.1 Pd-catalyzed dimerizations In the last few years, catalytic transmetalations involving group VI Fischer carbene complexes have experienced enormous attention.38 The dimerization of such Fischer carbene complexes catalyzed by palladium species (Scheme 1.14) is among the newly discovered reactions in this class. Active palladium catalysts 18 include Pd(OAc)2, Pd2(dba)3-CHCI3, PdCIz-(MeCN)2, PdCl2(PPh3)2, Pd(PPh3)4.39 As a general example, chromium carbene complexes of the type 109 could undergo dimerization to afford endiol ether 110 in the presence of Pd(OAc)2. The scope includes complexes 109 where R1 is an akenyl, aryl or alkynyl group and the yield varies significantly with different substrates. The mechanism of this reaction starts with a Pd—Cr exchange to give Pd-carbene complex 111. In the case where R1 is alkyl group containing an a-hydrogen, a B-hydride elimination occurs followed by a reductive elimination to give the vinyl ethers. Subsequent transmetallation with another molecular of chromium carbene complex generates Pd-biscarbene complex 112, which reductive eliminates Pd° and gives dimer 110. Similarly, intramolecular dimerization of bis-chromium carbene complex 113 afforded a cyclic enol-ether 114, with the best yields for six- or seven-membered rings. A special case is the allyloxy aryl chromium carbene complex 115, which underwent 2,3-sigmatropic rearrangement to furnish allyl aryl ketone 118 (Scheme 1.13).40 The mechanism of this reaction probably involves the Pd- alkene-carbene complex 116. 19 Scheme 1.13 Pd Catalyzed Transmetallation OR (OC)5Cr=l< 1 R 109 TEA, n R1 R1 10 mol% PdIOAc): “0 0” R1=alkenyl,aryl,alkynyl v 25-94% 110 ”I ~=<. r = 18* R R0 R1 111 on (OC)5Cr=( 1 “2 109 R Ph 0 items J0150015 10mol%Pd(OAC)2 I 3)) n=0 70% = n = 1 64°/o Ph o/Wo Ph TEA,rt Ph 0 " n=2 21% 113 114 __ R o O 1 mol% cat Pd(PPh3)4 /——< o (OC)SCr=< R e ./ o A ,ILE\—R ——»A,/u\/\,,R Ar 1 atm CO, DCM, rt [Pd]=< r R = H, Me 1.3.2 Rh-catalyzed annulations The first example of a rhodium-catalyzed annulation of a chromium Fischer carbene complex and an alkyne was reported by Aumann and coworkers in 1999.41 The annulation of carbene complex 119 with alkyne 120 generated cyclopentadiene 121 in the presence of a rhodium catalyst (Scheme 1.14).42 Mechanistically, this reaction starts with the transmetallation to give the rhodium- carbene complex 122. Alkyne insertion into 122 gives intermediate 123, which undergoes electrocyclization to give the rhodium bound cyclopentadiene 124. Demetallation of 124 gives the cyclopentadiene product 121 and regenerates the Rh catalyst. 20 Scheme 1.14 Rh Catalyzed Annulation of Fischer Carbene Complex with Alkynes R2 4 , OEt —12081 R Ph NR2 (0050' __ Ph e R2 / [cat] = 2 mol% RhCl3-HZO (71 -78%) NR THF/MeOH (4:1) 20 OC 25 mol% I (co d)RhCI]2 (53-63%) 119 2 [cat] 121 OEI 2.5 mol% [(CO)2RhCI]2 (74- I \ 770/0) 05: __ 03 Ph R1Ph NR2 — 2 / . [Rhlfiph alkyne [Rh] I R, NR2 R \ WW NR 0E1 122 2 R2 123 124 It's well known that electron-withdrawing alkynes gave poor yield in the benzannulation reaction.“ However, in the presence of a rhodium catalyst, electron withdrawing alkynes will react with vinyl Fischer carbene complexes smoothly to give cyclopentenones.441a As shown in Scheme 1.15, Fischer carbene complex 125 reacts with alkyne 126 to generate regioisomers 127-129, the ratio of which depends on the nature of alkyne. Presumably this reaction involves a metalIa-Diels-Alder cyclization to give intermediate 130 or 132. For terminal alkynes, the cyclization is sterically controlled to give intermediate 130 with the smaller H aligning near the metal. For internal alkynes, the steric factor is diminished and the cyclization is controlled by the interaction between the electrophilic metal and the more nucleophilic alkyne carbon. 21 Scheme 1.15 Rh Catalyzed Annulation of Fischer Carbene Complex with Alkynes II we [Rh] (10 l /), 00 Me 00 Cr m0 °° co Me 2 ( )5 =<=\ + p12 : Cone +{é/2 2 + 125 R1 126 CH20I2, 25 °C, R1 002MB R1 R2 R1 = Ph. 2'IUrYI, n'BU etc. 64-8996 127 129 R2 = H, Ph, Me, 1-cyclohexenyl R2- = H Y [th =[(naphthalene)Rh(cod)][SbF6] R2 at H [Rh] Rh MeO [Rh] H __ 2 _ MeO l l EWG | A _ COgMe JI/KOMe R —_ cone: U ewe R1 F12 1 R1 R 130 131 132 The other example of a catalyzed annulation involves the reaction of a transmetallated rhodium carbene complex with allenes.44b As demonstrated by the example in Scheme 1.16, Fischer carbene complex 133 can undergo transmetalation with a rhodium catalyst, followed by reaction with allene 134 to give a cyclopentene product 135. Presumably this transformation involves a non- concerted metalla—[4 + 2] cycloaddition to generate intermediate 136 followed by reductive elimination to give 135. Scheme 1.16 Rh Catalyzed Annulation of Fischer Carbene Complex with Allenes MeO OMe 3 10 mol% Rh(l) Meo "it'll: R3 (OC)SCr=<____\ + R. . R2 CH20I2, 25 °c 2 1 R R 42- 93% 1 33 134 1 36 22 1.3.3 Ni-mediated annulations Under nickel(0)-mediated conditions, alkenyl chromium carbene complexes can react with allenes, alkynes, and alkenes to provide a wide range of products. As reported by Barluenga’s group, alkenyl chromium carbene complexes can react with allenes and a stoichiometric amount of a nickel species to furnish cyclopentenol ethers (Scheme 1.17).44b This reaction starts with a Ni/Cr exchange, followed by a [2 + 2] cycloaddition of the less substituted C=C bond of the allene to give intermediates 138. This intermediate rearranges to structure 139, which is presumably driven by release of the ring strain, and then subsequent reductive elimination affords the final product. It should be noted that the selectivity for the two double bonds in the allene in this reaction is different from that of the Rh-catalyzed reaction, where the more substituted double bond reacted (Scheme 1.16). Scheme 1.17 Ni Catalyzed Reaction of Fischer Carbene Complex with Allenes R1 R3 tol, 25°C 1 R2 - o, R 133 l 134 60 70 / 137 1 R1 1 M60 \ R Ni Ni\ R3 R3 138 139 The annulation reaction of alkenyl chromium Fischer carbene complex with alkynes also requires a stoichiometric amount of nickel.45 The overall 23 reaction is a formal [3 + 2 + 2] annulation involving double insertion of the alkyne to form cycloheptatriene 144 (Scheme 1.18). The aryl chromium carbene complex 145 also provides cycloheptatriene products 146 by reacting with 3 equivalents of the alkyne. Scheme 1.18 Annulation of Fischer Carbene Complex Involving Ni° OMe OMe n—Pr (0050i _ lequiv.Ni(COD)2 LnNi=<_\ 140 LnNi __ _ + _ t _ Ph _\— MeCN Ph n-Pr I 83 140 141 Ph \ OMe 142 n-Pr "'PT n-Pr ..- n-Pr —. ............ Cf(CO)3 _. Ph... H_E ..... 'Cr(CO) Ph / 86% \ 3 OMe 143 149‘" OMe R R (OC)5Cr=< _ 1equiv.Ni(COD)2 ”Pr / ,,\OMe ,,_P, / ,.~OMe + — ‘ R _\— MeCN 7(OC)3Cr ....... \ -- / n-Pr + (OC)3Cr—-—\— / n-Pr 145 140 n-Pr "'P' syn-146 anti-146 R synzanti °/o Yield Ph 60:40 68 pMeO-CGH4 >982 83 2-Furyl 90:10 86 Alkenes are also known to react with Fischer carbene complexes under Ni-catalyzed reaction conditions to provide cyclopropanation products (Scheme 1.19).46 The reaction conditions are milder than without the Ni-catalyst (Scheme 1.10). The dimerization of Fischer carbene complexes could also be catalyzed by Ni species (Scheme 1.19).47 In both cases, the active intermediates were believed to be that of the corresponding nickel carbene complex via Ni/Cr exchange. 24 1.4 complex 151 upon photolysis. Ketene complexes generated in this way are very reactive and able to readily react with aldehydes or imines to form fi-Iactones or B-Iactams (Scheme 1.20). 48 For example, the reaction between carbene complex 89 and aldehyde 152 under photolytic conditions in the presence of DMAP and under a CO atmosphere provided B-lactones 153 as a pair of diastereomers. was found that certain substrates (electron-rich or unsaturated aldehydes) under Scheme 1.19 Ni Catalyzed Cyclopropanation and Dimerization OMe CC C OMe 10 mol% [Ni(cod)2] {Al’— ( )5 r=<=\ + -_——_/CN : NC —\ Ph 25 °C, MeCN Ph 83 147 850/0 148 OMe MeO OMe (QQSCri 10% Ni(acac)2, 50 °C fl Ph THF, 90% Ph Ph 83 149 Photolysis of Fischer carbene complexes It’s known that chromium carbene complexes will rearrange into a ketene these reaction conditions generated the decarboxylated product 154. 25 rag-swan»- 1.4 complex 151 upon photolysis. Ketene complexes generated in this way are very reactive and able to readily react with aldehydes or imines to form [ii-Iactones or B-lactams (Scheme 1.20). 48 For example, the reaction between carbene complex 89 and aldehyde 152 under photolytic conditions in the presence of DMAP and under a CO atmosphere provided B-lactones 153 as a pair of diastereomers. was found that certain substrates (electron-rich or unsaturated aldehydes) under Scheme 1.19 Ni Catalyzed Cyclopropanation and Dimerization OMe CC C OMe 10 mol% [Ni(cod)2] A’— ( )5 f —— 1' ___/ : NC —\ Ph 25 °C, MeCN Ph 83 147 850/0 148 OMe MeO OMe (()C)5(3r=<1 10% Ni(acac)2, 50 °C fl Ph THF, 90% Ph Ph 83 149 Photolysis of Fischer carbene complexes it’s known that chromium carbene complexes will rearrange into a ketene these reaction conditions generated the decarboxylated product 154. 25 Scheme 1.20 Photolysis of Fischer Carbene Complexes X hV R X (OC)50r=< [ T—CHCOM R ll 0 150 O O OMe O DMAP, THF 0 O R OMe (OC)5Cr=( + JLH h 30 _ CO | l_.\OMe + “l l_,\OMe "‘=< P“ R "' ”8' R Ph R“ Ph P" 89 152 syn-153 anti-153 154 151 R = alkyl, Ph 133-55% 153 OM R? MeQ 82 e N Et 0 ‘~ -' 1 (OC)SCr=I< + L __2._. P“ R Ph R2 R1 N. 3 hv o R 89 155 20-90°/o 156 1.5 Summary During the past few decades, Fischer carbene complexes, especially those of chromium, have been shown to have broad and powerful utility in synthetic organic chemistry. Such metal complexes offer versatile reactivities under a variety of reaction conditions to provide a broad scope of different products. Although many reactions are undoubtedly yet to be discovered and others have yet to be developed, many reactions of Fischer carbene complexes have been developed into mature, reliable, and useful synthetic protocols. The applications of such reactions have also been realized in total synthesis of natural products and in the preparation of chiral ligand for asymmetric catalyst.43 26 CHAPTER 2 A Competition Study in the Benzannulation Reaction of Fischer Chromium Carbene Complexes: Terminal vs. Internal Alkynes 2.1 Background As discussed in Chapter 1, the benzannulation reaction of chromium carbene complexes with alkynes has been widely used in organic syntheses to construct highly functionalized aromatic rings (Scheme 2.1).5'51 Scheme 2.1 Benzannulation Reaction OH OMe Be I f R2 RL nzannu 3 Ion (0059i + RL : RS R1” R2 R‘ R3 OMe 157 14 28 The product distributions from this reaction are generally dependent upon the concentration of alkynes, temperature and solvent. The phenolic product is favored under high concentrations, lower temperatures, and in non-coordinating solvents.52'54 Other side-reactions can also take place to generate a variety of side-products including indenes?” vinylcyclopentadienones,523 furans,52b cyclobutenones,53 and two-alkyne phenols.54 In nearly all cases, there is a preference for the larger alkyne substituent to be incorporated adjacent to the hydroxy group (Structure 28, Scheme 2.1).12 The reaction generates a single regioisomer for terminal alkynes, and two regioisomers for internal alkynes, and the ratio of the latter is dependent upon the steric bulk of the two substituents on 27 the alkyne. Electronic perturbations have rarely been reported to disturb the normal steric control of the regioselectivity.55 2.2 Competition reaction between terminal and internal alkynes Despite the numerous studies on the chemoselectivity”54 and regioselectivity‘z'55 of the benzannulation reaction, to the best of our knowledge, no previous studies investigated the competition between different alkynes in the benzannulation reaction. We expected that this competition study could potentially provide valuable information for employing substrates bearing multiple alkynes in the benzannulation reactions. The competition study was first carried out between terminal and internal alkynes. The benzannulation reaction with methoxy phenyl chromium carbene complex 89 was initially carried out using 15 equivalents of both 1-hexyne and 3- hexyne in benzene at 80 °C (Scheme 2.2).523 With large excesses of alkynes, the concentration of the two alkynes could be considered as a constant even if one of the two alkynes was consumed more rapidly. Thus, the difference in the concentration of the two alkynes could be considered negligible. Since the resulting phenolic products were unstable to air, these reactions were subjected to an oxidative workup with CAN (0.5 M cerium (IV) ammonium nitrate in 0.1 M HN03 solution) to convert the phenol products into the corresponding quinones and the major indene side-product into indenone. Such an oxidative workup should not be expected to introduce significant error in the product ratios, since previous studies in Wulff’s laboratory demonstrated that an oxidative workup 28 afforded quinines in the same isolated yields as phenols with an oxidative workup using air.54 We thus chose the more practical CAN oxidative workup protocol. It was quickly realized that the benzannulation reaction was very selective, as the ratio of annulated products 159 and 160 was determined to be 93:7 by GC analysis for the reaction in benzene at 80 °C (Table 2.1, Entry 1). Scheme 2.2 Benzannulation of Carbene Complexes with 1-Hexyne and 3- Hexyne O 0 OR 1) 15 equiv. 1-hexyne n -Bu Et "'3“ (OC)5Cr 15 equrv. 3-hexyne t 0‘ + 0‘ + O 2) CAN. rt. 3 h Et ' O O O 159 160 161 89 R = Me 158 R = i-Pr O "‘8U "'8U OH + _ 0 Ph 162 Having obtained such an encouraging initial result, more detailed studies were undertaken to investigate how other perturbations affect the selectivity of this reaction. Since temperature and the nature of the solvent are known to affect the yields and product distributions of the benzannulation reaction,53 the same reaction between methoxy phenyl carbene complex 89 and the 1-hexyne/3- hexyne mixture as shown in Scheme 2.2 was carried out in various solvents at 40 °C and 80 °C. In addition, the reaction of the iso-propoxy phenyl carbene complex 158 was also explored to determine the effect of the size of the group on oxygen stabilizing substituent (Table 2.1, Entries 8-14). 29 Table 2.1 Temperature and Solvent Effects in the Reaction of Fischer Carbene Complexes with 1-HexyneI3-Hexyne" b Entry Carbene Temp. Solvent % Yield Ratiod of complex (°C) 159° 159/160 T 1 89 (R = Me) " 80 Benzene 84 93:7 2 80 THF 42 94:6 3 80 CH3CN 41 98:2 4 40 Benzene 69 95:5 5 40 THF 35 98:2 6 40 CH3CN 33 98:2 7 40 Hexane 64 96:4 8 158 (R = i-Pr) 80 Benzene 84 94:6 9 80 THF 56 99:1 10 80 CH3CN 41 99:1 1 1 40 Benzene 74 >99:1 12 40 THF 55 99:1 13 40 CH3CN 40 98:2 14 40 Hexane 79 >99:1 a) All of the above reactions were run in 0.3 mmol scale with 5 mL solvent. The reaction time was 16 hours for 80 °C and 22 hours for 40 °C. b) Trace amount of 161 and 162 could be detected by GC-MS. c) Isolated yield; d) Determined by GC and GC-MS. As can be seen by the data in Table 2.1, the benzannulation reaction exhibits excellent selectivity for the reaction of 1-hexyne over 3-hexyne. The level of selectivity for the reaction of the methoxy complex 89 was between 93:7 to 98:2 for all temperatures and solvents that were examined. In all cases, 1-hexyne was far more reactive than 3-hexyne in this benzannulation reaction. This 30 selectivity can be attributed to steric differences between the two alkynes and the origins of this will be discussed in more detail below. A mechanistic account of the selectivity seen between 1-hexyne and 3- hexyne is shown in Scheme 2.3.10 The first step is a rate-limiting loss of CO to give the 16e' unsaturated carbene complex 164.10h Although not rate limiting, the next step involves a bimolecular reaction of 164 with an alkyne to give whether the alkyne complex 166, or with carbon—carbon bond formation to give the 111313- vinyl carbene complex 167. It is not known whether the formation of 166 or 167 from 164 involves reversible steps or not.10d The next involves insertion of CO into the Cr-C bond of 167 to give 168 or 170. There is evidence suggests that CO insertion is not reversible.10d The origins of the selectivity between 1-hexyne and 3-hexyne must lie in the kinetic formation of either 166 or 167, or if these steps are reversible, in the relative stability of 167 derived from 1-hexyne and from 3-hexyne. Thermodynamically, the former would be expected to give 167 with lower energy, given the close contacts expected between Rs (H vs. Et) and the alkoxy substituent. The same expectation would pertain to the transition state for the formation of 167 under kinetic conditions. Therefore, the reaction with 1- hexyne would be expected to be greatly faster and more favored. When the methoxy carbene complex 89 was substituted with the more sterically demanding iso-propoxy carbene complex 158, the chemoselectivity between 1-hexyne and 3-hexyne was even more pronounced. Greater than 99:1 selectivity (Entries 11 and 14, Table 2.1) could be observed in both benzene and hexanes. The more bulky iso-propoxy group in complex 158 would be expected 31 to induce a stronger interaction with R5 in the n1,n3-vinyl carbene complex 167 (Scheme 2.3), which should lead to a more selective process. Scheme 2.3 Proposed Mechanistic Accounting of the Selectivity s 1 OR (“Dumb 165:2} O/S RLCE MCRS\\Q RLC: cns on RLC= CR5 (OC)4 CT Co R (OC)5CI' _, (OC)4Cr J /RLC: CR3 CC' F13 - ‘ RUTK l’(CO)4 164 167 OR E :2 (OR / I RS C“ / H \ RL ""' 0=C;c\’:C'RS +3 0 Cr(CO)3 RL r(CO)3 169 168 V OR OR OR OR R \ RS / RS '8 / I S C "C\ ‘— ~ ' ~— \. ‘— 553% R rCO OH (OCBC' OH O CdCOb LS ( b 173 172 171 170 Other than the structure of the carbene complex, temperature and solvent both had an influence on the reaction. It was observed that the selectivity at a lower temperature (40 °C) was better than that at a higher temperature (80 °C) (Table 2.1). This is understandable from a basic kinetic point of view. Solvents also played a role in effecting the selectivity. Competition reactions carried out in non-coordinating solvents such as benzene and hexane were more sensitive to 32 temperature, while reactions in polar coordinating solvents such as THF and CH3CN were less sensitive, and the selectivity remained the same at both temperature. This may suggest that the 16e‘ chromium center in the unsaturated complex 164 can be intercepted by a coordinating solvent to give the saturated complex 165. This in turn could lead to a difference in the associative reaction of 164 versus 165 with an alkyne. The latter could have the largest difference in rate with the two alkynes. It was also found that compared to non-coordinating solvents, coordinating solvents tented to lead to poorer yields but better selectivity. The aforementioned results revealed a significant chemoselectivity difference between terminal and internal alkynes when they are allowed to compete in large excess. Although the results are quite dramatic, they may not be practical in syntheses because of the large excess of alkynes employed. Thus, further investigations using only 2 equivalents of each alkyne were performed (Table 2.2). In this .case, when the more reactive 1-hexyne is consumed, the relative ratio of 1-hexyne and 3-hexyne would decrease, and it would thus not be certain whether the same high selectivity would be observed. As the investigation was conducted, the results (Table 2.2, Entries 1 and 2) demonstrated that the same high selectivity is observed with 1.5 equivalents as it is with 10 equivalents of each alkyne. This suggests that 1-hexyne is still reactive enough in the presence of excess 3-hexyne to give the same high chemo- selectivity. This implies that it should be feasible to use substrates with multiple 33 alkynes in the benzannulation reaction with the expectation that a terminal alkyne should react selectively with an internal alkyne in the same substrate. In addition to 1-hexyne and 3-hexyne, the competition reaction between 1- hexyne and 2-heptyne was also examined (Table 2.2, Entries 3 and 4). The selectivity between them was similar to the selectivity between 1-hexyne and 3- hexyne. This result presumably can also be attributed to the steric difference of the two alkynes. Table 2.2 Competition Reactions with 1.5 Equivalents of Alkynesa' b 1) 1.5 equiv. n-Bu H OR 1.5 equiv. R1 -_- 92 0 O 1 Benzene 40 °C 22 h n-Bu R (OC)5Cr=( ' ' P“ 2) CAN, rl, 3 h *R2 88 R = Me O O ‘53 “=1“ 160R1=R2=Et 174 R1 = n-Bu r12: n-Bu 0 Entry Carbene R1 R2 % Yield Ratio of 159/160d complex 159b or 159/174 1 89 Et Et 78 96:4 2 158 Et Et 75 >99:1 3 89 n-Bu Me 70 97:3 4 158 n-Bu Me 85 >99:1 a) All of the above reactions were run in 0.3 mmol scale in 5 mL solvent; b) Trace amount of 161 and 162 could be detected by GC-MS. c) Isolated yield; d) Determined by GC and GC-MS. The data above demonstrates that 1-hexyne will preferentially react with the phenyl carbene complex over either 3-hexyne or 2-heptyne with very high 34 selectivity. Next attention was turned to further expand this study to alkenyl carbene complexes 175-178 which includes complexes with an a-substituent, a B-substituent and a,[3-disubstituents (Table 2.3).11 The competition involved 1- hexyne and 3-hexyne (2 equivalents each) for this study as well. It was observed that these carbene complexes all gave good to excellent selectivities in this competition and greater than 95:5 selectivity could be realized in each case. It was observed that (ll-substituted and a,8-disubstituted carbene complexes gave slightly better selectivity than B-substituted carbene complexes. Perhaps this is the case because the a-substituent is closer to the chromium atom lead to a stronger interaction with the alkyne as it becomes incorporated (Scheme 2.3). Although the effect was small, the overall finding from the experiments summarized in Table 2.3 is that there is a higher selectivity in the competition experiments for a-substituted alkenyl complexes. Table 2.3 Competition Reaction of Carbene Complex 175-178 with 1-Hexyne and 3-Hexynea' b 1)2equiv. : ".30 Zequiv. Et : Et 0 1 O 1 (OC)5Cr 40 °C. Benzene, 22 n H R E! n = + Fl‘ Fl2 2) CAN. rt..3h n-Bu n? E. Hz 0 o 175 Fl‘ =Me, R2=H 179 9‘ =H, R2=Me 177 91,92 = Me (8 R = Me, I) R =i-Pr) 179 91,92 = (0112)., R = Me 179 Fl‘ = Me, R2: H 180R1=H,R2=Me 191 R‘, 192: Me 192 R1,R2=(CH2)4 35 193 R‘ = Me, 92: H 194 1:11.92 = Me 195 R1, R2 = (0112),, Entry Carbene R1 R:2 Major % Yield ° Ratiod complex product 1 175a Me H 179° 62 99: 1 2 175b Me H 179° 73 >99:1 3 1 76a H Me 180‘3 41 96:4 4 176b H Me 180° 32 98:2 5f 177a Me Me 191 57 99:1 6f 177b Me Me 181 83 >99:1 7 178 -(CH2)4- 182 72 99:1 a) All of the above reactions were run in 0.3 mmol scale with 5 mL solvent; b) Trace amount of 186 and 187 could be detected by GC-MS; 0) Isolated yield; d) Determined by GC and GC-MS. e) Regioisomer was not detected by GC-MS. f) The reaction was performed with 1.5 equivalents of alkynes. 2.3 Competition reaction between different terminal alkynes and competition between different internal alkynes Having obtained good results from the competition reaction between terminal and internal alkynes, attention was then turn to a more challenging but also informative competition between different terminal alkynes or between different internal alkynes (Scheme 2.4). Thus, the benzannulation reaction of methoxy phenyl carbene complex 89 and the cyclohexenyl carbene complex 178 with 1.5 equivalents of n-butyl acetylene and t-butyl acetylene both afforded 2:1 ratio of corresponding products in 74% and 89% combined yields, respectively. The alkyne with smaller primary substituent was slightly preferred in the benzannulation reaction over the alkyne with the larger tertiary substituent, but there wasn’t a large difference in the relative rates. The competition between an aliphatic terminal alkyne and an aromatic terminal alkyne was also examined 36 (Scheme 2.4). However, no selectivity was observed between n-butyl acetylene and phenyl acetylene since equal amounts of the two quinones were obtained in the reactions with both carbene complex 89 and 178. Finally, the benzannulation reaction of complex 89 was carried out with two equivalents of 3-hexyne and 2- heptyne. The experiment gave approximately a 1:1 ratio. Scheme 2.4 Competition Reactions with Different Terminal Alkynes or Internal Alkynes B O O OMe 1) 1.5 equiv. Z n- u n-Bu l-Bu (OC)5Cr 1.5 equrv. : r-Bu k 00 O Benzene, 40 °C, 22 hi + 2 CAN ) O O 88 Phenyl 159 188 2:1, 74% 178 Cyclohexenyl 132 189 2.1. 89% OMe 1) 1.5 equiv. Z n-Bu O (OC)5Cr 1.5 equiv. : Ph A I n-Bu + 0" .Ph 0 Benzene, 40 °C, 22 h 7 O 2 CAN ) O 180 1:1 57% 88 Phenyl 159 . , a 178 Cyclohexenyl 132 191 1.1, 68 /o E O O OMe 1) 1.5 equiv. t : Et Et (OC)5Cr 1.5 equiv. Z n-Bu_ nBu Benzene, 40 °C, 22 h 7 Me + Et 2 CAN ) O O 89 174 160 1 :1, 62% 2.4 Competition studies between terminal alkyne and 1-sllyl protected terminal alkyne To address the problem of the unsatisfactory selectivity between two terminal alkynes in the benzannulation reaction (Scheme 2.4), a competition 37 study was conducted between terminal alkynes and 1-silyl alkynes, the latter of which could serve as a protected version of a terminal alkyne. Thus, the reaction of 1-hexyne and 1-trimethylsilyl-1-pentyne with methoxy cyclohexenyl chromium carbene complex 178 provided an 81% yield of compound 182 as the exclusive product.57 This suggests that the benzannulation reaction was completely selective against the 1-silyl alkynes. The same result was observed when 1-tert- butyldimethylsilyI-1-pentyne was used in place of 1-trimethylsinI-1-pentyne. In addition, when the phenyl carbene complex 89 or cyclohexenyl carbene complex 178 was used as the substrate in the competition between 1-octyne and 1- trimethylsilyl-1-hexyne, and the 1-silyl alkyne was completely unreactive and only the quinone 192 or 193 was formed (Scheme 2.5). Scheme 2.5 Competition Reaction between Terminal Alkyne and 1-Silyl Alkyne _ O OMe 1) 1.5 equiv. I n-Bu n-Bu (OC)5Cr 1-5 equ'v- R : "4’; n =TMS 91% Benzene, 40 °C, 22 h R = TBS, 78% 2 CAN ) O 178 184 , O OMe 1) 1.5 BQUIV. Z n-Hex n-Hex (OC)5Cr 1.5 equiv. TMS : n-Bu _ l Benzene, 40 °C, 22 h 7 O 2, O 89 Phenyl 192 710/0 178 Cyclohexenyl 193 80% 38 2.5 Summary In summary, the competition between two different alkynes in the benzannulation reaction with Fischer chromium carbene complexes has been systematically studied. Terminal alkynes react in preference to internal alkynes with excellent chemoselectivity in a variety of solvents and different temperatures. This selectivity was observed to be slightly higher for (ll-substituted and a,B-disubstituted carbene complexes than for B-substituted carbene complexes. The selectivity between two terminal alkynes is not synthetically significant and when there is a slight preference it is for the least bulky alkyne. This problem could be addressed by protecting one of the terminal alkynes with a silyl group at which point the reaction becomes completely selective for the unprotected alkyne. On the basis of the above results and other control experiments, it is clearly possible that the selectivity of the reaction of different alkynes in the benzannulation reaction can be controlled by the steric interaction of the carbene complex and the alkyne. 39 CHAPTER 3 Mechanistic Study on the Benzannulation Reaction: A Probe for Symmetrical Vinyl Carbene Complexed Intermediates 3.1 Introduction As mentioned in Chapter 1, the application of benzannulation reaction has been well established. However the mechanism of this reaction has not yet been fully elucidated.”59 The currently accepted mechanism (Mechanism I) for the formation of the phenolic product involves the generation of an n1,n3-vinyl carbene complexed intermediate 199 (Scheme 3.1).10 The initial rate-determining dissociation of a carbonyl ligand from the chromium Fischer carbene complex58 gives the unsaturated species 198 followed by an alkyne insertion generates 199. Migratory CO insertion into the chromium-carbene carbon bond leads to an 11“- vinyl ketene intermediate 200, which undergoes subsequent electrocyclization and tautomerization to give phenolic product 201 as the major product. Although this is the most widely accepted mechanism, experimental support for the existence of intermediate 199 is lacking. Scheme 3.1 Currently Accepted Mechanism for the Benzannulation Reaction (Mechanism I) OMe OMe (OC)5Cr=: _ co (OC)4Cr=: RLCECFIS 197 198 OH 0 \ “L I RS OMB Cr(CO)3 Nonetheless, in addition to this mechanism, other versions of mechanism differing in details have also been proposed for this benzannulation reaction (Mechanism II and Ill, Scheme 3.2) .5950 One mechanism proposed by Detz (Mechanism ll) early on involves a [2 + 2] cycloaddition of the Cr—carbene carbon bond in structure 198 with an alkyne to give a metallacyclobutene intermediate 203, followed by a retro-[2 + 2] ring-opening to afford the n1-intermediate 202 (Scheme 3.2). Although this intermediate was then proposed to be converted to, or to be in equilibrium with, the intermediate 199,‘so mechanism II has a key difference: the initial formation of 202 prior to the formation of 199. The origin of this proposal is based on the fact that the metallacyclobutenes have been isolated from the reactions of alkylidine complexes and alkynes.61 However, Hofmann’s extended Hackel calculations suggested that intermediate 203 should have higher energy than 199 and is not likely a real intermediate.60a Other DFT- level calculations also indicated that 199 is more stable than 202.10d However, 41 there is no existing experimental data that can directly support or disfavor mechanism ll. Scheme 3.2 Mechanisms Involving n1-Intermediate (Mechanisms II and Ill) 00 c OMe 0M9 OMe O Mechanism II 0 RL RS 197 198 203 RLCECRS Mechanism Ill J OMe 00 Cr < >5 _._. RL FIs 204 OH CI \ “L II Rs 0M9 cncob Or 201 189(COI4 Both of the above mechanisms are dissociative mechanisms involving a CO dissociation as the first step. An alternative mechanism has been proposed by Sola which is an associative mechanism involving the insertion of an alkyne into the saturated 18e' carbene complex 197. On the basis of DFT calculations using the Gaussian 94 program (Scheme 32),” he claimed that alkyne insertion and cyclization to give the metallacyclobutene intermediate 204 is a highly exothermic and nearly barrierless process, and that the loss of CO from 205 is less endothermic and easier to occur than the loss of CO from 197. He argued that several structures of seven-coordinated derivatives of group VI metal carbonyls were known.62 However, this mechanism does not agree with the 42 experimental facts. Kinetic studies have shown that the benzannulation reaction is first order in carbene complex and zero order in alkyne.58 Therefore, this mechanism is probably the easiest one to be ruled out.59 3.2 Mechanistic studies with deuterium labeled pseudo-symmetric vinyl intermediate 3.2.1 Introduction As indicated in Schemes 3.1 and 3.2, mechanisms l and Il only differ in the formation of intermediates 199 and 202. Mechanism I calls for the formation of 199 first, which gives rise to the ketene intermediate 200 directly. In this mechanism, the olefin-dissociated n1-intermediate 202 is either not formed, or formed as a dead-end compound along the reaction path. Mechanism II, on the other hand, calls for the formation of 202 first, which then is transformed to 199. It was envisioned that if intermediates 199 and 202 could give different products, it might be able to distinguish these two mechanisms. Toward this end, a pseudo- symmetric intermediate 206 or 207 was designed and both of which have the “same” substituents on either side of the carbene carbon (Scheme 3.3). However, one of the side arms is isotopically labeled by deuterium. The deuteriums are designed to be far away enough from the reaction center such that they would not be expected to contribute to an observable isotope effect. lnterrnediate 206 or 207 could be generated from carbene complex 178 and alkyne 208E* or from carbene complex 178* and alkyne 208E. 43 Scheme 3.3 Designed Intermediates 206 and 207 original carbene carbon original carbene carbon ,7, , - ‘ 0300 _ \ OCH3 0' ., OCH 2:) + // (Dem (0040i \ 3 ”“305 178‘ 208E 206 enyne 207 enyne nl—vinyl intermediate n1. ll3-virlyl intermediate The idea for using intermediate 206 or 207 as the probe for the mechanistic investigation lies in the following: if mechanism I is operating, the benzannulation reaction of carbene complex 178* with enyne 208E should initially generate the n1,n3-intermediate 207E*E (corresponding to 199) and bypass the intermediate 206 (corresponding to 202, Scheme 3.4). Unless the olefin dissociation to give 206 is substantially faster than CO insertion, 207E*E should undergo CO insertion followed by cyclization with the labeled arm to give product 209* exclusively. However, if mechanism II is operating, the benzannulation reaction of carbene complex 178* and enyne 208E should initially generate the n1-intermediate 206. Since the two arms now are the “same”, the cyclization would not have any preference for either side and therefore should give equal amounts of products 209 and 209*. Hence, the ratio of 209/209* should reflect the mechanism of the reaction: a less than unity ratio suggests mechanism l, where as a unity ratio suggests mechanism II. The same will apply to the reaction starting from carbene 178 and alkyne 208*: a greater than unity ratio of 209/209* suggests mechanism I, whereas a unity ratio suggests mechanism ll. However, it should be noted that such an analysis might be complicated by the relative rate of CO insertion and olefin dissociation. If the CO insertion is not substantially faster than the olefin dissociation, then the initially formed intermediate 207E*E can isomerize to n1-intermediate 206 and to 111,113- intermediate 207EE*. This will result in scrambling of the deuterium and the formation of 209* and 209 in a ratio close to unity. Nonetheless, performing such an intramolecular competition would provide information on the nature and symmetry of reaction intermediates in these reactions. Scheme 3.4 Possible Product Distributions 0003 OCH3 H3CO\'(© + // _ [>30on + // _ Cf(CO)5 CV(CO)5 2095* 179* 2095 Mech.l mm. ll Mech/ ”SCH/Q H300 / \ 0003 ./’ _ / \ 0003 (0%)4 (OC)4Cr 20755. .3. / \ l OCH3‘ OCDa‘ 209E 2095' 3.2.2 Preparation of carbene complexes and alkynes The ammonium acylate 211 was prepared from cyclohexenyl bromide 210 using the standard procedure (Scheme 3.5) as described in Chapter 1.4 45 Treatment of this acylate with methyl triflate or methyl-d3 triflate provided carbene complex 178 or the corresponding deuterium labeled complex 178*. Scheme 3.5 Syntheses of Carbene Complexes 178 and 178* 1) n-BuLi, THF, -79 °C ONMe4 OR Br 2) C'(00)6- n (OC)50r MeOTf or 003071 (0950' Gr 3) NMe4Br, H20, rt CHZCIZ, rt, 30 min 95% 210 211 178 R = CH3 77°/o 179' n = CD3 33% The methoxy enyne 208 was prepared from the bromo ester 212 (Scheme 3.6). Elimination of HBr followed by functional group manipulation afforded the key intermediate, Weinreb’s amide 214.63 Addition of TMS-protected propargyl lithium to this Weinreb’s amide followed by quenching with H20 gave propargyl ketone 215. Treatment of 215 with KHMDS in the presence of DMPU followed by the addition of MeOTf furnished Z-silyl enyne 216Z. The E-enyne 216E could be obtained by the photolysis of 216Z. This photolysis of 216Z led to an equilibrium between the Z- and E-isomers in a 121.3 ratio, but the stereoisomers could be separated by column chromatograph using EtaN-treated silica gel. The silyl group was then removed with a catalytic amount of sodium methoxide in methanol to afford enynes 2082 and 208E. The geometry of the double bonds is maintained during the desilylation process. Scheme 3.6 Syntheses of Z- and E-Alkynes Br 0 1 5 . ‘ l' O O . SQUIV. QUIDO ine NH Me OMe .HCI 0M9 : OMB ( )( ) : AIMGS; N:OM8 120 °C. 1 h, N 2 Benzene 87% Me 212 100% 213 214 1)LiH2C : TMS O TMS 1) KHMDS, THF OCH3 TMS 5120, -78 °C, 3 h // 2) DMPU \ é 2) H20 3) MeOTf E120. hV, 2411/ NaOMe/MeOH 13:1 [:72 rt 91% OCH3 OCHs 51% NaOMe, MeOH OCH3 H \ .——— \ \ // rt H 95% II 2095 H 2195 TMS 2082 3.2.3 Benzannulation reaction with deuterium labeled substrates Vlfith carbene complex 178* and enynes 208 in hand, the benzannulation reaction was carried out to probe the mechanism of this reaction (Table 3.1). Previously, Marcey Waters in our group had demonstrated that the benzannulation of 178 and 208Z* (Scheme 3.3) gave 1:1 ratio of scrambled products 209 and 209* in benzene as solvent and a 2:1 ratio in hexanes.64 She also found that carbene complex 178* with enyne 2082 gave 1:1 ratio of 209*:209 in CH2CI2, THF and benzene. But the same reaction in hexanes provided a 2:1 ratio of 209* over 209 (Table 3.1, Entries 1 and 2). This observation could be explained by the operation of mechanism I as outlined in Scheme 3.1 in which the scrambling of the deuterium via the intermediate 202 is completed in benzene but not in hexanes. Alternatively, this observation could be explained by mechanism II as shown in Scheme 3.2, which involves the initial formation of intermediate 202. As shown in more detail in 47 Scheme 3.7, the reaction of 178* and 2082 gives the intermediate 207E*Z which has the correct geometry about the deuterated enol ether to give 209*, but not on the unlabeled enol ether for cyclization to 209. Thus, the slightly higher ratio of 209*:209 in hexanes may be just the consequence of the fact that isomerization of the Z-enol ether in 207E*Z to give the E-enol ether in 207E*E may be slower in hexanes than in benzene relative to cyclization to 209*. Scheme 3.7 Detailed Mechanism for the Formation of 209 and 209* O 000 0“ o D3CO __. ‘\- _. \ + _ / \ OCH3 Cr(CO)5 // OCH3 OCH3 Cr(CO)4 OCDa 178' 2082 20757 209' OH O HSCQp prDa \ . ./’ . 0003 ‘— / \ 0003 — H300 (OC)4CI’ 00113 209 207EE‘ 207E‘E As shown in Scheme 3.4, the electrocyclization step must occur through the E-geometry. Therefore, initiating the reaction with pure E—stereoisomer of the enyne 208 would eliminate the complication that is caused by the EIZ isomerization step that must occur before cyclization. Unfortunately, Marcey Waters did not run the reaction of complexes 178* with enyne 208E in hexanes. One of the goals of the present work was thus to carry out this reaction with the E-enyne to see if the hexanes result means that mechanism II can be eliminated or if the situation of mechanism I shown in Scheme 3.7 pertains. The reaction of complex 178* with 208E was found to give a 1:1 mixture of 209* and 209 in both 48 hexanes and benzene. The products 209 and 209* were each isolated as mixtures of E and Z isomers which varied depending on workup. This is the result of the fact that isomerization can occur rapidly in either CDCI3 or on silica gel to give the more stable Z-isomer. For this reason, the ratio of the products was determined on the crude reaction mixture with ds-benzene as solvent. Table 3.1 Benzannulation of Deuterated Carbene Complex with Enyne 0003 OH . (OC)5Cr H3/ Solvent, 0.05 M \ + 45 °C, 12 h OCHa Entry Solvent Enyne Ratio of % Yield of Configuration 209*:209a 209* + 209b of 209* and 2098 1c Benzene 2082 1 :1 74 2 2° Hexanes 2082 2:1 73 2 3c Benzene 208E 1:1 77 1:3 E/Z 4 Benzene 2082 1 :1 67 Z 5 Hexanes 208Z 2:1 81 Z 6 Benzene 208E 1 :1 36 1 :10 E/Z 7 Hexanes 208E 1 :1 50 1 :10 E/Z a) Determined by crude 1H NMR in CeDs and fi'HNMR in CDCI3 after purification. b) Isolated yield as a mixture. 0) Performed by Marcey Waters. 3.2.4 Discussion As mentioned in the previous section, the 2:1 ratio of 209*:209 obtained from reaction of 178* with 208Z in hexanes supports the operation of mechanism I (Scheme 3.1) for the benzannulation reaction. The 1:1 product ratio in benzene 49 and other polar solvents could be consistent with mechanism I if there is a fast equilibrium between the eight isomers of intermediate 207 shown in Scheme 3.8. However, it is also consistent with mechanism ll shown in Scheme 3.2 and thus the experiments summarized in Table 3.1 do not allow for a determination of which mechanism is operating. If the more widely accepted mechanism l is operating, then the results in Table 3.1 could be explained by the mechanism in Scheme 3.8. The 1:1 ratio of products 209 and 209* from the reaction of 178* and 208E in hexanes could also be attributed to a faster equilibrium among the isomers of intermediate 207 than for those from the reaction of 178* and 2082. Such interconversion between 207E*E and 207EE* or 207E*Z and 207ZE* could occur directly by an associative displacement of OMe double bond by another or via a n1-intermediate 206 (Scheme 3.4) in which neither of the double bonds is chelated to the metal. As mentioned before, this non-unity ratio from the reaction of 178* and 208Z might just be due to the fact that the isomerization of the Z-enol ether in hexanes is slower than in other solvents (Scheme 3.7). Before a discussion of the possible equilibrium between 207E*E and 207EE* and the mechanism as a whole is undertaken, a few points need to be mentioned. The reactions of carbene complex 178* and 208 can serve to probe whether the alkyne insertion is reversible. According to the mechanism outlined in Scheme 3.8, the reaction of 178* and 208E would lead to the initial formation of the 11 1,1)3-vinyl carbene complexed intermediate 207E*E or 2072*E. lsomerization of 207E*E via the 16e' intermediated 206 as shown in Scheme 3.4 50 would led to the formation of 207EE*. If the alkyne insertion step is reversible, then the intermediate 207EE* should reverse to complex 178 and alkyne 208E* (Scheme 3.4). Thus, a probe for the reversibility of the alkyne insertion step could be performed by isolating unreacted enyne 208E from its reaction with carbene complex 178* and analyzing for deuterium incorporation. Based on Marcey Water’s observation, no detectable amount of deuterium substituted alkyne 208* was observed for the remaining alkyne in the 1H NMR of the crude mixture from the reaction of 178* and excess 208E. The same outcome was also observed when this reaction was repeated for the present work. This experimental outcome was consistent with the results obtained from a theoretical DFT study by Hess1°d and Sola59 which predicts that alkyne insertion will be irreversible. Furthermore, the E/Z isomerization of the olefin moiety of the starting enyne must occur between alkyne insertion and CO insertion. As mentioned previously, the electrocyclization step in the mechanism must occur through the E-geometry of the intermediate 207E*E or 207EE* (Scheme 3.7). Therefore, the double bond in 208Z must isomerize to E in order to produce phenol products. The isomerization does not occur before alkyne insertion, as Marcey Waters has demonstrated that the E-enyne 208E did not convert to Z-enyne 2082 under the reaction conditions.64 It is also unlikely to occur after the CO insertion, since Wulff has suggested that the cyclization of vinyl ketene intermediate 200 (Scheme 3.1) is extremely rapid since the vinyl ketene could not be trapped even by intramolecular reaction with an alcohol.65 Calculations by Hess also indicated that the vinyl ketene 200 (Scheme 3.1) does not have an energy minimium, and that 51 the CO insertion and electrocyclization occurred in a single exothermic step with a very low energy barrier.10d Thus existing evidence suggests that the vinyl ketene intermediate 200 (Scheme 3.1) undergoes immediate electrocyclization without leaving enough time for any other event to happen including isomerization of the olefin in the alkyne. The isomerization after the formation of phenol 209 is also unlikely to occur, since the products 2092 and 209E can both be isolated from the reaction. The isomerization of 209E to 209Z does however occur in the present of silica gel and CDCI3. If 209E was isomerizing to 2092 under the reaction condition, then the reactions from E— and Z-enyne should both give the same E/Z ratio in the products. With the above information and considerations in mind, a detailed mechanism explaining the results obtained in the previous section is presented in Scheme 3.8 and is based on mechanism l (Scheme 3.1). This scheme is far more detailed than Scheme 3.4 which is primarily due to the complication of the E/Z isomerization issue. The initial reaction between 178* and 208E affords directly two possible intermediates 207E*E and 207Z*E, which differ only at the geometry of the newly formed olefin. Intermediate 207E*E can directly undergo a CO insertion and cyclization to provide product 209E* or interconvert to 207EE*, while intermediate 207Z*E cannot directly undergo CO insertion and cyclization due to the geometry constraint. However, intermediate 207Z*E can undergo olefin displacement to exchange the olefin ligand at the chromium to afford 207EZ*, which can then undergo a CO insertion and cyclization to provide product 2092. Intermediate 207E*E can undergo the same process, namely an 52 olefin displacement to exchange the olefin ligand at the chromium, a CO insertion, and cyclization to provide 209E product. This olefin isomerization could also occur on 207EE* to afford 207EZ*, which could undergo CO insertion and cyclization to provide product 209Z. When the reaction was initiated from 178* and 208Z, the initial intermediates would be 207E*Z and 207Z*Z, and the formation of products 2092* and 209Z can be explained from the interconversion between all eight of the isomers of intermediate 207. When the reaction of 178* and 2082 was carried out in benzene and other polar solvents, the interconversion between the eight isomers of intermediate 207 is faster than the subsequent CO insertion since the ratio of 209* to 209 is 1:1 whether the reaction is carried out with the enyne 2082 or 208E (Table 3.1). Equilibration of all eight isomers of 207 is apparently not quite complete in benzene since a 1:10 ratio of [5:2 isomers of 209* and 209 were observed when starting with 208E, whereas, only the Z-isomers of 209* and 209 were observed when starting with 2082 (Table 3.1). The result also suggests that the CO insertion from 207EZ* and 207E*Z is faster than from 207EE* and 207E*E. When the reaction was carried out in hexanes, the interconversion between the eight isomers of intermediate 207 was further slowed down and became somewhat comparable with the subsequent CO insertion.66 When staring with 2082, the CO insertion in hexanes is slightly faster than, isomerization of 207E*Z to 207EZ*, and leads to preference of 209Z* over 2092. Where as starting with 209E, intermediate 207E*E and 207EE* apparently reach equilibrium very fast and lead to 209E* and 209E without any preference. It was though that the following 53 possibilities may contribute to some of the phenomena in the reactions, although the detailed reasons may be elusive. First, isomers of intermediate 207 do interconvert, but some interconversions are faster than others. This may result in the accumulation of certain intermediates rather than others, and lead to a formation of certain products in preference. Second, different intermediates may have different rates for the CO insertion step. Some intermediates may be faster in the subsequent CO insertion and lead to a predominate product. However, at this point, there is no sufficient data to provide a detailed explanation with regard to the product distribution. We hope that future work in this area may provide a more detailed picture of this mechanism. 54 Scheme 3.8 Proposed Mechanism for Product Distributions 00 o O \ b 0003 C’(CO)40003 2092* 20722. C r 2 C d 0300 CT(CO)5 // OCH3 178* 2082 2 a e A a ’ 00113 T DaCC) // Cl’(CO)5 / 2085 c 178' J a . 207EE' la OH I I \ 0003 a) Alkyne insertion ‘ b) Olefin isomerization OCHs c) Olefin displacement 209 d) CO insertion and electrocyclization 55 3.3 Electronic perturbation of the benzannulation reaction To further investigate the equilibrium between the vinyl carbene intermediates, an electronic perturbation of the vinyl carbene intermediate 207 was considered (Scheme 3.3) such that the two arms are differentiated by electronics. In fact, a similar example has been reported by Herdon.67 He demonstrated that the reaction of phenyl methoxy carbene complex 89 with aryl enyne 217 did not give the normal benzannulation product 224. Instead, the reaction generated exclusively phenol 218 with the incorporation of the aryl group on the enyne. Herndon proposed that this reaction involved a fast olefin disassociation/coordination between intermediates 219 and 221, and further more that the CO insertion was faster for intermediate 221 than 219. The chromium is coordinated to a more electron-deficient double bond in 221 than in 219 which leads to enhanced back-bonding from chromium to the olefin in 221 and therefore less back-bonding to the CO ligand and a more rapid CO insertion to give 222. The electrocyclization of the resulting ketene 222 led to the observed product 218. 56 Scheme 3.9 Herndon’s Studies dioxane FRO Me fl 0 6" 0,0, )3} Meo \ . (OC)5Cr OMe Based on Herndon’s result, it was envisioned that a double bond bearing a MOM group should have lower electron density than one bearing a methoxy group, and thus CO insertion and the cyclization should occur more rapidly on the MOMO-substituted olefin (Scheme 3.10). Intermediates 225EE and 226EE could be generated from the MOM carbene complex 227 and methoxy enyne 208E or from the methoxy carbene complex 178 and MOM enyne 228E. Scheme 3.10 Electronic Perturbation by MOMO-Substituent H3CO 57 The MOM-enyne 228 was also prepared from ketone 215 (Scheme 3.11). A standard MOM protection led to the enol acetal 2292. Photolysis of 2292 provided 2:1 ratio of 2292 and 229E, which were inseparable by chromatography. Fortunately, these compounds could be separated after removal of the trimethylsilyI-protecting group. The geometry of the double bonds was retained in this removal of the TMS group. Scheme 3.11 Preparation of MOM-Enyne 228 WWW 21531483 THF _ O/OQOM/TMS NaOMe,MeOHA OJZOM/H 3) MOMCI , rt W 215 47% 2292 2292 5120. 22110311 hv, 24h Z/E OMOM OMOM \ NaOMe,MeOH \ II n : II 2295 TMS 2295 H 89%2212/E Having both isomers of the enyne 228 in hand, the benzannulation reactions were carried out at 45 °C in different solvents (Table 3.2). The reaction of MeO-carbene 178 with Z-MOM-enyne 228Z gave a 1:1 ratio of 230/231 in benzene based on the crude 1H NMR analysis (Entry 1). The same reaction in hexanes provided 3:1 ratio of 230/231 (Entry 2). However, the reaction was carried out with MOM-carbene 227 and Z—MeO-enyne 2082, the ratio of products was reversed. Reaction in benzene provided a 1:4 ratio of 230/231 and the reaction in hexanes provided 1:5 ratio (Entried 3-4). The reaction of complex 178 and enyne 2082 had been previously reported by Marcey Waters who obtained a 124.7 ratio of 230 and 231.64 She also was able to assigned the structures of 230 58 n‘. a 7: and 231 by acid catalyzed cyclization of each to benzofurans. The reaction with E-enynes, regardless of the solvents and starting materials (178 + 228 or 227 + 208), gave a ratio of 230/231 that was consistently in favor of 231 in a ratio that varied from 1:3 to 1:5. The reactions with the E-enynes gave more complex crude mixtures than those with the Z-enynes, and the ratio of the products was simplified by measuring the ratio of the major Z-isomers. Table 3.2 Benzannulation of 178 with 228 and 227 with 208 on‘ 0R2 OH O OH 0 O Solvent. 0.05 M ( 050 + \ & 4v . \ + . \ OCH3 OMOM 178 R‘ = CH3 228 R?- = MOM 230 231 227n1=M0M 208R2=CH3 Entry R1 R2 Solvent Ratio of Yield of Yield of 230:231 230° 231° 1 Me MOM Z Benzene 1 :1 a 25 30 2 Z Hexanes 3: 1 a 32 15 3 MOM Me 2 Benzene 1:43 -d 32 4 Z Hexanes 1 :5‘ 12 74 5 Me MOM E Benzene 1:5” -d 37 6 E Hexanes 1 :4b -d 39 7 MOM Me E Benzene 1 :33 - 35° 8 E Hexanes 1 13" - 34° a) Determined by crude 1H NMR in CDCI3. b) Determined by crude 1HNMR in 0606 based on the major isomers. c) Isolated yield. d) The product was not pure. e) Combined yield of 230 and 231. The results obtained from the annulations with E-enynes are expected, because as mentioned before, it was expected that since the MOMO-substituted 59 olefin has less electron density it should therefore be able to coordinate to the chromium more tightly, resulting in the cyclization to occur more preferentially on the MOM-substituted arm (Scheme 3.12). In other words, the equilibrium between 225EE and 226EE should lie towards 225EE. Thus, the formation of 231 as the major product would follow. Scheme 3.12 Proposed Product Distribution .OH \OCH3 .OH OMOM OMOM OCH3 However, things are more complicated in the reactions with the Z-enynes. The ratio of products is dependent upon the starting materials and the reaction conditions. The product 230 resulting from cyclization to the methoxy bearing double-bond can be obtained in similar or even larger amounts than 231. Note that this is the situation where olefin isomerization must occur before cyclization (see discussion in section 3.2). Specially, the interconversion between intermediate 225EZ and intermediate 226EZ (Scheme 3.13) contains an olefin isomerization in addition to a double bond swap, and therefore is expected to be slower than the interconversion between 225EE and 226EE (Scheme 3.13). When the reaction starts from 227 and 2082, it is intermediate 225EZ that is 60 formed first. Similarly, when the reaction starts from 178 and 2282, it is intermediate 226EZ that is formed first. If it is assumed that CO insertion is faster in 225EZ than it is in 2265Z (k1 > kg) for the reasons discussed above. Then, the results can be explained by the situation where the CO insertion and cyclization of 225EZ is faster than isomerization to 226EZ. Whereas, the CO insertion and cyclization of 226EZ is slower than isomerization to 225EZ. The solvent effect can also be explained (Entries 2 and 4, Table 3.2). Using hexanes as solvent further reduces the rate of the interconversion of 226EZ to 225EZ, and therefore, the product distribution will be more reflective of the starting materials. Scheme 3.13 Proposed Mechanism for Product Distribution from Z-Enynes H3CO Cf(CO)5 // OMOM 61 Based on the above studies, the electronic effect plays an important role in the inverconversion between the vinyl carbene complexed intermediates. The CO insertion and cyclization in these intermediates is preferred to occur at the intermediate with the chromium coordinated to the more electron-deficient double bond. 3.4 Summary The mechanism of the benzannulation reaction was probed by a pseudo- symmetric intermediate assumed to generate along the reaction path. The product distributions suggest that the n1,n3-vinyl carbene complexed intermediates do interconvert via an olefin dissociation/re-association and can be accompanied with E/Z isomerization of the pendent olefins. A solvent effect is observed in these investigations, resulting in a finding that hexanes can suppress the interconversion between n‘,n3-vinyl carbene complexed intermediates. Between the two mechanisms that have been put fonlvard, mechanism I is considered the more likely but the results of the present study could not rule out mechanism ll. Electronic perturbation in the benzannulation was pursued by designing another pseudo-symmetric intermediate with two electronically differentiated arms. The benzannulation prefers to occur with the chromium coordinated to more electron-poor double bond in the n1,n3--vinyl carbene complexed intermediates, but the rate of interconversion between the two possible 111,113- vinyl carbene complexed intermediates is solvent dependent. 62 CHAPTER 4 Studies Toward Total Synthesis of Richardianidin-1 4.1 Background 4.1.1 Intramolecular Annulation of Fischer Carbene Complex In the previous chapters, we have discussed the intermolecular annulations of Fischer carbene complexes. Intramolecular reactions of carbene complexes with alkynes are also known and have been investigated. There are two types of intramolecular benzannulation reactions and these are shown in Scheme 4.1. The first type of reaction involves a carbene complex bearing an alkyne tethered to the heteroatom, and the second type involves the carbene complex bearing an alkyne tethered to either the or- or the B- carbon of the alkenyl carbene complex. Scheme 4.1 Intramolecular Benzannulation Reactions n qu Type I (00501 . _. _ RZR R1 232 233 (on: 1 to 3) 234001 > 8) OMe (OC) Cr Type II (0050i —> 5 —\2 235 The type I of intramolecular reaction has been thoroughly studied and has been utilized in the syntheses of natural products.“69 Semmelhack and 63 coworkers reported the first example of this type of intramolecular annulation and applied this methodology to the total synthesis of deoxyfrenolicin.68 The annulation gave good yields when the tether length was 2 to 4 carbons. It should be noted that in these intramolecular reactions, the regioselectivity of the alkyne insertion is reversed as a consequence of ring strain leading to the formation of 233. When the tether is long enough (n > 8), the meta-bridged phenol 234 is obtained with the same regioselectivity as the intermolecular annulation.69 The tautomer-arrested version of the type I intramolecular annulation is also known. However, it is limited to a single example published by Wulff et al (Scheme 4.2).70 In this example, thermolysis of carbene complex 239 gave hydrindenone 240 and the CO insertion product 241. The hydrindenone product 240 was favored with the formation of 6-membered oxacycle (n = 2), while the shorter tether (n = 1) preferentially gave the diketone 241, and longer tether (n = 3) gave decreased overall yield. Scheme 4.2 Tautomer-arrested Type I Intramolecular Annulation O O (OC)5Cr \\ Benzene O 0 Ar + 60 0C O )n O n 240 241 239 0” n 240 (°/o) 241 (°/o) 1 20 51 2 64 <5 3 26 14 On the other hand, only a few examples of the type II intramolecular annulation have been published.71 This type of annulation requires the tether to be longer than 6 carbons, due to the ring strain (see Scheme 5.8). As can be seen in Scheme 4.1, the carbene complex with an alkyne tethered to the B- carbon will afford the meta-bridged product, whereas the carbene complex with an alkyne tethered to the a-carbon will give the para-bridged product. The regioselectivity of these annulations results in the alkyne and the tether being attached to the arene ring in the product adjacent to the phenol which is the same as that for the intermolecular annulation. 4.1.2 Retrosynthetic analysis of Richardianidin-1 Richardianidin-1 (242) was isolated in 1988 from the leaves of Cluytia Richardiania (L.), which grows in the mountain regions of western and southern Saudi Arabia.72 The Cluytia species are used in folk medication and have significant hypoglycemic activities in vitro and in vivo.73 The structural challenge to the synthesis of Richardianidin-1 is highlighted by the tetracyclic system rich in stereogenic centers. Although having interesting bioactivity and possessing structural uniqueness, there has been no total synthesis of Richardianidin-1 reported. Only one approach to the framework of this natural product has been published.74 The key step in a synthesis to be examined in the present work is the construction of the BC rings of Richardianidin-1 (242) by‘the tautomer- arrested annulation. The retrosynthetic analysis for Richardianidin-1 (242) shown in Scheme 4.3 was previously studied by Mary Bos in this research group and her studies can be found in her thesis.75 The retrosynthesis starts with the ring opening of the la ctone to give intermediate 243 (Scheme 4.3). This intermediate is envisioned to 65 result from a 2,3-Wrttig rearrangement that ultimately leads back to hydrindenone 244,76 which in turn can be synthesized via either an inter- or intramolecular tautomer-arrested annulation of 4-hydroxy-2,6-dimethylphenyl carbene complexes 245 or 247 respectively. Between the two approaches, the intramolecular was initially favored, because it presumably offers better control of the regioselectivity. The applications of tautomer—arrested annulation in total synthesis never have been used, and thus would make this approach more favorable. Scheme 4.3 Retrosynthetic Analysis of Richardianidin-1 lactone Me / D O ring 0R2 2,3-wittig 2 , formation rearrangement - v. H 2 5 HO on1 t/ \) ’MBH 0A0 /O\ O O O 244 243 th b Rlchardlenldln-t . pa path a 242 intermolecular int r am 0' ecul ar tautomer-arrested I benzannulation 0R3 0R3 0 (OC)5Cr on1 \ \ / Q + HO 0 or \ 4.2 Intramolecular approach 4.2.1 Intramolecular annulation of Fischer carbene complexes containing an acetal tether The intramolecular approach was first examined with the target simplified model hydrindenone 248 (Scheme 4.4). It was envisioned that compound 248 could be easily obtained by hydrolysis of enol acetal 249, which could in turn be obtained from carbene complex 250 via an intramolecular tautomer-arrested annulation. The acetal in the tether is critical in this approach for two reasons. The first is that hydrolysis of the acetal in 249 liberates the properly oxygenated intermediate 248. The second is that, as mentioned before (Scheme 4.2), the hydrindenone product is only favored over the CO inserted product when the tether length is four atoms from the alkyne to the carbene carbon.70 Scheme 4.4 Intramolecular Annulation Analysis OBn OBn f / O OH —_—__—__> O :9 HO (O / 08" O O o o~/ Cr(CO)5 243 249 250 T880 /—0 OBn —___=> O'NMef + Cl \_:_<7 Cr(CO)5 251 252 OMeO 0/ \OH 0 I M90 0‘ ‘ 1)THF, 35°C (OC)5Cr —\—o ”THF'35 °C 00 - = 00 2) 000 Meo n-Pr 2) PlnBU)3 o \ 51% acetone OH \ 254 253 48% 255 Semmelhack has previously developed a cleavable tether and employed it in the total synthesis of deoxyfrenolicin.68""b This tether involved an ethylenoxy linkage which involves a total of 5 atoms in the liner (Scheme 4.4). In addition, cleavage of the linker involved an oxidation elimination sequence and thus would not be as convenient as a simple acetal linkage. Acetal linkers such as that 67 presented in carbene complex 250 have not been previously employed in intramolecular benzannulation reactions. It is anticipated that these complexes could be accessed from alkylation of the ammonium acylate 251 with the chloromethyl propargyl ether 257. A series of carbene complexes 259 were prepared such that the generally of these complexes in the annulation could be examined (Scheme 4.5). Thus, propargyl alcohol 256 was allowed to react with paraformadehyde and TMSCI to give the corresponding chloromethyl ether 257,77 which was then reacted with ammonium salt 251 to afford the TBS- protected carbene complex 258. This preparation was sensitive to the propargylic substituent. Unfortunately, compounds 264 and 266, with a phenyl or 2-furyl group at the propargylic carbon could not be prepared with this route. Removal of the TBS group in 258 could only be accomplished by treatment with sodium methoxide in methanol; using TBAF led to the decomposition of the carbene complex. It was pleasing to find that, the thermolysis of 259a, the simplest model compound, in benzene at 60 °C afforded hydrindenone 2603 as the major product in 51% yield. A trace amount of the indene product 262 resulting from methyl migration was also detected by 1H NMR. Thermolysis of 2592 in toluene gave the same product 260a in 49% yield accompanied with a trace amount of indene 262. However, when the substituent on the triple bond (R1) was changed from methyl to ethyl and iso-propyl, the yields of hydrindenone 260 dropped dramatically and the CO insertion product 261 was observed, all with a significant decrease in overall yield. In the isopropyl case, hydrindenone 260c was not 68 observed. This result gre approach to Richardianidin- atly reduces the prospects for this intramolecular 1. However, in the actual retrosynthesis, R2 would not be hydrogen in carbene complexes. Therefore, complex 259d was synthesized to study the effect of a-substituents (R2 a: H). The reaction of the a-substituted propargyl ether tethered carbene complex 259d afforded near a 1:1 ratio of the desired product 260d and the CO insertion product 261d. This result indicated that the a-substituent had a small impact at most on this annulation reaction. Scheme 4.5 Syntheses and Thermolysis of Carbene Complexes 259 R1 R2 Me Sic. R2 251, CHZCIZ / HO (CH20)3 O n.30min O R2 256 257 Cr(CO)5 258 R1 1 O // R n‘ NaOH/MeOH HO rO Benzene o R2 0 o n2 + 82 '1 60°C 0 Cr(CO)5 0~/ DVD 259 260 261 R1 Ph ‘ 2 \ _ / Me3SlCl v2 Cl Ph _ H0 00 R / - \ 7V ¥ >‘——<— HO (CH20)3 O O 04 263 264 O o 262 \ / l / Me38iCl I ———-)(-—> Cl : H0 (0420):, \—o 265 266 69 Table 4.1 Syntheses and Thermolysis of Carbene Complexes 259 Series R1 R2 % Yield 258 % Yield 259 % Yield 260 % Yield 261 a Me H 91 59 51 a - b Et H 97 46 9 25 c i-Pr H 68 55 - 16 d Pr Et 100 40 18 21 a) Thermolysis of carbene complex 259a in toluene provided 49% of 260a. As indicated in retrosynthetic analysis (Scheme 4.3) the most desirable substituent on the alkyne of carbene complex 247 is an alkenyl group. Therefore, carbene complex 259e with R1 as an iso-propenyl group was prepared. This complex was prepared as shown in Scheme 4.6. Perhaps the steric and electronic differences between an iso-propenyl and iso-propyl group would lead to a greater preference for the hydrindenone product. However, when carbene complex 259e was subjected to the thermolysis conditions in benzene, the desired product 260s was not detected at all. Nor was the CO insertion product 2619. The only product obtained in this reaction was the phenol 269 whose structure was determined after extensive NMR studies. This product is thought to form via vinyl ketene 268 and subsequent electrocyclic ring-closure. 70 Scheme 4.6 Thermolysis of Carbene Complex 259e 1) n-BuLi, THF, -78 °C. 30 min OH Me3SiCl Oj >——: > >———/: ———> >-——’: Cl 2) (CH20)3. -78 °C 10 f1 (CH20)3, l1 256e 257a 25131-12012 T880 (0% NaOMe/MeOH ¥ HO (CD/K n. 30 min 0 'l o 65°/o 50°/o Cl’(CO)5 267 69% Cf(CO)5 2580 2590 H0 QC HO 0 Benzene Benzene \\C_/< O l 60 OC (5(8):? 0 \Cr(CO)3 O _ O \_O O 268 269 O O + O i 04 DVD 2606 2619 Given the failure of tautomer-arrested annulation of the iso-propenyl substituted complex 259e, the complex 250 was next prepared which had a benzyloxy propyl group as a surrogate for the iso-propenyl group. The synthesis of 250 is shown in Scheme 4.7 and begins with the propargylic alcohol 252 which in turn was prepared from allylic alcohol 270. After Benzyl-protection and olefin migration to obtain 271, a hydroboration was performed, followed by lz-induced coupling of the alkyl group in the borane and alkyne 272.78 Desilylation afforded 252 in good overall yield. Then, following a route similar to that outlined in Schemes 4.5 and 4.6, alcohol 252 was then taken onto carbene complex 250, albeit in lowered yield. To our disappointment, thermolysis of 250 gave a complicated mixture of many compounds, which was not further characterized. 71 Scheme 4.7 Preparation and Thermolysis of Carbene Complex 250 1) BH3-THF, 0 °C 1) BnBr, NaH 2) 7OTBS —/—OH DMSO. rt ‘ fiOB” — 272 _ BnO OH 3) 12, -78 00 > — 2 DMSO, KOt-Bu 27o ) 100 OC 6 h 271 4) TBAF 252 5895 7795 M S'Cl BnO 0 251,011 on (CH20)3. rt 11. 30 min m o Cr(CO)5 273 86%: 274 /M H \/i\l Benzene NaOMe 90 : HO rO / OBn ———. inseparable mixtures rt 0 60 0C 36% Cr(CO)5 250 4.2.2 Intramolecular annulation of Fischer carbene complexes containing a silicon tether Finn and coworkers reported that thermolysis of silicon tethered carbene complex 275 in the presence of a large excess of diphenyl acetylene followed by CAN oxidation could afford the hydrolyzed benzannulation product 276 in good yield (Scheme 48).” Thus, it was of interest to see if the silicon-tethered carbene complex 277 (Scheme 4.8) could be used in the intramolecular tautomer—arrested annulation. It was hoped that this approach might provide desired hydrindenone product 279 upon thermolysis and hydrolysis of 277. 72 Scheme 4.8 Proposed Synthesis of 279 0 SiO . _ O (OC)5Cr 2:L\H 1) 10 equw. PhC =CPh~ H 2) Ce(| /HNO 0‘ V) 3 OH 60% O 276 o/\Si (0C) 50f 27::j\ 0 O ; E O ; : I O‘Si O OH I \ 278 279 Preparation of the TBS-protected carbene complex 281 could be achieved by treatment of alcohol 256a sequentially with MeZSiClz and ammonium salt 251. However, the silicon-tethered carbene complex 281 was unstable and readily decomposed upon quenching the reaction with NaHCOa or upon loading the reaction mixture directly onto a triethylamine-treated silica column. Thermolysis of the unpurified and unstable red compound in benzene followed by CAN workup did not furnish any cyclized product. The only detectable product was the carboxylic acid 282 which was isolated in 13% yield. The ammonium acylate 283 with a free hydroxy group failed to react with 280 to give any carbene complex. Thus, the plan to synthesize carbene complex 277 was abandonee. 73 Scheme 4.9 Synthesis of Carbene Complex Tethered with Silylether ONMe4 (OC)5Cr / O-Si—O (OC)5Cr \ \—:— “—3‘_\ MeZSiC'Z'“ * ‘E—WO s/ c: 251 0188 OH ' - 1— > 2562 quantitative yield 230 \ CHZCIQ. rt OTBS 281 1)Benzene, 80 °C,2h 4 TBSO COQH 2) CAN 13% 232 ONMe4 (OC)50r —_—:—fl / CH2Cl2,rt + O-Si-Cl = failed to give anycarbene complex \ 280 283 0” Vlfith these results in hand, the intramolecular approach has met a major obstacle. With the understanding gained in the present work on the reactivity of carbene complexes in the intramolecular tautomer-arrested annulation, it becomes clear that this reaction will not likely be able to provide an efficient access to the desired intermediate 244 in the synthesis of Richardianidin-1 (242) (Scheme 4.3). Thus, an alternative approach needs to be considered. 4.3 lntermolecularApproach Due to the difficulties encountered during the studies on the intramolecular approach, attention was turned to utilize the intermolecular tautomer—arrested annulation to construct the BC ring of Richardianidin-1 (Scheme 4.3). The biggest problem to be addressed in this approach is the regioselectivity. The regioselectivity is generally not high for internal alkynes in the benzannulation 74 reaction (Scheme 4.10).12 For example the reaction of carbene complex 33 and iso-propyl methyl acetylene gave a 4.8:1 ratio of 2842 and 284b.12 In addition, it is known that the regioselectivity decreases with increasing temperature.66 This is particularly troublesome for the prospects for regioselectivity for the tautomer- arrested annulation since this reaction requires higher temperatures (110 °C) than the normal benzannulation (45 °C). As expected on the basis of the discussion above, the reaction of complex 46 with iso-propyl methyl acetylene provided two products in a 3:1 ratio. However, after careful analysis, the two products were found not to be regioisomers. Instead, they were hydrindenone 285 (tautomer-arrested product) and indene 286 (methyl-migration product), respectively. Surprisingly enough, neither 285 nor 286 was contaminated by its regioisomers 285a or 286a. Thus, this annulation is completely regioselective. The reason for this excellent regioselectivity is still elusive, but the result made the intermolecular approach to Richardianidin-1 much more promising. The reaction between carbene complex 46 and methyl tert-butyl acetylene was also examined. This annulation also provided excellent regioselectivity, but the desired hydrindenone 287 now became the minor product in this case. 75 Scheme 4.10 Studies of the Regioselectivity in the Intermolecular Annulation OMe 0 O (OC)50r 1) THF, 45 °C, 24 n " ‘_<: = 0‘ + 0‘ MeO 2) CAN OMe O OMe O 33 2843 “-831 284D OMe (OC)5Cr Benzene, 110 °C 0 HO O + %—< > + o OMe OMe 45 OH 285 44% 266 15% O§ ; t j : HO I OMe OMe 2853 252. OMe O HO (OC)5Cr Benzene, 110 °C 0. + ———.<—: e + OMe OMe 46 OH 287 18% 268 41% The excellent regioselectivity for an alkyne bearing a methyl and iso- propyl groups prompted the design of alkyne 292 (Scheme 4.11). The annulation with carbene complex 46 should produce hydrindenone 293 as the product. Compound 293 contains all but one of the carbons on the BC ring in Richardianidin-1. Furthermore, compound 293 should be able to be converted to the key intermediate 244 (Scheme 4.3) by functional group manipulation. Alkyne 292 was prepared in 2 steps from 289. Deprotonation of the terminal alkyne followed by trapping with Weinreb amide 29063 led to compound 291. Subsequent Wrttig reaction with methoxymethylene phosphorane gave enyne 292 as a 1:1 mixture of E/Z isomers. This stereochemistry is not important, 76 since this enol ether will be converted to a ketone at a later stage in the synthesis. Thus, the annulation was performed with this E/Z-mixture. Thermolysis of alkyne 292 with carbene complex 46 did provide the desired product 293 as a single regioisomer, but the yield of this reaction is only 29%. Scheme 4.11 Annulation of Carbene Complex 46 and Alkyne 292 OMe :—_—\OTIPS 1) ('BUU, THF. ‘40 00 $ 0 : [phspCHZOMeld-Cl; \ : 2) CH3(CO)NMe(OMe) 290 “”33 f-BuLi OTIPS 289 291 67% 292 73% 46. benzene O / OMe 110 °C OTlPS 290/0 OMe 293 4.4 Mechanistic considerations During the investigations described in this chapter, it was noticed that the product distributions were quite different for the intra- and inter-molecular tautomer-arrested annulations. The intramolecular reaction generates hydrindenone 301 and CO insertion product 299 (Scheme 4.12), while the intermolecular reaction gives hydrindenone 301 and indene 302. A mechanism for the diverse array of outcomes is proposed and is presented in Scheme 4.12. It is believed that the initial steps, namely the dissociation of a CO ligand and alkyne insertion to generate a n‘,n3-vinyl intermediate 296, are the same in both inter— and intra-molecular reactions. In the normal benzannulation reaction, this intermediate prefers to undergo CO insertion to give intermediate 297. However 77 in the intermolecular tautomer-arrested annulation, such insertion of CO is not favored. The presence of the two ortho methyl groups on the phenyl must either depress the insertion of CO in 296 or if 296 and 297 are in equilibrium, it must slow down the cyclization of the vinyl ketene intermediate 297. Either would enhance the formation of the 5-membered cyclized intermediate 300, which then ultimately leads to 301 or 302. Possible reasons for the appearance of CO inserted products in the intra-molecular tautomer-arrested annulation have been discussed by Mary Bos who examined a series of complexes with different tether links between the alkyne and carbene carbon.75 Her work suggests that the strain in the ring bridging R5 and OR in structure 296 is the major contributing factor. When RL is a vinyl group in the intramolecular tautomer-arrested annulation, the vinyl ketene intermediate 303 is trapped by the vinyl group and gives cyclobutenone 304. In contrast, Wulff et al reported that in the regular benzannulation reaction, similar vinyl-substituted ketene intermediates are very reactive and could not be trapped in this manner but rather cyclize to the normal phenol product.65 Thus, the presence of the ortho methyl groups for presumably steric reasons must decrease the rate of the cyclization of the ketene onto the phenyl ring, so that the electrocyclic ring closure to 304 is favored. 78 Scheme 4.12 Mechanism of Tautomer-arrested Annulation HO HO HO M9 OR-n.‘ -CO RL : R3 (3/ x. OR fl on . Me \\C ' Cr(CO)5 Cr(CO)4 RL-—CH7' \R's 295 \ 294 OC—Cr—CO l Me RL "2/ CC 39% \CI'(CO)3 1 HO‘ \;r\ '00 L00 CO RL 297 HO Me 1 “RS! | Me ' HO R Me OR.-." ' L ........... Cr(CO) 302 \ R Me 03. H0 298 Me on--~~. ”0 C< , o n2 M 0\ M9 \ e \C\\‘C'/'"C\RS —__. 1 0 RL ._ R Cr-..,, R 2_ ‘\ ~00 RO RS Me QR S. R R‘ 00 CO 303 304 2” 4.5 Summary The studies toward the total synthesis approach to Richardianidin-1 are still underway. Currently, the intramolecular approach has encountered a major obstacle. An advanced intermediate with the carbene carbon and alkyne tethered though an acetal did not provide the desired cyclization product in acceptable selectivity and yield. An intermediate with the carbene carbon and alkyne tethered through a silicon linkage failed to give any desired cyclization product. 79 The intermolecular approach provides excellent regioselectivity for the desired application, but suffers from low yield in the key step of the annulation. 80 CHAPTER 5 Total Synthesis of Phomactin 32: the Application of an Intramolecular Cyclohexadienone Annulation of Fischer Carbene Complexes 5.1 Background on Phomactins 5.1.1 Isolation and bioactivity of Phomactins Phomactins (Figure 5.1) were isolated from the culture of marine fungus Phoma sp., a parasite on the shell of a crab Chinoecetes opilio harvested from the coast of Japan.80 Phomactins have shown remarkable bioactivity as platelet activating factor (PAF) antagonists. PAF is an ether-phospholipid that induces the release of histamine from platelet, and it is involved in platelet aggregation, cardiovascular, inflammatory, and respiratory diseases.81 Thus, Phomactins could offer potential treatment for these diseases. The Phomactin family shares a rare [9.3.1] pentadecane bicyclic ring system, which contains a highly substituted cyclohexane core and a bridged decane ring with multiple oxygen substituents. Among them, Phomactins A, 32 and D have the highest biological activity.80b Their unique structures, as well as their bioactivity, have made them attractive targets for synthesis.“2 Figure 5.1 Structures of Some Natural Occurring Phomactins Phomactin A Phomactin B2 Phomactin D Phomactin G 305 306 307 308 81 5.1.2 Previous total syntheses of Phomactins The two major challenges in the syntheses of Phomactins are the construction of the highly substituted cyclohexane core, and the formation of the macrocycle. Despite many efforts aimed at the construction of the structural framework of this natural product family, to date, only two total syntheses of Phomactin A (305),83 two total syntheses of Phomactin D (307),"'4 and one total synthesis of Phomactin G (308)85 have been completed. All of the reported strategies have in common the initial assembly of the cyclohexane core and then the construction of the 12-membered macrocycle. Different methods have been utilized for the latter task, including sulfone coupling?“ Suzuki coupling,83c and NHK coupling.33a'b' 85 The pioneering work of Yamada and coworkers lead to the first synthesis of a member of the phomactin family in 1996.843 Their strategy for the synthesis of Phomactin D (307) involved the later-stage sulfone coupling of an allylic chloride to construct the macrocycle (formation of CQ-C10 bond). The construction of precursor 312 was accomplished by sequential Michael addition reactions and an oxidative cleavage of the CZ-C19 bond in compound 311. A similar sulfone coupling strategy was also used by the Thomas group to make the macrocycle in their approach to the skeleton of Phomactins.86m The Halcomb group has also completed a total synthesis of Phomactin D but this is only published at this point in a thesis.84b 82 Scheme 5.1 Yamada's Total Synthesis of Phomactin D 0 Jr + w M‘ 11 IR 1' O 0 / C 028 1c ae eacror; R? COzEt 309 310 3119 Sulfone Coupling 39°/o Phomactin D 1 3 6 307 The first total synthesis of racemic Phomactin A (305) was published by Pattenden’s group in 2002.583” Their approach involved the intramolecular Nozaki-Hiyama-Kishi (NHK) coupling reaction to construct the C2-C3 bond in the macrocycle. The precursor 319 was in turn obtained by straightforward manipulations from 317. The same group also published the first total synthesis of Phomactin G using a similar strategy.85 83 Scheme 5.2 Pattenden's Total Synthesis of Phomactin A o PMBO m0 Dialkylation~ OJ .2 :2 317 PMBO NHK Coupling 36% Phomactin A 305 Almost at the same time, Halcomb and coworkers accomplished the first enantioselective synthesis of (+)-Phomactin A (305).83c They used (R)-(+)- pulefgone (321) from the chiral pool to build the enantiomerically pure multiple substituted cyclohexene 322, which was coupled with epoxy aldehyde 323 to synthesize 324. After functional group manipulations, a key Suzuki coupling closed the macrocycle which ultimately led to the desired target molecule. 84 Scheme 5.3 Halcomb's Total Synthesis of (+)-Phomactin A ODMB O \ l ,h 0 “H DO\‘.'LO + __ ., ,. . Mono If“ "’OTBS T830 ‘ (H) (+) -pulefgone 321 323 324 1) 9-BBN 2) Suzuki Coupling 37% Phomactin A 305 The total syntheses of phomactin employ a variety of methods to construct the macrocycle. However, all of the above strategies discussed above suffered from the low yield (~ 40%) in the key macrocyclization step. In addition to the above total syntheses, a number of synthetic approaches to Phomactins have also been published involving other methods to construct the macrocycle,86 86m including sulfone coupling, oxa-[3+3] cycloaddition,“ Stille coupling,‘mi and ring-closing metathesis83b 5.1.3 Retrosynthetic analysis of Phomactins and previous work in our group Our synthetic strategy towards the total synthesis of Phomactins involves the cyclohexadienone annulation of the Fischer carbene complex. An introduction to the cyclohexadienone annulation was presented in Chapter 1 (Scheme 1.5).19 Retrosynthetic approaches to the phomactins have been designed for both inter- and intramolecular variations of the cyclohexadienone 85 annulation. The intermolecular cyclohexadienone annulation will utilize carbene complex 329 and alkyne 330 to construct cyclohexadienone 328, followed by a ring-closing metathesis (RCM) to form the macrocycle (Scheme 5.4). The resultant cyclohexadienone 327 could serve with proper manipulation to provide a convergent approach to several members of the Phomactins. The annulation of carbene complex 329 and alkyne 330 has been attempted by Ms. Ying Liu in the group and resulted in an 88% yield of 328 with a 98:2 diastereoselectivity.87 However, the RCM reaction of 328 with Grubb’s generation I catalyst failed to give any desired bicyclic product. Only dimer was observed in this reaction. Now, with newer RCM catalysts available,88 it might be expected this problem can be overcome and this will be discussed in Chapter 6. Scheme 5.4 Retrosynthesis of Phomactins (Intermolecular Version) . OMe (OC)5CI' Cyclohexadienone 329 Phomactlns 1 e Annulation 2 + OTr / 2 Q | 330 An intramolecular strategy was also proposed based on results from a model study performed by Dr. Jie Huang (Scheme 5.5).89 Dr. Huang demonstrated that thermolysis of carbene complexes 336 with a 6-carbon tether between the B-carbon of the carbene complex and the alkyne give dimer and trimer products, whereas carbene complexes with 8- and 10-carbon tethers will cyclize to afford the desired bicyclic products 337 in moderate yields (Scheme 86 5.5). Accordingly, the bicyclic intermediate 331 could be expected from'the thermolysis of carbene complex 332, which contains a 9-carbon tether between the B-carbon of the carbene complex and the alkyne. The diastereoselectivity of this annulation and the stereochemistry at C2 are not important in a racemic synthesis, since CZ will be converted to a ketone at a later stage in the synthesis. Carbene complex 332 is envisioned to be obtained from vinyl iodine 333, which in turn was designed to be derived from the known allylic bromide 334.90 Scheme 5.5 Retrosynthesis of Phomactins (Intramolecular Version) .— o (OC)5Cr=( _ \\1 w... 332 334 geranlol (335) 333 Model studies: tether length-dependent inter- vs intra-molecular annulation e 0 0 OMe o ’9 overnight OMe n 336 CH2)n D 337 (°/..) 338 (%) 337 OMe - 1 8 45 - 43 64 33:: II II II II 4.2mm 030 87 5.2 Synthesis of key intermediates 331 5.2.1 Synthesis of vinyl iodine 333 With the strategy set, the synthesis of vinyl iodine 333 became the target of the first stage. The synthesis of 333 follows that developed by Dr. Huang with some modifications.91 Thus, starting from the commercially available geraniol (335), which contains the desired double bond geometry in intermediate 331, a 3- step operation following literature procedures afforded allylic bromide 334.90 The coupling reaction of allylic bromide 334 with 4 equivalents of TMS-protected propargyl lithium elongates the carbon chain and simultaneously deprotectes the benzoyl-protecting group to give silyl acethylene 339. The stoichiometry of the lithium reagent was critical, as lower equivalents led to a complex mixture. Desilylation of 339 with TBAF afforded terminal alkyne 340 in 78% yield for the two steps from allylic bromide 334. This terminal alkyne was then subjected to Negishi’s carbometallation with 3 equivalents of AlMea and a catalytic amount of ZI‘Cp2C12 to afford vinyl iodine 341 in 67% yield.” Using a stoichiometric amount of Zprzciz actually gave a slightly lower yield. Dess-Martin oxidation,93 followed by alkylation with ethynyl magnesium bromide provided vinyl iodine 333 in 94% yield from compound 341. 88 Scheme 5.6 Synthesis of Vinyl Iodine 333 from Geraniol (335) 1) BzCl, Pyr. 2) TBP, 8e02 Br OBz 4.0 equiv. _ ___. OH re15.8 -20 °C to 0 °C 6 h \\ 1) 0.25 equiv. ZGCzClz TBAF W0” 2) 3 equiv. AlMe3 o c 12 n 78% (2 steps) — 3) 12 THF 30 °c to 0 °C 340 67% __ ' ‘\ DMP. CH2C'2 H 0 : M95" 7 mag—OH . e __ — THF, -30 °C, 111' —— 30 min, rt 94 % (2 steps) 333 342 5.2.2 Synthesis of carbene complexes On the basis of Dr. Huang’s model study, the best diastereoselectivity for the intramolecular cyclohexadienone annulation was achieved when the propargyl alcohol was protected as tri-iso-propylsilyl (TIPS) ether (Scheme 5.7).91 Thus, we chose to protect the propargyl alcohol 333 as a TIPS ether (346) (Scheme 5.8). Scheme 5.7 1.4-Asymmetric Induction in Intramolecular Cyclohexadienone Annulation 0 OR OMe (OC)5Cr THF, 5 mM — OR —’ + O 55 C OMe \\ (CH2)9 3‘3 344 345 Ft over all yield 344:345 Tr 65 1021.1 TIPS 45 3021.0 Me 66 21:10 MOM 44 1 0 1 1 89 VWth compound 346 in hand, the preparation of carbene complex 349 was 1 which carried out according to the procedure developed by Jie Huang,9 employed the dianion procedure developed by Huan Wang.94 Wang noted that the presence of the terminal acetylene proton caused problems in the lithium/halogen exchange step. His solution was to deprotonate the alkyne using PhLi before the lithium/halogen exchange. This process begins with the addition of PhLi to the vinyl iodine 346 to deprotonate the acetylene proton, followed by addition of t-BuLi and Cr(CO)5 subsequentially to give dianion 348. Methylation of dianion 348 with Meerwein’s salt (MeaOBF4) or MeOTf in 1:1 mixture of CH2Cl2/H20 yielded the desired carbene complex 349. The addition of water to protonate the acetylene anion in 348 but not the oxygen anion of the carbene complex was crucial for success. Without water, the acetylene anion was also methylated and afforded carbene complex 350 as the only product. Scheme 5.8 Synthesis of Carbene Complex 349 ' __ \\ ' .— \\ H TIPSCI, DMAP i OTIPS — _ CHZCIZ, n. 12 n — — 333 96% 346 C9 ' _ a 0 e PhLi 1) I-BULI (OC)5Cr \\ —-——-’ OTIPS ———'- '— THF, -78 °C __ _ 2) Cr(CO)5 OTIPS 347 348 Me308F4 or MeOTf CH20'2/H20 (131). rt CHZCIQ, MeOTf 0 10 50% 34% O— (OC)50r \\ (OC)50r OTIPS 349 5.2.3 Modification of the carbene complex preparation Although the synthetic route to carbene complex 349 outlined in Scheme 5.7 worked well on small scales, upon scale up, the conversion of vinyl iodine 346 to carbene complex 349 became quite capricious. For unknown reasons, the yields of this reaction were not reproducible and varied from 0-50% for different runs. It was thought that the presence of the acetylene proton was the main reason for the low and irreproducible yield. Thus, to optimize the yield for the preparation of carbene complex 349, the synthetic route need to be modified. It was considered that the quality of the PhLi might affect the subsequent reactions. Thus, the use of an alternative aryl lithium source was considered for the deprotonation step. The organolithium should be basic enough to 91 deprotonate the acetylene proton but not reactive enough to cause the lithium/halogen exchange with the vinyl iodine to occur. Alkyl lithium were not considered on the basis of the studies by Huan Wang who found that they effected lithium/halogen exchange.94 The search for an optimal aryl lithium was carried out on the model vinyl iodine 353, which contains a 10-carbon tether between the B-carbon and the tethered alkyne (Scheme 5.9).91 The synthesis of compound 353 starts from the commercially available trimethylsilyl acetylene. Deprotonation followed by coupling with 1,10-diiododecane provided 351 in 97% yield. Desilylation with TBAF affords diyne 352 in 66% yield. Compound 352 was then subjected to Negishi’s carbometallation-iodination reaction with 1 equivalent of AlMe3 and a catalytic amount of Zl’Cp2Clz to provide vinyl iodine 353 in moderate yield (34%).92 With model compound 353 in hand, the efficiency of different aryl lithium species to serve as bases for the deprotonation of 353 was evaluated in the preparation of the carbene complex 354 as outlined in Table 5.1. Unfortunately, aryl lithiums with either electron withdrawing groups or electron donating groups on the aryl ring provided no general trend and in no cases high yield of the carbene complex 354 was obtained (Entries 1 to 4). The best results were obtained using either phenyl or 4-fiuorophenyl lithium as base, and the carbene complex 354 was obtained in 40-50% yield (Entries 11 and 3). The use of heteroaromatic lithiums did not provided even moderate yields of 354 (Entries 8 to 10). 92 Scheme 5.9 Preparation of Vinyl Iodide 353 l \% n-BuLi TMS TMS TBAF arMs e = \\ é ——. \\ // THF HMPA 10 66%) 0 97% 351 352 1) ZGCZCIZ, AlMe3 l > V 2) 12 0 34% 353 Table 5.1 Model Study of Carbene Complex Synthesis I _... / . M - . OMe n-BuLl 353 nBuLi‘ Cr(CO)6‘ Me308F4‘ ArH or ArBr _ 4 (OC)5Cr fig o\\ Entry ArBr or ArH Yield of 354a (%) 1 1-bromo-4-methoxybenzene Trace” 2 1-bromo—4—(trifluoromethyl)benzene 29 3 1-bromo—4-fluorobenzene 42 4 4-bromobenzonitrile Trace 5 2-bromo-1,3-dimethylbenzene Trace 6 1-bromonaphthalene 13 7 2—bromonaphthalene 0 8 2-bromothiophene 1 8 9 1-benzyI-1H-imidazole 0 1O 1-methyl-1H-imidazole 0 1 1 Phenyllithium ‘ 49c a). The yields listed are isolated yield. b) Less than 5% yield. c) The reaction was performed by Dr. Huang in a 49% yield. With the lack of success in identifying an optimal organolithium, improvement in the preparation of the carbene complex 349 was sought by protection of the terminal acetylene (Scheme 5.10). Thus the vinyl iodine 355 93 with a TMS-protected acetylene moiety was prepared from aldehyde 342 via alkynylation and TIPS protection. Conversion of 356 to carbene complex 357 could be achieved without the deprotonation and a 47% yield was obtained according to the aforementioned procedure. The overall yield could be improved to 65% by altering the order of addition. In this new procedure, the chromium carbonyl is mixed together with the vinyl iodine 356 and then the lithium reagent was added to effect metal/halogen exchange. Scheme 5.10 Preparation of Carbene Complex with Protected Acetylene TMS TMS 1) n-BuLi, I r THF _30 °c __ \\ TIPSCI, DMAP \\ Z—TMS ' > e — OH 2) 342 __ CHZCIZ, n. 12 n _ OT'PS 79% — __ 69% 355 356 1) t-BuLi, THF, -78 ac (OC)5Cr \\ 2) Cr(CO)5, -78 °C to rt _ e OTIPS 3) Me3OBF4, 011201271420 (1 :1). n — _ 47°/o 357 1) Cr(CO)5, -78 °C 2) n-BuLi, THF, -78 °C to rt 3) M6308F4, CHzciz/Hzo (1 21), 1'1 65°/o Although it may be possible to convert carbene complex 357 to our desired carbene complex 349 by a simple deprotection, a perhaps even better solution would be if the new order of addition could improve the reliability of the original procedure. Delightfully, it was found that when this new procedure was applied to substrate 346, a reproducible 50% yield was obtained even with scaled up reactions with different scales. A MOM-protected version of vinyl iodine 94 358 was also prepared from propargyl alcohol 333. The corresponding carbene complex 359 could be obtained in 43% yield using the optimized procedure. Scheme 5.11 Optimized Synthesis of Carbene Complexes O..— l _ \\ 1) Cr(CO)5 (0050' __ \\ 2) PhLi, THF, -78 °c OTIPS e OTIPS — — 3) n-BuLi, -78 0c to n — _ 4) M8308F4, CH2012/H2O (1:1), [1 345 ~ 50% yield 349 O— MOMCI, ' _ \\ 1) CrICOIe (0050' _ \\ DIPEA OMOM 2) PhLi, THF, -78 0c OMOM 333 a CH2012 — 3) n-BuLi, -79 °c to n — — 359 800/0 CH2C12/H20 (121), I1 359 43% 5.2.4 Thermolysis of carbene complexes 349 and 359 The thermolysis of carbene complex 349 was performed in THF at 80 °C until the color of the carbene complex was pale (around 12 hours). As had been previously reported by Jie Huang and as indicated in Table 5.2, bicyclic product 360 was formed as the major isomer at a concentration of 0.005 M (Entry 1).91 The yield and diastereoselectivity of the annulation dropped slightly when the concentration was increased to 0.02 M. The relative stereochemistry of the two diastereomers had been determined by Jie Huang by an X-ray diffraction of the more crystalline minor isomer 361.91 It’s noteworthy that no dimer was formed under these conditions even at a concentration of 0.02 M. Thermolysis of MOM- carbene complex 359 at 0.005 M provided 362 and 363 in 29% yield, but the reaction did not show any observable diastereoselectivity, as isomers 362 and 95 363 were obtained in a 1:1 ratio. Evidence suggests that the diastereoselectivity of the cyclohexadienone annulation is controlled by stereoelectronic effects.21d Table 5.2 Cyclization of Carbene Complex O... (OC)5Cr — \\ THF _ OR 30 ‘c + R = TIPS 349 R = TIPS 360 (major) R = TIPS 361 (minor) R=MOM359 R=MOM362 R=MOM383 Entry Carbene Concentration Overall yield Diastereomeric complex (M) (%)“ ratiob 1 349 0.005 60 3:1 2 349 0.02 56 2:1 3 359 0.005 26 1 :1 a). Isolated yield. b). Diastereomeric ratio was determined by crude 1H NMR based on vinyl proton on C12. c). Configuration of 361 was determined by X-ray analysis. With the success of the intra-molecular cyclohexadienone annulation of complexes 349 and 359, the syntheses of the Phomactins were taken forward with the TIPS-protected isomers 360 and 361 given the higher yields of the former rather than with the MOM-protected compounds 362 and 363. 5.3 Total synthesis of Phomactin 82 from the minor isomer 361 With the bicyclic intermediates 360 and 361 in hand, a straightforward synthetic strategy toward Phomactin 82 was proposed (Scheme 5.12). Olefination of 360/361 should be able to install the exo double-bond at C15 to give compound 366. After hydrolysis of the enol ether in 366, it should be 96 possible to methylate at the a-position of the resulting dienone stereoselectively to give compound 365, which has the complete carbon skeleton of Phomactin BZ. A hydroxy-directed epoxidation followed by subsequent oxidation of the epoxy alcohol and deprotection would finish the total synthesis of Phomactin 82. Scheme 5.12 Retrosynthesis of Phomactin 32 from 360 and 361 0 Oxidation Epoxidation Reduction Deprotection Methylation Olefination Hydrolysis 360/361 5.3.1 Synthesis of key intermediate 370 The synthesis of phomactin B2 was first carried out with the more crystalline minor isomer 361 (Scheme 5.13). The structure of 361 is drawn as the enantiomer that is shown in Table 5.2 to be consistent with the absolute configuration of the natural occurring Phomactin 82. The first step in the plan is an olefination of the highly congested carbonyl of 361. Considering the steric challenge, the Peterson olefination95 reaction was chosen instead of the V\fittig olefination reaction to install the exo double-bond given its higher reactivity and known effectiveness for hindered ketones.96 Compound 361 was allowed to react with trimethylsilylmethyllithium to give intermediate 367. Although this reaction is very fast, for unknown reasons, 3 equivalents of the lithium reagent were required. The use of less than 3 equivalents resulted in no reaction. Elimination could be accomplished by various potassium bases, including KH, KOtBu and KHMDS.91 In all cases, the elimination reactions provided enol ether 368 as the single product in the crude reaction mixture. This enol ether 368 was very sensitive to acid and thus was not isolated but rather converted to the more stable ketone 369 by hydrolysis with HCI. The transformation from 361 to 369 could be carried out in ~85% overall yield for either a one-pot process where KOtBu is added directly to the reaction mixture in which 367 is generated, or in a process that involves the quenching of the reaction and treatment of crude 367 with KOtBu. The methylation at the a-position of ketone 369 was performed with LHMDS and Mel, since the methylation of model compound 371 demonstrated that LHMDS was more efficient than LDA in this reaction.91 The methylation reaction gave a single diastereomer 370 in 98% yield. This newly installed methyl group was expected to be on the top face opposite to the macrocycle. This hypothesis was conformed by the X-ray diffraCtion of ketone 370 (Figure 5.2) which revealed the relative stereochemistry. 98 Scheme 5.13 Peterson Olefination and Methylation O OTIPS ‘ 3 equiv. LICHZTMS HCI. MeOH THF, rt r1. 5 min 15 min 85% from 361 1) LHMDS, -78 °C, THF, 1 h ‘. 2) Mel, rt, 12 h 98% OTMS LDA then Mel OTMS 21 % + 47% SM. fl LHMDS then Mel 0 707—" O 371 ° 372 Figure 5.2 X-ray structure of 370 5.3.2 Synthesis of allylic alcohol Upon the successful installation of the methyl group, all of the carbon atoms present in Phomactin 32 have been introduced. The next plan was to synthesize the allylic alcohol 375a as a precursor to the epoxide 376a (Scheme 5.14). Before the desilylation of the TIPS-protecting group, it was necessary to reduce the ketone to obtain the desired (X-aiCOhOI 373a. According to the X-ray structure of 370 (Figure 5.2), the methyl group at the a—position to the ketone 370 is axial-oriented. Accordingly, since the macrocycle obviously blocks the other face of the ketone, it's very difficult to predict the stereoselectivity of the reduction. A variety of reductants were examined, in an effort to optimize the yield and selectivity of this reduction, and the results are summarized in Table 5.3. Due to the steric hindrance of this ketone, sterically small reduction reagents were first considered and examined (Entries 1 though 5). As can be seen from Table 5.3, NaBH4 provided the best yield, while LiBEt3 provided the best selectivity. The more sterically demanding KS-selectride and L-selectride did not react with ketone 370. All of the reducing reagents provided the same major isomer 373b. The structure of the major isomer as 373b ultimately was determined upon the completion of the total synthesis of Phomactin B2. 100 Table 5.3 Reduction of Ketone 370 OTIPS Reduction 370 3739 3735 Entry Reagent Solvent Temp. Time Yield Ratio”c (°C) (%)" 373a: 373b 1 NaBH4 MeOH/EtZO rt 2 d 94 1: 3 2 NaBH4/CeCI3 MeOH -20 to rt 1 d 44 1: 3 3 LiBHEta THF -78 to rt 1 d 37 1: 7 4 LiBH4 THF 0 to rt 1 d 71 1: 6 5 LiAIH4 THF 0 5 min 58 1: 4 6 Red-Al THF 0 to rt 1 d 80 2: 3 7 KS-selectride THF 0 to rt 15 h 0 - 8 L-selectride THF rt 2 d 0 - a) Isolated yield. b) Determined by crude 1H NMR. 0) See text for the assignment (page X) The diastereomers 373a and 373b could be separated by chromatography, but the relative stereochemistry of these two alcohols was not determined at this stage. Instead, both of them were carried on independently in the following functional group manipulations. Acetylation and desilylation of 3733 and 373b gave allylic alcohol 375a and 375b in good yields. The choice of acetyl as a protecting group was to electronically aid in the differentiation of the two olefins of the bis-allylic alcohol. Such that epoxidation is chemoselectively directed to the more electron-rich allylic double bond (C3—C4) in the macrocycle. lOl Scheme 5.14 Synthesis of Allylic Alcohol 78°/o 80°/o 5.3.3 Epoxidation and end-game of the synthesis of Phomactin 82 According to the X-ray structures of 361 (Figure 5.3) and 370 (Figure 5.2), the two sides of C3-C4 olefin are sterically differentiated. The undesired si-face is sterically blocked by the bicyclic core of the molecule, and therefore is not available for epoxidation. Hence, the epoxidation of 375a or 375b would be expected to occur on the desired re-face if molecules 375a and 375b adopt the same conformation as 361 and 370. This expectation proved correct (Scheme 5.15). The epoxidation of 3752 was both stereoselective and chemoselective with VO(acac)2 and tBuOOH.97 Only one stereoisomer was observed from the epoxidation. However, the exocyclic olefin was expoxidized to a small extent, giving the undesired, over epoxidized side-product 3773 (3763/3773 10:1). The other olefin (C1-C14) was completely intact. For reasons are not completely clear, this epoxidation has to be carried out using a fresh bottle of tBuOOH. Serious overepoxidation was observed with an old bottle giving nearly equal amounts of 376a and 3772. 102 Since 376a and 377a were inseparable, this epoxidation mixture was converted to epoxy ketones 378a and 3793 by treatment with NaHCOa buffered Dess-Martin periodinane (DMP). The buffer was important to prevent the decomposition of the epoxide. Fortunately, the acetate derivative 3783 had been previously prepared from Phomactin BZ and its spectroscopic data has been published (Table 5.4).80b Therefore, the stereochemistry of 3783 was unambiguously assigned, which led to the assignment of stereochemistry for both the ketone reduction (Table 5.3) to 373a/373b and the epoxidation of 3753. Deacetylation of 378a with NaOH afforded the desired natural product Phomactin BZ (306) in 94% yield. A comparison of the 13C NMR data of synthetic phomactin BZ (306) and literature data for the natural product is summarized in Table 5.4 as well as those of natural and synthetic samples of acetate 3783.83b The epoxidation of the isomer 375b gave a 6.521 mixture of mono-epoxy alcohol 376b and bis-epoxy alcohol 377b, which were subjected to Dess-Martin oxidation to give mono-epoxy ketone 378b and bis-epoxy ketone 379b. Based on NMR studies, the second epoxide of the bis-epoxy ketone 37% was assigned to be at position C15-021. The stereo outcome of the second epoxidation was proposed to be B-oriented, since the macrocycle blocks the a-face of the exo double-bond. Two possible reasons could account for the formation of the second epoxide: first, the exo double-bond was homoallylic to the hydroxy group; second, the inductive effect of the acetyl group might predominately fall on the allylic double bond in the 6-membered ring and reduce the electron density dramatically to prevent the occurrence of epoxidation at that position. 103 Deacetylation of 378b by treatment with NaOH provided alcohol 380, which was not identical to Phomactin 82. But a simple Mitsunobu inversion followed by a hydrolysis converted 380 to Phomactin 82.98 This confirmed that, despite the different stereochemistry at C13, 3753 and 375b were epoxidized to give epoxides with the same stereochemistry. Scheme 5.15 Total Synthesis of Phomactin 32 VO(acac)2, TBP Benzene, n DMP, NaHCO3 CH2C12, 11 a - OAC 77% 10:1 VO(acac)2, TBP Benzene, rt DMP, NaH003 0112012, rt 6 - OAC 75% 65:1 NaOH MeOH/T HF 90% NaOH MeOH/T HF 94% 378b 3788 Phomactln 32 306) 1)PNBOH. DEAD. PPh3 I 2) K2003, MeOH 69°/o 104 Table 5.4 13C NMR Chemical Shifts of Phomactin B2 and Compound 3783 (CD300) Phomactin 82 (306) Compound 378a Natural Synthetic Difference Natural Synthetic Difference (ppm) (ppm) (ppm) (ppm) (ppm) (ppm) 14.7 14.62 0.08 14.8 14.74 0.06 15.4 15.35 0.05 14.8 14.77 0.03 16.6 16.53 0.07 16.4 16.38 0.02 23.8 23.70 0.10 21.1 21.06 0.04 24.5 24.51 -0.01 22.7 22.63 0.07 34.7 34.66 0.04 24.7 24.69 0.01 35.3 35.34 -0.04 34.5 34.54 -0.04 38.4 38.34 0.06 35.1 35.06 0.04 42.4 42.45 -0.05 38.9 38.93 -0.03 45.9 45.90 0.00 42.7 42.93 -0.23 64.7 64.75 -0.05 44.5 44.56 -0.06 66.1 66.14 -0.04 64.9 64.93 —0.03 72.0 71.98 0.02 66.3 66.33 -0.03 117.0 117.04 -0.04 74.4 74.43 -0.03 123.7 123.66 0.04 119.0 118.99 0.01 134.3 134.28 0.02 123.4 123.39 0.01 137.9 137.93 -0.03 129.2 129.22 -0.02 142.4 142.42 -0.02 137.9 137.91 -0.01 146.6 146.62 -0.02 144.6 144.63 -0.03 201.8 201.82 -0.02 145.0 145.06 -0.06 171.8 171.83 -0.03 200.7 200.84 -0.14 Both of the epimeric alcohols 373a and 373b could be taken on to Phomactin BZ since the intermediates 3753 and 375b both gave the same stereoselectivity in the epoxidation. Final convergent to Phomactin 32 occurs in 105 the last step, the Mitsunobu inversion in alcohol 380. A more efficient utilization of the alcohols 373a and 373b would be a direct interconversion of 373b to 3733. The first attempt was directly convert 373b to 3743 via a Mitsunobu reaction with acetic acid, which would not only effect the necessary inversion but also install the oxygen on the proper protected form for the epoxidation. However, this reaction met with failure. It was pleasing to find that alcohol 373b could be converted to p-nitrobenzoate 381, which gave a-alcohol 3733 in good yield after treatment with K2C03. With this conversion, the synthesis of Phomactin 82 is now more convergent. Scheme 5.16 Mitsunobu Reaction of Compound 373b AcOH. DEAD ‘ No Reaction PPh3, toluene, rt 20 h PNBOH, DEAD, PPh3 K2003, MeOH r 90 % 2 steps 5.4 Total synthesis of Phomactin 32 from major isomer 360 Upon finishing the total synthesis of Phomactin BZ from the minor isomer 361, the next undertaking was to convert the major isomer 360 to Phomactin BZ utilizing a similar pathway. 106 5.4.1 Peterson olefination Right from the beginning there was doubt that a synthesis of Phomactin BZ could be achieved from the major isomer 360. Jie Huang had shown that while the Peterson olefination was facile for the minor isomer 361,91 this reaction was completely shut down for the major isomer. Compound 361 reacted in 10 minutes at room temperature, but compound 360 failed to react with trimethylsilylmethyl lithium after 2 days at room temperature. At 40 °C, the reaction was rapid and gave a complex mixture. An alternative Peterson olefination reagent trimethylsilylmethyl magnesium chloride also failed to react with 360 (Scheme 5.17). An explanation for the different reactivity between the major isomer 360 and the minor isomer 361 was proposed on the basis of the X-ray structure of 383 and 361 (Figure 5.3). As can be seen from Figure 5.3, the hydrogen of the carbinol carbon (CZ) in 361 is anti to the carbonyl, which should allow TMSCHzLi to attack the carbonyl at the Burgi-Dunitz angle. However, the same hydrogen in 383 is syn to the carbonyl. Assuming that the conformation of 360 is similar to that of 383, this would result in the situation that the O-substituent in 360 blocks the approaching of TMSCHzLi. It was thus rationalized that if the protecting group on oxygen was capable of chelating to the organolithium, it may assist in delivering the nucleophile rather than sterically blocking it. 107 Figure 5.3 X-ray Structures of 383 and 361 X-ray structure of 383 X-ray structure of 361 TMSCH2Li / "“50qu 4 Mom TIPSO \ OMe . H H 2°C C 2 Proposed comformatlon in 360 Comformation in 361 Thus, a series of analogues of 360 were prepared from alcohol 383, which was prepared from 360 by treatment with TBAF (Scheme 5.17). A variety of different protecting groups were investigated. As a test of the steric effects of the OTIPS group, compound 384 with the less hindered TES group was first subjected to the Peterson olefination condition, but as with the OTIPS group no reaction occurred. Compounds 362, 385 and 386 with MOM-, MEM- and SEM- protecting group were next synthesized from alcohol 383. It was found more convenient to prepare the MOM-compound 362 from alcohol 383 rather then directly from the thermolysis of carbene complex 359 due to the poor yield and diastereoselectivity (Table 5.2). Among these analogues, only the MOM- protected derivative 362 reacted with TMSCHzLi. The reaction of 362 with TMSCHzLi was very fast and finished within 15 minutes. However, the elimination 108 step in 387 was sensitive to the nature of base. The MOM-protected hydroxy group was eliminated if KOtBu was used as the base which resulted in a substantial amount of an unexpected polyene, which upon hydrolysis with HCI gave rise to compound 389. The use of KOtBu was further disfavored by the low conversion and low yield, even when freshly sublimed KOtBu was used. At this point it was imperative to find another base for the elimination of silyl alcohol 387. A search of the literature revealed 3 Peterson olefination reaction in which KHMDS gave better results than KOtBu,99 and proved to be the right choice. After acidic workup, ketone 388 could be obtained in 74% yield from 383. The overall transformation of 362 to 388 was best performed in two steps since it gives better yield and less elimination product 389 than for the one-pot reaction. The Peterson olefination using unprotected alcohol 383 as substrate gave a complex mixture.100 109 Scheme 5.17 Peterson Olefination O OTIPS TMS OH OTIPS Nucleophile Temterature (°C) Results Nucleophile LiCHzTMS r1 No reaction LiCHzTMS 40 Decomposed ClMgCHgTMS rt No reaction LiCHzTMS No reaction THF 384 R = TES, 92% 385 F1 = MEM, 71% 336 R = SEM, 63°/o 1)KHMDS, THF, n. 1 n 2) HCI, MeOH rt, 5 min 74% 88% from 383 5.4.2 Synthesis of allylic alcohols The methylation of 388 was accomplished by treating with LHMDS and Mel which gave 390 as a single stereoisomer in 96% yield. The orientation of the newly installed methyl group was assumed to be on the B-face, since this same stereochemistry was shown by X-ray to occur for the related structure 370 (Scheme 5.13). The reduction of 390 with NaBH4 at room temperature was extremely slow, and the reaction was not complete after 2 days. However, the reduction was finished in 2 hours when the temperature was increased to 45 °C. Two inseparable over-reduction products were also observed by 1H NMR in this reaction. The stronger reducing reagent LAH led to a complex mixture within 15 minutes. The reduction with super hydride provided the unreacted ketone 390 110 and an unknown compound, and none desired alcohols 3913 or 391b were detected by 1H NMR. The diastereomeric alcohols 391a and 391b could be separated by chromatography, but each were isolatied with inseparable over- reduced products. Table 5.5 Synthesis of Intermediate 391a and 391b OMOM OMOM OMOM 1) LHMDS Reduction ———-> ————> S + 2) Mel 96% 390 3919 391b Entry Reagent Temperature (°C) Time Yield Ratioa (%) 3913: 391b 1 NaBH4 rt 2 d 37b 1: 2 2 LiAlH4 rt 15 min -° - 3 LiBHEt3 rt 2 d -° - 4 NaBH4 45 2 n 69d 1: 2 a) Determined by crude 1H NMR. b) Isolated yield. c) Complex mixture. d) The products could not be isolated in pure form, which accompanied with the 1.6-over reduction product. See experimental for details. Alcohols 391a and 391b were then separately acetylated to afford acetates 392a and 392b (Scheme 5.18). In preparation for the key epoxidation, the next step required was the removal of the MOM group to give alcohol 393a and its C13-epimer 393b. However, it was disappointing to find that, all attempts to cleave the MOM group were unsuccessful.104 In most cases, compound 392b decomposed very rapidly. Although occasionally it was possible to observe the 111 desired product (Entries 1, 6 and 7), the low yield of this reaction made this approach impractical. Scheme 5.18 Acetylation of Compounds 391a and 391b OMOM OMOM OMOM ACZO A020 pyridine pyridine 37% 67% Table 5.6 Cleavage of MOM-protected Group in 392b OMOM 393b Entry Reagent Temp. (°C) Time (h) Results 1 1N HCI/EtOH (5 equiv.) 45 16 Complex mixturea 2 1N HCI/T HF (5 equiv.) 45 to 75 2 Decomposition 3 BF3.OEt2, PhSH (2 equiv.) -78 to -20 0.67 Decomposition 4 TMSBr (5 equiv.) -30 0.25 Decomposition 5 TMSCI+Bu4NBr (5 equiv.) -30 0.67 No reaction 6 TMSCI+ Bu4NBr (3 equiv.) rt 24 ~ 20% yield 7 Crotylbromoborane (1 equiv.) -78 0.25 Complex mixture" 8 Crotylbromoborane (1 equiv.) rt 0.33 Decomposition a) Alcohol 393b could be detected by 1H NMR as part of a mixture of products. 5.4.3 Synthesis of Phomactin 82 from 390 The failure of the removal of MOM group removal in 3923 and 392b promoted the design of an alternative strategy. It was decided to deprotect the 112 MOM group at an earlier stage and then protect the resulting alcohol with another protecting group or to invert the stereocenter at C2. Based on the fact that only the MOM-protected compound 362 could undergo Peterson olefination, compound 390 represented an ideal intermediate for removal of the MOM group (Scheme 5.19). It was pleasing to find that the MOM group in compound 390 could be smoothly removed with 6 M HCI at 55 °C to give the alcohol 394 in 93% yield. Alcohol 394 was then protected as a TIPS ether to give compound 395, which was then reduced with NaBH4 to afford inseparable mixture alcohols with 2:1 diastereoselectivity. Acetylation followed by desilylation of these 2 alcohols afforded the isomeric and separable allylic alcohols 393b and 3933 in a 2:1 ratio. Scheme 5.19 Preparation of Allylic Alcohol 393b and 3933 OTIPS OMOM 6 M HCI (2 equiv.)/MeOH TIPSCI, DMAP 12 h, 50 °C 93% CH2C12, I1. 5 d 97% 1) NaBH4 EtOH/EIZO (2:1), rt, 2 d TBAF 2) Ac20, Py., rt, 4 h 66% 3steps 396 (2:1 d!) At this stage, an attempt was made to invert the stereocenter at CZ in either the intermediate 394 or the intermediate 393b such that the synthesis from the major isomer 360 was convergent with the synthesis from the minor isomer 361 via either the intermediate 370 (Scheme 5.13) or intermediate 373a (Scheme 5.14). However, both attempts were unsuccessful. The Mitsunobu reaction of 113 393b using p-nitrobenzoic acid as the nucleophile did not proceed at all. The Mitsunobu reaction of 394 using p-nitrobenzoic acid or triisopropylsilanol as nucleophile also failed to proceed (Scheme 5.20). Scheme 5.20 Mitsunobu Reaction of 393b and 394 QPNB toluene, rt, No reaction PNBOH, PPh 3x; DEAD. CHZCIZ, 45 °C, No reaction TIPSOH, PPh3 PNBOH, PPh3 X_. No reaction DEAD, DEAD, toluene, 50 °C, 18 h toluene, 0 °C, 30 min No reaction then 11 3 h Since it was not possible to invert the C2 stereochemistry of either 394 or 393b and converge the total synthesis, it was decided to push fowvard with the epoxidation of 393b and 3933 (Scheme 5.21). The epoxidation of allylic alcohol 3933 produced a single mono-epoxy alcohol 3983 together with only a trace amount of a bis-epoxy alcohol. Oxidation of 3983 by Dess-Martin periodinate gave an epoxy ketone, whose NMR data matched the NMR data of the epoxy ketone 3783 synthesized from the minor cyclized product 361 (Scheme 5.15). When the same two chemical steps were applied to 393b, it also produced a single epoxy ketone, which was identical to compound 378b synthesized from the minor cyclized product 361. These results suggests that the epoxidation of both 3933 and 393b occur from the desired B—face. Therefore, the 114 stereochemical outcome of the epoxidation is independent of the CZ stereochemistry. The structures of epoxy ketones generated from 3933 and 393b were further confirmed by deacetylation to afford Phomactin BZ and its C-13 epimer 380, as outlined in Scheme 5.15. Scheme 5.21 Synthesis of Phomactin 82 from 393b and 3933 TBP, VO(acac)2 Benzene, rt CH20l2, rt 93% 88% TBP. VOIacaC)2 DMP. N3H003 Benzene, rt CHZCIZ, rt 88°70 89°43 As discussed above, it was found that the epoxidation step provided the same stereochemical outcome regardless of the orientation of CZ hydroxy group, it was curious to see what the outcome of the epoxidation would be if the CZ hydroxy group was protected. Thus, compound 370 was subjected to the epoxidation conditions (Scheme 5.22). However, it was found that the epoxidation reaction did not occur with compound 370. Clearly, the directing effect of the free hydroxyl is crucial in the epoxidation of 3933, 393b (Scheme 5.21) and 3733, 373b (Scheme 5.15). 115 Scheme 5.22 Epoxidation of Compound 370 91196 TBP, VO(acac)2 _ Benzene, rt 7 No reaction While the stereochemical outcome of the epoxidations described in this work are independent of the configuration at C-2, 3 very different observation was made by Pattenden in his total synthesis of Phomactin A. Pattenden and coworkers reported that the epoxidation of a-alcohol 401 gave the correct [3- orientated epoxide 402 accompanied with bis-epoxide 403.83!) In contrast, the epoxidation of B-alcohol 399 under a similar reaction conditions produced an isomeric a-epoxide 400 in excellent yield. They determined the conformation of alcohol 401 and it’s B-epimer at C-2 by molecular mechanics calculations (Scheme 5.23). The results reveal 401 was confon'nationally predisposed to form the correct B-epoxide. This was reversed in the C-2 epimer of 401 where the low energy conformation exposes the a-face of the trisubstituted double-bond of the allylic alcohol 116 5.5 Scheme 5.23 Epoxidation in Pattenden's Total Synthesis of Phomactin A PMBO PMBO comformation of 401 TBP VO(acac)2 90% TBP VO(acac)2 HO conformational CZ-epimer of 401 Attempts to invert the stereocenter at C2 5.5.1 Conversion of stereocenter at C2 from B to a As described in previous sections, the total synthesis of Phomactin 82 could be achieved from either of the diastereomers 360 and 361, obtained from the cyclohexadienone annulation reaction. However, overall efficiency suffers from the need for the lengthy repetitive manipulation of these two isomers in separate and parallel processing. It would thus be very beneficial to convert 360 to 361 at an early stage, to reduce the total number of steps required for the total synthesis. The conversion from 361 to 360 was not considered at this stage, since the total synthesis of Phomactin BZ from the major isomer 360 requires additional four steps for the protecting group manipulations. However, a 117 conversion from B-alcohol 404 into a-alcohol 383 will be described in Scheme 5.29 after discussing the conversion of 360 to 361. To effect conversion of 360 to 361, an attempt was made to invert the configuration of the hydroxyl group in 383, which was obtained from 360 via a single deprotection step (Scheme 5.17). When p-nitrobenzoic acid was used as the nucleophile in a Mitsunobu reaction on 383, a mixture of at least two compounds were obtained that were inseparable. The use of benzoic acid also provided mixtures of products that were not characterized. The mixture of compounds obtained from the Mitsunobu reaction of 383 with nitrobenzoic acid was hydrolyzed with K2C03 in methanol. However, neither of the resulting alcohols was identical with 404, which was prepared independently from 361 in 98% yield. A trace amount of alcohol 383 with retention of configuration at CZ was detected from the crude reaction mixtures by 1H NMR. The mixture of products obtained from the Mitsunobu reaction of 383 by mass spectrum were found to have the proper molecular weight for the desired benzoates of alcohol 404. However, since hydrolysis of this mixture did not give 404, it is possible an SNZ’ reaction of 383 and a reaction with configuration retention occurred instead of an SNZ reaction. However, this could not be confirmed since these compounds could not be obtained in pure form. 118 Scheme 5.24 Mitsunobu Reaction of B-Alcohol 383 . O . PNBOH, DEAD, PPh3 78 C No reaction Toluene or THF Complex Mixture -20 °C X- ray structure of 383 O OH PhCOOH, DEAD, PPh3 . K2003 —. Mixture of compounds Toluene, 0 °C TBAF, THF 98% The next oxygen nucleophile examined for the Mitsunobu reaction was the silanols (Table 5.7).101 This reaction would allow for conversion of 383 directly to 361 in a single step. However, it was found that this reaction did not proceed with triethylsilanol in either the presence or absence of Et3N (Entries 1 and 2). When imidazole was added as additive,102 the reaction with triethylsilanol gave mixtures of the starting material 383 and a silyl ether (Entry 3). Surprisingly, the silyl ether has B-configuration at CZ instead of the inverted cit-configuration, since the 1H NMR of this silyl ether matches the NMR of compound 384 prepared from alcohol 383. The reaction with a less hindered phosphine (Entry 4) did not give significantly different results. The Mitsunobu reaction with the more sterically demanding triisoproylsilanol did not give any silyl ether (Entries 5 and 6). 119 Table 5.7 Mitsunobu Reaction with Silanols n? = Et 384 R2 = 1.131 360 Entry R1 R2 Solvent Additive Temperature Time Results“ (°C) 1 Ph Et Toluene None 0 to rt 40 min 383 only Ph Et Toluene Et3N rt 18 h 383 only Ph Et THF lmidazole rt 50 min 2:1 383/384 2 3 4 n-Bu Et THF lmidazole rt 1 h then 50 °C 20 h 4:1 383/384 5 Ph i-Pr THF lmidazole rt 16 h 383 only 6 Ph i-Pr THF lmidazole 50°C 7h Decomposed a) The ratios were determined by crude 1H NMR and the products were not isolated. It's known in the literature that Mitsunobu reactions could sometimes give products with retention of configuration if the alcohol is sterically hindered (Scheme 5.25).103 The most probable reason for this is that the steric hindrance of the alcohol prohibits the attack of the alcohol on the PhaP-DEAD complex 406. In such cases, the deprotonated silyloxy anion 407 then displaces the hydrazide ion to give the acyloxyphosphonium ion 412. Nucleophilic attack by the hydroxyl group of the substrate on the activated silyl group leads to the silyl ether 4103 with retention of configuration.103 Given the situation that alcohol 383 is sterically encumbered, the failure in the Mitsunobu inversion can be understood. 120 Scheme 5.25 Mechanistic Pathways for the Mitsunobu Reaction (.9 I (9 R331? OH Ph3P\ '(NHCOZR )2 408 QPPh3 OSiRs 1’\ + ’N—Ni" = 1’:\ 2 407 n n? 9'02c 0029' R n -Ph3PO 9‘ R2 405 406 409 4100 inversion on (+) R1"\R2 Ph3P osrn3 :N-NH + 1336109 e (+) - 405 _ 12K R'OZC b02R' \ e Ph3POStR3 w R R2 406 407 ,N-NH 412 'lNHCOzR'iz 4109 R020 002” 'Ph3PO retention 411 The next effort to invert the alcohol was an attempt to convert the hydroxy group in 383 into a better leaving group. Pattenden and coworker reported an alternative to the Mitsunobu reaction via an allylic chloride in their synthesis of Phomactin A (Scheme 5.26).83a An attempt was made to applied the similar transformation to substrate 383. However, treatment of alcohol 383 with thionyl chloride only resulted in the hydrolyzed dione 416. Scheme 5.26 Mitsunobu Reaction via Allylic Chloride Reported example PMBO 413 SOCIZ 0 °C to rt 121 Another pathway for the inversion of an alcohol is an oxidation/reduction sequence (Scheme 5.27). Treatment of alcohol 383 with DMP in the presence of NaH003 provided dione 417 in 88% yield. The carbonyl at the CZ position should be less hindered than the carbonyl in the 6—membered ring, and therefore should be much easier to reduce. Reaction of 417 with NaBH4 at room temperature for one minute gave a mixture of over reduced products. When the reduction was carried out at - 78 °C, no reaction occurred, and increasing the temperature slowly afforded complex mixtures. An alternative reducing reagent DIBAL also suffered from failure. It did not react with 417 at room temperature and gave mixtures at a higher temperature. Fortunately, the reduction with NaBH4/CeCl3 at —78 °C for 15 minutes gave exclusively a single alcohol. However the result was not what was desired: the reduction gave back the B-alcohol 383. According to a Chem-3D structure of dione 417, the B-face of the ketone in the macrocycle is blocked by the methyl group on C4. Thus, the reducing reagent could only approach from the a-face to give the (ii-alcohol. 122 Scheme 5.27 Reduction of Dione 417 O O NaBH4/CeCl3 -78 °C, 15 min 96% 417 DIBAL 0. 0 Q ( 611 NaBH4 Chem 30 predicted comformation of 417 A final attempt to convert 360 into 361 was by made photolysis. Since 360 and 361 are formed by electrocyclization of ketene 418, photolysis of 360 might prompt the re-opening and closure of the cyclohexadienone and the generation of 361 (Scheme 5.28). Thus, compound 360 was dissolved in a deuterated solvent in the NMR tube and irradiated with UV light by a Rayonet reactor. When 360 was irradiated in CDCI3 for 1 hour, 10% of 361 was detected. Longer irradiation resulted in the formation of an unknown product but the ratio of 3612360 did not substantially change. Photolysis in (303013 resulted in the very rapid decomposition of 360. Photolysis of the unprotected alcohol 383 in CDCI3 led to the decomposition of the starting material in a very short period. Therefore, while photo isomerization of 360 did occur, it was not sufficiently favorable for the formation of 361 to be synthetically useful. 123 383 No reaction at -78 °C and rt decomposed at 50 °C rt over reduction 7 -78 °C, no reaction, -78 °C to -30 °C mixtures Scheme 5.28 Photolysis of 360 and 383 OMe 0 OTIPS Solvent Time 360/361/unknown hv CDCIS 1h 1:0.11 2h 1:0.15:0.10 4h 120172042 16 h decomposed CD3OD 3h decomposed OTIPS / 416 5.5.2 Conversion of stereocenter at C2 from a to 0 Several different methods to invert the stereocenter of C2 in compound 383 failed including the Mitsunobu reaction, oxidation/reduction sequence and photolysis. However, as described in Scheme 5.27, the reduction of dione 417 with NaBH4/CeCI3 gave alcohol 383 as the only product. Thus, it is possible to invert the B-configuration in alcohol 404 into cat-configuration via an oxidation/reduction sequence reaction. It was delightful to find that the oxidation of alcohol 404 with DMP smoothly gave dione 417. Scheme 5.29 Conversion of Alcohol 404 into Dione 417 124 With this conversion, the total synthesis of Phomactin BZ is more convergent. Attention next was turned to the asymmetric synthesis of Phomactin B2, which will be the subject of the next chapter. 5.6 Summary In summary, a total synthesis of Phomactin BZ was accomplished via the intramolecular cyclohexadienone annulation of Fischer carbene complex as the key step. This annulation provided two diastereomers and both isomers could be converted to the natural product. This is the first application of the cyclohexadienone annulation reaction in natural product synthesis and the route developed here is more efficient than other published total synthesis of Phomactins. 125 CHAPTER 6 Intermolecular Cyclohexadienone Annulation Approach to the Formal Total Synthesis of Phomactin 32 The successful synthesis of Phomactin 82 using the intramolecular cyclohexadienone annulation as the key step encouraged the design of an alternative synthetic strategy that would potentially allow for an enantioselective synthesis. Obviously, the aforementioned intramolecular approach (Chapter 5) gave a pair of diastereomers in less than ideal selectivity (See Table 5.2) and is therefore not well qualified for such requirement. The new strategy would utilize the intermolecular cyclohexadienone annulation to construct the cyclohexane core, it was expected that if a single stereoisomer at the alkyne partner was used, the stereochemistry of this partner would be successfully transferred to the stereochemistry at the bridgehead carbon C11 (See Scheme 6.2 for details). 6.1 Background 6.1.1 Diastereoselective cyclohexadienone annulation Hsung and co-workers reported the first example of 1,4-asymmetric induction in the cyclohexadienone annulation.21d As indicated in Table 6.1, this annulation reaction was both stereoselective and stereospecific with alkyne 421a and 421b. The annulation gave compound 422 as the major product, which contained the OR group syn to R1. The selectivity dropped from around 90:10 to 82:18 when the substituent in the alkyne changed from trityl (Tr, CPh3) group to 126 fert-butyl dimethyl silyl (TBS) group. This outcome was believed to be due to the electronic effect.105 Table 6.1 Asymmetric Cyclohexandienone Annulation c on 0 on OMe 1 OF1 90°C 12 h R1 R12 (OC)5Cr _ n + ___ < . 112‘ + R .. =<_= 433 434 60% 1) Cr(CO)5, THF. -78 °C OMe 1) AlMea. Zr092C12. CH20I2- n I \_<—>= 2) n-BuLi, -78 °C to rt (OC)SC,;<_<—>: 2) I2, THF. 0 OC 3) M63OBF4. CH2C|2/H20. ft 329 47% 2 steps 435 70% The synthesis of alkyne 431 was more straightfonlvard (Table 6.2). Aldehyde 436 was prepared from geraniol acetate according to the literature.83b Treatment of 436 with ethynyl magnesium bromide afforded propargyl alcohol 437. A series of propargyl ether 431 were synthesized in order to study the diastereoselectivity of the intermolecular cyclohexadienone annulation. 130 Table 6.2 Preparation of Alkyne 431 W0 : MgBr V\J\20H\ V\J\)OR\ __ _ = \ ———> \ THE-30 °C, 1 h \ Q Q 437 431 436 Series Product R Reagent Yield (%) a 330 Tr TrCl, DBU 98 b 431 b TIPS TIPSCI, DMAP 84 c 431c SiPh3 SiPh3Cl, DMAP 94 d 431d TES TESOTf, Et3N 73 e 431 e MOM MOMCI, DIEPA 86 6.2.2 Annulation of carbene complex 329 and alkyne 431 Having the required precursors 329 and 431 in hand, the cyclohexadienone annulation was performed at 55 °C in CH30N at a concentration of 0.02 M. As shown in Table 6.3, trityl and TIPS protected compounds (Series a and b) provided the best diastereoselectivity (98:2). However, other protecting group proved far less satisfactory. Triphenyl silyl and triethyl silyl-protected propargyl alcohols gave a 2:1 diastereomeric ratio, and MOM-protected one gave a 3:1 ratio. Obviously, both electronics and sterics had to come to play in order to explain this dramatically different behavior, but the exact reason for such variation remains elusive. The structures of the major isomers in the annulations were assigned to 429 on the basis of the previous studies in the group. 131 Table 6.3 Cyclohexadienone Annulation of 329 with 431 OOR (OC)5Cr We on MeCN. 55°C w + M __._.____. s + \ 0.02M | OMe 329 431 / 429 Series R Yield (%)3429 + 430 Ratiob429l430 a CPh3 83 96:4 b TIPS 78 98:2 c SiPh3 63 67:33 d SiEt3 64 67:33 e MOM 63 75:25 a) Isolated yield. b) Determined by crude 1H NMR. 6.2.3 Optimization of annulation reaction between 329 and 431s Although the Tr and TIPS protected 328 and 429b could be prepared with excellent stereoselectivity, the precious experience mentioned in Chapter 5 somewhat discounted their value as the synthetic intermediate toward Phomactin B2. This is because after RCM, series of compound 429 would be converted to bicycle 331, and only MOM-protected compound 362 could be further manipulated to Phomactin B2. Compound 360 already experienced a failure in the critical Peterson olefination step, and compound 327 was expected to give a failure in this Peterson olefination either. Therefore, an optimization of the reaction condition for the thermolysis with MOM-alkyne 431e was attempted for an improved diastereoselectivity (Table 6.4). 132 It was disappointing to find that this optimization did not lead to a satisfactory point. The reaction carried out at a lower temperature (40 °C) suffered from poorer diastereoselectivity and a much slower reaction rate (Entry 2). Increasing the concentration to 0.1 M or decreasing the concentration to 0.005 M also resulted in poorer selectivity (Entries 3 and 4). Usage of other solvents in place of CH3CN also proved no success. The annulation reaction performed in non-polar solvent benzene, polar solvent THF and coordinating solvent CH3CN gave essentially the same results. This failure led to the discard the use of the MOM group in the preparation of 429e. Either Trityl or TIPS was used as the protecting group and hoped that the Peterson olefination problem could be avoided by running the Peterson olefination before the RCM step, or a protecting group swap after RCM could satisfy the need for MOM protecting group. 133 Table 6.4 Optimization of Annulation Reaction of 329 with 431e O OMOM O OMOM (OC)5CF=<::e<—_>= * w ——" + , S S101“ 329 431e / 4299 Entry Solvent Temp. Conc. Time 429e + 4309 4299/430eb (°C) (M) (h) (%)":I 1 CH3CN 55 0.02 12 63 3:1 2 CH3CN 40 0.02 60 45 1.521 3 CH3CN 55 0.005 12 41 1.421 4 CH3CN 55 0.1 12 59 2:1 5 THF 55 0.02 12 42 3:1 6 Benzene 55 0.02 12 50 3:1 a) Isolated yield. b) Determined by crude 1H NMR. 6.3 Ring-closing metathesis 6.3.1 Ring-closing metathesis of 328 Although RCM has been widely used in the syntheses of natural products.88a To the best of our knowledge, such reaction has not been successfully applied to the synthesis of phomactin families. The only published example was in Pattenden’s total synthesis of Phomactin A, where RCM was used to construct the C3—C4 olefin in a low 27% yield.83b 134 Scheme 6.4 RCM in Pattenden’s Synthesis of Phomactin A O OTBS O OTBS / 3 30 mol% Grubbs | catalyst I t 4 DEA CHZCIZ, reflux, 10 h 0E1 ___. 27% / 438 439 Another attempt of using RCM in the synthesis of Phomactins was performed by Ms. Ying Liu in the group. Her studies of RCM using Grubbs generation I catalyst 441 showed only dimer formation and no detectable desired macrocycle in different solvents and concentrations.87 Scheme 6.5 RCM of 328 with Grubbs Generation I Catalyst o cum 0 OCPh3 Ph3CQ o PCy3 : I Ph C": , _ Catalyst 441 CI’RTJ PCY3 Grubbs gereration I catalyst 441 80 °c I OMe To date, more catalysts for ring-closing metathesis have been invented 440 and become commercially available. The next catalyst being examined was Grubbs’s generation ll catalyst 442. This reaction was initially performed by Barabanov and the desired cyclized product 327 was obtained in excellent yield and the resultant olefin has exclusively E-geometry.134 In a parallel reaction, 328’s diastereomer 430a failed to give any cyclized product under the same reaction conditions. The difference in the reactivity between 328 and 430a might due to their different conformations. It was envisioned that in order to minimize 135 the strain induced by the C2 substituent, compound 430a has to adopt a conformation, where the two olefin unites were simply too far away to react. Scheme 6.6 RCM of 328 and 430a with Grubbs II Generation Catalyst o OCPh3 o OCPh3 MesN Nb Mes 5 mol% 442, 3 h Clrhlj/ = U: 1 mM, Toluene, 100 °C Cl, I Ph 94% PCYS Grubbs gereration II catalyst 442 5 mol% 442, 8 h 4' 3:1 4303 Idimer 1 mM, Toluene, 100 °C 430a Proposed Conformatlon of 4303 6.3.2 Cleavage of the trityl group in 327 With compound 327 in hand, the next plan was to install the exo double- bond at C15. Unfortunately, the Peterson olefination reaction did not work with compound 327 due to the reason proposed in Chapter 5 for compound 360 (Figure 5.3). Scheme 6.7 Peterson Olefination of Compound 327 o OCPh3 L'CHZTMS No reaction THF, rt Therefore, the trityl group in 327 needs to be cleaved before running the Peterson olefination. However, with the presence of the enol ether functional 136 group in 327, the trityl group cleavage was challenging. As indicated in the Table 6.5, cleavage of the trityl group selectively while keeping the enol ether intact reached complete failure under a variety of conditions. Using TFA with Et3,SiH1°6 (Entry 1) provided compound 416 with both enol ether hydrolysis and trityl group cleavage. The reaction with Lewis acids ZHBI'2107 and BCI3108 (Entries 2 and 4) did not give compound 383 nor 416. Other methods using If”, CAN on silicagel“° and CBr4m (Entries 5, 6, 7) also failed to react with compound 327. Even a mild acid PPTS (Entry 3) failed to react with 327. Thus, the synthesis needs to reroute either by using different protecting groups or different order of reactions. Table 6.5 Cleavage of Trityl Group in Compound 327 Entry Reagent Solvent Temp. (°C) Time Resultsa 1 1% TFA/5% Et3SlH CH2C|2 rt 2 h 416 only 2 ZnBrz MeOH 0 20 min 327 only 3 PPTS MeOH rt 10 h 327 only 4 BCI3 CH2CI2 -30 30 min 327 only 5 I; MeOH rt 1 h 327 only 55 5 h Decomposition CAN/SiOz CH30N rt 1 h 327 only 7 CBr4 MeOH rt 1 h 327 only 60 3.5 h 416 only ‘5) Monitored by TLC and checked by crude 1H NMR. 137 6.3.3 Ring-closing metathesis of 429b The failure of removing trityl group in 327 prompted an investigation of the RCM of compound 4296. The reaction was first carried out under similar conditions applied to compound 328. But the reaction only gave 1:1 ratio of the starting material 429b and dimer. After several attempts (Table 6.6), it was found that the desired product 360 could be obtained in 83% yield when the concentration of 429b was reduced to 0.2 mM (Entry 3). However, this concentration was too dilute and impractical for the scaling up of the synthesis. The slow addition of substrate was also attempted by adding 429b slowly to the solution of catalyst 442 in toluene using syringe pump (Entry 4) to reach the transient low concentration, but this led to a complete failure. Increasing the loading of the catalyst or changing to a more polar solvent did not provide better results (Entries 5-8). Hoveyda catalyst 443 was another generally used catalyst in the ring-closing metathesis reaction to form multi-substituted double-bond.112 Thus, RCM with catalyst 443 was also performed (Entries 9-11), but again no satisfied results were obtained under these conditions. Table 6.6 RCM of 429b with Catalysts 442 and 443 O OTIPS O OTIPS ,——‘ MesN NMes MesN NMes T o, Cllr. R Ru__ '1 u Cl’ | ph C" t _\ _ PCy3 i-PrO Grubbs gereration II 429!) 360 catalyst 442 Hoveyda Catalyst 443 138 Entry Catalyst Conc. Solv. Temp. Time Resulta Yield of (mM) (°C) (h) 360/429bl 360 (%) dimer 1 5 mol% 442 2 Tol. 90 21 Ndz1 :1 - 2 5 mol% 442 1 Tol. 100 3 3:N:1 39b 3 5 mol% 442 0.2 Tol. 100 8 360 only 83 4 ° 5 mol% 442 2 Tol. 100 5.5 N:3:1 - 5 20 mol% 442 1 Tol. 100 0.33 1:1:0.3 24 6 5 mol% 442 1 CHZCIZ 40 48 1:2:N 29 7 5 mol% 442 1 DCE 75 3 Mixture - 8 5 mol% 442 1 CHzclz 40 24 2:1:N 55 9 10 mol% 443 1 CHzclz rt 20 429b/trace dimer - 10 10 mol% 443 1 CH20I2 40 48 1:3:N.25 ' 21 11 10 mol% 443 1 Tol. 100 32 1:2:2 - a) Determined by crude TH NMR. b) The product 360 was inseparable with 429b and dimer, and the yield was obtained by calculation. c) Slow addition of 429b over 3.5 hours. d) Not detectable by 1H NMR. 6.3.4 Ring-closing metathesis of 444 Inspired by Nicolaous’s results that a prenyl group could participate in RCM to form macrocycle,113 compound 444 bearing a prenyl group on the right- side arm was synthesized for the RCM reaction (Scheme 6.8). Scheme 6.8 RCM with Substrate 444 O OTIPS O OTIPS 139 Compound 444 was prepared straightforward from the commercial available geraniol. Dess-martin periodinate oxidation of geraniol (335) gave rise to aldehyde 445 in 95% yield. Alkylation of 445 with ethynyl magnesium bromide provided propargyl alcohol 446, which was then protected as TIPS ether (447). Annulation of alkyne 447 with carbene complex 329 in CH3CN at the concentration of 0.02 M gave 444 as the only diastereomer in 63% yield. However, RCM of 444 with 5 mol% 442 at 100 °C or with 10 mol% 442 at 40 °C did not afford any desired macrocycle 360. Scheme 6.9 RCM of Compound 444 OH DMP,CH20|2 —o .E—MgBr M rt. 30 min THF,-40°C,1h \ 950/0 ° geraniol (335) 445 82 /° 446 TIPSCL DMAP WE carbene complex 329 > \ : CHZCIZ, n \ § CHacN, 0.02 M, 65 °C, 6 n 77°/o 63°/o 447 10 mol% 442, 1 mM 5 mol% 442, 1 mM _ No Reaction : 444 ; dimer CHZCIZ, 40 °C, 24 h Toluene, 100 °C, 5 h 6.3.5 Ring-closing metathesis of 429e-e The RCM reaction of PhaSi-substituted 429e, TES—substituted 429d and MOM-substituted 429e were next examined for more information (Scheme 6.10). Hopefully, the ring-closing metathesis of these dienes could provide some information for the intricate cyclization of 429b. Treatment of 4290 with 5 mol% of 442 in toluene at 100 °C provided the expected cyclized product 331c in 74% 140 yield. TES-protected compound 429d and 430d were inseparable and were subjected to RCM reaction together under similar condition. It was not surprising to find that only cyclized product from 429d was found and no corresponding cyclized product from 430d was detected. RCM of MOM-substituted compound 429e under similar condition provided 362 in 76% yield as the single product. Successful as they are, these results throw more questions as why specifically TIPS-substituted 429b failed in the ROM reaction, while very similar PhaSi or TES-substituted analogues went on RCM successfully. Scheme 6.10 RCM of 429c-e o OSiPh3 O OS'Ph3 5 mol% 442, 1 mM 0 Toluene, 100 °C, 8 h , 74°/o / 331C 0 OSiEt3 O OSiEt3 I 5 mol% 442, 1 mM = + dimer OMe Toluene, 100 °C, 8 h 45%) / 429d + 430d 384 2:1 dr 0 OMOM O OMOM 5 mol% 442, 1 mM 0 Toluene, 100 °C, 8 h 76%) / 362 6.3.6 Mini-conclusion As to this point, the original proposed synthesis plan (Scheme 6.2) has to be considerably revised. The RCM reaction on epimer 430 was not successful 141 and the RCM on epimer 429 experienced incompatible protecting group with reactivity. The Tr-protected 328 was able to undergo RCM, but removal of Tr failed. The TIPS-protected 429b suffered from an impractical RCM condition. Other protecting groups were compatible with RCM but came with low diastereoselectivity in the annulation. Therefore, there is no perfect strategic compound that could satisfy all the desirable criteria. For these reasons, the preparation of 430 and 429 from annulation between 432 and 431 was suspended due to the failed RCM, and an alternative pathway was considered involving running Peterson olefination prior to the RCM reaction. 6.4 Peterson olefination of 328 and 429b The next strategy considered was installing the exo double-bond at C15 before RCM (Scheme 6.11). This revision of order of reactions has two purposes: first, it was hoped that RCM would be more smooth after this olefination, and second, as mentioned in Scheme 5.16, such Peterson olefination does not work with C2-(S) stereochemistry once the macrocycle is constructed. Therefore, switching these two steps was potentially the key to both of the problems above. Delightfully, compound 328 and 429b could undergo Peterson olefination smoothly. The reaction took only 30 minutes at room temperature. The following elimination and hydrolysis afforded dienone 448 and 449 in excellent yields. It was reasoned that the success of this olefination is due to the absence of the macrocycle. The more free conformation the molecule could adopt that allowed for the nucleophile to approach. 142 Scheme 6.11 Peterson Olefination of 328 and 429b O OCPh3 LiCHZTMS KHMDS A THF, rt, 30 min THF, rt, 1.5 h 328 O OTIPS UCHzTMS KHMDS HCI/MeOH THF, rt, 30 min , THF, rt, 1.5 11’ 94% 429b The next step was the methylation to install the“ methyl group or ring- closing metathesis to form the macrocycle ring. The RCM reaction was examined first, since the methylation of 448 and 449 might lead to a mixture of diastereomers without the constructed macrocycle. The ring-closing metathesis of compound 448 was first carried out under the conditions described in Scheme 6.10. This reaction provided 2:1 ratio of the inseparable E/Z isomers of cyclized products 450. The dimer was not observed since the terminal alkene protons were not detected in 1H NMR. Ring-closing metathesis of TIPS protected substrate 449 under the same conditions resulted in a low conversion and 62% of the starting material 449 was recovered. Although higher loading of the catalyst and longer reaction time was able to push the reaction to complete with satisfied yield, the 1:0.8 of E/Z isomer was far from being satisfactory. 143 Table 6.7 RCM of Compound 448 and 449 100 °C, Tol Grubbs II 442 448 R = Tf‘ 449 R = TIPS Reactant mol% of cat. Time (h) % Yield 528 448 5 8 70 2:1 449 5 8 27b 3:1 449 10 24 82 1 :0.8 a) The E/Z isomers were inseparable by chromatography and the ratio was determined by 1HNMR. b) The starting material 449 was recovered in 62% yield. Since both compounds 450 and 451 were obtained as inseparable E/Z isomers, the structures of the desired E-isomers were verified by converting the mixture to known compound. Thus, compound 450, as a mixture of isomers, was subjected to methylation condition to give inseparable E/Z mixture 452. The newly installed methyl groups in both isomers of 452 were incorporated exclusively from one face and were assumed to be [ES-oriented. Treatment of 452 with 6 M HCI at room temperature for 5 hours successfully cleaved the trityl group and gave 2:1 ratio of isomers 394, which were still inseparable by chromatography. However, E—394 has been prepared in Chapter 5, and the major stereoisomer in 450 was assigned to E-configuration by comparing the NMR spectra. To verify the structure of compound 451, compound 388 obtained from Chapter 5 was carried on to standard protecting-group manipulation. Again, 144 the major stereoisomer in 451 was also assigned to E-configuration by comparing the NMR spectra. Scheme 6.12 Verification of Structure E452 and E451 1) LHMDS, THF -78 °C24 h : HCI/MeOH c 2) Mel, ~78 °C to rt rt, 5 h 12 h 91% 79% 450 2:1 E/Z 452 2:1 E/Z 394 2:1 E/Z HCI, MeOH TIPSCI, DMAP 55 °C, 12 h CH20I2. 4 d 91% 2 steps 453 451 Due to the low E/Z selectivity in the RCM reaction of 448 and 449, an alternative pathway that installing the methyl group before ring-closing metathesis was next considered and performed (Scheme 6.13). The methylation reaction of 448 with LHDMS and Mel resulted in less than 40% conversion. Luckily, the methylation proceeded smoothly with KHDMS and Mel to afford 454 in 74% yield as a single stereoisomer. The newly incorporated methyl group was assumed to install from the less hindered 8-face. However, the ring-closing metathesis of 454 came with even lower E/Z selectivity. This time, the undesired Z-isomer was obtained as the major isomer. As these isomers were again inseparable, and all of the attempts have reached less than ideal results, the synthesis of Phomactin B2 via this intermolecular annulation route was halted and give way to the asymmetric synthesis. 145 Scheme 6.13 Methylation and RCM of Compound 448 1) KHMDS 2) Mel 5: 1 448: 454 74% 10 mol% Grubbs II 442 Tol, 100 °C, 1 mM, 7 h 82% 0.621 E/Z 6.5 Summary In summary, the intermolecular cyclohexadienone annulation approach has been attempted to the total synthesis of Phomactin BZ. In this route, carbene complex 329 could be successfully coupled with alkynes 330 and 431b with excellent diastereoselectivity. The resultant annulated product with a TIPS- protecting group could be converted to 360 via RCM at a dilute concentration. The MOM-protected analogue 429e was obtained from the annulation reaction with lower diastereoselectivity. This diene could undergo smooth RCM to afford 362 in acceptable yield. Both 360 and 362 were mutual intermediates in the intramolecular version of synthesis. Thus, the formal total synthesis of Phomactin B2 could be realized via the intermolecular pathway. This was the first time that RCM was used successfully in the total synthesis of Phomactin families. 146 Scheme 6.14 Summary of Total Synthesis of Phomactin 32 o— 0 OT'PS o OTIPS o OMOM (OC)5Cr ' 349 _ Intramolecular Approach OMe (OC)5Cr 13295 Intermolecular Approach phomactin 32 6.6 Future Work The asymmetric synthesis of Phomactin B2 will be accessible via the pathway described in Scheme 6.15. Alkylation of aldehyde 436 with lithium TMS acetylene will provide propargyl alcohol 455. Dess-Martin oxidation will convert this alcohol to ketone 456. Asymmetric reduction of 456 with CBS is anticipated to provide alcohol 457 with high enantioselectivity. A similar reduction has been attempted by Keith in our group on compound 458 with 98% ee induction. Desilylation of 457 followed by protection will produce enantiomerically pure alkyne 437. With 437 in hand, the asymmetric synthesis of Phomactin B2 will follow the procedure described before in the racemic synthesis to give the natural product in a pure enantiomeric form. 147 Scheme 6.15 Asymmetric Approach to Phomactin BZ O OH 0 — TMS _ Ll flJ ................ - \ a -3545--- \ \ g TMS TMS 455 455 436 9H 9” OTIPS "53.83- \ \ s T245- \ \ T'PSC' M TMS .- DMAP \ 457 437 4315 ........ , '—"___. (+)-Phomactin B2 0 9H \ . \ \ § CBS \ Q TMS TMS 458 BHa-THF (Si-459 67% yield, 98% ca 148 CHAPTER 7 Preliminary Studies toward the Synthesis of Phomactins C and D Upon the completion of the total synthesis of Phomactin B2, the attention was moved on to synthesize other Phomactins. Due to the limit of time and effort, only preliminary studies were performed in this area. 7.1 Peterson olefination for the total synthesis of Phomactins C and D Phomactin D has the strongest PAF antagonist activity among Phomactins. A synthetic pathway parallel to the synthesis of Phomactin B2 was designed for the synthesis of Phomactin D (Scheme 7.1). In fact, the proposed total synthesis of Phomactin D starts from compound 361, a known intermediate along the synthesis of Phomactin B2. The first step will also be Peterson olefination to introduce another enol ether at C15. Hydrolysis of both two enol ethers should provide keto-aldehyde 461. The formal group was expected to epimerize to the B-face away from the macrocycle for thermodynamic reasons. Selective protection of the aldehyde followed by methylation should give ketone 462. Removal of the carbonyl in 462 might be the most challenging step. If this step could be accomplished, the synthesis of Phomactin C and D would be very straightforward from compound 463 149 Scheme 7.1 Proposed Total Synthesis Route for Phomactins C and D 0 OTIPS CHO OTIPS 1) protection ............. - 2) methylation 1) decarbonylation 2) desilylation CH0 0 1) epoxidation 2) oxidation .............. .p 3) deprotection Phomactin C (464) Phomactin D (307) The Peterson olefination in this case used a different silylmethyllithium species. This trimethylsilylmethoxymethyl lithium was generated in situ from trimethylsilylmethoxymethane and sec-butyl lithium.114 It is known to react with cyclohexanone to give cyclohexanecarbaldehyde after treatment with formic acid.115 However, this lithium reagent did not react with 361 at different temperatures. The less reactive diastereomer 360, another known intermediate along the synthesis of Phomactin B2, also failed to react with TMSCH(OMe)Li. Thus, this proposed olefination encountered a failure. 150 Scheme 7.2 Peterson Olefination of 360 and 361 O . . CH0 TMSCH(OMe)Li ‘ formic aCId‘ 42% ‘55 455 OMe O 97'” TMS OH OTIPS TMSCH(OMe)Li )( No reaction THF -78 °C to it 361 467 TMSCH(OMe)Li )9. No reaction THF, rt, 24 h 7.2 Simmon-Smith cyclopropanation Meanwhile, an alternative pathway was considered which introduces the methyl group at C12 via Simmon-Smith cyclopropanation (Scheme 7.3).116 The electron rich C12-C13 olefin should be more active to the organozinc reagent and the cyclopropane was expected to be chemoselectively formed at this position from the face opposite to the macrocycle. Acid catalyzed ring opening of the cyclopropane would lead to a-methyl ketone 469. Scheme 7.3 Proposed Simmon-Smith Reaction of 360 and 361 o OTIPS o OTIPS 0 OTIPS Simmon-Smith ring-opening 151 However, treatment of 360 with ZnEtz and CH2I2 resulted in no reaction. The reaction of its diastereomer 361 under similar condition gave similar results. Since C12—C13 olefin was conjugated with the carbonyl, the electron density might be reduced by the carbonyl through conjugation and led to the lowered reactivity. Due to the limited quantity of the substrates 360 and 361, a model study was performed for Simmon-Smith reaction using 470 as the simplified substrate. When 470 was treated with diethyl zinc and methylene iodine, no desired cyclopropane 473 was observedmb Instead, the undesired cyclopropane 471 was isolated in 36% yield with the 3-member ring formation at the wrong place and ethyl group addition to the ketone. It was envisioned that this result may come from an initial diethyl zinc addition to the carbonyl, followed by the subsequent O'-directed cyclopropanation at the allylic double bond. Other procedures were attempted to perform the cyclopropanation, including adding enol ether 470 to the mixture of diethyl zinc and methylene iodine, and the procedure involving use of zinc-copper couple."7 However, neither of these attempts gave desired product 473, and the starting material was simply recovered in those reactions. Dr. Jie Huang has demonstrated that the Simmon- Smith reaction can be performed on a reduced model 474 to obtain cyclopropane 475 in 96% yield.91 Based on the results of the model study, the carbonyl in 360/361 needs to be reduced before the cyclopropanation.91 152 Scheme 7.4 Simmon-Smith Reaction and Model Study O OTIPS O OTIPS ZnEt2 (2 eq) CH2'2 No reaction with both isomers I X ; Toluene, 0 °C to rt 0 OH OH ant2 (2 GQ)’ CH2'2 : dilute HCI Toluene, 0 °C to rt OMe 36°/o 0MB 0 470 471 472 O 0 OH OH Zn-Cu couple. CH2I2 ZnEt2, CH2l2 No reaction 96° A 470 473 474 475 7.3 Reduction of Compounds 360 and 361 Understanding the necessity to reduce the carbonyl, compound 360/361 was then planned to subject to a 1,4-reduction, followed by a subsequent reduction of the resulting ketone to generated 474-type alcohol (Scheme 7.4). But the attempts for such 1,4-reduction of 360 and 361 were not successful at 0°C and resulted in no reaction. When the temperature increased to room temperature, the minor isomer 361 was converted to a new compound within 1 hour. The reduction of the major isomer 360 took longer time, but essentially gave the same product. The structure of this new compound was determined to be compound 476 by NMR and MS analysis. It was envisioned that when 360 or 361 was treated with L-selectride, a 1.4-reduction occurred to give anion 477, which underwent a fi-elimination of the OTIPS group to afford another (1,8- unsaturated ketone 478. A subsequent 1,4-reduction of 478 gave compound 476 153 as the final product. With all that being said, the 1,4-reduction announced a failure, and it was considered to run a 1,2-reduction of the carbonyl in compound 360 and 361. The resulting alcohol from 1,2-reduction might be able to facilitate the Simmon-Smith cyclopropanation. Scheme 7.5 Reduction by L-Selectride 0 QTIPS o OTIPS L-Selectride, THF rt,1h Vrt.24h O OTIPS 1 ,4-reduction elimination 1.4-reduction —> -————-—-> _._—_. — The 1.2-reduction of compound 360 was performed with NaBH4, DIBAL, superhydride, and LAH (Table 7.1). Among all these reducing agent, only LAH was be able to reduce compound 360 at room temperature to afford 479. This reduction gave 479 as a single diastereomer, but it was inseparable with 10% of starting martial. The resultant mixture was then subjected to the Simmon-Smith reaction, but complex mixtures were obtained. Obviously, simply removing the carbonyl seemed not enough to restore the reactivity of the enol ether olefin toward the Simmon-Smith cyclopropanation. 154 Table 7.1 1.2-Reduction of 360 o OTIPS OH OTIPS 1, 2- reductioL 350 479 Reagent Equivalents Temperature Time Results“l (°C) NaBH4 2 rt 3 d No conversion NaBH4/CeCI3 10 . rt 3 d No conversion DIBAL 2 rt 24 h No conversion Superhydride 2 -78 - rt 20 h No conversion Superhydride 4 rt 30 min Decomposition LAH 4 rt 15 h 85” a) Monitored by crude H 1NMR. b) Isolated yield. Having announced a failed Simmon-Smith cyclopropanation, a more traditional method was considered for the installation of the C12 methyl group. Along these lines, compound 479 was first hydrolyzed to the ketone 480 in quantitative yield. The directed methylation of enone 480 with the free hydroxy group gave complicated mixtures. Thus, the hydroxy group in 480 needs to protect before the methylation. An acetate was initially considered, since it could have some electronic perturbation to help differentiate the double bonds in the macrocycle and the one in 6-membered ring, and hence should be able to drive the later-stage epoxidation at the desired position. However, no reaction happened when 480 was treated with A020 in the presence of pyridine and DMAP at room temperature. Increasing the temperature to 80 °C did not improve the condition, and in both cases compound 480 could be recovered. Compound 155 480 also did not react with the more reactive acetic Chloride. At this time, the plan to synthesize Phomactin D was suspended. Scheme 7.6 Methylation of Compound 480 CH OTIPS 9H OTIPS 9H OTIPS HCI/MeOH LHMDS, Mel "' 1min Messy NMR 479 480 481 A020, Pyridine Cat. DMAP, DMF, 80 °C _ 481 NO reaction Dioxane, AcCl NaH, rt 156 THE APPLICATIONS OF THE ANNULATIONS OF FISCHER CARBENE COMPLEXES VOLUME II By Chunrui Wu A DISSERTATION Submitted to Michigan State University In partial fulfillment of the requirements For the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 2007 EXPERIMENTAL SECTION GC spectra were recorded on a Varian Star 3600 instrument with capillary Alltech ECONO-CAP SE 54 column (30m * 0.53 mm ID * 1.2um). GC-MS spectra were recorded on either a Varian Saturn 2000R GC-MS instrument, or a HP 5890 Series II G0 in tandem with a Trio-1 MS instrument. The latter instrument was also used to record MS spectra with direct-probe inlet. Infrared spectra were obtained on a Nicolet IRI42 spectrometer. Melting Points were measured on a Thomas Hoover capillary melting point apparatus and are uncorrected. 1H NMR and 13C NMR spectra were recorded on Varian Gemimi- 300, Varian lnova-300, Varian VXR-500 and Varian Unity-plus 500 spectrometers (300, 500 MHz for 1H, respectively, and 75, 125 MHz for 13C, respectively). Chemical shifts for 1H and 13C were reported in part-per—million (ppm) values relative to the residue peaks of solvent CDCI3 (8 7.24 for 1H and 77.0 for 13C). High-resolution mass spectra were obtained at Michigan State University Mass Spectrometry Service Center with a JOEL-AX505 mass spectrometer (resolution 7000). General procedure for the preparation of methoxy/isopropoxy Fischer chromium carbene complex (Procedure I) To a flame dried round bottom flask under argon, was added 1 equivalent of halide in THF (0.1 M). The solution was cooled to -78 °C, and 2 equivalents of 157 t—BuLi or 1 equivalent of n-BuLi was added dropwise. The resulting solution was stirred at —78 °C for 30 minutes, and then cannulated to a flask with 1.1 equivalents of Cr(CO)6 in THF (0.05 M) at room temperature. The solution was allowed to stir at room temperature for 2 hours. The resulting carbene lithium acylate solution was concentrated in vacuo, and allowed to stand under high vacuum for 10 minutes. At this point the methoxy and isopropoxy carbene complexes were prepared using different methods. Method A (for methoxy carbene complex) 1) t-BuLi or n-BuLi, THF, -78 °C 0— RBr 2) C'(CO)5 ' n = (OC)5Cr=-( 3) Me3OBF4, CHZCl2/I-l20, rt R The acylate was dissolved in 1:1 CH20I2/HZO, and then 1.5 equivalents of MeaOBF4 was added to the solution and kept stirring for 30 minutes at room temperature under argon. The reaction was quenched by pouring into a separatory funnel with saturated NaHCO3 and pentane. The aqueous layer was separated and extracted with pentane until no red color was seen in the aqueous layer. The combined organic layer was washed with brine twice, and then dried over MgSO4, The dried solution was filtered through a fritted funnel dry packed with Celite 503. The product was purified by silica gel chromatography using pure pentane as eluent. 158 Method B (for methoxy carbene complex) 1) t—BuLi or n-BuLi, THF, -78 0C 2) Cr(CO)5 , rt 0.— RB' ' (OC)5Cr=< R 3) Me4NBr, H20, rt 4) MeOTf, CHZCIQ, rt The acylate was dissolved in 20 mL water, and then 1.5 equivalents of Me4NBr was added with vigorously shaking. The solution was stirred at room temperature for 30 minutes. At this time, the crude carbene ammonium salt was extracted with CHZClz three times. The organic layer was dried over M9304, and then the solvent was removed in vacuo. The crude ammonium salt was dissolved in dried CH2CI2, and 1.5 equiv. of methyltriflate was added. The reaction was stirred at room temperature for 30 minutes and worked up with the same method mentioned in method A. Method C (for isopropoxy carbene complex) 1) f-BuLi or n-BuLi, THF, -78 °C 2) Cr(CO)6 . rt 04 “Br 6 (OC)5Cr=< n 3) Me4NBr, H20, rt 4) TfOiPr, CH20I2, rt The acylate was dissolved in 20 mL water, and then 1.5 equivalents of Me4NBr was added with vigorously shaking. The solution was stirred at room temperature for 30 minutes. At this time, the crude carbene ammonium salt was extracted with CH2CI2 three times. The organic layer was dried over MgSO4, and then the solvent was removed in vacuo. The crude ammonium salt was dissolved in dried CH2CI2, and 1.5 equiv. of freshly prepared isopropyltriflate was added as 159 a concentrated solution in CHZCI2. The reaction was stirred at room temperature for 30 minutes and worked up with the same method mentioned in method A. Preparation of isopropyltriflate 197118 pyridine TfZO + i-PrOH -—> >—OTf To a 25 mL flame dried round bottom flask was added 4 mL CH2CI2 and 1.1 mL triflate anhydride (6.6 mmol) at 0 °C. A solution made with 0.51 mL (6.6 mmol) isopropanol, 0.52 mL (6.6 mmol) pyridine and 3 mL CH20I2 was added dropwise to the triflate anhydride solution in 10 minutes. The solution was kept Stirring at ice bath for extra 30 minutes, and then worked up with H20 (8 mL). The organic layer was dried over MgSO4, filtered and then used without further purification. 1H NMR (CDCI3, 300 MHz) 61.7 (d, 6H), 5.7 (m, 1H), 7.2-7.5 (m, 5H). OMe (OC)5Cr ab Phenyl methoxy chromium carbene complex 89119 Carbene complex 89 (0.88 g, 2.82 mmol) was prepared from bromobenzene (0.40 mL, 4 mmol) according to Procedure I in 70% yield. 1H NMR (CDCI3, 500 MHz) 8 4.69 (s, 3H), 7.24-7.27 (m, 2H), 7.38-7.40 (m, 3H); 13C NMR (CDCI3, 125 MHz) 6 67.09, 122.98, 128.17, 130.32, 153.71, 216.14, 224.10, 351.09. 160 (OC)50r ‘< b Phenyl isopropoxy chromium carbene complex 158119 Carbene complex 158 (1.28 g, 3.76 mmol )was prepared from bromobenzene (1.05 mL, 10 mmol) according to Procedure I in 38% yield. 1H NMR (CDCI3, 500 MHz) 6 1.56 (d, 6H, J = 6.1 Hz), 5.64 (br s, 1H), 7.19-7.19 (m, 2H), 7.28-7.40 (m, 3H); 13C NMR (CDCI3, 125 MHz) 6 22.63, 85.73, 122.40, 128.14, 129.76, 153.78, 216.26, 224.39, 345.82. 0— (OC)5Cr=§: I s o-propenyl methoxy chromium carbene complex 175a120 Carbene complex 175a (0.767 g, 2.78 mmol) was prepared from the corresponding ammonium salt (1.42 g, 4 mmol) according to Procedure I in 69% yield. (OC)5Cr=§;< lso-propenyl isopropoxy chromium carbene complex 175b Carbene complex 175b (0.302 g, 0.99 mmol) was prepared from the corresponding ammonium salt (0.50 g, 1.4 mmol) according to Procedure I in 71% yield. 1H NMR (CDCI3, 500 MHz) 6 1.49(d, 6H, J = 5.4 Hz), 1.85 (s, 3H), 4.83 (br, 1H), 4.98 (br, 1H), 5.50 (br, 1H); 13C NMR (CDCI3, 125 MHz) 6 19.54, 22.68, 85.16, 157.26, 216.39, 224.07, 349.75 (1 sp2 Carbon was not located); IR (neat) 19805, 1920brs, 1611w cm"; mass spectrum m/z (% rel intensity) 304 M" 161 (3), 276 (14), 248 (10), 164 (100), 122 (42). Red solid, mp 63-64 °C; Rr = 0.30 (hexanes) O— (00.50% Propenyl methoxy chromium carbene complex 176a120 Carbene complex 176a (0.63 g, 2.28 mmol) was prepared from 1-bromoprop-1- ene (0.43 mL, 5 mmol) according to Procedure I in 46% yield from the corresponding vinyl bromide. O ' A (OC)5Crakfi‘ Propenyl isopropoxy chromium carbene complex 176b121 Carbene complex 176b (0.91 g, 3.0 mmol) was prepared from 1-bromoprop-1- ene (0.86 mL, 10 mmol) according to Procedure I in 30% yield. (OC)SCr=§:\ _ Sec-butenyl methoxy Chromium carbene complex 177a122 Carbene complex 177a (0.71 g, 2.45 mmol) was prepared from the corresponding ammonium salt (1.0 g, 2.87 mmol) according to Procedure I in 85% yield. The ammonium salt (5.88 g, 16.8 mmol) was prepared from (E)-2- bromobut—2—ene (1.85 mL, 20 mmol) in 84% yield. 1H NMR (CDCI3, 500 MHz) 6 1.47 (d, 3H, J = 7.1 Hz), 1.35 (s, 3H), 4.24 (br, 3H), 4.97 (q, 1H, J = 7.0 Hz); 13C NMR (CDCI3, 125 MHz) 6 14.49, 19.52, 63.91, 114.00, 146.11, 216.26, 224.29, 361.48. 162 (OC)5Cr fl Sec-butenyl isopropoxy chromium carbene complex 177b Carbene complex 177b (0.896 g, 2.81 mmol) was prepared from the corresponding ammonium salt (1.02 g, 3 mmol) according to Procedure I in 94% yield. 1H NMR (CDCI3, 500 MHz) 6 1.46 (s, 3H), 1.50 (d, 6H, J = 6.1 Hz), 1.85 (s, 3H), 4.93 (br, 1H), 5.09 (br, 1H); 13C NMR (CDCI3, 125 MHz) 6 15.04, 20.09, 22.62, 23.03, 83.23, 113.69, 146.07, 216.55, 224.47, 356.31; IR (neat) 2986, 2084, 1991, 1379, 1254, 1178, 1082, 988, 878, 711, 661, 621 cm"; mass spectrum m/z (% rel intensity) 318 M+ (1), 178 (31), 136 (28), 135 (41), 126 (42), 107 (28), 105 (20), 84 (100), 83 (83), 80 (18), 67 (26), 55 (93). Anal Calcd for CraHuCrOs: C, 49.06; H, 4.43. Found: C, 49.01; H, 4.60. Red oil; Rf = 0.29 (pentane). 0— (0050223 Cyclohexenyl methoxy chromium carbene complex 17812o Carbene complex 178 (1.62 g, 5.13 mmol) was prepared from the corresponding ammonium salt (2.50 g, 6.67 mmol) according to Procedure I in 77% yield. The ammonium salt (9.55 g, 25.5 mmol) was prepared from 1-bromocyclohex-1-ene (4.85 g, 30 mmol) in 85% yield. 1H NMR (CDCI3, 500 MHz) 6 1.50-1.60 (m, 2H), 1.63-1.68 (m, 2H), 2.13-2.14 (m, 2H), 2.28-2.30 (m, 2H), 4.61 (s, 3H), 6.31 (br, 1H); 13C NMR (CDCI3, 125 MHz) 6 21.42, 21.84, 25.29, 25.71, 66.11, 135.39, 154.21, 216.80, 223.88, 350.72. 163 General procedure for the benzannulation of carbene complexes with 15 equivalent of 1-hexyne and 15 equivalents of 3-hexyne (Procedure II) O 0 OR 1) 15 equiv. 1-hexyne n -Bu Et (00,50, 15 equiv. 3-hexyne _ D. + 0‘ 2) CAN, rt. 3 h B O O 159 160 89 R = Me 158 R = i-Pr To a 50 mL flame dried Shlenk flask equipped with a Teflon screw top was added carbene complex 89 or 158 in a certain solvent (~0.06 M). 15 equivalents of 1-hexyne and 15 equivalents of 3-hexyne were added to this solution. The system was degassed by running 3 cycles of freeze-pump-thaw. After the third cycle, the flask was back-filled with Ar, and sealed. The reaction was heated to 80 °C for 16 hours or 40 °C for 22 hours. The crude reaction mixture was diluted with 320 and treated with 10 equivalents of 0.5 M CAN solution. The biphasal reaction was stirred for 3 hours at room temperature. At this point, the reaction was poured into a 125 mL separatory funnel and diluted with 320. A saturated NaHCOa solution was added to the funnel to quench the CAN solution, and separated without shaking to avoid emulsion. The organic layer was washed with saturated NaHC03 (2 * 10 mL). The aqueous layer was then back extracted with ether (2 * 10 mL). The combined organics were then washed with brine (15 mL) and dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in 20 mL 320, kept 1 mL solution for GC and GC-MS analysis, the rest crude product was subjected on silica gel Chromatography (usually 2 * 25 cm, 5% 164 EtOAc in hexanes) to gain yields. The yield was calculated based on 95% of the starting material. Reaction with carbene complex 89 in benzene at 80 °C; Carbene complex 89 (0.125 g, 0.40 mmol), 1-hexyne (0.75 mL, 6.5 mmol) and 3-hexyne (0.70 mL, 6.2 mmol) was dissolved in 5 mL benzene and thermolyzed according to Procedure II to give 159 (0.0682 g, 0.32 mmol, 84%) and 160 in 93:7 ratio. Reaction with carbene complex 89 in THF at 80 °C; Carbene complex 89 (0.0995 g, 0.319 mmol), 1-hexyne (0.60 mL, 5.2 mmol) and 3-hexyne (0.60 mL, 5.2 mmol) was dissolved in 5 mL THF and thermolyzed according to Procedure II to give 159 (0.0274 g, 0.128 mmol, 42%) and 160 in 94:6 ratio. Reaction with carbene complex 89 in CchN at 80 “C: Carbene complex 89 (0.104 g, 0.33 mmol), 1-hexyne (0.60 mL, 5.2 mmol) and 3-hexyne (0.60 mL, 5.2 mmol) was dissolved in 5 mL CH3CN and thermolyzed according to Procedure II to give 159 (0.0276 g, 0.128 mmol, 41%) and 160 in 98:2 ratio. Reaction with carbene complex 89 in benzene at 40 °C: Carbene complex 89 (0.157 g, 0.50 mmol), 1-hexyne (0.75 mL, 6.5 mmol) and 3-hexyne (0.70 mL, 6.2 mmol) was dissolved in 5 mL benzene and thermolyzed according to Procedure II to give 159 (0.0703 g, 0.33 mmol, 69%) and 160 in 95:5 ratio. 165 Reaction with carbene complex 89 in THF at 40 °C; Carbene complex 89 (0.105 g, 0.31 mmol), 1-hexyne (0.60 mL, 5.2 mmol) and 3-hexyne (0.60 mL, 5.2 mmol) was dissolved in 5 mL THF and thermolyzed according to Procedure II to give 159 (0.0222 g, 0.104 mmol, 35%) and 160 in 98:2 ratio. Reaction with carbene complex 89 in CH3CN at 40 °C; Carbene complex 89 (0.104 g, 0.33 mmol), 1-hexyne (0.60 mL, 5.2 mmol) and 3-hexyne (0.60 mL, 5.2 mmol) was dissolved in 5 mL CH3CN and thermolyzed according to Procedure II to give 159 (0.0222 g, 0.104 mmol, 33%) and 160 in 98:2 ratio. Reaction with carbene complex 89 in hexane at 40 °C; Carbene complex 89 (0.150 g, 0.48 mmol), 1-hexyne (0.60 mL, 5.2 mmol) and 3-hexyne (0.60 mL, 5.2 mmol) was dissolved in 5 mL hexane and thermolyzed according to Procedure II to give 159 (0.0630 g, 0.294 mmol, 64%) and 160 in 96:4 ratio. Reaction with carbene complex 158 in benzene at 80 °C; Carbene complex 158 (0.12 g, 0.35 mmol), 1-hexyne (0.60 mL, 5.2 mmol) and 3-hexyne (0.60 mL, 5.2 mmol) was dissolved in 5 mL benzene and thermolyzed according to Procedure II to give 159 (0.0602 g, 0.28 mmol, 84%) and 160 in 94:6 ratio. Reaction with carbene complex 158 in THF at 80 °C; Carbene complex 158 (0.105 g, 0.309 mmol), 1-hexyne (0.60 mL, 5.2 mmol) and 3-hexyne (0.60 166 mL, 5.2 mmol) was dissolved in 5 mL THF and thermolyzed according to Procedure II to give 159 (0.0355 g, 0.166 mmol, 56%) and 160 in 99:1 ratio. Reaction with carbene complex 158 in CchN at 80 °C; Carbene complex 158 (0.104 g, 0.31 mmol), 1-hexyne (0.60 mL, 5.2 mmol) and 3-hexyne (0.60 mL, 5.2 mmol) was dissolved in 5 mL CH3CN and thermolyzed according to Procedure II to give 159 (0.0259 g, 0.121 mmol, 41%) and 160 in 99:1 ratio. Reaction with carbene complex 158 in benzene at 40 °C; Carbene complex 158 (0.108 g, 0.32 mmol), 1-hexyne (0.60 mL, 5.2 mmol) and 3-hexyne (0.60 mL, 5.2 mmol) was dissolved in 5 mL benzene and thermolyzed according to Procedure II to give 159 0.0482 g, 0.225 mmol, 74%) and 160 in >99:1 ratio. Reaction with carbene complex 158 in THF at 40 °C; Carbene complex 158 (0.108 g, 0.32 mmol), 1-hexyne (0.60 mL, 5.2 mmol) and 3-hexyne (0.60 mL, 5.2 mmol) was dissolved in 5 mL THF and thermolyzed according to Procedure II to give 159 (0.0362 g, 0.168 mmol, 55%) and 160 in 99:1 ratio. Reaction with carbene complex 158 in CH3CN at 80 °C; Carbene complex 158 (0.105 g, 0.31 mmol), 1-hexyne (0.60 mL, 5.2 mmol) and 3-hexyne (0.60 mL, 5.2 mmol) was dissolved in 5 mL CH3CN and thermolyzed according to Procedure II to give 159 (0.0250 g, 0.117 mmol, 40%) and 160 98:2 ratio. 167 Reaction with carbene complex 158 in hexane at 40 °C; Carbene complex 158 (0.146 g, 0.43 mmol), 1-hexyne (0.60 mL, 5.2 mmol) and 3-hexyne (0.60 mL, 5.2 mmol) was dissolved in 5 mL hexane and thermolyzed according to Procedure II to give 159 (0.0688 g, 0.321 mmol, 79%) and 160 in >99:1 ratio. 0 w“ o 2-butylnaphthalene-1,4-dione 159123 1H NMR (CDCI3, 500 MHz) 5 0.93 (t, 3H, J = 7.3 Hz), 1.35-1.42 (m, 2H), 1.52-1.55 (m, 2H), 2.55 (td, 2H, J = 7.9, 1.3 Hz), 5.77 (t, 1H, J = 1.3 Hz), 7.59-7.71 (m, 2H), 8.03-8.09 (m, 2H); 13C NMR (CDCI3, 125 MHz) 5 13.31, 22.47, 29.27, 30.12, 125.00, 125.57, 132.12, 132.34, 133.57, 133.59, 134.72, 151.98, 185.23, 185.27. General procedure for the benzannulation of carbene complex with a alkyne (Procedure III for the preparation of minor product in the competition reaction) To a 50 mL flame dried Shlenk flask equipped with a Teflon screw top was added carbene complex in benzene (~0.06 M) and 2 equivalents of alkyne. The system was degassed by running 3 cycles of freeze-pump-thaw. After the third cycle, the flask was back-filled with Ar, and sealed. The reaction was heated to 80 °C for 16 hours. The crude reaction mixture was diluted with 320 and treated with 10 equivalents of 0.5 M CAN solution. The biphasal reaction was stirred for 3 hours at room temperature. At this point, the reaction was poured into a 125 mL separatory funnel and diluted with Etzo. A saturated NaHC03 solution was 168 added to the funnel to quench the CAN solution, and separated without shaking to avoid emulsion. The organic layer was washed with saturated NaHCO:, (2 * 10 mL). The aqueous layer was then back extracted with ether (2 * 10 mL). The combined organics were then washed with brine (15 mL) and dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified on silica gel chromatography (usually 2 * 25 cm, 5% EtOAc in hexanes). O 0 2,3-diethylnaphthalene—1,4-dione 160119 Quinone 160 (0.869 g, 0.406 mmol, 90%) was prepared from carbene complex 158 (0.153 mg, 0.45 mmol) and 3-hexyne according to procedure Ill. 1H NMR (CDCI3, 500 MHz) 6 1.13 (t, 6H, J = 7.5 Hz), 2.62 (q, 4H, J = 7.5 Hz), 7.66 (dd, 2H, J = 5.8, 3.3 Hz), 8.04 (dd, 2H, J = 5.7, 3.3 Hz); 130 NMR (CDCI3, 125 MHz) 6 13.94, 20.12, 126.13, 132.24, 133.24, 148.05, 185.00. General procedure for the benzannulation of carbene complexes with 1.5 or 2 equivalents of two different alkynes (Procedure IV) To a 50 mL flame dried Shlenk flask equipped with a Teflon screw top was added carbene complex in benzene (~0.06 M). 1.5 or 2 equivalents of two different alkynes were added to this solution. The system was degassed by running 3 cycles of freeze-pump-thaw. After the third cycle, the flask was back- filled with Ar, and sealed. The reaction was heated to 40 °C for 22 hours. The crude reaction mixture was diluted with 820 and treated with 10 equivalents of 169 0.5 M CAN solution. The biphasal reaction was stirred for 3 hours at room temperature. At this point, the reaction was poured into a 125 mL separatory funnel and diluted with 320. A saturated NaHCOa solution was added to the funnel to quench the CAN solution, and separated without shaking to avoid emulsion. The organic layer was washed with saturated NaHCOa (2 * 10 mL). The aqueous layer was then back extracted with ether (2 * 10 mL). The combined organics were then washed with brine (15 mL) and dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in 20 mL 320, kept 1 mL solution for GC and GC-MS analysis, the rest crude product was subjected on silica gel chromatography (usually 2 * 25 cm, 5% EtOAC in hexanes) to gain yields. The yield was calculated based on 95% of the starting material. 1) 1.5 equiv. IrBu = H 1.5 equiv. R1 -_-_-_ F12 0 0 OR Benzene, 40 °C, 22 h n-Bu Ft1 W5 00 + so P“ 2) CAN, rt, 3 n H H2 89 R = Me O O 158 R = i-Pr 1_ 2_ 159 160R1—F1 -82 174R =n-BUR =Me Reaction of carbene complex 89 with 1-hexyne and 3-hexyne: Carbene complex 89 (0.107 g, 0.34 mmol), 1-hexyne (0.060 mL, 0.52 mmol) and 3-hexyne (0.058 mL, 0.51 mmol) was dissolved in 5 mL benzene and thermolyzed according to Procedure IV to give 159 (0.0540 g, 0.252 mmol, 78%) and 160 in 96:4 ratio. 170 Reaction of carbene complex 158 with 1-hexyne and 3-hexyne: Carbene complex 158 (0.128 g, 0.38 mmol), 1-hexyne (0.065 mL, 0.57 mmol) and 3-hexyne (0.065 mL, 0.57 mmol) was dissolved in 5 mL benzene and thermolyzed according to Procedure IV to give 159 (0.0580 g, 0.271 mmol, 78%) and 160 in >99:1 ratio. Reaction of carbene complex 89 with 1-hexyne and 2-heptyne: Carbene complex 89 (0.101 g, 0.32 mmol), 1-hexyne (0.055 mL, 0.48 mmol) and 2-heptyne (0.062 mL, 0.48 mmol) was dissolved in 5 mL benzene and thermolyzed according to Procedure IV to give 159 (0.0525 g, 0.245 mmol, 81%) and 174 in 97:3 ratio. Reaction of carbene complex 158 with 1-hexyne and 2-heptyne: Carbene complex 158 (0.101 g, 0.30 mmol), 1-hexyne (0.052 mL, 0.45 mmol) and 2-heptyne (0.058 mL, 0.45 mmol) was dissolved in 5 mL benzene and thermolyzed according to Procedure IV to give 159 (0.0521 g, 0.243 mmol, 85%) and 174 in > 99:1 ratio. 0 O 2-butyl-3-methylnaphthalene-1,4-dione 174124 Quinone 174 (0.0500 g, 0.22 mmol, 73%) was prepared from carbene complex 158 (0.102 mg, 0.30 mmol) and 2-heptyne according to procedure lll. 1H NMR (CDCI3, 500 MHz) 5 0.93 (t, 3H, J = 7.1 Hz), 1.41-1.45 (m, 4H), 2.17 (s, 3H), 2.51-2.54 (m, 171 2H), 7.66-7.68 (m, 2H), 8.05-8.07 (m, 2H); 13C NMR (CDCI3, 125 MHZ) 6 12.60, 13.88, 23.08, 26.82, 30.86, 126.16, 126.25, 132.17, 132.21, 133.25, 133.29, 143.09, 147.56, 184.72, 185.38. 1) 2 equiv. : n-Bu 2 equiv. Et : E1 40 °C, Benzene, 22 h (OC)5Cr H1 R2 2) CAN, rt., 3 h 175R1=Me,Fi2=H 1751=i1 =H, R2=Me 177 1:11.92 = Me 173 1:11.92 = (CH2)4 179 H‘ = Me, R2 = H 130 H‘ = H, 92 = Me 181R1,R2=Me 133 H1=Me,n2=H 134 R1,R2 = Me 135 9‘. F12 = (CH2)4 1 2_ (aR=Me,bR=i-Pr) "329 »Fi -(CH2)4 Reaction of carbene complex 175a with 1-hexyne and 3-hexyne: Carbene complex 175a (0.170 g, 0.616 mmol), 1-hexyne (0.141 mL, 1.23 mmol) and 3-hexyne (0.1.40 mL, 1.23 mmol) was dissolved in 6.2 mL benzene and thermolyzed according to Procedure IV to give 179 (0.0642 g, 0.360 mmol, 62%) and 183 in 99:1 ratio. Reaction of carbene complex 175b with 1-hexyne and 3-hexyne: Carbene complex 175b (0.157 g, 0.50 mmol), 1-hexyne (0.115 mL, 1.0 mmol) and 3-hexyne (0.114 mL, 1.0 mmol) was dissolved in 5 mL benzene and thermolyzed according to Procedure IV to give 179 (0.0620 g, 0.348 mmol, 73%) and 183 in >99:1 ratio. 172 O W O 2-butyI-5-methylcyclohexa-2,5-diene-1,4-dione 179125 1H NMR (CDCI3, 500 MHZ) 6 0.91 (t, 3H, J = 7.2 HZ), 1.33-1.37 (m, 2H), 1.43-1.48 (m, 2H), 2.01 (d, 3H, J = 1.6 HZ), 2.36-2.40 (m, 2H), 6.52 (t, 1H, J = 1.5 HZ), 6.56 (q, 1H, J = 1.5 Hz); 13C NMR (CDCI3, 125 MHz) 3 13.75, 15.42, 22.37, 23.40, 29.91, 132.38, 133.56, 145.48, 149.62, 187.82, 188.28. 29¢ g, 0.18 mmol, 36%) was prepared from carbene complex 176b (0.152 mg, 0.50 2,3-Diethyl-5-methyI-[1,4]benzoquinone 183 Quinone 183 (0.032 mmol) and 3-hexyne according to procedure lll. 1H NMR (CDCI3, 500 MHz) 6 1.04 (t, 3H, J = 7.4 Hz), 1.05 (t, 3H, J = 7.4 Hz), 2.00 (d, 3H, J = 1.5 Hz), 2.44 (q, 2H, J = 7.4 Hz), 2.46 (q, 2H, J = 7.4 Hz), 6.52 (q, 1H, J = 1.5 Hz); 13C NMR (CDCI3, 125 MHz) 6 13.94 (br, 2C), 15.81, 19.43, 19.70, 133.21, 145.31, 145.38, 145.54, 187.67, 188.02; IR cm"; mass spectrum m/z (% rel intensity) 178 M+ (100), 164 (11), 163 (85), 149 (32), 135 (38), 121 (40), 107 (23), 91 (22), 79 (17), 77 (14), 67 (18), 53 (12). Yellow oil, Rr= 0.35 (5% EtOAc in hexanes). Reaction of carbene complex 176a with 1-hexyne and 3-hexyne: Carbene complex 176a (0.138 g, 0.50 mmol), 1-hexyne (0.115 mL, 1.0 mmol) and 3-hexyne (0.114 mL, 1.0 mmol) was dissolved in 5 mL benzene and 173 thermolyzed according to Procedure IV to give 180 (0.0350 g, 0.197 mmol, 41%) and 183 in 96:4 ratio. Reaction of carbene complex 176b with 1-hexyne and 3-hexyne: Carbene complex 176b (0.152 g, 0.50 mmol), 1-hexyne (0.115 mL, 1.0 mmol) and 3-hexyne (0.114 mL, 1.0 mmol) was dissolved in 5 mL benzene and thermolyzed according to Procedure IV to give 180 (0.0270 g, 0.152 mmol, 32%) and 183 in 98:2 ratio. 0 mm o 2-ButyI-6-methyl-[1,4]benzoquinone 130 1H NMR (CDCI3, 500 MHz) 3 0.91 (t, 3H, J = 7.2 Hz), 1.34-1.33 (m, 2H), 1.43-1.43 (m, 2H), 2.03 (d, 3H, J = 1.5 Hz), 2.40 (t, 2H, J = 7.7 Hz), 6.47-6.48 ( m, 1H), 6.52-6.53 (m, 1H); 13C NMR (CDCI3, 125 MHz) 6 13.65, 15.89, 22.27, 28.73, 29.82, 132.17, 132.94, 145.78, 149.45, 187.70, 187.79; IR (neat) 2959, 2932, 2874, 1653, 1614, 1294, 914 cm"; mass spectrum m/z (% rel intensity) 178 M+ (79), 163 (63), 135 (100), 121 (11), 107 (26), 91 (22), 79 (12), 77 (11). Anal Calcd for CttH1402: C, 74.13; H, 7.92. Found: C, 74.54, H, 8.29. Yellow oil; Rf: 0.30 (5% EtOAc in hexanes). Reaction of carbene complex 177a with 1-hexyne and 3-hexyne: Carbene complex 177a (0.38 g, 1.31 mmol), 1-hexyne (0.226 mL, 1.97 mmol) and 3-hexyne (0.223 mL, 1.0 mmol) was dissolved in 13 mL benzene and 174 thermolyzed according to Procedure IV to give 181 (0.0136 g, 0.708 mmol, 57%) and 184 in greater than 99:1 ratio. Reaction of carbene complex 177b with 1-hexyne and 3-hexyne: Carbene complex 177b (0.268 g, 0.842 mmol), 1-hexyne (0.145 mL, 1.26 mmol) and 3-hexyne (0.143 mL, 1.26 mmol) was dissolved in 8.4 mL benzene and thermolyzed according to Procedure IV to give 181 (0.1270 g, 0.66 mmol, 83%) and 184 in greater than 99:1 ratio. 0 5-butyl-2,3-dimethylcyclohexa—2,5-diene-1,4-dione 131126 1H NMR (CDCI3, 300 MHz) 3 0.35 (t, 3H, J = 7.1 Hz), 1.23-1.43 (m, 4H), 1.93 (s, 3H), 1.95 (s, 3H), 2.33 (t, 2H, J = 7.4 Hz), 5.42 (s, 1H); 13C NMR (CDCI3, 75 MHz) 3 11.95, 12.33, 13.75, 22.34, 23.53, 29.35, 131.91, 140.31, 140.35, 143.95. 187.41, 187.53. >99 NMR (CDCI3, 500 MHZ) 6 1.04 (t, 6H, J = 7.6 HZ), 1.98 (s, 6H), 2.46 (q, 4H, J = 2,3-diethyl-5,6-dimethylcyclohexa-2,5-diene-1,4-dione 134127 1H 7.5 Hz); 13C NMR (CDCI3, 125 MHz) 3 12.23, 14.01, 19.59, 140.41, 145.04, 187.49. _ Reaction of carbene complex 178 with 1-hexyne and 3-hexyne: Carbene complex 178 (0.16 g, 0.5 mmol), 1-hexyne (0.115 mL, 1.0 mmol) and 3- hexyne (0.114 mL, 1.0 mmol) was dissolved in 5 mL benzene and thermolyzed according to Procedure IV to give 182 (0.075 g, 0.344 mmol, 72%) and 185 in 99:1 ratio. 0 gig/w o 2-butyl-5,6,7,8-tetrahydronaphthalene-1,4-dione 132127 1H NMR (CDCI3, 500 MHz) 3 0.90 (td, 3H, J = 7.3, 1.3 Hz), 1.33-1.37 (m, 2H), 1.44— 1.47 (m, 2H), 1.55-1.57 (m, 4H), 2.35-2.40 (m, 5H), 5.44-5.45 (m, 1H); 13C NMR (CDCI3, 125 MHz) 3 13.53, 20.39, 21.03, 22.23, 22.30, 22.53, 23.53, 29.35, 131.91, 141.88, 142.31, 148.99, 187.49, 187.68. €99 NMR (CDCI3, 500 MHZ) 6 1.04 (t, 6H, J = 7.5 Hz), 1.63-1.65 (m, 4H), 2.37-2.37 2,3-diethyl-5,6,7,8-tetrahydronaphthalene-1,4-dione 135128 1H (m, 4H), 2.44 (q, 4H, J = 7.5 Hz); 13C NMR (CDCI3, 125 MHZ) 6 14.01, 19.52, 21.20, 22.53, 141.90, 144.97, 187.53. Reaction of carbene complex 89 with n-butyl acetylene (1-hexyne) and t-butyl acetylene: Carbene complex 89 (0.247 g, 0.79 mmol), 1-hexyne (0.136 mL, 1.19 mmol) and t-butyl acetylene (0.142 mL, 1.19 mmol) was 176 dissolved in 8 mL benzene and thermolyzed according to Procedure IV to give 159 (0.079 g, 0.369 mmol, 49%) and 188 (0.040 g, 0.187 mmol, 25%) in 2:1 ratio. The ratio determined by crude 1H NMR of 159/188 was 2:1. 0 o 2-tert-butylnaphthalene-1,4-dione 133129 1H NMR (CDCl3, 500 MHz) 3 1.34 (s, 9H), 5.31 (s, 1H), 7.55-759 (m, 2H), 7.99-3.01 (m, 1H), 3.04- 3.05 (m, 1H); 13C NMR (CDCI3, 125 MHz) 3 29.35, 35.71, 125.57, 125.34, 131.52, 133.24, 133.54, 133.69, 133.82, 158.32, 184.91, 185.88. Reaction of carbene complex 178 with n-butyl acetylene (1-hexyne) and t-butyl acetylene: Carbene complex 178 (0.236 g, 0.75 mmol), 1-hexyne (0.129 mL, 1.12 mmol) and t-butyl acetylene (0.138 mL, 1.12 mmol) was dissolved in 7.5 mL benzene and thermolyzed according to Procedure IV to give 182 (0.089 g, 0.408 mmol, 57%) and 189 (0.050 g, 0.229 mmol, 32%) in 2:1 ratio. The ratio determined by crude 1H NMR of 182/189 was 2:1. : :0 o 2-tert-butyl-5,6,7,8-tetrahydronaphthalene-1,4-dione 139130 1H NMR (CDCI3, 500 MHz) 3 1.23 (s, 9H), 1.53-1.55 (m, 4H), 2.35-2.33 (m, 4H), 6.48 (s, 1H); 13C NMR (CDCI3, 125 MHZ) 6 20.92, 21.29, 22.07, 22.84, 29.27, 35.07, 131.13, 140.91, 143.91, 155.60, 187.42, 188.37. 177 Reaction of carbene complex 89 with n-butyl acetylene (1-hexyne) and phenyl acetylene: Carbene complex 89 (0.156 g, 0.50 mmol), 1-hexyne (0.086 mL, 0.75 mmol) and phenyl acetylene (0.082 mL, 0.75 mmol) was dissolved in 5 mL benzene and thermolyzed according to Procedure IV to give 159 (0.0397 g, 0.186 mmol, 39%) and 190 (0.0204 g, 0.087 mmol, 18%) in 55:45 ratio. The ratio determined by crude 1H NMR of 159/190 was 1:1. 0 0W" O 2-phenylnaphthalene-1,4-dione 190131 1H NMR (CDCI3, 500 MHZ) 6 7.04 (S, 1H), 7.43-7.46 (m, 3H), 7.54-7.56 (m, 2H), 7.73-7.75 (m, 2H), 3.07-3.09 (m, 1H), 3.14-3.15 (m, 1H); 13C NMR (CDCI3, 125 MHz) 3 125.37, 126.95, 128.38, 129.36, 129.94, 131.99, 132.36, 133.31, 133.73, 133.79, 135.12, 148.00, 184.26, 185.01. Reaction of carbene complex 89 with n-butyl acetylene (1-hexyne) and phenyl acetylene: Carbene complex 89 (0.102 g, 0.33 mmol), 1-hexyne (0.076 mL, 0.66 mmol) and phenyl acetylene (0.075 mL, 0.66 mmol) was dissolved in 5 mL benzene and thermolyzed according to Procedure IV to give 160 and 174 (0.0460 g in total, 62% by calculation) in 1:1 ratio. Reaction of carbene complex 178 with n-butyl acetylene (1-hexyne) and phenyl acetylene: Carbene complex 178 (0.158 g, 0.50 mmol), 1-hexyne 178 (0.086 mL, 0.75 mmol) and phenyl acetylene (0.082 mL, 0.75 mmol) was dissolved in 5 mL benzene and thermolyzed according to Procedure IV to give 159 (0.0386 g, 0.180 mmol, 38%) and 191 (0.0333 g, 0.142 mmol, 30%) in 1:1 ratio. The ratio determined by crude 1H NMR of 159/191 was 1:1. 0 Cflfifiah O 5,6,7,8-tetrahydro-2-phenylnaphthalene-1,4-dione 191132 1H NMR (CDCI3, 500 MHz) 6 1.68-1.70 (m, 4H), 2.43-2.47 (m, 4H), 6.74 (s, 1H), 7.37-7.40 (m, 3H), 7.42-7.44 (m, 2H); 13C NMR (CDCI3, 125 MHz) 3 20.33, 21.10, 22.30, 22.82, 128.22, 129.10, 129.56, 132.28, 133.14, 142.12, 142.50, 145.47, 186.54, 187.47. Reaction of carbene complex 178 with 1-hexyne and 1-TMS-1- pentyne: Carbene complex 178 (0.158 g, 0.50 mmol), 1-hexyne (0.086 mL, 0.75 mmol) and 1-TMS-1-pentyne (0.138 mL, 0.75 mmol) was dissolved in 5 mL benzene and thermolyzed according to Procedure IV to give 159 (0.0884 g, 0.406 mmol, 81%) as the only product. TMS-substituted quinone 194 was not detected by GC-MS and crude 1H NMR. 5,6,7,8-tetrahydro-2-(trimethylsi|yI)-3-propylnaphthalene-1,4- dione 194 Quinone 194 (45 mg, 0.145 mmol, 44%) was prepared from carbene complex 178 (103 mg, 0.33 mmol) with 1-TMS-1-pentyne. 1H NMR (CDCI3, 500 179 MHz) 3 0.25 (s, 9H), 0.93 (t, 3H, J = 7.3 Hz), 1.35-1.40 (m, 2H), 1.52-1.54 (m, 4H), 2.33-2.37 (m, 4H), 2.45-2.43 (m, 2H); 13C NMR (CDCI3, 125 MHz) 3 1.50, 14.25, 21.11, 21.17, 22.45, 22.55, 24.57, 30.57, 141.93, 143.47, 145.50, 155.53, 186.76, 192.03; IR 2942, 2874, 1644, 1273, 868, 844 cm"; mass spectrum m/z (% rel intensity) 275 M+ (34), 252 (22), 251 (100), 233 (25). HRMS (CI) calcd for C15H25028i m/z 277.1624, meas 277.1619. Yellow oil; R = 0.51 (20:1:1 hexanes/EtZO/CHZCI2). Reaction of carbene complex 178 with 1-hexyne and 1-TBS-1-pentyne: Carbene complex 178 (0.158 g, 0.50 mmol), 1-hexyne (0.086 mL, 0.75 mmol) and 1-TBS-1-pentyne (0.138 g, 0.75 mmol) was dissolved in 5 mL benzene and thermolyzed according to Procedure IV to give 159 (0.0848 g, 0.389 mmol, 78%) as the only product. TBS-substituted quinone was not detected by GC-MS and crude 1H NMR. Reaction of carbene complex 89 with 1-octyne and 1-TMS-1-hexyne: Carbene complex 89 (0.109 g, 0.35 mmol), 1-octyne (0.0774 mL, 0.52 mmol) and 1-TMS-1-hexyne (0.105 mL, 0.52 mmol) was dissolved in 6.9 mL benzene and thermolyzed according to Procedure IV to give 192 (0.0596 g, 0.246 mmol, 70%) and trace amount of the TMS-substituted quinone 195 (>100:1) based on crude ‘HNMR. 180 0 2-hexylnaphthalene-1,4-dione 192131 1H NMR (CDCI3, 500 MHZ) 6 0.83-0.86 (m, 3H), 1.25-1.29 (m, 4H), 1.34-1.37 (m, 2H), 1.50-1.55 (m, 2H), 2.50-2.53 (m, 2H), 6,74 (1, 1H, J = 1.4 HZ), 7.66-7.68 (m, 2H), 7.99-8.01 (m, 1H), 8.03-8.05 (m, 1H); 13C NMR (CDCI3, 125 MHZ) 6 13.98, 22.46, 27.91, 28.98, 29.50, 31.48, 125.92, 126.49, 132.04, 132.26, 133.48, 133.51, 134.62, 151.91,185.11, 185.15. 0 CO ms 0 2-butyl-3-(trimethylsilyl)naphthalene-1,4-dione 195127 Quinone 195 (27.8 mg, 0.087 mmol, 25%) was prepared from carbene complex 89 (107 mg, 0.343 mmol) with 1-TMS-1-hexyne. A side-product 3-butyI-2,3- dihydroinden-1-one (35.3 mg, 0.188) was also isolated in 55% yield. 1H NMR (CDCI3, 500 MHz) 6 0.36 (s, 9H), 0.93-0.95 (m, 3H), 1.41-1.45 (m, 4H), 2.67-2.70 (m, 2H), 7.64-7.67 (m, 2H), 7.96-7.98 (m, 1H), 8.01-8.03 (m, 1H); 13C NMR (CDCI3, 125 MHz) 6 1.76, 13.94, 23.17, 29.23, 33.48, 125.97, 126.15, 132.21, 133.06, 133.29, 133.34, 148.80, 159.37, 184.64, 189.64. Reaction of carbene complex 178 with 1-octyne and 1-TMS-1-hexyne: Carbene complex 178 (0.0778 g, 0.25 mmol), 1-octyne (0.0404 mL, 0.38 mmol) and 1-TMS-1-hexyne (0.075 mL, 0.38 mmol) was dissolved in 5 mL benzene and thermolyzed according to Procedure IV to give 193 (0.0492 g, 0.20 mmol, 80%) 181 and trace amount of the TMS-substituted quinone 196 (>100:1) based on crude 1HNMR. o 2-Hexyl-5,6,7,8-tetrahydro-[1,4]naphthoquinone193 1H NMR (CDCI3, 500 MHz) 3 0.35 (t, 3H, J = 5.5 Hz), 1.25-1.34 (m, 6H), 1.45-1.43 (m, 2H), 1.55 (m, 4H), 2.35-2.40 (m, 6H), 5.44 (t, 1H, J = 1.5 Hz); 13C NMR (CDCI3, 125 MHz) 3 13.93, 20.90, 21.09, 22.24, 22.42, 22.50, 27.73, 23.34, 23.33, 31.43. 131.91, 141.39, 142.32, 149.03, 137.51, 137.71; IR (neat) 2932, 2351, 1551, 1616, 1294 cm"; mass spectrum m/z (% rel intensity) 246 M+ (50), 203 (38), 178 (24), 177 (100), 175 (33), 175 (21), 151 (25), 149 (15). 143 (23), 147 (15), 91 (15), 79 (15), 77 (15). Anal Calcd for C16H2202: C, 73.01; H, 9.00. Found: C, 77.84; H, 9.14. Yellow oil; Rr= 0.30 (20: 1: 1 hexanes: EtZO: CHzClz). / SK 0 2-ButyI-3-trimethylsilanyl-5,6,7,8-tetrahydro-[1,4] naphthoquinone 196 Quinone 196 (50.1 mg, 0.155 mmol, 47%) was prepared from carbene complex 178 (103 mg, 0.33 mmol) with 1-TMS-1-hexyne. 1H NMR (CDCI3, 500 MHz) 6 0.26 (s, 9H), 0.89 (t, 3H, J = 7.1 Hz), 1.32-1.35 (m, 4H), 1.52-1.54 (m, 4H), 2.34-2.35 (m, 4H), 2.47-2.49 (m, 2H); 13C NMR (CDCI3, 125 MHz) 6 1.62, 13.89, 21.11, 21.17, 22.45, 22.56, 23.10, 28.66, 33.50, 141.93, 143.48, 145.36, 156.75, 186.77, 192.03; IR (neat) 2938, 1645, 1273, 868, 847 182 cm'1; mass spectrum m/z (% rel intensity) 290 M+ (10), 276 (35), 275 (36), 247 (18), 234 (31), 233 (84), 73 (18). HRMS (CI) calcd for C17H27028i (Ms-H)“ m/z 291.1780, measd 291.1782. Yellow oil; Rf = 0.41 (20:1 :1 hexanes/Et20/CH2CI2). Preparation of methyl cyclohex-1-enecarboxylate 21316 (Commercially available) BrC) C) OMe Juinoline : OMe 120°C,1h,N2 212 213 A solution of 212 (20.0 g, 90.5 mmol) and freshly distilled quinoline (17.1 mL, 145 mmol) was heated at 120 °C with stirring under N2 for 1 hour. After 15 minutes of heating, a slight exothermic reaction was noted. The mixture was cooled, washed with brine, and dried over MgSOa. Removal of the solvent and distillation of the residue gave 213 (12.69 g, 90.5 mmol) as colorless oil in quantitative yield. 1H NMR (CDCI3, 300 MHz) 6 1.56-1.63 (m, 4H), 2.15-2.18 (m, 2H), 2.20-2.24 (m, 2H), 3.59 (s, 3H), 5.94-5.95 (m, 1H). b.p. (75-73 °C at 9 torr). Preparation of N-methoxy-N-methyIcyclohex-1-enecarboxamide 214133 O O NH M OM °HCI OMe ( e)( e) : AIMe3t N:OMe Benzene M9 213 214 To a solution of N-methoxymethanamine hydrochloride (0.90 g, 0.92 mmol) in 5 mL benzene at 0 °C was added AIMe3 (4.6 mL, 2.0 M in hexanes, 9.2 183 mmol) dropwise. After the addition was completed, the reaction was warmed to room temperature and stirred one hour. The solution was then transferred via cannula to a solution of methyl 1-carboxy-1-cyclohexene 213 (0.60 mL, 4.40 mmol) in 10 mL benzene at room temperature, and then heated to reflux for 2 hours. The reaction mixture was quenched carefully with ice Chips and extracted with CHZCIZ (3 * 10 mL). The combined organic layer was dried over MgSO4, filtered and concentrated in vacuo. The product was purified by chromatography on silica gel (2:1:1 hexanes/EtzO/CHzclz) to afford 87 % of 214 (0.648 g, 3.80 mmol). Some of the following data was taken from the thesis of Marcey Waters. 1H NMR (CDCI3, 300 MHz) 6 1.61-1.63 (m, 4H), 2.11-2.13 (m, 2H), 2.20-2.24 (m, 2H), 3.20 (s, 3H), 3.53 (s, 3H), 5.12 (br s, 1H); 13C NMR (CDCI3, 75 MHz) 3 21.35, 21.88, 24.70, 25.26, 33.42, 60.68, 130.68, 133.51, 171.57; IR (neat) 29345, 2859m, 1657s, 16425, 1477m, 1410m, 13763, 1357m, 1187m, 989m cm' 1; mass spectrum m/z (% rel intensity) 169 M+ (3), 110 (8), 109 (100), 81 (77), 79 (25), 55 (7). Anal Calcd for C9H15N022 C, 63.88; H, 8.94; N, 8.27. Found: C, 63.85; H, 9.04; N, 8.40. Colorless oil; Rf = 0.10 (4:1:1 hexanes/EtzO/CHzClz). Preparation of 1-cycIohexenyI-4-(trimethylsiIyl)but-3-yn-1-one 215 o 1)LiH2C : TMS o TMS N,OMe THF/E120, -73 °C, 3 h. // 214 215 To a solution of 1-trimethyI-1-propyne (3.98 mL, 24.67 mmol) in 44 mL THF at 0 °C was added t-BuLi (1.7 M, 14.5 mL, 24.67 mmol) dropwise. The 184 reaction was stirred at that temperature for 1 hour, and then transferred via cannula to a solution of amide 214 in 88 mL Et20 at —78 °C. The solution was stirred at —78 °C for 3 hours and quenched with H20. The solution was transferred to a separatory funnel and washed with 30 mL portions of H20 until the aqueous layer was no longer basic. The aqueous layer was neutralized with 3 N HCI and extracted once with 820. The combined organic layer was dried over NaZSO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (10:1:1 hexanes/Et20/CH20l2) to afford 60% of 215 (3.26 g, 14.8 mmol). Some of the following data was taken from the thesis of Marcey Waters. 1H NMR (CDCI3, 300 MHz) 6 0.16 (s, 9H), 1.60-1.70 (m, 4H), 2.05-2.23 (m, 4H), 3.54 (s, 2H), 5.94 (br s, 1H); 13C NMR (CDCI3, 75 MHz) 3 0.19, 21.29, 21.67, 23.03, 26.00, 30.41, 88.88, 99.33, 137.71, 141.84, 193.62; IR (neat) 2937, 2178, 1675, 1638, 1250, 843, 760 cm"; mass spectrum m/z (% rel intensity) 220 M+ (51), 205 (75), 109 (100), 96 (25), 81 (100), 74 (65), 53 (95). Colorless oil; Rf = 0.41 (10:1:1 hexanes/Et20/CH20l2). Preparation of ((3Z)-4-cyclohexenyl-4-methoxybut-3-en-1-ynyI) trimethylsilane 216Z 1) KHMDS, THF, -78 °C, 30 min 0 TMS . OMe TMS 4 2) DMPU, 15 min ; \ 3) MeOTf, -78 °C, 1 h then 0 0C, 1.5 h 215 2162 \\ To a solution of KHMDS (22.35 mmol, 44.7 mL, 0.5 M solution in toluene) in THF (25 mL) at -78 °C was added ketone 215 (4.47 g, 20.32 mmol), which 185 was dissolved in 10 mL THF. After stirring for 30 minutes, 25 mL DMPU was added and the solution was stirred for an additional 15 minutes. Upon addition of the MeOTf (2.41 mL, 21.33 mmol), the solution turned yellow-orange. The reaction was stirred at —78 °C for 1 hour and 0 °C for 1.5 hours, and then quenched with 50 mL saturated NaHCOa. The solution was diluted with 820, washed with H20 (3 * 30 mL) and brine (30 mL). The combined organic layer was dried over NaZSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography using Et3N-treated silica gel with hexanes as eluent to give 72 % of Z-silyl enyne 2162 (3.43 g, 14.63 mmol). Some of the following data was taken from the thesis of Marcey Waters. 1H NMR (CDCI3, 500 MHz) 6 0.16 (s, 9H), 1.52-1.56 (m, 2H), 1.60-1.65 (m, 2H), 2.00-2.03 (m, 2H), 2.10-2.14 (m, 2H), 3.97 (s, 3H), 4.95 (s, 1H), 6.29 (t, 1H, J = 4.2 Hz); 13C NMR (CDCI3, 125 MHz) 6 -0.08, 21.83, 22.53, 24.89, 25.65, 59.70, 85.71, 99.35, 102.48, 128.26, 131.72, 166.22; IR (neat) 2956, 2937, 2929, 2126, 1630, 1592, 1248, 1224, 1070, 1043, 865, 759 cm"; mass spectrum m/z (% rel intensity) 234 M+ (25), 219 (25), 89 (50), 73 (35), 59 (40). Anal calcd for C14H2208i: C. 71.73; H, 9.46. Found: C, 71.82; H, 9.69. Yellow oil; Rf = 0.60 (20:1:1 hexanes/EtZO/CHzclz). 72% yield. 186 Preparation of E-silyl methoxyl enyne 216E OMe TMS size, we W hv,24h 027 II 2152 2155 TMS Preparative photochemistry was carried out in a Rayonet reactor equipped a Pyrex, water-cooled immersion well with a 450 W Hanovia medium pressure mercury arc light source. Submerging the immersion well in deionized water in a mirrored dewar maintained the temperature between 17~23°C, which fluctuated with the temperature of the cooling water. The immersion well was fitted with a Pyrex (>290 nm) sleeve. The Z-silyl enyne 216Z (2.51 g, 10.7 mmol) was photolyzed in deoxygenated ether (100 mL) for 24 hours using a quartz filter, resulting in a 121.3 ratio of Z- to E- isomers. These isomers could be separated by running column chromatography (4 cm * 40 cm) 3 times using Et3N-treated silica gel with hexanes as eluent to give combined E-isomer in 51% yield (1.28 g, 5.47 mmol) and Z-isomer in 43% yield (1.07 g, 4.57 mmol). Some of the following data was taken from the thesis of Marcey Waters. 1H NMR (CDCI3, 500 MHz) 6 0.14 (s, 9H), 1.57-1.60 (m, 2H), 1.61-1.66 (m, 2H), 2.12-2.14 (m, 2H), 2.28-2.29 (m, 2H), 3.55 (s, 3H), 4.68 (s, 1H), 6.39-6.40 (m, 1H); 13C NMR (CDCI3, 125 MHz) 6 0.05, 21.86, 22.50, 25.29, 25.99, 55.30, 78.90, 96.07, 103.75, 131.09, 132.61, 168.88; IR (neat) 2957, 2936, 2131, 1591, 1248, 1221s, 1124, 941, 758 cm"; mass spectrum m/z (% rel intensity) 234 M+ (14), 220 (26), 219 (100), 204 (12), 203 (15), 189 (11), 161 (13), 160 (12), 159 (16), 145 (13), 129 (10), 75 (14), 73 (13), 59 (31). Anal calcd for C14H22osr C. 71.73; H, 9.45. 187 Found: C, 71.68; H, 9.46. Yellow oil; Rf = 0.65 (20:1:1 hexanes/Et20/CHzCI2), 51% yield. Preparation of 1-(Z-1-methoxybut-1-en-3-ynyl)cyclohex-1-ene 2082 OMe TMS OMe H \ ¢ NaOMe I M90; \ // rt 2162 2082 The silyl enyne 216Z (1.07 g, 4.57 mmol) was dissolved in 8 mL methanol. Approximately 20 mg of freshly prepared NaOMe was added and the solution was stirred at room temperature until all of the starting material was comsumed (monitored by TLC). The reaction was diluted with 20 mL B20 and washed three times with 15 mL H2O. The aqueous layer was back extracted with 20 mL 320. The combined organic layer was dried with Na2S04, filtered and concentrated in vacuo. The crude product was purified by column Chromatography using Et3N- treated silica gel with hexanes as eluent to give 91% of 2082 (0.67 g, 4.14 mmol). Some of the following data was taken from the thesis of Marcey Waters. 1H NMR (CDCI3, 500 MHz) 6 1.53-1.58 (m, 2H), 1.62-1.67 (m, 2H), 2.03-2.06 (m, 2H), 2.11-2.16 (m, 2H), 3.12 (d, 1H, J = 2.7 Hz), 3.93 (s, 3H), 4.92 (t, 1H, J = 1.4 Hz), 6.27-6.30 (m, 1H); 13C NMR (CDCI3, 125 MHz) 6 21.85, 22.51, 24.99, 25.63, 59.83, 80.71, 81.91, 85.35, 128.53, 131.53, 166.96; IR (neat) 3297, 2931, 2091w, 1631, cm"; mass spectrum m/z (% rel intensity) 162 M“ (75), 163 (10), 161 (30), 147 (37), 134 (55), 119 (30), 105 (38), 104 (38), 91 (100), 79 (71), 77 (58), 65 (56), 63 (29), 55 (25), 53 (69), 52 (30), 51 (70), 50 (30), 45 (23). Anal 188 calcd for C11H14O: C. 81.44; H, 8.70. Found: C, 81.26; H, 8.66. Yellow oil; Rr = 0.62 (10:1 :1 hexanes/Et2O/CH2CI2). Preparation of 1-(E-1-methoxybut-1-en-3-ynyl)cyclohex-1-ene 208E OMe OMe \ NaOMe / MeOH \ l l n l | 216E TMS 208E H The silyl enyne 216E (2.50 g, 10.7 mmol) was dissolved in 8 mL methanol. Approximately 30 mg of freshly prepared NaOMe was added and the solution was stirred at room temperature until all of the starting material was comsumed (monitored by TLC). The reaction was diluted with 20 mL 320 and washed three times with 15 mL H2O. The aqueous layer was back extracted with 20 mL 820. The combined organic layer was dried with Na2804, filtered and concentrated in vacuo. The crude product was purified by column chromatography using EtaN- treated silica gel with hexanes as eluent to give 95% of 208E (1.64 g, 10.1mmol). Some of the following data was taken from the thesis of Marcey Waters. 1H NMR (CDCI3, 500 MHz) 6 1.57-1.60 (m, 2H), 1.63-1.65 (m, 2H), 2.11-2.13 (m, 2H), 2.26-2.27 (m, 2H), 2.90 (d, 1H, J = 1.7 Hz), 3.56 (s, 3H), 4.61 (d, 1H, J= 1.7 Hz), 6.35 (t, 1H, J = 1.5 Hz); 130 NMR (CDCI3, 125 MHz) 6 21.81, 22.46, 25.25, 25.99, 55.28, 77.66, 79.00, 81.65, 130.95, 132.59, 169.08; IR (neat) 3299, 2934, 2099, 1601, 1221, 1186, 1107 cm"; mass spectrum m/z (% rel intensity) 162 M+ (65), 163 (18), 161 (49), 147 (42), 135 (15), 134 (99), 131 (54), 129 (18), 121 (22), 119 (68), 115 (26), 105 (23), 104 (40), 103 (25), 91 (100), 79 (24), 78 (37), 189 77 (41), 65 (26) 63 (15), 51 (23), 50 (23). Anal calcd for C11H1401 C. 81.44; H, 8.70. Found: C, 81.35; H, 8.83. Yellow oil; Rf = 0.50 (20:1:1 hexanes/Et2O/CH2CI2). Preparation of ((32)-4-cyclohexenyI-4-(methoxymethoxy)but-3-en-1-ynyl) trimethylsilane 2292 1) KHMDS, THF, -78 °C, 30 min 0 TMS . OMOM TMS ¢ 2) DMPU, 15 min ‘ \ // 3) MOMCI, -78 °C, 1 h then 0 °C, 1.5 h 21 5 2292 To a solution of KHMDS (33 mmol, 66 mL, 0.5 M solution in toluene) in 40 mL THF at -78 °C was added ketone 215 (6.61 g, 30 mmol), which was dissolved in 15 mL THF. After stirring for 30 minutes, 40 mL DMPU was added and the solution was stirred for an additional 15 minutes. Upon addition of the MOMCI (2.51 mL, 33 mmol), the solution turned yellow-orange. The reaction was stirred at -78 °C for 1 hour and 0 °C for 1.5 hours, and then quenched with saturated NaHC03 (30 mL). The solution was diluted with 320, washed three times with H20, and once with brine. The combined organic layer was dried over N32304, filtered and concentrated in vacuo. The crude product was purified by column chromatography using Et3N-treated silica gel with hexanes as eluent to furnish 47% of 2292 (3.73 g, 14.1 mmol) as yellow oil. Some of the following data was taken from the thesis of Marcey Waters. 1H NMR (CDCI3, 500 MHz) 6 0.16 (s, 9H), 1.53-1.56 (m, 2H), 1.62-1.65 (m, 2H), 2.02-2.04 (m, 2H), 2.14-2.15 (m, 2H), 3.53 (s, 3H), 5.07 (s, 1H), 5.18 (s, 2H), 6.33 (br s, 1H); 13'C NMR (CDCI3, 190 125 MHz) 6 -0.10, 21.78, 22.42, 24.93, 25.67, 57.46, 89.35, 97.57, 99.46, 102.07, 128.92, 131.66, 164.30; IR (neat) 2934, 2134, 1590, 1248, 1159, 1011, 841 cm"; mass spectrum m/z (% rel intensity) 264 M+ (21), 249 (17), 234 (55), 233 (53), 110 (73), 109 (63), 89 (19), 82 (59), 80 (31), 75 (19), 74 (80), 72 (33), 60 (23), 54 (19), 43 (100). HRMS calcd for C15H2502Si (M+H)+ m/z 265.1624, meas 265.1624. Yellow oil; Rr = 0.42 (10:1 :1 hexanes/Et2O/CH2CI2). Preparation of E-silyl MOM enyne 229E OMOM/ TMS 5120' OMOM W IN, 24 h 027 2292 2295 TMS Preparative photochemistry was carried out in a Rayonet reactor equipped a Pyrex, water-cooled immersion well with a 450 W Hanovia medium pressure mercury arc light source. Submerging the immersion well in deionized water in a mirrored dewar maintained the temperature between 17~23°C, which fluctuated with the temperature of the cooling water. The immersion well was fitted with a Pyrex (>290 nm) sleeve. The Z-silyl enyne 2292 (3.03 g, 15.8 mmol) was photolyzed in deoxygenated ether (100 mL) for 24 hours using a quartz filter, resulting in a 3:1 ratio of Z- to E- isomers. These isomers could not be separated by column Chromatography. After passing though a short flash column with Et3N- treated silica gel, the mixture went directly to the desilylation step. The following data for 229E was extracted from the spectra on a mixture of E— and Z- isomers. Partial spectrum for 229E 1H NMR (CDCI3, 300 MHz) 6 0.14 (s, 9H), 19] 1.57-1.65 (m, 4H), 2.11-2.14 (m, 2H), 2.28-2.32 (m, 2H), 3.55 (s, 3H), 4.68 (s, 2H), 6.40-6.42 (m, 1H); mass spectrum m/z (% rel intensity) 264 M+ (25), 249 (17), 235 (14), 234 (31), 233 (100), 221 (13), 219 (12), 205 (23), 204 (14), 182 (31), 181 (10), 131 (14), 109 (60), 106 (52), 81 (35), 79 (22), 77 (44), 75 (16), 73 (29), 51 (13), 50 (14); Yellow oil; R; = 0.42 (10:1:1 hexanes/EtzolCHzClz). Preparation of 1 -((Z/E)-1-(methoxymethoxy)but-1-en-3-ynyl)cyclohex-1-ene 228 OMOM TMS OMOM H W NaOMe / MeOH : W IT 229 228 The silyl enyne 229 (3.0 g, 113 mmol, 3:1 Z/E) was dissolved in 30 mL methanol. Approximately 40 mg of NaOMe was added and the solution was stirred at room temperature until all of the starting material had disappeared (monitored by TLC). The reaction was diluted with 30 mL 320 and washed three times with 20 mL H2O. The aqueous layer was back extracted with 30 mL 320. The combined organic layer was dried with Na2804, filtered, and concentrated in vacuo. The isomers were purified by column chromatography (4 cm * 40 cm) three times using Eth-treated silica gel with hexanes as eluent to give 1.90 g of 228 (3:1 Z/E, 100 mmol, 89%). Z-MOM enyne 2282 Some of the following data was taken from the thesis of Marcey Waters. 1H NMR (CDCI3, 500 MHz) 6 1.53-1.55 (m, 2H), 1.62- 1.64 (m, 2H), 2.03-2.06 (m, 2H), 2.13-2.14 (m, 2H), 3.10 (d, 1H, J = 2.6 HZ), 3.51 192 (s, 3H), 5.01 (s, 1H), 5.15 (s, 2H), 6.31 (s, 1H); 13C NMR (CDCI3, 125 MHz) 6 21.72, 22.34, 24.95, 25.57, 57.39, 80.42, 81.89, 88.29, 97.48, 129.03, 131.50, 164.77; IR (neat) 3292m, 2929s, 2829m, 2090w, 1590m, 11585, 1048m, 9975, 973m cm"; mass spectrum m/z (% rel intensity) 192 M” (12), 109 (78), 81 (27), 45 (100). HRMS (Cl) calcd for C12H1702 (M+H)+ m/z 193.1229, meas 193.1236. Colorless oil; Rr = 0.35 (10:1:1 hexanes/EtzO/CH2CI2). E-MOM enyne 228E 1H NMR (CDCI3, 500 MHz) 6 1.58-1.62 (m, 2H), 1.63-1.66 (m, 2H), 2.14-2.16 (m, 2H), 2.28-2.31 (m, 2H), 2.93 (d, 1H, J = 2.7 Hz), 3.41 (s, 3H), 4.94 (s, 2H), 4.98 (d, 1H, J = 2.7 Hz), 6.37 (t, 1H, J = 1.8 Hz); 13C NMR (CDCI3, 125 MHz) 6 21.80, 22.45, 25.33, 26.11, 56.25, 79.69, 81.33, 82.51, 94.35, 131.44, 132.19, 166.45; IR (neat) 3297, 2934, 2097, 1597, 1156, 1061, 1049, 976 cm“; mass spectrum m/z (% rel intensity) 192 M+ (4), 109 (88), 81 (29), 45 (100). HRMS calcd for C12H1702 (M+H)" m/z 193.1229, meas 193.1236. Colorless oil; Rf = 0.45 (10:1:1 hexanes/Et2OlCH2CI2). Preparation of MOM-carbene complex 227 O'NMe4" OMOM (OC)5Cr MOMC' : (OC)5Cr CH2CI2, I1, 30 min 211 227 Carbene complex 227 (1.07 g, 3.09 mmol) was prepared from the corresponding ammonium salt 211 (1.50 g, 4.0 mmol) and MOMCI (0.334 mL, 4.4 mmol) according to Procedure I in 77% yield. 1H NMR (CDCI3, 500 MHz) 6159-168 (m, 4H), 2.17-2.30 (m, 4H), 3.64 (s, 3H), 5.76 (s, 2H), 6.26 (br, 1H); 193 13C NMR (CDCI3, 125 MHz) 3 21.37, 21.73, 25.52, 25.59, 53.24, 102.31, 134.40, 154.05, 215.54, 223.93, 349.53; IR (neat) 2337, 2352, 2050, 1905, 1517, 1451, 1192, 1161, 1065, 656 cm”; mass spectrum m/z (% rel intensity) 346 M+ (0.1), 313 (1), 290(2), 253 (43), 232 (20), 231 (13), 109 (100), 91 (22), 31 (77), 79 (79). Red oil, Rr= 0.19(hexanes). General procedure for the thermolysis of the following carbene complexes and enynes (Procedure V) Solvent, 0. 05 M (00) )ORsCr=: 0):; 45 °C, 12 h 173 R‘1=M 205192: 209191 =CD3. R2=CH3 209R1=CH3.R2=C03 173* R =C03 223 R2: MOM 230 R1 = Me, n?- = MOM 231 R1 = MOM, n2 = Me 227 n‘ = MOM The carbene complex, alkyne (2 equiv.) and solvent (0.05 M) were combined in a Schlenk flask equipped with a threaded high-vacuum Teflon stopcock. The mixture was deoxygenated with three freeze-pump-thaw cycles, and then warmed to room temperature and filled with Ar. The stopcock was then sealed and the reaction was placed in a 45 °C oil bath for 12 hours. The reaction was cooled to room temperature, and completion of the reaction was verified by TLC against starting carbene complex. The solution was transferred to a round bottom flask and concentrated in vacuo. The remaining brown film was dissolved in 10 mL 320 and stirred in air at room temperature for 2 hours to demetallate the products. The solution was then filtered through Celite, concentrated, and a 194 crude 1H NMR spectrum was taken to determine the product ratio. The product was then purified by column chromatography with Eth-treated silica gel using 20:1 :1 hexanes/CH2CI2/Et20 as eluent. The ratio of 209/209* was determined by the integral of crude 1H NMR in CsDe for the following peaks: 6 3.22 (vinyl OMe) and 6 3.49 (aryl OMe). This ratio was further conformed by 1H NMR in CDCI3 of isolated phenol mixtures: 6 3.53 (vinyl OMe) and 6 3.74 (aryl OMe). . The ratio of 230 to 231 was determined by the integral of the major isomer (Z-isomer) in crude 1H NMR in CsDe (for E-enyne) or CDCI3 (for Z-enyne) for the following peaks: 6 4.63, 4.99 ( in C6D6) or 4.76, 5.10 (in CDCla). Since the crude 1H NMR for reactions with E-enyne was quite complex and could contain some E-isomers of 230 and 231, the product ratio in entry 5 in Table 3.2 was determined by the following ways: first, the crude products were taken in CDCI3 and completely isomerized to Z-isomers; second, the products were pass through a short silica gel column; third, the products were combined after isolating on silica gel Chromatography. In all there cases, the ratio of the products was 1:3, which was consistent with the ratio taken in the aforementioned method. Annulation of carbene complex 178* with alkyne 2082 in benzene (R1 = C03, R2 = CH3) The reaction of carbene complex 178* (112 mg, 0.35 mmol) with alkyne 2082 (113 mg, 0.70 mmol) in 7 mL benzene was performed according to the general procedure to give 75 mg of 209/209* (0.235 mmol, 67%) in 1:1 ratio. 195 Annulation of carbene complex 178* with alkyne 2082 in hexanes (R1 = CD3, R2 = CH3) The reaction of carbene complex 178* (112 mg, 0.35 mmol) with alkyne 2082 (113 mg, 0.70 mmol) in 7 mL hexanes was performed according to the general procedure to give 90 mg of 209/209* (0.283 mmol, 81%) in 1:2 ratio. Annulation of carbene complex 178* with alkyne 208E in benzene (R1 = CD3, R2 = CH3) The reaction of carbene complex 178* (112 mg, 0.35 mmol) with alkyne 208E (113 mg, 0.70 mmol) in 7 mL benzene was performed according to the general procedure to give 40 mg of 209/209* (0.126 mmol, 36%) in 1:1 ratio. Annulation of carbene complex 178* with alkyne 2085 in hexanes (R1 = CD3, R2 = CH3) The reaction of carbene complex 178* (112 mg, 0.35 mmol) with alkyne 208E (113 mg, 0.70 mmol) in 7 mL hexane was performed according to the general procedure to give 55 mg of 209/209* (0.174 mmol, 50%) in 1:1 ratio. Annulation of carbene complex 227 with alkyne 2082 in benzene (R1 = MOM, R2 = CH3) The reaction of carbene complex 227 (112 mg, 0.35 mmol) with alkyne 2082 (113 mg, 0.70 mmol) in 7 mL benzene was performed according to the 196 general procedure to give 38 mg of 231 (0.11 mmol, 32%). The ratio of 231/230 was 4:1 based on the crude 1H NMR. Annulation of carbene complex 227 with alkyne 2082 in hexanes (R1 = MOM, R2 = CH3) The reaction of carbene complex 227 (121 mg, 0.35 mmol) with alkyne 2082 (113 mg, 0.70 mmol) in 7 mL hexanes was performed according to the general procedure to give 89 mg of 231 (0.26 mmol, 74%). The ratio of 231/230 was 5:1 based on the crude 1H NMR. Annulation of carbene complex 178 with alkyne 2282 in benzene (R1 = CH3, R2 = MOM) The reaction of carbene complex 178 (94.8 mg, 0.30 mmol) with alkyne 2282 (115 mg, 0.60 mmol) in 6 mL benzene was performed according to the general procedure to give 26 mg of 231 (0.076 mmol, 25%) and 32 mg of 230 (0.093 mmol, 31%). The ratio of2311230 was 1:1 based on the crude 1H NMR. Annulation of carbene complex 178 with alkyne 2282 in hexanes (R1 = CH3, R2 = MOM) The reaction of carbene complex 178 (94.8 mg, 0.30 mmol) with alkyne 2282 (115 mg, 0.60 mmol) in 6 mL hexanes was performed according to the general procedure to give 15 mg of 231 (0.044 mmol, 15%) and 33 mg of 230 (0.096 mmol, 32%). The ratio of2311230 was 1:3 based on the crude 1H NMR. 197 Annulation of carbene complex 227 with alkyne 208E in benzene (R1 = MOM, R2 = CH3) The reaction of carbene complex 227 (173 mg, 0.50 mmol) with alkyne 208E (162 mg, 1.0 mmol) in 10 mL benzene was performed according to the general procedure to give 60.2 mg of 231 and 230 (0.175 mmol, 35%). The ratio of2311230 was 3:1 based on the crude 1H NMR, and the 1H NMR of the combined isolated products. Annulation of carbene complex 227 with alkyne 208E in hexanes (R1 = MOM, R2 = CH3) The reaction of carbene complex 227 (173 mg, 0.50 mmol) with alkyne 208E (162 mg, 1.0 mmol) in 10 mL hexanes was performed according to the general procedure to give 58.6 mg of 231 (0.170 mmol, 34%). The ratio of 231/230 was 3:1 based on the crude 1H NMR, and the 1H NMR of the combined isolated products. Annulation of carbene complex 178 with alkyne 228E in benzene (R1 = CH3, R2 = MOM) The reaction of carbene complex 178 (47.4 mg, 0.15 mmol) with alkyne 228E (57.6 mg, 0.30 mmol) in 3 mL benzene was performed according to the general procedure to give 19 mg of 231 (0.055 mmol, 37%). The ratio of 231I230 was 5:1 based on the crude 1H NMR. 198 Annulation of carbene complex 178 with alkyne 228E in hexanes (R1 = CH3, R2 = MOM) The reaction of carbene complex 178 (47.4 mg, 0.15 mmol) with alkyne 228E (57.6 mg, 0.30 mmol) in 6 mL hexanes was performed according to the general procedure to give 20 mg of 231 (0.058 mmol, 39%). The ratio of 231/230 was 4:1 based on the crude 1H NMR. Some of the following data was taken from the thesis of Marcey Waters. OH WW) 0914003) Phenol 209 and 209* (R1, R2 = Me, C03) 1H NMR (CD013, 500 MHz) 3 1.50-1.54 (m, 2H), 1.70-1.75 (m, 6H), 2.19-2.24 (m, 4H), 2.52 (t, 2H, J = 5.3 Hz), 2.72 (t, 2H, J = 5.3 Hz), 3.53 (s, 3H), 3.74 (s, 3H), 5.93 (s, 1H), 5.21 (t, 1H, J = 3.9 Hz), 5.33 (s, 1H), 3.24 (s, 1H); 13C NMR (CDCI3, 125 MHz) 3 22.04, 22.25, 22.52, 22.54, 23.54, 24.05, 25.39, 25.53, 55.55, 50.35, 103.54, 110.59, 117.35, 125.90, 127.42, 127.47, 130.57, 145.04, 150.35, 153.55; 1H NMR(C505, 500 MHz,) 3 1.40-1.43 (m, 2H), 1.47-1.51 (m, 2H), 1.53-1.53 (m, 4H), 1.97-2.02 (m, 4H), 2.33 (t, 2H, .1 = 5.0 Hz), 3.07 (t, 2H, J = 5.1 Hz), 3.22 (s, 3H), 3.49(s, 3H), 5.03 (s, 3H), 5.13 (t, 1H, .1 = 4.0 Hz), 5.43 (s, 1H), 3.51 (s, 1H); IR (neat) 3245m, 2933s, 2357s, 2335s, 2247w, 1943w, 1727w, 1713w, 1632m, 1612m, 1477s, 1454s, 1435s, 1320s, 1310s, 1245s, 1114s, 1093s, 1065s, 1033s cm"; mass spectrum m/z (% rel intensity) 317 M+ (27), 237 (21), 235 (100), 233 (24), 282 (91), 274 (33), 257 (38), 254 (37), 251 (20), 141 (18), 128 (19), 77 (35). 199 HRMS (FAB) calcd for (C20H23D303+H)+ m/z 317.2070, meas 317.2072.Ye|low Oil; R: = 0.32 (20:1:1 hexanes/CH2Cl2/Et20). HO 4'.' OMOM Phenol 231 (R1 = MOM, R2 = Me) 1H NMR (CDCI3, 500 MHz) 6 1.59-1.63 (m, 2H), 1.72-1.75 (m, 6H), 2.19-2.20 (m, 4H), 2.65 (t, 2H, J = 6.0 Hz), 2.71-2.72 (t, 2H, J = 5.8 Hz), 3.47 (s, 3H), 3.52 (s, 3H), 5.10 (s, 2H), 5.90 (s, 1H), 6.20 (s, 1H), 6.63 (5, 1H), 8.40 (5, 1H); 13’C NMR (CDCI3, 125 MHz) 6 22.03, 22.26, 22.51, 22.63, 23.78, 24.05, 25.39, 25.63, 55.89, 60.41, 95.18, 110.65, 113.12, 117.77, 125.93, 127.27, 128.37, 130.67, 147.02, 148.02, 153.49; IR (neat) 3230m (br), 29305, 2857m, 2096w, 1475m, 1314m, 1151m, 1090m, 1048s, 1036s, 982m cm"; mass spectrum m/z (% rel intensity) 344 M+ (29), 299 (36), 267(22), 128 (27), 115 (22), 109 (21), 91 (21), 81 (23), 79 (25), 77 (17), 45 (100). HRMS calcd for C21H2904 (M-I-H)+ m/z 345.2066, meas 345.2058. Yellow oil; Rf = 0.45 (10:1:1 hexanes/CH2Cl2/Et20). HO Il' ~\ ‘QI' OMOM OCHa Phenol 230 (R1 = Me, R2 = MOM) 1H NMR (CDCI3, 500 MHz) 3 1.50-1.53 (m, 2H), 1.59-1.75 (m, 6H), 2.13-2.21 (m, 2H), 2.22-2.25 (m, 2H), 2.50-2.52 (m, 2H), 2.53-2.59 (rn, 2H), 3.32 (s, 3H), 3.74 (s, 3H), 4.75 (s, 2H), 5.02 (s, 1H), 5.25 (t, 1H, J = 4.1 Hz), 5.41 (s, 1H), 7.55 (s, 1H); 13C NMR (CDCI3, 125 MHZ) 6 21.98, 22.23, 22.48, 22.59, 23.49, 24.02, 25.59, 25.62, 200 55.47, 57.95, 98.23, 108.38, 111.23, 117.81, 126.64, 127.25, 127.30, 131.37, 145.33, 150.52, 151.05; IR (neat) 3300m (br), 29285, 2066w, 1473m, 1448m, 1436m, 1318m, 1264w, 1246w, 1162m, 1123m, 1111m, 1093m, 1083m, 1064m, 1006m, 960w cm"; Mass spectrum m/z (% rel intensity) 344 M“ (17), 219 (19), 217 (72), 204 (27), 203 (36), 175 (19), 128 (26), 115 (23), 109 (69), 105 (17), 91 (26), 81 (92), 79 (38), 67 (15), 53 (21), 45 (100). HRMS calcd for Cthng4 (M+H)" m/z 345.2066, meas 345.2080. Yellow oil; Rr = 0.37 (10:1:1 hexanes/CH2CI2/Et20). General procedure for the preparation of carbene complexes 259 illustrated for complex 259a. (Procedure VI) 069 O NMe4 (OC)50r R2 /\ O)\ 2 (0C) Cr 0 \ R1 R2 TMSCI 1 R 251 0155 5 1 —- - Z 2 R :—< v R ——_-—:—\ CI O—/ pentyn-1-ol (392 mg, 4.00 mmol) according to the general procedure. 1H NMR The chloromethyl ether 257C was prepared from 4-methyl-2- (CDCI3, 300 MHz) 3 1.17 (d, 6H, J = 7.1 Hz), 2.55-2.59 (m, 1H), 4.35 (d, 2H, J = 2.2 Hz), 5.57 (s, 2H). 205 0A0 \\ (OC)5CT: ; OTBS The carbene complex 258c (1.16 g, 2.04 mmol) was prepared from the salt 251 (1.61 g, 3.00 mmol) and chloromethyl ether 257C in 68% yield as red oil. 1H NMR (CDCI3) 6 0.18 (s, 6H), 0.96 (s, 9H), 1.14 (d, 6H, J = 6.9 Hz), 2.10 (s, 6H), 2.55 (m, 1H), 4.55 (d, 2H, J = 2.2 Hz), 5.25 (br s, 2H), 6.48 (5, 2H); 13C NMR (CD013)6 —4.47, 18.14, 19.51, 19.56, 20.39, 22.39, 22.73, 25.57, 65.56, 93.45, 97.36, 119.43, 119.63, 127.87, 128.30, 144.88, 155.20, 216.32, 224.63, 364.69; IR (neat) 2936m, 2250w, 20865, 1935v5, 1601m, 1474w, 1315m, 1156s, 9105, 8415, 6565 cm“; mass spectrum m/z (% rel intensity) 538 (M+ — CO) (0.03), 426 (M+ — 5C0, 32), 397 (31), 396 (100), 358 (19), 357 (79), 351 (21), 329 (25), 303 (36), 301 (39), 263 (57), 229 (18), 219 (18), 215 (17), 191 (15), 179 (40), 163 (22), 126 (21), 125 (20), 108 (19), 103 (18), 102 (21), 91 (19), 82 (34), 81 (38), 79 (52), 75 (40), 74 (30), 73 (91), 72 (77), 57 (19), 52 (68). Red Oil; Rf = 0.40 (4:1 hexanes/Et20). 0A0 \\ (OC)5CT: ; OH The carbene complex 258c (467 mg, 0.825 mmol) was desilylated according to the above procedure to give a 55% yield of phenol carbene complex 259C (206 mg, 0.456 mmol) as red oil. 1H NMR (CDCI3, 300 MHz) 6 1.13 (d, 6H, J = 6.9 Hz), 2.11 (s, 6H), 2.56 (sept, 1H, J = 6.9 Hz), 3.76 (br s, 1H), 4.55 (d, 2H, J = 1.9 Hz), 5.25 (s, 2H), 5.43 (s, 2H); 13C NMR (CDCI3, 75 206 MHz) 6 19.52, 20.48, 22.62, 57.64, 72.49, 94.85, 96.95, 114.93, 128.69, 144.30, 155.18, 216.24, 224.56, 365.33; IR (neat) 3402brm, 2976m 2936w, 2257vw, 20685, 1927vs, 1608m, 1590m, 1454m, 1308m, 1237m, 11505, 10705, 8985, 7095 cm"; mass spectrum m/z (% rel intensity) 452 M+ (0.03), 312 (M - 5C0) 1 (2), 187 (30), 180 (15), 149 (100), 121 (30), 91 (15), 90 (18), 80 (27), 79 (19), 77 (31), 53 (16), 52 (42). Red oil; Rr = 0.15 (1:1 hexanes/CH2CI2). Series d (R1 = n-Pr, R7- = Et) H Cl O_/ (315 mg, 2.50 mmol) according to the general procedure. 1H NMR (CDCI3, 300 The chloromethyl ether 257d was prepared from 4-Octyn-3-ol MHZ) 6 0.97 (t, 3H, J = 7.4 Hz), 0.98 (t, 3H, J = 7.1 Hz), 1.52 (m, 2H), 1.72 (m, 2H), 2.19 (td, 2H, J = 7.2 HZ, 1.9 Hz), 4.46 (t, 1H, J = 6.3 Hz), 5.56 (d, 1H, J = 5.4 HZ), 5.72 (d, 1H, J = 5.4 Hz). OTBS The carbene complex 258d (1.16 g, 1.95 mmol) was prepared from the salt 251 (1.05 g, 1.95 mmol) and chloromethyl ether 257d in 100% yield as red oil. 1H NMR (CDCI3, 300 MHz) 6 0.18 (s, 6H), 0.94 (t, 3H, J = 7.4 Hz), 0.96 (s, 9H), 1.03 (t, 3H, J = 7.5 Hz), 1.49 (q, 2H, J = 7.5 Hz), 1.80 (m, 2H), 2.10 (s, 6H), 2.16 (td, 2H, J = 6.8, 1.9 Hz), 4.67 (t, 1H, J = 6.4 Hz), 5.20 (br 207 s, 1H), 5.43 (br s, 1H), 5.47 (s, 2H); 13C NMR (CDCI3, 75 MHz) 3 -4.43, 9.43, 13.35, 13.14, 19.44, 19.54, 20.53, 21.92, 25.53, 29.03, 71.05, 33.59, 97.57, 119.45, 119.52, 127.90, 123.24, 145.00, 155.21, 215.33, 224.53, 354.34; IR (neat) 2963m, 2936m, 2886w, 2237vw, 2084s, 1940vs, 1601m, 1471m, 1315m, 1253m, 1155s, 1064m, 912m, 341s, 555s cm“; mass spectrum m/z (% rel intensity) 594 M+ (0.03), 454 (M — 5CO)" (19), 425 (13), 424 (47), 423 (37), 422 (91), 420 (25), 335 (15), 373 (15), 372 (24), 371 (22), 353 (20), 357 (33), 355 (39), 343 (15), 330 (20), 329 (53), 327 (25), 315 (23), 271 (17), 253 (53), 257 (33), 243 (17), 191 (23), 155 (15), 153 (13), 123 (19), 125 (13), 115 (19), 75 (35), 74 (24), 73 (100), 72 (54), 59 (13), 57 (35), 55 (23), 55 (24), 52 (47), 51 (25). Anal calcd for C29H33Cr03Si: C, 58.57; H, 6.44. Found: C, 57.88; H, 6.58. Red oil; R; = 0.13 (hexanes). Et QAO)\ (OC)5Cr: ; ”Pr OH The carbene complex 258d (951 mg, 1.60 mmol) was desilylated according to the above procedure to give a 40% yield of phenol carbene complex 259d (309 mg, 0.643 mmol) as red oil. 1H NMR (CDCla, 300 MHz) 6 0.93 (t, 3H, J = 7.4 Hz), 1.03 (t, 3H, J = 7.4 Hz), 1.49 (q, 2H, J = 7.1 Hz), 1.80 (m, 2H), 2.12 (5, 6H), 2.17 (t, 2H, J = 7.1 Hz), 4.67 (br s, 1H), 5.28 (br s, 1H), 5.44 (br, 1H), 5.43 (s, 2H); 13C NMR (CDCla, 75 MHz) 3 9.43, 13.37, 19.44, 19.55, 20.58, 21.90, 29.07, 71.15, 88.72, 97.54, 114.88, 115.02, 128.46, 128.82, 144.40, 155.12, 216.31, 224.56, 364.30; IR (neat) 3400brw, 2970w, 2933w, 208 2881w, 2237vw, 2064s, 1943vs, 1149m, 904m, 654m cm"; mass spectrum m/z (% rel intensity) 430 M“ (0.03), 313 (32), 290 (15), 239 (77), 275 (15), 251 (22), 25), 247 (43), 245 (47), 231 (25), 220 (17), 219 (17), 213 (19), 217 (100), 203 (40), 189 (39) 187 (20), 175 (42), 161 (27), 159 (15), 149 (65), 147 (22), 145 (16), 13 (20), 128 (18), 122 (31), 121 (31), 119 (19), 115 (24), 109 (18), 108 (49), 107 939), 105 (30), 97 (24), 95 (15), 94 (13), 93 (25), 91 (53), 31 (37), 30 (75), 79 (69), 78 (19), 77 (69), 69 (23), 67 (54), 65 (25), 57 (35), 55 (46), 53 (38), 52 (98). Red oil; R = 0.25 (4:1 hexanes/Et20). Series e (R1 = i-Propenyl, R2 = H) kfl CI O—/ ene-2-yn-1-ol (384 mg, 4.00 mmol) according to the general procedure. 1H The chloromethyl ether 2579 was prepared from 4-methylpent-4- NMR (CDCI3, 300 MHz) 3 1.37 (s, 3H), 4.43 (s, 2H), 5.25 (s, 1H), 5.32 (s, 1H), 5.57 (s, 2H). O/\O/\f (OC)5C?—:§ OT 88 The carbene complex 2583 (919 mg, 1.63 mmol) was prepared from the salt 251 (1.34 g, 2.50 mmol) and chloromethyl ether 257e in 65% yield and obtained as red oil. 1H NMR (CDCI3, 300 MHz) 6 0.18 (s, 6H), 0.96 (s, 9H), 1.86 (s, 3H), 2.10 (s, 6H), 4.69 (s, 2H), 5.27-5.30 (m, 4H), 6.48 (s, 2H); 13C NMR (CDCI3, 75 MHz) 3 -4.44, 13.15, 19.54, 23.07, 25.59, 57.53, 209 81.24, 89.47, 97.03, 119.58, 123.29, 125.72, 128.19, 144.86, 155.30, 216.25, 224.64, 365.59; IR (neat) 2957w, 2932w, 2220vw, 20645, 19405, 1601w, 1315w, 1155w, 841m, 653m cm'1; mass spectrum m/z (% rel intensity) 564 M" (0.08), 263 (17), 262 (25), 221 (23), 220 (40), 207 (46), 191 (16), 179 (94), 177 (12), 163 (16), 149 (14), 107 (62), 105 (27), 86 (64), 84 (98), 80 (100), 77 (16), 75 (100), 73 (47), 59 (55), 57 (16), 51 (100), 49 (94), 45 (27). Red oil; Rf = 0.24 (9:1 hexanes/CH2CI2). 0A0 % (OC)5Cr: ; OH The carbene complex 2575 (722 mg, 1.28 mmol) was desilylated according to the above procedure to give a 50% yield of phenol carbene complex 548e (287 mg, 0.637 mmol) as red oil. 1H NMR (CDCI3, 300 MHz) 6 1.86 (s, 3H), 2.12 (s, 6H), 4.69 (s, 2H), 5.05 (br s, 4H), 6.47 (5, 2H); 13C NMR (CDCI3, 75 MHz) 619.53, 23.09, 57.66, 81.19, 89.48, 96.84, 114.97, 123.37, 125.69, 128.75, 144.27, 155.18, 216.23, 224.56, 365.52; IR (neat) 3384brw, 2959w, 2928w, 2228vw, 2064sm 1940vs, 1609m, 1456m, 1307m, 1236m, 1150m, 1064m, 897m, 6535 cm”; mass spectrum m/z (% rel intensity) 394 (M" - 2C0) (0.2), 228 (12), 213 (15), 187 (10), 185 (16), 149 (100), 121 (16), 115 (12), 108 (11), 91 (29), 80 916), 79 (30), 78 (14), 77 (52), 53 (15), 52 (23), 51 915). Red oil; Rf = 0.21 (2:1 hexanes/Et20). 210 Sefiesf BnO ‘>—:—\ Cl O—/ ((benzyloxy)methyl)pent-2-yn-1-ol (334 mg, 1.64 mmol) according to the general The chloromethyl other 273 was prepared from 4 - procedure. 1H NMR (CDCI3) 3 1.19 (d, 3H, J = 5.9 Hz), 2.77 (m, 1H), 3.37 (m, 1H), 3.49 (m, 1H), 4.35 (d, 2H, J = 2.2 Hz), 4.54 (s, 2H), 5.55 (s, 2H), 7.32 (m, 5H). OBn 0A0 \\ (OC)50I': ; OT 88 The carbene complex 274 (748 mg, 1.11 mmol) was prepared from the salt 251 (700 mg, 1.30 mmol) and chloromethyl ether 273 in 86% yield and obtained as red Oil. 1H NMR (CDCI3, 300 MHz) 6 0.18 (s, 6H), 0.96 (s, 9H), 1.18 (d, 3H, J = 7.1 Hz), 2.08 (s, 6H), 2.77 (m, 1H), 3.36 (m, 1H), 3.47 (m, 1H), 4.51 (s, 2H), 4.56 (d, 2H, J = 2.2 Hz), 5.24 (br s, 2H), 6.47 (s, 2H), 7.27-7.35 (m, 5H); 13C NMR (CDCI3, 75 MHz) 3 —4.44, 17.45, 13.15, 19.54, 25.59, 26.83, 57.56, 73.02, 73.60, 74.30, 91.03, 97.00, 119.55, 127.57, 127.65, 128.17, 128.35, 138.05, 144.91, 155.27, 216.26, 224.64, 365.58; IR (neat) 2959w, 2933w, 2862w, 2243w, 2064s, 1943vs, 1601m, 1471w, 1316m, 1156m, 341m, 6555 cm". Red Oil; R; = 0.45 (9:1 hexanes/EtOAc). The carbene complex 274 (560 mg, 0.832 mmol) was desilylated according to the above procedure to give a 36% yield of phenol carbene complex 250 (175 mg, 0.313 mmol) as red Oil. 211 Preparation of1-(furan-3-yl)-4-methylpent-2-yn-1-oI O L) a. n-BuLi, THF, -78 °C to 0 °C OHC : : — 7 -78°Ctort 7 /\ 266 To a solution of isopropyl acetylene (1.0 mL, 9.8 mmol) in 20 mL THF at —78 °C was added n-BuLi (2.5 M, 4.0 mL, 10 mmol) dropwise. The mixture was stirred at --78 °C fro 10 minutes then warmed up to 0 °C for 1 hour. After cooling down again to —78 °C, the aldehyde (1.15 mL, 13.3 mmol) was added dropwise. The reaction was allowed to warm to room temperature and then quenched with saturated NH4C| solution (20 mL). The aqueous layer was isolated and extracted with B20 (2 * 20 mL). The combined organic layer was dried over MgSOa, concentrated. The crude product was isolated by chromatography using 9:1 hexanes/Et2O as eluent to give 1.63 g of alcohol 266 (9.8 mmol, 99%). 1H NMR (CDCI3, 500 MHz) 6 1.17(d, 6H, J = 6.9 Hz), 1.99 (d, 1H, J= 6.9 Hz), 2.59-2.62 (septet, 1H, J = 6.9 Hz), 5.35 (d, 1H, J = 6.3 Hz), 6.48 (d, 1H, J = 1.4 Hz), 7.36 (t, 1H, J = 1.4 Hz), 7.48 (t, 1H, J = 1.5 Hz); 13C NMR (CDCI3, 125 MHz) 6 20.48, 22.83, 57.42, 78.62, 91.44, 109.21, 127.08, 140.11, 143.51; IR (neat) 3350 br, 2971m, 2933w, 2871w, 2253w, 1503w, 1320w, 1159w, 10225, 875m cm"; mass spectrum m/z (% rel intensity) 164 M+ (55), 149 (49), 148 (17), 147 (100), 135 (28), 121 (97), 117 (17), 107 (25), 105 (18), 103 (22), 95 (31), 93 (37), 91 (72), 79 (29), 77 (55), 67 (25), 65 (40), 55 (18), 53 (32), 51 (28), 50 (22). Colorless oil; R, = 0.23 (10% B20 in hexanes). 212 General procedure for the intramolecular tautomer-arrested annulation of carbene complex 259 illustrated for complex 259a. (Procedure V) R2 0 1 1 O R R (00) Cr OJ \\ Benzene O 82 H0 82 0 R1 . = + 03 + 2 Fl1 50 00.0.01 M \ R O 0 DVD 250 252 259 CH 261 Thermolysis of 259a. (R1 = Me, R2 = H) The carbene complex 2593 (155 mg, 0.365 mmol) was dissolved in 36.5 mL benzene (0.01 M) and transferred to a schlenk flask equipped with a threaded Teflon high vacuum stopcock. The reaction was deoxygenated by the freeze-thaw procedure for 3 cycles. The flask was filled with argon at room temperature, sealed and heated at 60 °C. After the reaction was completed (indicated by the color of the carbene complex), the reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was dissolved in 1:1 mixture of CH2CI2 and B20 and stirred in air at room temperature. After stirring 2 hours, the solution was passed through Celite 503, concentrated, and then purified by Chromatography to afford 51% of the cyclized product 260a (44.5 mg, 0.193 mmol). O I I 0-/0 Compound 260a 1H NMR (CDCI3, 300 MHz) 6 1.06 (s, 3H). 1.79 (s, 3H), 1.88 (d, 1H, J = 14.8 HZ), 2.17 (s, 3H), 2.43 (d, 1H, J = 14.8 HZ), 4.59 (s, 2H), 5.15 (s, 2H), 5.51 (s, 1H); 13C NMR (CDCI3, 75 MHz) 3 10.15, 20.50, 213 22.55, 46.28, 51.47, 65.28, 92.16, 120.14, 120.80, 125.38, 150.03, 150.30, 152.07, 198.81; IR (neat) 2958w, 2920w, 16425, 15755, 1443w, 1424w, 1180m, 1072m cm'1; mass spectrum m/z (% rel intensity) 233 (48), 232 M+ (94), 203 (17), 202 (96), 187 (75), 174 (85), 159 (100), 131 (51), 115 (21), 91 (27), 51 (15). Yellow solid, mp 88-90 °C; Rr = 0.23 (9:1 hexanes/Et20). Thermolysis of 25%. (R1 = Et, R2 = H) A solution of carbene complex 25% (134 mg, 0.307 mmol) in 30.7 mL benzene was heated according to the general procedure to give 9% of compound 260b (7.0 mg, 0.0284 mmol) and 25% of compound 261b (21.0 mg, 0.0768 mmol) after purification. O \ 040 Compound 260b 1H NMR (CDCI3, 300 MHz) 6 1.07 (t, 3H, J = 7.7 Hz), 1.10 (s, 3H), 1.95 (d, 1H, J = 14.8 Hz), 2.19 (s, 3H), 2.22-2.32 (m, 2H), 2.42 (d, 1H, J = 14.8 Hz), 4.76 (s, 2H), 5.18 (s, 2H), 5.65 (s, 1H); 13C NMR (CDCI3, 75 MHz) 6 13.09, 19.30, 20.65, 22.57, 46.54, 51.76, 65.50, 91.98, 119.72, 120.84, 125.53, 150.15, 150.36, 157.90. 198.86; IR (neat) 2924m, 16355, 15785, 1456m, 1180m, 1074m, 918m cm"; mass spectrum m/z (% rel intensity) 246 M+ (55), 216 (30), 188(100), 187 (73), 160 (28), 159 (38), 131 (27), 91 (15). HRMS (Cl) calcd for (C15H1303+H)+ m/z 247.1334, meas 247.1323. Yellow Oil; Rf = 0.25 (2:1 Hexanes/EtOAc). 214 O O \ Ovo Compound 261b 1H NMR (CDCI3, 300 MHz) 3 0.93 (t, 3H, J = 7.4 Hz), 1.19 (s, 3H), 2.10-2.20 (m, 1H), 2.26 (d, 1H, J = 16.8 Hz), 2.30 (s, 3H), 2.35-2.44 (m, 1H), 2.35 (d, 1H, J = 15.3 Hz), 4.31 (q, 2H, J = 15.5 Hz), 5.09 (d, 1H, J = 5.7 Hz), 5.24 (d, 1H, J = 5.7 Hz), 5.34 (s, 1H); 13C NMR (CDCI3, 75 MHz) 6 12.12, 17.83, 24.79, 26.96, 44.07, 48.57, 65.18, 90.63, 122.56, 127.60, 135.37, 136.66, 145.81, 151.81, 196.97, 200.84; IR (neat) 2971, 1659, 1626, 1363, 1251, 1184, 1076 cm"; mass spectrum m/z (% rel intensity) 274 M+ (38), 259 (15), 231 (25), 230 (21), 229 (100), 215 (33), 215 (27), 202 (17), 201 (55), 133 (27), 159 (23), 93 (19), 91 (17), 77 (20), 65 (15). Yellow solid, mp 126-128 °C; Rf = 0.11 (2:1 hexanes/EtOAc). Thermolysis of 259s. (R1 = i-Pr, R2 = H) A solution of carbene complex 259C (206 mg, 0.456 mmol) in 45.6 mL benzene was heated according to the general procedure to give 16% of compound 261C (20.3 mg, 0.705 mmol) after purification. O O \ Ovo Compound 261C 1H NMR (CDCI3, 300 MHz) 6 1.15 (s, 3H), 1.16 (d, 3H, J = 6.8 Hz), 1.27 (d, 3H, J = 6.8 Hz), 2.27 (d, 1H, J = 17.0 Hz), 2.31 (s, 3H), 2.58 (m, 1H), 2.81 (d, 1H, J = 17.0 Hz), 4.72 (d, 1H, J = 16.8 Hz), 4.95 (d, 1H, J = 16.8 Hz), 5.07 (d, 1H, J = 5.5 Hz), 5.23 (d, 1H, J = 5.5 Hz), 5.86 (s, 1H); 13C NMR (CDCla, 75 MHz) 3 13.53, 21.22, 24.91, 25.90, 27.35, 29.70, 215 43.45, 55.47, 90.41, 121.93, 127.72, 135.55, 133.50, 145.15, 151.40, 197.20, 201.32; IR (neat) 2926m, 1661s, 1615m, 1383m, 1251m, 1186m, 1074s cm"; mass spectrum m/z (% rel intensity) 239 (15), 233 M+ (57), 273 (13), 259 (20), 253 (35), 245 (52), 244 (100), 243 (25), 231 (25), 215 (33), 215 (40); 203 (17), 201 (24), 139 (13), 133 (24), 137 (43), 175 (19), 173 (24), 159 (25), 145 (20), 131 (15), 115 (20), 91 (23), 77 (30), 51 (15). Yellow solid; R, = 0.22 (1:1 hexanes/Et20). Thermolysis of 259d. (R1 = n-Pr, R2 = Et) A solution of carbene complex 259d (120 mg, 0.250 mmol) in 25.0 mL benzene was heated according to the general procedure to give 18% of compound 260d (13.1 mg, 0.0455 mmol) and 21% of compound 261d (16.8 mg, 0.0532 mmol) after purification. \ O 0‘“ Compound 260d 1H NMR (CDCI3, 300 MHz) 3 0.95 (t, 3H, J = 7.4 Hz), 1.01 (t, 3H, J = 7.4 Hz), 1.09 (s, 3H), 1.12-1.40 (m, 2H), 1.50-1.62 (m, 1H), 1.81-1.88 (m, 2H), 1.93 (d, 1H, J= 14.7 Hz), 2.10-2.26 (m, 1H), 2.19 (s, 3H), 2.53 (d, 1H, J = 14.7 Hz), 4.70 (t, 1H, J = 6.1 Hz), 5.09 (d, 1H, J = 5.8 Hz), 5.25 (d, 1H, J = 5.8 Hz), 5.63 (s, 1H); 13C NMR (CDCI3, 75 MHz) 6 9.33, 14.69, 20.68, 22.51, 22.76, 25.69, 28.83, 46.77, 51.77, 76.13, 88.87, 119.58, 120.72, 129.67, 150.42, 150.90, 157.34, 198.89; IR (neat) 2963m, 1657m, 16325, 15685, 1557m, 1425w, 1182w, 1065m, 922m cm"; mass spectrum m/z (% rel intensity) 288 M+ (34), 258 (46), 243 (21), 229 (25), 217 (16), 216 (96), 215 (100), 201 (39), 188 216 (39), 137 (57), 173 (23), 171 (15), 159 (31), 145 (20), 143 (17), 141 (20), 129 (25), 123 (51), 115 (32), 105 (21), 93 (13), 91 (39), 77 (25), 55 (19), 57 (15), 55 (13), 53 (17). HRMS (Cl) calcd for (CrgH2403+H)* m/z 239.1304. meas 239.1313. Yellow gel; Rf = 0.30 (1:1 Hexanes/Et20). O \ Ovo Compound 261d 1HNMR (CDCI3, 300 MHZ) 6 0.97 (t, 3H, J = 7.5 Hz), 1.04 (t, 3H, J = 7.4 Hz), 1.16 (s, 3H), 1.33-1.40 (m, 1H), 1.45-1.49 (m, 1H), 1.82-1.88 (m, 2H), 2.10-2.16 (m, 1H), 2.28 (dd, 1H, J = 16.7, 1.1 Hz), 2.31 (5, 3H), 2.37-2.39 (m, 1H), 2.82 (dd, 1H, J = 16.7, 1.1 Hz), 4.94 (dd, 1H, J = 7.1, 4.0 Hz), 4.97(d, 1H, J = 5.8 Hz), 5.21 (d, 1H, J = 5.8 Hz), 5.86 (t, 1H, J = 1.1 Hz); 13CNMR (CDCI3, 75 MHz) 6 9.12, 14.54, 21.90, 24.81, 26.49, 28.14, 28.61, 43.79, 48.42, 74.79, 88.10, 121.12, 127.34, 135.42, 141.05, 148.85, 151.33, 197.06, 202.44; IR (neat) 2967m, 2930w, 2874w, 1771w, 1663s, 1620w, 1361w, 1076, 1012w cm"; mass spectrum m/z (% rel intensity) 316 M+ (17), 286 (39), 271 (100), 257 (22), 243 (63), 173 (43), 215 (55), 201 (25), 187 (39), 159 (24), 149 (29), 129 (16), 128 (37), 115 (24), 107 (23), 93 (20), 92 (38), 91 (45), 79 (27), 77 (19), 76 (35), 67 (27), 64 (15), 57 (19), 55 (26), 53 (20). HRMS (FAB) calcd for C19H2404 m/z 317.1755, meas 317.1753. Yellow gel; Rr = 0.27 (2:1 hexanes/Et2O). 217 Thermolysis of 259e. _/0 o O ( OC)5 Cr \\ Benzene : HO / 60 °C, 0.01 M / O v0 OH 2599 269 A solution of carbene complex 2593 (184 mg, 0.408 mmol) in 40.8 mL benzene was heated according to the general procedure to give 58% of compound 269 (59.1mg, 0.207 mmol) after purification. Compound 269 1H NMR (CDCI3, 300 MHz) 6 1.56 (s, 3H), 2.20 (s, 6H), 2.96 (s, 2H), 4.61 (s, 2H), 5.15 (s, 2H), 5.40 (s, 1H), 6.50 (s, 2H); 13C NMR (CDCI3, 75 MHz) 6 16.49, 19.75, 51.67, 64.53, 90.38, 105.44, 114.53, 126.31, 139.23, 140.96, 150.59, 156.03, 168.65, 188.81; IR (neat) 3400br, 2924m, 2857w, 17545, 1611m, 1318m, 1194s, 1157m, 1017m, 904w, 736w cm"; mass spectrum m/z (% rel intensity) 286 M+ (20), 241 (59), 213 (58), 185 (23), 149 (100), 121 (28), 91 (33), 77 (27). HRMS (FAB) calcd for 017H1304 m/z 286.1204, meas 286.1205. Light yellow solid, mp. 152-154 °C; Rf = 0.31 (1:1 hexanes/Et2O). Thermolysis of 250 A solution of carbene complex 250 (87.0 mg, 0.156 mmol) in 15.6 mL benzene was heated according to the general procedure to give unstable cyclized product, which was decomposed during isolation. 218 Reaction of complex 46 with iso-propylmethylacetylene O...— (OC)5Cr Benzene, 0.05 M O HO + ———<: : + o 110 °C. 8 h \ O OH OMe 07- 285 286 46 A solution containing 0.486 mmol carbene complex 46 (173 mg) and 0.97 mmol alkyne (79.5 mg) in 9.72 mL benzene was deoxygenated by the freeze- thaw method and heated at 110 °C for 8 hours. The reaction mixture was cooled to RT, and then diluted with 320. After stirring 2 hours at RT in air, the solution was passed through Celite 503, concentrated, and then purified by Chromatography (2:1 hexanes/EtOAc as eluent) to give 44% of compound 285 (52.1 mg, 0.212 mmol) and 15% of compound 286 (17.9 mg, 0.0728 mmol). \ 011- Compound 235 1H NMR (CDCI3, 500 MHz) 3 1.05 (s, 3H), 1.12 (d, 3H, J = 7.1 Hz), 1.20 (d, 3H, J = 7.2 Hz), 1.33 (d, 1H, J = 15.1 Hz), 1.93 (s, 3H), 2.21 (s, 3H), 2.55 (d, 1H, J = 15.0 Hz), 2.52 (sept, 1H, J = 7.1 Hz), 3.72 (s, 3H), 5.57 (s, 1H); 13C NMR (CDCI3, 125 MHz) 3 10.75, 20.29. 21.31, 21.70, 21.79, 27.04, 45.34, 52.35, 50.73, 122.59, 123.07, 131.32, 149.44, 159.39, 153.19, 199.55; IR (neat) 2953m, 2932w, 1655s, 1626m, 1570s, 1445w, 1318m, 1119w cm"; mass spectrum m/z (% rel intensity) 247 (54), 246 M+ (100), 245 (22), 244 (44), 231 (57), 204 (37), 203 (39), 201 (35), 139 (33), 133 (15), 137 (17), 175 (15), 175 (53), 173 (22), 171 (17), 151 (25), 150 (13), 159 (17), 145 219 (22), 115 (15), 91 (21), 77 (16). Anal calcd for C15H2202: C. 78.01; H, 9.00. Found: C, 77.67; H, 8.95. Yellow solid, 30-32 °C; Rf = 0.24 (2:1 hexanes/Et2O). H000 0- Compound 235 1H NMR (CDCI3, 300 MHz) 3 0.54 (d, 3H, J = 5.5 Hz), 0.94 (d, 3H, J = 5.5 Hz), 1.15 (s, 3H), 1.79 (s, 3H), 1.39 (m, 1H), 2.44 (s, 3H), 3.72 (s, 3H), 4.31 (s, 1H), 5.43 (s, 1H), 5.54 (s, 1H); 13C NMR (CDCI3, 75 MHz) 3 3.72, 17.32, 17.91, 21.35, 33.33, 51.92, 50.14, 50.20, 103.45, 115.24, 129.35, 130.04, 130.55, 151.55, 152.95, 153.37; IR (neat) 3335 br, 2983s, 2932m, 2874w, 1644w, 1509 m, 1468m, 1350m, 1306m, 1145m cm"; mass spectrum m/z (% rel intensity) 247 (31), 245 M" (95), 231 (51), 204 (29), 203 (100), 139 (25), 175 (33), 171 (17), 151 (25), 149 (32), 91 (13). HRMS (FAB) calcd for 016H22O2 m/z 246.1619, meas 246.1620. Yellow Oil; Rr = 0.37 (2:1 hexanes/Et20). Reaction of complex 46 with tert-butylmethylacetylene O— (OC)5Cr Benzen, 0.05 M O HO + ———<—: = + o 110 °C. 8 I1 \ O OH OMe 0‘ 237 288 45 A solution containing 0.40 mmol carbene complex 46 (142 mg) and 0.60 mmol alkyne (77.0 mg) in 8 mL benzene was deoxygenated by the freeze-thaw method and heated at 110 °C for 8 hours. The reaction mixture was cooled to RT, and then diluted with 320. After stirring 2 hours at RT in air, the solution was 220 passed through Celite, concentrated. The crude product was purified by Chromatography (2:1 hexanes/EtOAc as eluent) to give 18% of compound 287 (18.6 mg, 0.0715 mmol) and 41% of compound 288 (42.8 mg, 0.165 mmol). \ OMe Compound 287 1H NMR (CDCI3, 300 MHz) 6 1.24 (s, 3H), 1.28 (s, 9H), 1.99 (s, 3H), 2.07 (d, 1H, J = 15.3 Hz), 2.22 (s, 3H), 2.98 (d, 1H, J= 15.3 Hz), 3.69 (s, 3H), 5.72 (s, 1H); 13C NMR (CDCI3, 75 MHz) 6 12.40, 20.48, 22.70, 30.83, 35.96, 47.26, 53.88, 60.83, 122.84, 129.05, 133.40, 149.13, 159.45, 164.43, 199.83; IR (neat) 2961m, 16555, 16225, 1570m, 1547m, 1447m, 1395m, 1329m, 1124m cm"; mass spectrum m/z (% rel intensity) 261 (47), 260 M+ (100), 245 (18), 204 (53), 203 (20), 189 (69), 175 (17), 161 (22); yellow solid, mp 50-55 °C; Rr = 0.21 (2:1 hexanes/Et20). H000 Os Compound 288 1H NMR (CDCI3, 300 MHZ) 6 0.90 (s, 9H), 1.18 (s, 3H), 1.90 (s, 3H), 2.44 (s, 3H), 3.72 (s, 3H), 4.69 (brs, 1H), 6.42 (s, 1H), 5.71 (s, 1H); 13C NMR (CDCIa, 75 MHz) 3 11.72, 17.72, 17.35, 27.22, 35.31, 54.76, 59.87, 110.13, 115.13, 129.43, 130.54, 130.79, 152.37, 152.78, 154.85; IR (neat) 3387brm, 2961s, 1635m, 1597m, 13595, 1302m, 1251m, 1155m, 1136m, 1708m, 1007m, 860w cm“; mass spectrum m/z (% rel intensity) 260 M+ (5), 204 (17), 203 (100), 188 (9), 145 (5). HRMS (FAB) calcd for C17H24O2 m/z 260.1777; meas 260.1776. White solid; decomposed at >140 °C; R; = 0.38 (2:1 hexanes/Et20). 221 Preparation of triisopropyl(prop-2-ynyloxy)silane 28970 imidazole //\OH + TIPSCI —-—-- //\OTIPS / / CH2C12,I1 289 To the solution of propargyl alcohol (1.28 mL, 22 mmol) and TIPSCI (4.28 mL, 20 mmol) was added imidazole (1.77 g, 26 mmol). The mixture was stirred at room temperature for 12 hours, and then quenched with saturated NaHCOa (20 mL). The solution was diluted with 320 (20 mL), washed three times with H20 (20 mL), and once with brine (20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The product 289 (4.14 g, 19.5 mmol, 97%) was purified by distillation. 1H NMR (CDCI3, 300 MHz) 6 1.09 (m, 21H), 2.39 (t, 1H, J = 2.4 Hz), 5.06 (d, 2H, J = 2.4 Hz); 13C NMR (CDCI3, 75 MHZ) 6 11.89, 17.81, 51.69, 72.57, 82.34. Preparation of ketone 29170 O O f—BuLi, Et20 )- ,OMe _ N ))—-—\_ 289 7 291 To a round bottom flask containing alkyne 289 (10.62 g, 50 mmol) and 100 mL 320 at —78 °C, tert-butyl lithium (32.3 mL, 55 mmol) was added dropwise. The reaction mixture was stirred for 1 hour at —78 °C, and then the amide 290 was added dropwise. The reaction was stirred for 1 more hour at —78 °C, and then warmed up to —20 °C for 2 hours and 1 hour at room temperature. 222 After addition of 50 mL water, the separated aqueous layer was extracted with B20 (3 * 25 mL). The combined organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (9:1 hexanes/Et2O as eluent) to give 73% of ketone 291 (9.65 g, 36.5 mmol). 1H NMR (CDCI3, 300 MHz) 6 1.08 (m, 21H), 2.36 (s, 3H), 4.55 (s, 2H); 13C NMR (CDCI3, 75 MHz) 6 11.85, 17.80, 32.50, 51.73, 84.04, 90.25, 184.19; IR (neat) 29455, 2893m, 28885, 2209w, 1684s, 1464m, 1360m, 12215, 11055, 1071m, 997w, 883m, 685m cm”; mass spectrum m/z (% rel intensity) 212 (M-42)" (22), 211 (100), 169 (54), 153 (10), 142 (12), 141 (74), 139 (16), 125 (33), 113 (12), 111 (13), 75 (13), 61 (10), 45 (10). ). Anal calcd for C14H2502Si: C, 66.09; H, 10.30. Found: C, 65.78; H, 10.56. Yellow oil; Rf = 0.55 (9:1 hexanes/Et20). Preparation of enol other 29270 OMe 0 SE _ i -7 o )—:OT| PS + (.Bu Li 1' P113 PCH 20MeCl EtZO 8 C t : OTI PS 291 292 In a round bottom flask containing 10 mL B20 was introduced Ph3PCH2OMeCI (0.754 g, 2.2 mmol). The solution was cooled to —78 °C, and t- BuLi (1.29 mL, 1.7 M, 2.2 mmol) was added dropwise. The red reaction mixture was stirred for 0.5 hour. Then the ketone 291 (0.300 g, 1.2 mmol) was added and the mixture was stirred at —78 °C for 2 more hours. Before warming up to room temperature, 5 mL H2O was added. The separated aqueous layer was extracted 223 with B20 (3 * 15 mL). The combined organic layer was dried over MgSO4, filtrate and the amount of B20 was reduced to about 10 mL. Hexanes (10 mL) was added to the solution to remove maximum amount of phosphine oxide. After filtration and evaporation, the mixture was purified on a column chromatography using 2% EtOAc in hexanes as eluent to give cis-isomer (69 mg, 0.244 mmol) in 20% yield and trans-isomer (48 mg, 0.170 mmol) in 14% yield. Cis-2927°: 1H NMR (CDCI3, 500 MHz) 3 1.07 (m, 21H), 1.55 (d, 3H, J = 1.5 Hz), 3.64 (s, 3H), 4.53 (5, 2H), 6.14 (q, 1H, J: 1.5 Hz); 13C NMR (CDCI3, 125 MHz) 6 12.05, 17.26, 17.95, 52.64, 60.11, 81.82, 92.19, 94.67, 151.87; IR (neat) 2942, 2867, 2218, 1684, 1647, 1464, 1258, 1211, 1145, 883, 683 cm”; mass spectrum m/z (% rel intensity) 282 M+ (1), 267 (16), 247 (19), 239 (100), 233 (22), 209 (79), 198 (22), 197 (99), 184 (48), 167 (37), 152 (45), 145 (38), 139 (29), 109 (78), 89 (23), 79 (19), 77 (24), 75 (30), 59 (17). Light yellow oil; Rf = 0.50 (95:5 hexanes/EtOAc). Trans-292m: 1H NMR (CDCI3, 500 MHz) 3 1.07 (m, 21H), 1.57 (d, 3H, J = 1.6 Hz), 3.64 (s, 3H), 4.45 (s, 2H), 6.33 (q, 1H, J = 1.5 Hz); 13C NMR (CDCI3, 125 MHz) 6 12.06, 13.73, 17.95, 52.49, 60.08, 85.10, 85.24, 96.71, 152.91; IR (neat) 2946, 2868, 2220, 1645, 1464, 1233, 1138, 1091, 886, 683 cm"; mass spectrum m/z (% rel intensity) 282 M+ (1), 281 (5), 267 (15), 247 (17), 239 (42), 216 (28), 152 (26), 145 (33), 137 (25), 120 (15), 117 (21), 109 (100). Light yellow oil; Rf = 0.60 (95:5 hexanes/EtOAc). 224 Annulation of carbene complex 46 with alkyne 292 OMe (OC)5Cr OMe O ’ OMe + \ benzene r>—'——\-_—‘ ; OTIPS OTIPS 110 °C, 0.05 M \ OMe OH °. 46 292 25 / 293 A solution containing carbene complex 46 (150 mg, 0.42 mmol) and alkyne 292 (1 :1 (:72, 0.63 mmol 178.0 mg) in 8.4 mL benzene was deoxygenated by the freeze-thaw method and heated at 110 °C for 8 hours. The reaction mixture was cooled to RT, and then diluted with 820. After stirring 2 hours at RT in air, the solution was passed through Celite, concentrated, and then purified by chromatography to give 25% of compound 293 (47 mg, 0.105 mmol) as mixture. 15-2937o 1H NMR (CDCI3, 300 MHz) 3 1.05 (m, 24H), 1.75 (s, 3H), 2.09 (d, 1H, J = 15.1 Hz), 2.25 (s, 3H), 2.68 (d, 1H, J= 15.1 Hz), 3.64 (s, 3H), 3.87 (s, 3H), 4.37 (d, 1H, J = 11.2 Hz), 4.52 (d, 1H, J = 11.2 Hz), 5.70 (s, 1H), 6.04 (s, 1H); 13CNMR (CDCI3, 75 MHz) 3 12.11, 13.35, 13.03, 20.57, 23.20, 47.22, 52.71, 59.64, 59.81, 61.12, 108.45, 122.79, 128.98, 135.76, 147.67, 150.36, 159.31, 160.10, 199.33. 229370 1H NMR (CDCI3, 300 MHz) 3 1.03 (m, 21H), 1.07 (s, 3H), 1.70 (s, 3H), 2.13 (d, 1H, J = 15.0 Hz), 2.24 (s, 3H), 2.58 (d, 1H, J = 15.0 Hz), 3.47 (s, 3H), 3.94 (s, 3H), 4.36 (d, 2H, J = 3.2 Hz), 5.69 (s, 1H), 5.97 (s, 1H); 13CNMR (CDCI3, 75 MHz) 6 11.99, 18.00, 18.56, 20.68, 22.68, 47.78, 52.23, 57.74, 59.40, 60.14, 107.01, 122.46, 128.61, 136.90, 145.37, 150.90, 156.28, 159.16, 199.96. 225 Preparation of (E,6E)-3, 7-dimethyI-11-(trimethylsiIyl)undeca-2,6-dien-10- yn-1-ol 339 Br OBz n-BuLi 334 \\ TMS : 7 7' OH THF, -20 0C, 30 min THF, 0 00, 12 h 339 This procedure for the preparation of 339 was adopted from that reported by Jie Huang.91 To a solution of TMS propyne (26 mL, 175 mmol) in THF (100 mL) at —20 °C was added n-BuLi (2.5 M, 70.0 mL, 175 mmol) dropwise. After 30 minutes, the bromide 334 (14.73 g, 43.7 mmol) in THF (50 mL) was transferred by cannulated to the above solution and the temperature was raised to 0 °C slowly. The reaction mixture was stirred for 12 hours at 0 °C and then quenched with H2O. The aqueous layer was separated and extracted with 320 (2 * 50 mL). The combined organic layer was washed with saturated aqueous NaHCO:, (3 * 30 mL), brine (30 mL) and dried over MgSO4. Concentration followed by flash Chromatography on silica gel with a 4:1 mixture of hexanes/EtOAc as eluent provided the title compound 339 which was not further purified but taken on directly in the next step. A sample can be further purified for Characterization. 1HNMR (CDCI3, 300 MHz) 6 0.07 (s, 9H), 1.58 (5, 3H), 1.66 (s, 3H), 2.02-2.28 (m, 8H), 4.12-4.14 (d, 2H, J = 6.6 Hz), 5.14 (t, 1H, J = 6.6 Hz), 5.39 (t, 1H, J = 6.6 Hz); 13C NMR (CDCI3, 75 MHz) 3 0.09, 15.30, 15.22, 19.17, 25.13, 33.52, 39.37, 59.36, 84.55, 107.18, 123.33, 125.04, 133.75, 139.61; IR (neat) 3360br, 2925, 2176, 1250, 1003, 8145, 760 cm'l; MS (EI) m/z (% rel intensity): 264 M“ (0.03), 226 249 (1.30), 159 (31), 149 (30), 135 (21), 119 (21), 105 (21), 96 (47), 83 (32), 81 (32), 75 (49), 73 (100), 59 (68). Anal calcd for CreHzaOSi: C. 72.66; H, 10.67. Found: C, 72.83; H, 10.39. Colorless oil; R; = 0.35 (3:1 hexanes/EtOAc). Preparation of (2E,6E)-3,7-dimethylundeca-2,6-dien-10-yn-1-oI 340 TMS \\ TBAF ( 2 equiv.) \\ OH = OH _ THF, rt, 12h _ — 339 340 This procedure for the preparation of 340 was adopted from that reported by Jie Huang.91 The trimethylsilyl protected acetylene 339 prepared by the previous procedure was treated with TBAF (1.0 M in THF, 100 mL) at room temperature for 12 hours followed by quenching with saturated aqueous NaHCO3. The aqueous layer was separated and extracted with 320 (2 * 50 mL). The combined organic layer was washed with saturated aqueous NaHCO;; (3 * 30 mL), brine (30 mL) and dried over MgSO4. Concentration followed by Flash chromatography on silica gel with a 4:1 mixture of hexanes/EtOAC as eluent provided the desired product 340 as a colorless oil (6.09 9, 0.0317 mmol, 71% 2 steps). 1HNMR (CDCI3, 300 MHz) 6 1.59 (s, 3H), 1.65 (s, 3H), 1.93 (t, 1H, J = 2.4 Hz), 2.00-2.29 (m, 8H), 4.12-4.14 (d, 2H, J = 6.9 Hz), 5.16 (t, 1H, J = 6.3 Hz), 5.40 (t, 1H, J = 6.6 Hz); 13CNMR (CDCI3, 75 MHz) 6 15.79, 16.25, 17.56, 26.19, 38.21, 39.34, 59.39, 68.36, 84.37, 123.50, 125.13, 133.55, 139.53; IR (neat) 3350br, 3304, 2922, 2857, 2118, 1725, 1668, 1445, 1383 cm”; MS (EI) m/z (% rel intensity): 191 (M-1)+ (0.02), 177(1), 173 (0.23), 151 (3), 159(5), 105 (43), 91 227 (100), 79 (76). Anal calcd for C13HzoO: C. 81.20; H, 10.48. Found: C, 81.36; H, 10.38. Colorless oil; Rr = 0.29 (3:1 hexanes/EtOAc). Preparation of (2E,6E,10E)-11-iodo-3,7,10-trimethylundeca-2,6,10-trien-1-ol \\ 1) ZGCzCl2,CH2CI2, 0 °C, 30 min ' __ 2 AlMe , 12 h 0H ) 3 s OH — 3) 12, THF, -30 °C to 0 °C — — 340 341 341 TO a solution of zirconocene dichloride (1.25 g, 4.28 mmol) in CH2CI2 (34 mL) at room temperature under an argon atmosphere, was added dropwise a solution of trimethylaluminum in pentane (2 M in pentane, 25.7 mL, 51.4 mmol). After 15 minutes, the solution was cooled to 0 °C, and a solution of alkyne 340 (3.25 g, 17.1 mmol) dissolved in CH2CI2 (34 mL) was added to the above lemon yellow solution. The reaction mixture was stirred at 0 °C for 12 hours and then cooled to —30 °C. Iodine (8.69 g, 34.2 mmol) was added as a solution in 20 mL of THF. The resulting brown slurry was raised to 0 °C and poured slowly with stirring into an iced saturated aqueous NaH003. The aqueous layer was extracted with B20 (3 * 50 mL). The combined organic layer was washed with saturated aqueous NaHCOa and dried over MgSOa. Concentration followed by flash chromatography on silica gel with 4:1 hexanes/EtOAC as eluent provided the desired product 341 as a colorless oil (3.69 g, 11 mmol, 65%). 1H NMR (CDCI3, 300 MHz) 6 1.57 (s, 3 H), 1.66 (s, 3 H), 1.80 (s, 3 H), 1.97-2.10 (m, 6 H), 2.27 (t, 2H, J = 6.6 Hz), 4.13 (d, 2H, J = 6.9 Hz), 5.08 (t, 1H, J =6.9 HZ), 5.39 (t, 228 1H, J = 6.9 Hz), 5.83 (s, 1 H); 13C NMR (CDCI3, 75 MHz) 6 15.82, 26.26, 23.85, 26.17, 37.84, 38.21, 39.41, 59.39, 74.66, 123.41, 124.70, 134.21, 139.60, 147.82; IR (neat) 3312br, 2919, 2858, 1441 cm"; MS (EI) m/z (% rel intensity): 239 (3), 207 (M-127)+ (2), 189 (11), 181 (44), 121 (80), 107 (98), 93 (100), 53 (73). Anal calcd for C14H230I: C. 50.31; H, 6.94. Found: C, 50.64; H, 6.90. Colorless oil; Rr = 0.30 (3:1 hexanes/EtOAc). Preparation of (2E,6E,10E)-11-iodo-3,7,10-trimethylundeca-2,6,10-trienal 342 — DMP, CHzclz — H OH f O — rt. 30 min - 341 342 This procedure for the preparation of 342 was adopted from that reported by Jie Huang.91 To a solution of allylic alcohol 341 (0.80 g, 2.4 mmol) in CH2CI2 (10 mL) was added freshly prepared DMP93 (1.10 g, 2.6 mmol) as powder. The reaction mixture was stirred at room temperature for 30 minutes before quenching with 10% aqueous NaOH (10 mL). The stirring was continued for another 5 minutes, and then Et20 (3 * 10 mL) was added to extract the product from the reaction mixture. The combined organic layer was dried over MgSO4. Removal of the solvent under reduced pressure followed by flash Chromatography on a silica gel column (9:1 hexanes/EtOAc as eluent) provided the desired aldehyde 342 as a colorless oil (0.784 g, 2.36 mmol, 98%). 1H NMR (CDCI3, 300 MHz) 6 1.58 (s, 3H), 1.80 (s, 3H), 2.15 (s, 3H), 2.05-2.29 (m, 8H), 5.02-5.08 (m, 1H), 5.83-5.86 (m, 1H), 5.83 (s, 1H), 9.97 (d, 1H, J = 7.8 Hz); 13C 229 NMR (CDCI3, 75 MHz) 6 15.89, 17.61, 23.83, 25.57, 37.77, 38.13, 40.50, 74.79, 123.45, 127.46, 135.43, 147.63, 163.47, 191.22. IR (neat) 2939m, 2853m, 2772w, 1684s, 1437m, 1194m, 1122m, 827w, 667w cm"; MS (EI) m/z (% rel intensity): 332 M“ (3), 205 (22), 187 (34), 181 (77), 177 (33), 161 (17), 159 (16), 149 (16), 145 (24), 135 (16), 133 (24), 125 (20), 121 (100), 107 (76), 105 (28), 95 (67), 93 (73), 84 (30), 81 (100), 67 (63), 55 (85), 53 (86). Anal calcd for C14H21Ol: C. 50.61; H, 6.37. Found: C, 50.28; H, 6.64. Colorless Oil; R; = 0.6 (3:1 hexanes/EtOAC). Preparation of (4E,8E,12E)-13-iodo-5,9,12-trimethyltrideca-4,8,12-trien-1-yn- 3-ol 333 l I —— H E—MgBr (2.0 equiv.) — \\ O 2 OH _ — THF, -30 °C. 1 h — 342 333 To a solution of aldehyde 342 (0.16 g, 0.48 mmol) in THF (2 mL) at —30 °C under an argon atmosphere was added ethynyl magnesium bromide (0.5 M solution in THF, 1.92 mL, 0.96 mmol) dropwise. The reaction mixture was stirred at —30 °C for 1 hour and quenched with saturated aqueous NH4CI (8 mL). The aqueous layer was extracted with 820 (3 * 5 mL). The combined organic layer was washed with brine (15 mL) and dried over MgSOa. Flash Chromatography on a silica gel column using 15% EtOAC in hexanes as eluent provided the desired propargylic alcohol 333 as a colorless oil (0.16 g, 0.45 mmol, 93%). 1H NMR (CDCIa, 500 MHZ) 6 1.57 (s, 3H), 1.70 (s, 3H), 1.80 (s, 3H), 2.01-2.10 (m, SH), 230 2.27 (t, 2H, J = 7.2 Hz), 2.47 (d, 1H, J = 2.1 Hz), 5.07-5.12 (m, 2H), 5.37 (d, 1H, J = 3.4 Hz), 5.33 (s, 1H); 13C NMR (CDCI3, 125 MHz) 3 15.37, 15.59, 23.35, 25.94, 37.32, 33.22, 39.13, 53.39, 72.49, 74.59, 34.44, 124.09, 124.35, 134.45, 140.77, 147.31; IR (neat) 3400 (broad), 3299, 2919, 2353, 2120 (weak), 1955, 1557 cm". HRMS (CI) calcd for C15H22l (M-H2O+H)+ m/z 341.0766, meas 341.0771. Colorless oil; Rr = 0.43 (3:1 hexanes/EtOAC). Preparation of ((4E,8E,2E)-13-iodo-5,9,12-trimethyltrideca-4,8,12-trien-1-yn- 3-yloxy) triisopropylsilane 346 '_ \\ '_ \\ TIPSCI, DMAP OH = OTIPS _ — CH2CI2, rt, 12 II _ T" 333 345 This procedure for the preparation of 346 was adopted from that reported by Jie Huang.91 TO a solution of propargyl alcohol 333 (1.0 g, 2.8 mmol) in CH2CI2 (10 mL) was added DMAP (0.68 g, 5.6 mmol) and TIPSCI (1.2 mL, 5.6 mmol). The reaction mixture was stirred at room temperature for 12 hours and quenched with H20 (10 mL). Diethyl ether (3 * 20 mL) was added to extract the product from the aqueous layer. The combined organic layer was washed with saturated aqueous NH4CI (50 mL), brine (50 mL), and then dried over MgSOa. Removal of the solvent under reduced pressure followed by flash chromatography on silica gel (19:1 hexanes/EtOAc as eluent) provided the desired product 346 as a colorless Oil (1.43 g, 2.8 mmol, 100%). 1H NMR (CDCI3, 500 MHZ) 6 1.03-1.13 (m, 21H), 1.57 (s, 3H), 1.65 (s, 3H), 1.80 (s, 3H), 23] 1.93-2.03 (m, 6H), 2.53 (t, 2H, J = 2.7Hz), 2.41 (d, 1H, J = 2.1Hz), 5.07-5.12 (m, 2H), 5.32-5.34 (d, 1H, J = 7.3 Hz), 5.34 (s, 1H); 13C NMR (CDCI3, 125 MHz) 3 12.19, 15.39, 15.53, 17.90, 23.33, 25.93, 37.90, 33.29, 39.03, 59.94, 71.43, 74.51, 35.03, 124.54, 125.19, 134.25, 135.55, 147.91; IR (neat) 3303, 2942, 2339, 1452 cm"; MS (EI) m/z (% rel intensity) 514 M“ (0.04), 471 (1.4), 131 (31), 103 (100), 75 (33). Anal calcd for C25H43OlSi: C. 53.35; H, 3.42. Found: C, 53.50; H, 8.77. Colorless oil; Rr = 0.20 (hexanes). Preparation of carbene complex 349 | 1) Cr(CO)6, THF, -73 0C 0" \\ 2) PhLi, 30 min (OC)5C' \\ OTIPS : — 3) n-BuLi, -78 °C to rt, 2 h OTIPS 4) Me3OBF4, CH2C12/H20, 30 min _ 346 349 This is a modification of a procedure Jie Huang reported for the preparation of 349.91 To a solution of vinyl iodine 346 (375 mg, 0.73 mmol) in THF (15 mL) at room temperature was added Cr(CO)6 (177 mg, 0.80 mmol) as a powder. The reaction mixture was cooled to -78 °C, and PhLi (0.456 mL, 0.73 mmol, 1.6 M solution) was added dropwise. The mixture was stirred for 30 minutes at -78 °C, and then n-BuLi (0.34 mL, 0.73 mmol, 2.27 M) was added dropwise. The solution was stirred for another 30 minutes, and then warmed up to room temperature and stirred for 1.5 hours. The solvent of the reaction was then removed in vacuo, and the residue was dissolved in 1:1 HzO/CH2CI2 (15 mL). Upon addition of Me3OBF4 (210 mg, 1.47 mmol), the solution turned red immediately. After stirring 30 minutes at room temperature, saturated aqueous 232 NaHC03 and B20 was added to quench the alkylation. The aqueous layer was extracted with 820 until the color of the aqueous layer was pale. The combined organic layer was washed with brine, and then dried over MgSOa a n of concentrated in vacuo. The residue was purified by flash column Chromatography on silica gel using 2% EtOAC in hexanes as eluent to give carbene complex 349 (233 mg, 0.37 mmol, 51%) as a red oil. 1H NMR (CDCI3, 500 MHz) 6 1.03-1.10 (m, 21), 1.60 (s, 3 H), 1.65 (s, 3H), 1.82 (s, 3H), 2.00-2.15 (m, 8H), 2.40 (d, 1 H, J = 2.1Hz), 4.69 (s, 3H), 5.01-5.12 (m, 2H), 5.32 (d, 1 H, J = 7.8Hz), 7.20 (s, 1H). 13C NMR (CDCI3, 125 MHz) 6 12.10, 15.87, 16.57, 17.85, 17.91, 20.61, 25.86, 37.80, 38.96, 39.74, 59.86, 66.13, 71.43, 84.97, 124.66, 126.15, 133.94, 136.40, 140.95, 142.79, 216.75, 223.94, 339.37; IR (neat) 2946w, 2868w, 20585, 1935vs, 1250w, 1061w, 667s, 650m cm'1. Anal calcd for Cg2H46Cr07Si: C. 61.71; H, 7.44. Found: C, 62.05; H, 7.76. Red oil; Rf = 0.63 (3:1 hexanes/EtOAC). Carbene complex 350 Methylated carbene complex 350 was obtained in a 34% yield when CH2CI2 was the only solvent in the methylation step of the above reaction. 1H NMR (CDCI3, 500 MHz) 6 1.03- 1.09 (m, 21H), 1.60 (5, 3H), 1.63 (s, 3H), 1.80 (d, 3H, J = 2.1 Hz), 1.82 (s, 3H), 1.97-2.15 (m, 6H), 2.17-2.20 (m, 2H), 4.69 (s, 3H), 5.05 (dd, 1H, J = 8.1, 2.0 Hz), 5.12 (t, 1H, J = 5.3 Hz), 5.30 (dd, 1H, J = 3.1, 1.0 Hz), 7.20 (s, 1H); 13C NMR (CDCI3, 125 MHz) 6 3.67, 12.28, 15.91, 16.56, 17.94, 20.56, 26.02, 37.88, 39.04, 39.75, 60.75, 66.14, 79.59, 80.60, 124.92, 127.02, 133.89, 135.37, 140.98, 233 142.77, 216.80, 223.97, 339.94; IR (neat) 2946, 2869, 2058, 1939, 1585, 1455, 1250, 557 cm". Red Oil. General procedure for preparation of model carbene complex 35491 {L— \\ OMe n-BuLi 353 0 n'Buli Cr(CO)6A Me3OBF4‘ ArH or ArBr E = (OC)50r fig o\\ TO a flame dried round bottom flask filled with an argon atmosphere was added the appropriate aryl lithium precursor (Table 5.1) and THF (0.02 M) and cooled to -78 °C. n-BuLi (1 equiv.) or t-BuLi (2 equiv.) was added dropwise to the above solution. After 30 minutes, a solution of vinyl iodine 353 (1 equiv.) in THF (0.02 M) was added dropwise. The mixture was stirred for 30 minutes at -78 °C, then n-BuLi (1 equiv.) or t-BuLi (2 equiv.) was added. After 30 minutes, Cr(CO)6 (1.1 equiv.) was added to the solution as a powder and the cooling bath was removed. The solution was warmed to room temperature and stirred for 1.5 hours before the solvent was removed on rotary evaporator. The residue was taken up in a two-phase solvent system of CH2CI2 and H20 (1:1), and Me30BF4 (2 equiv.) was added to the above mixture as a solid at room temperature. The reaction mixture was stirred for 30 minutes before quenching with saturated aqueous NaHCOa. The aqueous layer was extracted three times with 820. The combined organic layer was washed with brine, and dried over MgSO4. Concentration followed by chromatography on a silica gel column with 2% EtOAC in hexanes as eluent provided the carbene complex 354 in yields that are 234 listed in Table 5.1. 1H NMR (CDCI3, 500 MHZ) 6 1.26-1.30 (m, 10 H), 1.37-1.38 (m, 2H), 1.45-1.52 (m, 4H), 1.82 (d, 3H, J = 1.0 HZ), 1.92 (t, 1H, J = 2.7 HZ), 2.10 (t, 2H, J = 7.7 HZ), 2.19 (td, 2H, J = 7.2, 2.7 Hz), 4.70 (s, 3H), 7.23 (s, 1H); 130 NMR (CDCI3, 125 MHZ) 6 18.37, 20.56, 27.77, 28.45, 28.71, 29.04, 29.23, 29.40, 41.19, 66.15, 68.01, 84.74, 141.02, 143.48, 216.83, 223.98, 339.50 (2 sp3 carbons were not located). Red oil; Rr = 0.11 (hexanes). Preparation of alcohol 355 —O TMS n-BuLi,THF 342 E‘TFHS : : -78°CtoO°C 0°Ct°"'2h “ _ OH 355 To a solution of trimethylsilyl acetylene (0.22 mL, 1.5 mmol) in 2.0 mL of THF at —78 °C was added n-BuLi (0.60 mL, 1.5 mmol, 2.5 M in hexanes) dropwise. The solution was stirred 'at -78 °C for 30 minutes then at 0 °C for 50 minutes, and then the aldehyde 342 (166 mg, 0.50 mmol) in 1 mL of THF was added to the above solution. The solution was stirred at 0 °C for 1 hour then warmed up to room temperature for another 1 hour. The reaction mixture was quenched with 5 mL Of saturated aqueous NH4CI, and the aqueous phase was separated and extracted with 320 (2 * 10 mL). The combined organic layer was washed with brine (10 mL), dried over Na2804 and concentrated in vacuo. The residue was purified by flash column Chromatography on silica gel using 9:1 hexanes/EtOAC as eluent to give 355 (169 mg, 0.392 mmol, 79%) as a colorless 235 oil. 1H NMR (CDCI3, 500 MHz) 3 0.13 (s, 9H), 1.55 (s, 3H), 1.53 (d, 3H, J = 1.2 Hz), 1.73 (d, 3H, J = 1.0 Hz), 1.95-2.01 (m, 3H), 2.04-2.10 (m, 4H), 2.24-2.27 (m, 2H), 5.03 (dd, 1H, J = 3.5, 3.9 Hz), 5.05 (td, 1H, J = 5.5, 1.2 Hz), 5.32 (dd, 1H, J = 3.5, 1.2 Hz), 5.32 (q, 1H, J = 1.2 Hz); 13C NMR (CDCI3, 125 MHz) 3 -0.13, 15.32, 15.55, 23.30, 25.37, 37.75, 33.14, 39.10, 59.32, 74.74, 33.35, 105.07.124.27, 124.39, 134.25, 140.29, 147.55; IR (neat) 3322 br, 2913, 1353, 2172, 1553, 1250, 1023, 343 cm". Anal calcd for C19H31IOSi: C, 53.02; H, 7.25. Found: C, 53.20; H, 7.45. Colorless oil; Rf = 0.25 (9:1 hexanes/Et2O). Preparation of alkyne 356 TMS TMS '_ \\ '_ \\ 0'" TIPSCI, DMAP OTIPS CH2Cl2, rt 355 356 To a solution of alcohol 355 (86 mg, 0.20 mmol) in 2 mL of CH2CI2 at room temperature was added DMAP (48.4 mg, 0.40 mmol) and TIPSCI (0.086 mL, 0.40 mmol) respectively. The solution was stirred overnight and then quenched with H2O. The aqueous phase was separated and extracted with 320 (2 * 10 mL). The combined organic layer was washed with brine (15 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column Chromatography on silica gel using 2% EtOAC in hexanes as eluent to give 356 (80.4 mg, 0.137 mmol, 69%) as a colorless oil. 1H NMR (CDCI3, 500 MHz) 6 0.12 (s, 9H), 1.04-1.10 (m, 21H), 1.57 (s, 3H), 1.64 (d, 3H, J =2.2 Hz), 1.81 (d, 236 3H, J: 1.1 Hz), 1.98-2.05 (m, 2H), 2.06-2.09 (m, 4H), 2.25-2.28 (m, 2H), 5.07 (s, 1H), 5.09 (t, 1H, J = 3.3 Hz), 5.29 (dq, 1H, J = 9.3, 2.2 Hz), 5.84 (q, 1H, J = 1.1 Hz); 130 NMR (CDCI3, 125 MHz) 6 -0.15, 12.24, 15.89, 16.71, 17.95, 23.89, 25.98, 37.91, 38.31, 39.14, 60.46, 74.66, 87.88, 106.98, 124.64, 126.16, 134.15, 136.47, 147.88; IR (neat) 29445, 28675, 2172w, 1464m, 1250m, 1059s, 8435 cm' 1. Anal calcd for C23H51IOSI2: C, 57.31; H, 8.76. Found: C, 57.33, H, 9.04. Colorless oil; Rf: 0.22 (hexanes). Preparation of carbene complex 357 TMS 0M6 TMS l \\ 1) Cr(CO)6, THF, -78 °C (OC)5Cr \\ 2) n-BuLl or t-BuLl, -78 °C to rt — OTIPS 6 OTIPS — 3) M83OBF4, 1Z1 CHQCIz/HQO. rt —— .— 356 357 To a solution of vinyl iodine 356 (50 mg, 0.085 mmol) in 2 mL of THF at room temperature was added Cr(CO)6 (20.6 mg, 0.094 mmol) as a powder. The solution was cooled to -78 °C, and t-BuLi (1.0 mL, 0.17 mmol) was added dropwise. The solution was stirred for 30 minutes at —78 °C, and then warmed up to room temperature slowly and stirred for 1.5 hours. The solvent of the reaction was removed in vacuo, and the residue was dissolved in 2 mL of 1:1 mixture of H20/CH2CI2. Upon addition of Me30BF4, the solution turned red immediately. After stirring 30 minutes at roomtemperature, 10 mL of saturated aqueous NaH003 and 10 mL of B20 was added to the above solution. The aqueous layer was extracted with Et2O until the color of the aqueous layer was pale. The 237 combined organic layer was washed with brine (20 mL), dried over M2804 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 2% EtOAC in hexanes as eluent to give carbene complex 357 (38.6 mg, 0.056 mmol, 65%) as a red Oil. 1H NMR (CDCI3, 500 MHz) 6 0.12 (s, 9H), 1.04-1.08 (m, 21H), 1.60 (s, 3H), 1.64 (s, 3H), 1.82 (s, 3H), 1.98-2.20 (m, 8H), 4.69 (s, 3H), 5.08 (d, 1H, J = 8.0 Hz), 5.13 (t, 1H, J = 6.4 Hz), 5.29 (t, 1H, J = 7.6 Hz), 7.20 (s, 1H); ”C NMR (CDCI3, 125 MHz) 6 -0.16, 12.24, 15.90, 16.68, 17.89, 17.94, 20.59, 26.01, 37.88, 39.09, 39.76, 60.48, 66.15, 87.91, 106.98, 124.89, 126.19, 133.90, 136.44, 141.01, 216.80, 223.99, 339.86; IR (neat) 2946m, 2869m, 2170w, 20585, 1941vs, 1250m, 843m, 667m cm". Red oil; Rf: 0.45 (hexanes). Preparation of MOM protected vinyl iodine 358 l I , -' \\ MOMCl, DIPEA — \\ OH = OMOM -" CH2CI2, I1, 24 I1 — 333 358 To a solution of 333 (562 mg, 1.57 mmol) in 10 mL of CH2CI2 at room temperature was added DIPEA (0.820 mL, 4.71 mmol) and MOMCI (0.238 mL, 3.14 mmol). The resulting solution was stirred for 1 day, and then quenched with saturated aqueous NaHCOa (10 mL). The aqueous layer was extracted with 320 (2 * 10 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SOa, filtered and concentrated. The crude product was purified by Chromatography on silica gel using 9:1 hexanes/EtOAC as eluent to give an 80% 238 yield of MOM ether 358 (504 mg, 1.25 mmol). 1H NMR (CDCI3, 500 MHz) 6 1.57 (s, 3H), 1.71 (d, 3H, J = 1.3 Hz), 1.30 (d, 3H, J = 1.1 Hz), 2.02-2.14 (m, 6H), 2.25-2.27 (m, 2H), 2.43 (d, 1H, J = 2.1 Hz), 3.33 (s, 3H), 4.50 (d, 1H, J = 5.9 Hz), 4.32 (d, 1H, J = 5.9 Hz), 5.02-5.09 (m, 2H), 5.29 (dq, 1H, J = 3.9, 1.2 Hz), 5.33- 5.34 (m, 1H); 13C NMR (CDCI3, 125 MHz) 315.33, 15.57, 23.35, 25.94, 37.34, 33.24, 39.20, 55.51, 51.45, 73.13, 74.55, 32.13, 93.13, 121.53, 124.35, 134.44, 141.55, 147.32; IR (neat) 3295, 2925, 1449, 1150, 1094, 1023, 924, 529 cm"; HRMS (CI) calcd for (C13H2702I+H)+ m/z 403.1134, meas 403.1124. Colorless oil; Rr = 0.34 (9:1 hexanes/EtOAC). Preparation of carbene complex 359 O— l 1) Cr(CO)6, THF, -73 °C \\ 2) PhLi, -73 °C (OC)5cr __ \\ OMOM = _ — 3) n-BuLi, -78 °C to rt 3) Me3OBF4, DCM/H20 — 358 35g OMOM To a solution of vinyl iodine 358 (49.1 mg, 0.122 mmol) in THF (5 mL) at room temperature was added Cr(CO)6 (30 mg, 0.136 mmol) as a powder. The solution was cooled to —78 °C, and PhLi (0.076 mL, 0.122 mmol, 1.6 M in THF) was added dropwise. After stirring for 30 minutes at -78 °C, n-BuLi (0.047 mL, 0.122 mmol, 2.6 M in hexanes) was added dropwise. The solution was stirred for another 30 minutes, and then warmed up to room temperature and stirred for 1.5 hours. The solvent of the reaction was removed in vacuo, and the residue was dissolved in 1:1 mixture of H2O/CH2CI2. Upon addition of M83OBF4 (36 mg, 0.249 239 mmol), the solution turned red immediately. After stirring 30 minutes at room temperature, saturated aqueous NaHC03 (10 mL) and B20 (10 mL) was added to quench the alkylation reaction. The aqueous layer was extracted with 320 until the color of the aqueous layer was pale. The combined organic layer was washed with brine, dried over M9804 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 9:1 hexanes/EtOAC as eluent to give carbene complex 359 as a red oil (26.6 mg, 0.052 mmol, 43%). 1H NMR (CDCI3, 500 MHz) 6 1.60 (s, 3H), 1.71 (d, 3H, J = 1.1 Hz), 1.82 (s, 3H), 2.03-2.21 (m, 8H), 2.44 (d, 1H, J = 2.2 Hz), 3.38 (s, 3H), 4.60 (d, 1H, J = 6.9 Hz), 4.70 (s, 3H), 4.83 (d, 1H, J = 6.9 Hz), 5.05 (dd, 1H, J = 8.9, 2.2 Hz), 5.10-5.13 (m, 1H), 5.28-5.30 (m, 1H), 7.21 (s, 1H); 13C NMR (CDCI3, 125 MHz) 6 15.60, 16.55, 20.60, 25.98, 37.88, 39.18, 39.75, 55.64, 61.54, 66.18, 73.14, 82.22, 93.20, 115.23, 121.77, 124.57, 134.27, 141.02, 141.47, 216.82, 223.97 (The carbene carbon was not located); IR (neat) 3308, 2919, 2058, 1931, 555 cm". Red Oil; R, = 0.19 (9:1 hexanes/EtOAC). Thermolysis of carbene complex 349 O OTIPS O QTIPS O— T (0050' _ \\ THF, 0.02 M OTIPS 80°C.12h 349 This procedure for the themolysis of 349 was adopted from that reported by Jie Huang.91 The carbene complex 349 (212 mg, 0.341 mmol) was dissolved 240 in THF (17 mL) and transferred to a Schlenk flask equipped with a threaded Teflon high vacuum stopcock. The reaction mixture was deoxygenated by the freeze-pump-thaw procedure with 3 cycles. Then the flask was back filled with an argon atmosphere at room temperature, sealed and heated to 80 °C. After the reaction was completed (indicated by the fading of the red color of 349), the solvent was removed in vacuo. The residue was taken up in 1:1 mixed solvent of 820 and CH2CI2, and stirred in air for 12 hours. Then the solvent was removed again and the residue was taken up in pure 320. The insoluble material was removed by filtration through silica gel in a pipette-sized column using Et20 as the eluent. Concentration of the filtrate provided the crude product mixture, which was further purified by flash column chromatography on silica gel (45:1:1 hexanes/Et2O/CH2CI2 as the eluent) to give a 37% yield of major isomer (57.7 mg, 0.126 mmol) and a 19% yield of minor isomer (29.7 mg, 0.065 mmol). The 2:1 ratio of diastereomers 360 and 361 was also verified on the crude reaction mixture by 1H NMR based on the integral of the following vinyl peaks: 6 6.99 for 360 and 6.42 for 361. Major isomer 360 1H NMR (CDCI3, 500 MHz) 6 0.98-1.06 (m, 21H), 1.10 (s, 3H), 1.34-1.42 (m, 2H), 1.52 (s, 3H), 1.64 (s, 3H), 1.67-2.09 (m, 4H), 2.26-2.39 (m, 2H), 3.63 (s, 3H), 4.48 (d, 1H, J = 11.4 Hz), 4.67 (d, 1H, J = 8.1 Hz), 4.90 (d, 1H, J = 3.3 Hz), 5.42 (dd, 1H, J = 9.0, 0.9 Hz), 6.99 (dd, 1H, J = 3.3, 0.9 Hz); 13C NMR (CDCI3, 125 MHz) 6 12.13, 15.28, 15.67, 17.91, 17.96, 25.53, 29.85, 36.24, 37.96, 46.70, 54.71, 64.93, 65.83, 110.40, 124.70, 129.97, 134.18, 134.38, 134.86, 141.82, 151.12, 202.25; IR (neat) 2944, 2867, 1647 cm'1; MS(EI) 241 m/z (% rel intensity) 458 M+ (10), 430 (7), 415 (18), 347 (19), 324 (52), 279 (66), 241 (80), 189 (41), 131 (30), 115 (34), 103 (48), 81 (100), 75 (100). HRMS calcd for C23H45038i m/z 458.3216, meas 458.3218. Light yellow Oil; Rf = 0.65 (10:1:1 hexanes/Et2O/CH2CI2). Minor isomer 361 1H NMR (CDCI3, 500 MHz) 6 0.99-1.03 (m, 21H), 1.12 (s, 3H), 1.35-1.56 (m, 2H), 1.43 (5, 3H), 1.45 (s, 3H), 1.85-2.13 (m, 5H), 2.30 (t, 1H, J = 11.4 Hz), 3.60 (s, 3H), 4.59 (t, 1H, J = 8 Hz), 4.86 (d, 1H, J = 8.1 Hz), 4.93 (d, 1H, J = 2.7 Hz), 5.72 (d, 1H, J = 8.1 Hz), 6.42 (d, 1H, J = 3.0 Hz); 13C NMR (CDCI3, 125 MHz) 6 12.19, 15.45, 15.50, 17.99, 25.29, 28.30, 36.01, 38.11, 39.43, 50.14, 54.80, 72.73, 111.05, 123.03, 130.67, 132.29, 134.92, 137.11, 138.35, 149.65, 201.08; IR (neat) 2940, 2864, 1651 cm"; MS (EI) m/z (% rel intensity) 458 M+ (2), 415 (33), 347 (15), 279 (100), 241(11), 189 (13), 131 (30), 103 (38), 81 (67), 75 (68); HRMS calcd for C28H45038i m/z 458.3216, meas 458.3216. Light yellow solid, mp 84-86 °C; Rf = 0.60 (10:1:1 hexanes/Et2O/CH2CI2). Thermolysis of carbene complex 359 (OC)5Cr \\ THF, 5 mM OMOM 30 °C. 12 h 359 The carbene complex 359 (26.6 mg, 0.052 mmol) was dissolved in THF (10.4 mL) and transferred to a Schlenk flask equipped with a threaded Teflon 242 high vacuum stopcock. The reaction mixture was deoxygenated by the freeze- pump-thaw procedure with 3 cycles. Then the flask was back filled with an argon atmosphere at room temperature, sealed and heated to 80 °C. After the reaction was completed (indicated by the fading of the red color of 359), the solvent was removed in vacuo. The residue was taken up in a 1:1 mixture of B20 and CH2C12, and stirred in air for 12 hours. Then the solvent was removed again and the residue was taken up in pure 320. The insoluble material was removed by filtration through silica gel in a pipette-sized column using 820 as the eluent. Concentration of the filtrate provided the crude product mixture, which was further purified by flash column chromatography on silica gel (15:1:1 hexanes/EtzO/CH2CI2 as the eluent) to give a 1:1 ratio of 362 (2.2 mg, 0.0064 mmol, 12%) and 363 (2.5 mg, 0.0072 mmol, 14%). The ratio of diastereomers 362 and 363 was determined on the crude reaction mixture by 1H NMR based on the integral of the following vinyl peaks: 6 6.92 for 362 and 6.58 for 363. Isomer 362 1H NMR (CDCI3, 500 MHz) 6 1.14 (s, 3H), 1.39-1.42 (m, 1H), 1.52 (s, 3H), 1.69 (s, 3H), 1.71-1.76 (m, 1H), 1.87-1.89 (m, 1H), 1.93-2.02 (m, 2H), 2.08-2.12 (m, 1H), 2.24-2.36 (m, 2H), 3.34 (s, 3H), 3.63 (s, 3H), 4.50 (d, 1H, J = 11.3 Hz), 4.55 (d, 1H, J = 6.4 Hz), 4.57 (d, 1H, J = 7.8 Hz), 4.71 (d, 1H, J = 6.4 Hz), 4.90 (d, 1H, J = 3.2 Hz), 5.37 (4.57 (d, 1H, J = 9.8 Hz), 6.92 (dd, 1H, J = 3.1 Hz, 1.0 Hz); 13’0 NMR (CDCI3, 125 MHz) 6 15.37, 15.71, 25.41, 29.59, 35.93, 38.16, 39.33, 49.56, 54.77, 55.49, 67.56, 93.66, 110.64, 124.55, 126.48, 134.60, 135.07, 138.80, 138.90, 150.80, 202.12; IR (neat) 2919, 1647, 1383, 1036 cm-1; mass spectrum m/z (% rel intensity) 346 M+ (1), 318 (5), 284 (14), 243 253 (12), 241 (10), 212 (17), 203 (22), 189 (81), 175 (16), 164 (14), 151 (19), 91 (24), 81 (23), 67 (16), 45 (100). HRMS (FAB) calcd for (C21H3004+H)* m/z 347.2221; meas 347.2222. Light yellow solid, mp. 77-79 °C; Rr = 0.28 (9:1 hexanes/Et2O). Isomer 363 1H NMR (CDCI3, 500 MHz) 6 1.17 (s, 3H), 1.30-1.37 (m, 1H), 1.45 (s, 3H), 1.48 (s, 3H), 1.84-1.89 (m, 1H), 1.92-2.06 (m, 3H), 2.10-2.15 (m, 2H), 2.25 (ddd, 1H, J= 13.9, 11.9, 2.1 Hz), 3.30 (s, 3H), 3.60 (s, 3H), 4.58 (d, 1H, J = 6.8 Hz), 4.59-4.62 (m, 1H), 4.65 (d, 1H, J = 6.8 Hz), 4.77 (d, 1H, J = 8.6 Hz), 4.98 (d, 1H, J = 3.0 Hz), 5.64 (d, 1H, J = 8.3 Hz), 6.58 (d, 1H, J = 3.0 Hz); 13C NMR (CDCI3, 125 MHz) 6 15.58, 15.65, 25.07, 27.32, 35.16, 38.18, 39.44, 50.29, 54.79, 55.33, 75.07, 93.81, 111.96, 123.52, 126.42, 135.55, 136.01, 136.48, 137.65, 149.53, 201.88; IR (neat) 2917, 2849, 1649, 1390, 1042 cm"; mass spectrum m/z (% rel intensity) 346 M’ (0.5), 318 (12), 241 (12), 189 (38), 91 (22), 81 (30), 45 (100). HRMS (Cl) calcd for (C21H3004+H)+ m/z 347.2222, meas 347.2213. Yellow oil; R; = 0.20 (9:1 hexanes/E120). Preparation of dienone ketone 369 O OTIPS 1) LICHZTMS, THF, rt, 15 min 2) KOtBu, rt. 1.5 h 3) HCI, rt, MeOH. 5 min This procedure for the preparation of 369 was adopted from that reported by Jie Huang.91 Trimethylsilylmethyllithium (0.13 mmol, 0.13 mL, 1.0 M in THF) 244 was added dropwise to a solution of compound 361 (20 mg, 0.0437 mmol) in 4.3 mL of THF at room temperature. The solution was stirred for 10 minutes, and then potassium tert-butoxide (10 mg, 0.89 mmol) was added and stirred for 1.5 hours. The light brown solution was quenched with H2O. The aqueous phase was separated and extracted with 320 (3 * 10 mL). The combined organic layer was washed with brine (15 mL), dried over Na2SO.r and concentrated in vacuo to give an unstable enol ether. The residue was dissolved in 1 mL of methanol, then treated with 1 mL of 1% aqueous HCI and stirred at room temperature for 5 minutes. The mixture was diluted with 320 (5 mL) and neutralized with saturated aqueous NaHCO:, (5 mL). The aqueous phase was separated and then extracted with 320 (3 * 10 mL). The combined organic layer was washed with brine (15 mL), and then dried over M9804 and concentrated in vacuo. The residue was purified by flash column Chromatography on silica gel using 9:1 hexanes/Et20 as eluent to give ketone 369 (15.4 mg, 0.037 mmol, 35%). 1H NMR (CDCI3, 500 MHz) 6 0.98-1.06 (m, 24H), 1.34 (s, 3H), 1.38 (s, 3H), 1.52-1.68 (m, 2H), 1.95- 2.11 (m, 6H), 2.17 (d, 1H, J= 15.6 Hz), 2.42 (d, 1H, J= 15.6 Hz), 4.62 (d, 1H, J= 10.4 Hz), 4.98 (d, 1H, J = 7.4 Hz), 5.42 (d, 1H, J = 7.4 Hz), 5.46 (s, 1H), 5.78 (s, 1H), 6.44 (5, 1H); 13C NMR (CDCI3, 125 MHz) 6 12.07, 14.89, 15.22, 17.92, 24.12, 24.63, 34.32, 35.51, 39.28, 42.84, 53.24, 76.25, 120.81, 124.86, 125.85, 129.64, 134.73, 134.81, 143.72, 156.09, 200.74; IR (neat) 2944, 2867, 1676, 1464, 1080, 1051, 881 cm“; mass spectrum m/z (% rel intensity) 442 M+ (3), 399 (41), 130 (30), 103 (54), 91 (20), 81. (40), 75 (100), 62 (63), 58 (45). HRMS calcd 245 for (C23H46028i+H)+ m/z 443.3341, meas 443.3345. White solid, mp. 72-74 °C; Rf = 0.42 (9:1 hexanes/Et2O). Methylation of dienone 369 1) LHMDS,THF, -73 °C, 1 h 7 2) Mel, -78 °C to rt, 11 h This procedure for the preparation of 370 was adopted from that reported by Jie Huang.91 To a solution of ketone 359 (37 mg, 0.0337 mmol) in THF (4.0 mL) at -78 °C was added LHMDS (0.167 mL, 0.167 mmol, 1.0 M solution in THF) dropwise. After stirring for 1 hour at —78 °C, iodomethane (15.6 uL, 0.167 mmol) was added. The cooling bath was removed immediately and the reaction mixture was allowed to warm to room temperature. After stirring for 11 hours, 5 mL of saturated aqueous NH4CI was added to the flask. The aqueous layer was extracted with 320 (2 * 10 mL). The combined organic layer was washed with brine (10 mL), and then dried over MgSOa. The residue was purified by flash column Chromatography on silica gel using 9:1 hexanes/Et20 as eluent to give ketone 370 (37.4 mg, 0.082 mmol, 98%). 1H NMR (CDCI3, 500 MHz) 6 0.95- 1.06 (m, 27H), 1.23-1.29 (m, 2H), 1.34 (s, 3H), 1.37 (s, 3H), 1.64-1.71 (m, 1H), 1.90-2.15 (m, 6H), 4.62 (d, 1H, J = 10.4 Hz), 4.98 (d, 1H, J = 7.5 Hz), 5.42 (d, 1H, J = 8.0 Hz), 5.45 (s, 1H), 5.66 (s, 1H), 6.54 (s, 1H); 13C NMR (CDCla, 125 MHz) 6 12.06, 13.69, 14.93, 15.14, 17.90, 17.93, 21.22, 24.22, 34.66, 36.46, 246 39.33, 45.85, 55.03, 76.28, 122.88, 123.75, 124.99, 129.79, 134.77, 134.83, 142.13, 155.05, 205.70; IR (neat) 2941s, 28875, 16785, 1462w, 1267w, 1057m, 885w cm'1; mass spectrum m/z (% rel intensity) 456 M+ (2), 413 (33), 265 (10), 157 (13), 135 (31), 115 (33), 105 (25), 104 (40), 103 (79), 95 (19), 93 (20), 91 (23), 82 (27), 81 (36), 79 (21), 75 (52), 75 (100), 73 (28), 61 (80), 59 (43), 55 (41). HRMS calcd for (C29H4802SI+H)+ m/z 457.3500, meas 457.3502. White solid, mp. 78-80 °C; Rr = 0.44 (9:1 hexanes/Et2O). Reduction of dienone 370 NaBH4, EtOH/Eth, rt, 2 d To a solution of enone 370 (74 mg, 0.162 mmol) in 3.0 mL of 2:1 mixture Of EtOH/Et20 at room temperature was added NaBH4 (28 mg, 0.823 mmol). The reaction mixture was stirred until 370 was totally consumed (monitored by TLC). Then the reaction was quenched with H20 (20 mL). The aqueous layer was extracted with 320 (3 * 10 mL). The combined organic layer was washed with brine (15 mL) and dried over Na2SO4. Filtration and concentration followed by flash Chromatography on silica gel using 19:1 hexanes/EtOAC as eluent provided a 3:1 mixture of alcohol 373b and alcohol 373a as a colorless oil (70 mg in total, 0.153 mmol, 94%). These compounds can be completed separate with these chromatographic conditions but are most easily isolated together. 247 Major isomer 373b 1H NMR (CDCI3, 500 MHz) 6 0.73 (d, 3H, J = 6.8 Hz), 1.00 (s, 3H), 1.01-1.03 (m, 21H), 1.23-1.27 (m, 1H), 1.32 (s, 3H), 1.32-1.40 (m, 1H), 1.43 (s, 3H), 1.69-1.72 (m, 1H), 1.76-1.91 (m, 3H), 1.97-2.13 (m, 3H), 4.58 (t, 1H, J = 6.2 Hz), 4.65 (d, 1H, J = 10.8 Hz), 4.84 (d, 1H, J = 7.2 Hz), 5.02 (s, 1H), 5.35 (s, 1H), 5.46 (d, 1H, J = 7.2 Hz), 6.03 (s, 1H); 13C NMR (CDCI3, 125 MHz) 6 7.96, 12.06, 14.56, 15.28, 17.95, 18.02, 21.94, 23.85, 33.59, 35.27, 39.25, 45.41, 45.50, 68.32, 115.67, 124.77, 127.77, 131.36, 132.36, 135.49, 140.19, 142.51. IR (neat) 3397br, 2942, 2868, 1464, 1385, 1082, 1053, 883 cm'1; mass spectrum m/z (% rel intensity) 458 M+ (0.3), 440 (4), 397 (3), 359 (6), 266 (7), 173 (14), 171 (14), 131 (84), 119 (22), 115 (21), 105 (21), 103 (84), 91 (25), 81 (24), 75 (100), 61 (35), 59 (23). HRMS (FAB) calcd for (C29H,c,oO2Si-H)+ m/z 457.3500, meas 457.3502. Colorless oil, Rr = 0.31 (9:1 hexanes/Et2O). Minor isomer 373a 1H NMR (CDCI3, 500 MHz) 6 0.77 (d, 3H, J = 7.3 Hz), 0.94 (s, 3H), 0.98-1.03 (m, 21H), 1.37 (s, 3H), 1.44 (s, 3H), 1.46-1.61 (m, 3H), 1.69-1.73 (m, 1H), 1.90-2.13 (m, 5H), 3.91 (t, 1H, J= 4.4 Hz), 4.66 (d, 1H, J = 9.3 Hz), 4.88 (d, 1H, J = 7.4 Hz), 5.11 (t, 1H, J = 1.6 Hz), 5.45 (d, 1H, J = 7.4 Hz), 5.53 (d, 1H, J = 4.5 Hz), 6.08 (d, 1H, J = 1.5 Hz); 13C NMR (CDCI3, 125 MHz) 6 12.08, 12.15, 14.95, 15.28, 17.95, 17.97, 22.11, 23.88, 35.27, 37.19, 39.06, 42.08, 46.15, 72.58, 116.25, 124.72, 125.40, 130.95, 132.61, 135.60, 139.44, 143.11; IR (neat) 3368, 2941, 2868, 1462, 1385, 1082, 1055, 884 cm"; mass spectrum m/z (% rel intensity) 458 M+ (1), 440 (11), 359 (20), 167 (18), 185 (15), 173 (25), 171 (24), 157 (27), 145 (18), 143 (17), 133 (19), 131 (94), 129 (16), 119 (24), 115 (25), 105 (24), 103 (81), 95 (16), 91 (23), 87 (16), 81 (33), 79 248 (16), 79(16), 75 (100), 73 (40), 61 (44), 59 (32); HRMS (FAB) calcd for (C29H5002Si)+ m/z 458.3578, meas 458.3580. Colorless Oil; Rf = 0.28 (9:1 hexanes/EtzO). Preparation of PNB ester of alcohol 381 OTIPS PNBOH, DEAD, PPh3 v Tol, 0 °C to rt, 2.5 h To a solution of para-nitrobenzoic acid (27.7 mg, 0.166 mmol), alcohol 373b (38 mg, 0.083 mmol) and PPh3 (43 mg, 0.166 mmol) in 1.0 mL of toluene at 0 °C was added DEAD (27.7 uL, 0.166 mmol) dropwise. The reaction mixture was stirred at 0 °C for 1 hour, and then allowed to warm up to room temperature for 1.5 hours. The reaction was quenched with 5 mL of a saturated aqueous NaH003. The aqueous layer was extracted with 320 (3 * 5 mL). The combined organic layer was washed with brine (10 mL) and dried over Na2SO4. Filtration and concentration followed by flash chromatography on silica gel using 19:1 hexanes/EtOAc as eluent provided ester 381 (46.3 mg, 0.076 mmol, 91%) as a colorless oil. 1H NMR(CDC13, 500 MHz) 6 0.92 (d, 3H, J = 7.3 Hz), 0.98 (5, 3H), 1.00-1.04 (m, 21H), 1.32 (s, 3H), 1.41-1.47 (m, 2H), 1.49 (s, 3H), 1.73-1.84 (m, 3H), 1.92-2.25 (m, 4H), 4.70 (d, 1H, J = 10.4 Hz), 4.92 (d, 1H, J =7.3 Hz), 5.28 (s, 1H), 5.29 (d, 1H, J = 0.8 Hz), 5.47 (d, 1H, J = 4.0 Hz), 5.58 (d, 1H, J = 4.8 Hz), 6.20 (s, 1H), 8.16 (d, 2H, J = 9.0 Hz), 8.27 (d, 2H, J = 9.0 Hz); 13C NMR 249 (CDCI3, 125 MHz) 6 12.11, 14.70, 14.90, 15.21, 17.95, 17.99, 21.62, 23.84, 35.00, 37.17, 39.25, 42.05, 43.78, 75.83, 117.99, 120.11, 123.57, 125.09, 130.52, 130.94, 133.11, 135.19, 136.13, 142.15, 142.72, 150.55, 164.01; IR (neat) 2944, 2866, 1723, 1532, 1348, 1271, 1115, 1101, 1082, 918, 735, 720, 682 cm"; mass spectrum m/z (% rel intensity) 607 M” (0.2), 280 (60), 266 (18), 185 (21), 173 (47), 171 (42), 159 (25), 157 (36), 150 (85), 143 (26), 133 (28), 131 (100), 119 (40), 115 (27), 105 (30), 104 (39), 103 (98), 95 (31), 81 (95), 75 (100), 61 (58), 59 (52). HRMS (CI) calcd for (C29H4QOSI)+ m/z 441.3553 meas 441.3562. Colorless oil; Rf = 0.40 (19:1 hexanes/EtOAC). Cleavage of PNB ester 381 K2C03 MeOH/E120, TI, 1 h To a solution of PNB-ester 381 (30.8 mg, 0.051 mmol) in 4.5 mL of a mixture of MeOH/Et2O (2:1) at room temperature was added K2C03 (35 mg, 0.25 mmol) as a powder. The reaction mixture was stirred at room temperature until the starting material was totally consumed, and then quenched with saturated aqueous NH4CI (5 mL). The aqueous layer was extracted with 320 (3 * 5 mL). The combined organic layer was washed with brine (10 mL) and dried over Na2SOa. Filtration and concentration followed by flash chromatography on silica 250 gel using hexanes/EtOAC (9:1) as eluent provided alcohol 373a (23.1 mg, 0.050 mmol, 99%) as a colorless oil. Preparation of acetate 374b ACQO, Py., It, 4 h To a solution of alcohol 373b (12.9 mg, 0.0282 mmol) in 1.0 mL of pyridine was added 0.2 mL of acetic anhydride. The mixture was stirred at room temperature for 4 hours and then was evaporated to dryness. The residue was purified by silica gel column chromatography using 9:1 hexanes/EtOAc as eluent to give acetate 374b (14.3 mg, 0.0282 mmol, 100%) as a colorless oil. 1H NMR (CDCI3, 500 MHz) 6 0.72 (d, 3H, J = 6.8 Hz), 0.95 (s, 3H), 1.00-1.04 (m, 21H), 1.31 (s, 3H), 1.44 (s, 3H), 1.46-1.60 (m, 2H), 1.76-1.93 (m, 4H), 2.00-2.13 (m, 3H), 2.05 (s, 3H), 4.65 (d, 1H, J = 10.9 Hz), 4.84 (d, 1H, J =7.3 Hz), 5.04 (s, 1H), 5.25 (5, 1H), 5.46 (d, 1H, J = 7.1 Hz), 5.64 (dd, 1H, J = 6.0, 2.2 Hz), 6.05 (s, 1H); 13C NMR (CDCI3, 500 MHz) 6 9.03, 12.04, 14.61, 15.38, 17.96, 21.28, 21.70, 23.87, 33.72, 35.37, 39.25, 42.65, 45.60, 71.87, 76.64, 116.09, 123.62, 124.77, 131.13, 132.60, 135.53, 141.14, 142.21, 170.83; IR (neat) 2944, 2867, 1742, 1242, 1082, 883 cm"; mass spectrum m/z (% rel intensity) 500 M+ (0.2), 398 (2), 359(2), 268(8), 173 (100), 131 (24), 103 (18), 81 (35), 75 (28), 61 (17), 59 (15), 251 43 (35). HRMS (FAB) calcd for (C31H52038i)+ m/z 500.3682, meas 500.3686. Colorless oil; R; = 0.33 (19:1 hexanes/EtOAC). Preparation of acetate 374a OTIPS ACZO, Py., rt, 4 h To a solution of alcohol 373a (28 mg, 0.061 mmol) in 1.0 mL of pyridine was added 0.5 mL of acetic anhydride. The mixture was stirred at room temperature for 4 hours and then was evaporated to dryness. The residue was purified by silica gel column Chromatography using 9:1 hexanes/EtOAC as eluent to give acetate 3743 (30.5 mg, 0.061 mmol, 100%) as a colorless oil. 1H NMR (CDCI3, 500 MHz) 6 0.82 (d, 3H, J = 7.4 Hz), 0.93 (s, 3H), 0.98-1.01 (m, 21H), 1.34 (s, 3H), 1.45 (5, 3H), 1.58-1.71 (m, 3H), 1.93-2.14 (m, 6H), 2.00 (s, 3H), 4.65 (d, 1H, J = 10.8 Hz), 4.87 (d, 1H, J = 7.3 Hz), 4.96 (d, 1H, J = 4.8 Hz), 5.13 (t, 1H, J = 1.5 Hz), 5.44-5.45 (m, 2H), 5.13 (s, 1H); 1'~“C NMR (CDCI3, 125 MHz) 3 12.09, 14.69, 14.79, 14.97, 17.98, 21.40, 21.80, 23.88, 34.91, 36.56, 39.27, 41.96, 43.49, 74.19, 77.18, 117.15, 121.12, 124.58, 130.94, 132.86, 135.67, 141.69, 142.51, 170.56; IR (neat) 2941, 2867, 1734, 1240, 1082, 882 cm"; mass spectrum m/z (% rel intensity) 500 M“ (0.1), 457 (2), 397 (7), 267 (11), 174 (15), 173 (100), 171 (25), 157 (26), 145 (25), 142 (16), 133 (21), 129 (70), 115 (16), 105 (27), 103 (44), 95 (22), 81 (56), 75 (60), 61 (38), 59 (40). HRMS (FAB) calcd 252 for (031H5203Si-H)+ m/z 499.3605, meas 499.3608. Colorless oil; Rr = 0.30 (19:1 hexanes/EtOAC). Preparation of allylic alcohol 375b TBAF, THF, rt. 12 L 375b To a solution of compound 374b (39.5 mg, 0.079 mmol) in 2.0 mL of dry THF at room temperature was added TBAF (0.16 mL, 0.16 mmol, 1.0 M in THF) dropwise. The mixture was stirred overnight and then quenched with H2O. The aqueous layer was extracted with Et20 (3 * 10 mL). The combined organic layer was washed with brine (15 mL) and dried over Na2SOa. Filtration and concentration followed by flash chromatography using 4:1 hexanes/EtOAc as eluent provided alcohol 375b (21.8 mg, 0.063 mmol, 80%) as a colorless oil. 1H NMR (CDCI3, 500 MHz) 6 0.74 (d, 3H, J = 6.8 Hz), 0.98 (s, 3H), 1.29-1.34 (m, 1H), 1.36 (5, 3H), 1.44 (s, 3H), 1.48-1.57 (m, 2H), 1.77-1.81 (m, 2H), 1.87-1.96 (m, 3H), 2.10-2.16 (m, 2H), 2.07 (s, 3H), 4.65 (d, 1H, J = 10.8 Hz), 4.93 (d, 1H, J = 7.6 Hz), 5.09 (s, 1H), 5.41 (d, 1H, J = 1.2 Hz), 5.49 (d, 1H, J = 8.3 Hz), 5.66 (dd, 1H, J = 6.0 Hz, 2.3 Hz), 5.97 (s, 1H); 13C NMR (CDCI3, 125 MHz) 6 9.15, 14.79, 15.30, 21.22, 21.71, 23.94, 33.73, 35.02, 39.24, 42.42, 45.57, 71.61, 76.36, 115.95, 124.91, 125.08, 128.09, 135.44, 135.56, 140.90, 141.95, 170.58; IR (neat) 3416br, 2977, 2917, 2851, 1740, 1242, 1020 cm"; mass spectrum m/z 253 (% rel intensity) 344 M+ (0.5), 302(1), 234 (5), 259 (5), 203 (23), 201 (13), 137 (23), 135 (21), 175 (13), 171 (34), 151 (31), 150 (13), 159 (49), 157 (31), 149 (30), 147 (53), 145 (50), 143 (25), 137 (44), 135 (53), 131 (34), 129 (21), 121 (75), 115 (25), 107 (35), 105 (35), 95 (23), 91 (45), 31 (72), 55 (49), 43 (100). HRMS (FAB) calcd for (C22H3203)+ m/z 344.2352, meas 344.2352. White solid, mp. 134-135 °C; Rf = 0.32 (3:1 hexanes/EtOAc). Preparation of allylic alcohol 375a TBAF. THF, rt, 12 h; To a solution of compound 374a (30.5 mg, 0.061 mmol) in 1.2 mL of dry THF at room temperature was added TBAF (0.12 mL, 1.0 M in THF) dropwise. The mixture was stirred overnight and then quenched with H20. The aqueous layer was extracted with B20 (3 * 10 mL). The combined organic layer was washed with brine (15 mL) and dried over Na2804. Filtration and concentration followed by flash chromatography using 4:1 hexanes/EtOAC as eluent provided alcohol 375a (16.4 mg, 0.048 mmol, 78%) as a colorless oil. 1H NMR (CDCI3, 500 MHz) 6 0.84 (d, 3H, J = 7.3 Hz), 0.95 (s, 3H), 1.40 (s, 3H), 1.45 (s, 3H), 1.59- 1.63 (m, 1H), 1.69-1.73 (m, 3H), 1.92-1.95 (m, 2H), 2.01 (s, 3H), 2.04-2.19 (m, 4H), 4.65 (d, 1H, J = 10.7 Hz), 4.95 (d, 1H, J = 8.3 Hz), 4.96 (d, 1H, J = 5.6 Hz), 5.17 (s, 1H), 5.47 (d, 1H, J = 7.8 Hz), 5.60 (d, 1H, J = 4.6 Hz), 6.02 (s, 1H); 13C 254 NMR (CDCI3, 125 MHz) 6 14.89. 14.93, 14.95, 21.36, 21.83, 23.99, 34.94, 36.15, 39.28, 42.03, 43.30, 73.82, 76.86, 116.79, 122.87, 124.68, 127.98, 135.66, 135.89, 141.12, 142.37, 170.48; IR (neat) 3441br, 2917, 1732, 1240, 1017 cm'1; mass spectrum m/z (% rel intensity) 344 M+ (2), 187 (16), 173 (28), 171 (18), 159 (28), 149 (34), 147 (30), 145 (29), 135 (20), 133 (39), 131 (21), 121 (36), 119 (49), 107 (18), 105 (35), 95 (20), 91 (36), 81 (45), 79 (27), 67 (23), 54 (39), 53 (18), 43 (100). HRMS (FAB) calcd for (C22H3203)+ m/z 344.2352, meas 344.2352. Colorless Oil; Rf: 0.29 (3:1 hexanes/EtOAc). Epoxidation of allylic alcohol 375b VO(acac)2, TBP, ‘ Benzene, rt, 1.5 h A solution of newly opened tert-butyl hydroperoxide (75% WNV) in H2O (0.016 mL) was added dropwise to a stirred solution of vanadyl acetylacetonate (25 mol%, 0.011 mmol) and the allylic alcohol 375b (15.0 mg, 0.0436 mmol) in 1.0 mL of benzene at room temperature. The light green solution was turned to yellow brown and was stirred at room temperature for 90 minutes. The mixture was quenched with saturated aqueous Na2S203 (5 mL) and stirred for another 15 minutes. The aqueous layer was extracted with E120 (3 * 5 mL). The combined organic layer was washed with brine (10 mL) and dried over Na2SO4. Filtration and concentration followed by flash Chromatography on silica gel using 2:1 255 hexanes/EtOAc as eluent provided mono-expoxide 376b and bis-epoxide 377b as an inseparable mixture (1 :0.3, 11.7 mg total). This mixture was taken on to the next step without further purification. The following spectral data for 376b was collected on a sample of 6.5:1 mixture of 376bz377b. Mono-epoxide 376b 1H NMR (CDCI3, 500 MHz) 6 0.76 (d, 3H, J = 6.8 Hz), 1.03 (s, 3H), 1.09-1.15 (m, 1H), 1.16 (s, 3H), 1.52 (s, 3H), 1.58-1.65 (m, 1H), 1.81-1.85 (m, 1H), 1.93-1.98 (m, 2H), 2.00-2.25 (m, 4H), 2.07 (s, 3H), 3.28 (d, 1H, J = 8.5 Hz), 3.96 (dd, 1H, J = 8.4, 2.2 Hz), 4.83 (t, 1H, J = 6.1 Hz), 5.15 (s, 1H), 5.41 (s, 1H), 5.74 (dd, 1H, J = 6.1, 2.1 Hz), 6.07 (s, 1H); 13C NMR (CDCI3, 125 MHz) 6 9.05, 15.69, 16.46, 21.18, 22.60, 23.52, 32.81, 33.71, 38.79, 42.18, 45.50, 61.20, 65.54, 71.33, 79.52, 116.48, 121.84, 127.51, 136.71, 137.87, 142.44, 170.56; IR (neat) 3441, 2924, 1728, 1385, 1242, 1022 cm". White solid (not pure); Rr = 0.20 (2:1 hexanes/EtOAc). Oxidation of epoxy alcohol 376b and 377b O DMP, NaH003 ‘ CHZCIZ, 0 °C to rt. 2.5 h Freshly prepared DMP93 (0.064 mmol, 27 mg) was added to a mixture of NaHC03 (22 mg, 0.26 mmol) and a mixture of the epoxy alcohols 376b land 377b (11.7 mg) in 1 mL of dry CH2CI2 at 0 °C. The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature over a period of 2.5 256 hours. The reaction was quenched with saturated aqueous NaHCOa (10 mL). The aqueous layer was extracted with 320 (3 * 10 mL). The combined organic layer was washed with brine (15 mL) and dried over Na2SO4. Filtration and concentration followed by flash chromatography on silica gel using 3:1 hexanes/EtOAc containing 1% Et3N as eluent provided epoxy ketone 378b (10.2 mg, 65% 2 steps) and diepoxyketone 37% (1.6 mg, 10% 2 steps). Mono-epoxy ketone 378b 1H NMR (CDCI3, 500 MHz) 3 0.72 (d, 3H, J = 7.0 Hz), 1.079 (s, 3H), 1.082 (s, 3H), 1.15-1.23 (m, 2H), 1.47-1.53 (m, 1H), 1.55 (s, 3H), 1.86-1.94 (m, 2H), 1.96-2.02 (m, 1H), 2.07 (s, 3H), 2.07-2.21 (m, 3H), 4.04 (s, 1H), 4.98 (t, 1H, J = 6.8 Hz), 5.20 (s, 1H), 5.31 (s, 1H), 5.83 (dd, 1H, J = 5.9, 2.3 Hz), 5.86-5.87 (m, 1H); 13C NMR (CDCI3, 125 MHz) 6 9.16, 14.25, 16.82, 21.04, 22.22, 23.71, 32.30, 32.71, 38.23, 42.40, 45.85, 63.48, 65.18, 70.30, 116.76, 121.43, 129.92, 136.75, 142.80, 143.26, 170.50, 198.01. 1H NMR (CD300, 500 MHz) 6 0.70 (d, 3H, J = 7.0 Hz), 1.03 (d, 3H), 1.09 (s, 3H), 1.12- 1.23 (m, 2H), 1.55 (s, 3H), 1.48-1.63 (m, 1H), 1.89-2.18 (m, 6H), 2.04 (s, 3H), 4.10 (s, 1H), 5.02 (t, 1H, J = 6.3 Hz), 5.26 (s, 1H), 5.34 (s, 1H), 5.77-5.78 (m, 2H); 13C NMR (CD3OD, 125 MHz) 6 9.46, 14.57, 16.74, 20.91, 22.58, 24.61, 33.52, 33.80, 39.01, 43.47, 46.98, 64.69, 66.66, 71.76, 117.86, 122.91, 131.23, 137.91, 144.14, 144.42, 172.04, 199.92. IR (neat) 2926, 1740, 1696, 1385, 1238, 1215, 1024 cm"; mass spectrum m/z (% rel intensity) 358 M+ (0.05), 316 (2), 288 (1), 283(2), 255(2), 149 (17), 147 (26), 121 (24), 109 (22), 105 (21), 93 (17), 91 (29), 81 (24), 79 (20), 55 (23), 43 (100); HRMS (FAB) calcd for (C22H3104)+ m/z 359.2223, meas 359.2222. Colorless oil; Rf = 0.21 (3:1 hexanes/EtOAC). 257 Bis-epoxy ketone 379b 1H NMR (CDCI3, 500 MHz) 6 0.90 (s, 3H), 1.02 (d, 3H, J = 7.2 Hz), 1.15 (s, 3H), 1.22-1.31 (m, 2H), 1.55-1.61 (m, 1H), 1.62 (s, 3H), 1.97-2.06 (m, 2H), 2.09 (s, 3H), 2.10-2.35 (m, 4H), 3.07 (d, 1H, J = 3.2 Hz), 3.12 (d, 1H, J = 3.2 Hz), 3.67 (s, 1H), 5.20 (t, 1H, J = 6.4 Hz), 5.84 (dd, 1H, J = 6.4, 2.3 Hz), 6.01 (dd, 1H, J = 2.3, 1.5 Hz); 13C NMR (CDCI3, 125 MHz) 6 9.71, 14.75, 17.66, 18.03, 20.99, 23.46, 31.39, 31.44, 37.65, 41.89, 42.97, 47.56, 55.63, 63.33, 65.94, 70.41, 119.98, 135.38, 136.52, 142.95, 170.50, 196.09; IR (neat) 2924, 1738, 1730, 1691, 1381, 1235, 1024 cm"; mass spectrum m/z (% rel intensity) 374 M+ (0.01), 163 (19), 131 (18), 119 (23), 91 (25), 81 (26), 79 (20), 67 (22), 54 (17), 43 (100). HRMS (FAB) calcd for (C22H3105)+ m/z 375.2172, meas 375.2171. Colorless oil; Rf = 0.13 (3:1 hexanes/EtOAC). Cleavage of Acetate 378b NaOH, THF/MeOH rt, 45 min 7 A solution of acetate 378b (7.5 mg, 0.0208 mmol) in 1.0 mL of 1:4 mixture of THF/MeOH containing 8.3 mg of NaOH (0.21 mmol) was stirred at room temperature for 45 minutes. The reaction was then quenched with saturated aqueous NH4CI. The aqueous layer was extracted with 820 (3 * 10 mL). The combined organic layer was washed with brine (15 mL) and dried over Na2SO4. Filtration and concentration followed by flash chromatography on silica gel with 258 1:1 hexanes/EtOAc containing 1% Et3N as eluent provided the C13-epimer of phomactin B2 380 (5.9 mg, 0.0186 mmol, 90%) as a colorless oil. 1H NMR (CDCI3, 500 MHz) 6 0.74 (d, 3H, J = 6.9 Hz), 1.09 (s, 3H), 1.10 (s, 1H), 1.13-1.23 (m, 2H), 1.39-1.45 (m, 2H), 1.54 (s, 3H), 1.57 (br, 1H), 1.85-1.95 (m, 3H), 2.08- 2.18 (m, 4H), 4.03 (s, 1H), 4.77 (s, 1H), 4.97-5.00 (m, 1H), 5.17 (s, 1H), 5.28 (s, 1H), 5.94 (s, 1H); 13C NMR (CDCI3, 125 MHz) 6 8.15, 14.25, 16.77, 22.50, 23.74, 32.11, 32.64, 38.25, 44.98, 45.79, 63.34, 65.25, 67.72, 116.31, 121.34, 133.54, 136.79, 142.16, 143.67, 198.35. 1H NMR (coaoo, 500 MHz) 6 0.70 (cl, 3H, J = 6.8 Hz), 1.02 (s, 3H), 1.08 (s, 3H), 1.14-1.20 (m, 1H), 1.35 (s, 1H), 1.39-1.45 (m, 1H), 1.54 (s, 3H), 1.77-1.79 (m, 1H), 1.98-1.98 (m, 1H), 2.06-2.17 (m, 4H), 4.12 (s, 1H), 4.70 (dd, 1H, J = 5.8, 2.2 Hz), 5.01 (t, 1H, J = 6.8 Hz), 5.20 (s, 1H), 5.27 (s, 1H), 5.37 (t, 1H, J = 0.7 Hz); 13C NMR (C0300, 125 MHz) 3 3.34, 14.54, 16.70, 22.83, 24.66, 33.62, 33.84, 39.15, 46.55, 46.97, 64.59, 66.80, 67.87, 116.79, 122.88, 136.14, 138.08, 142.87, 145.32, 200.40; IR (neat) 3483, 2973, 2924, 1689, 1251, 1039, 887 cm"; mass spectrum m/z (% rel intensity) 316 M+ (1), 301 (2), 189 (18), 175 (19), 165 (56), 164 (33), 163 (26), 161 (22), 149 (84), 147 (27), 145 (15), 137 (20), 135 (66), 121 (60), 109 (40), 107 (44), 105 (40), 93 (46), 91 (73), 81 (60), 69 (33), 67 (37), 55 (30), 43 (100). HRMS (FAB) calcd for (C20H2303+H)+ m/z 317.2116, meas 317.2117. Colorless Oil; Rr = 0.31 (1:1 hexanes/EtOAc). 259 Epoxidation of allylic alcohol 375a VO(acaC)2, TBP, A Benzene, rt, 1.5 h A solution of newly opened tert-butyl hydroperoxide (75% WNV) in H2O (0.008 mL) was added dropwise to a stirred solution of vanadyl acetylacetonate (3.2 mg, 0.012 mmol) and the allylic alcohol 375a (16.5 mg, 0.048 mmol) in 1.0 mL of benzene at room temperature. The light green solution was turned to yellow brown and was stirred at room temperature for 90 minutes. The mixture was quenched with saturated aqueous Na2S203 (5 mL) and stirred for another 15 minutes. The aqueous layer was extracted with 320 (3 * 10 mL). The combined organic layer was washed with brine (15 mL) and dried over Na2SO4. Filtration and concentration followed by flash chromatography on silica gel using 2:1 hexanes/EtOAc as eluent provided mono-epoxy alcohol 376a and bis-epoxy alcohol 377a as a 10:1 inseparable mixture (10:1, 11.7 mg in total), 78% based on recovered starting material. A small amount of starting material was also isolated (3.5 mg). The following spectral data for 376a was collected on a sample of 10:1 mixture of 376az377a. Spectrum of mono-epoxy alcohol 376a 1H NMR (CDCI3, 500 MHz) 6 0.86 (d, 3H, J = 7.3 Hz), 1.00 (s, 3H), 1.11-1.18 (m, 2H), 1.19 (s, 3H), 1.28-1.34 (m, 1H), 1.52 (s, 3H), 1.64-1.78 (m, 1H), 1.73-1.78 (m, 1H), 1.94-2.10 (m, 5H), 2.03 (s, 3H), 3.26 (d, 1H, J = 8.8 Hz), 3.97 (d, 1H, J = 8.5 Hz), 4.84-4.86 (m, 1H), 4.99 (dd, 1H, J = 4.8, 3.4 Hz), 5.23 (s, 1H), 5.59 (d, 260 1H, J = 4.5 Hz), 5.13 (s, 1H); 13C NMR (CDCI3, 125 MHz) 3 14.73, 15.94, 15.05, 21.34, 22.35, 23.53, 34.19, 34.52, 33.73, 42.00, 42.35, 51.59, 55.23, 73.55, 79.71, 117.25, 121.90. 125.23. 135.75, 133.23, 142.93, 170.33; IR (neat) 3443, 2924, 1732, 1385, 1240, 1020 cm"; Rr = 0.21 (2:1 hexanes/EtOAc). Oxidation of epoxy alcohols 376a and 3773 O DMP, NaHCO3 ~ CH2C|2, 0 °C to rt, 2.5 h Freshly prepared DMP93 (24.7 mg, 0.058 mmol) was added to a mixture of NaHCOa (20 mg, 0.24 mmol) and a mixture of the epoxy alcohols 376a and 377a (10.5 mg mixture, 0.0264 mmol of 376a) in 0.5 mL of dry CH2CI2 at 0 °C. The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature over a period of 2.5 hours. The reaction was quenched with saturated aqueous NaHC03 (5 mL). The aqueous layer was extracted with 320 (3 * 10 mL). The combined organic layer was washed with brine (15 mL) and dried over Na2804. Filtration and concentration followed by flash chromatography on silica gel using 3:1 hexanes/EtOAC containing 1% Et3N as eluent provided epoxy ketone 378a (6.5 mg, 0.018 mmol, 69%) as a colorless oil. Trace amount of 379a was isolated, but not characterized. Mono-epoxy ketone 378a 1H NMR (CDCI3, 500 MHz) 6 0.83 (d, 3H, J = 7.3 HZ), 1.06 (s, 3H), 1.13 (s, 3H), 1.20-1.26 (m, 1H), 1.29-1.35 (m, 1H), 1.55 (s, 261 3H), 1.71-1.75 (m, 1H), 1.33-1.33 (m, 1H), 2.05 (s, 3H), 2.10-2.19 (m, 4H), 2.27- 2.29 (m, 1H), 4.03 (s, 1H), 5.01-5.02 (m, 1H), 5.05 (dd, 1H, J = 4.5, 1.5 Hz), 5.30 (CI, 1H, J = 1.7 Hz), 5.33 (s, 1H), 5.97-5.93 (m, 1H); 13C NMR (CDCI3, 125 MHz) 3 14.43, 14.51, 15.33, 21.24, 22.25, 23.79, 33.00, 33.33, 33.12, 41.47, 43.43, 53.55, 54.75, 73.02, 117.35, 121.30, 127.93, 135.71, 143.23, 143.75, 170.05, 193.91. 1H NMR (coaoo, 500 MHz) 3 0.79 (d, 3H, J = 7.3 Hz), 1.02 (d, 3H, J = 0.5 Hz), 1.05 (s, 3H), 1.17-1.22 (m, 1H), 1.32-1.37 (m, 1H), 1.53 (s, 3H), 1.70- 1.72 (m, 1H), 1.35-1.39 (m, 1H), 2.00 (s, 3H), 2.02-2.23 (m, 5H), 4.03 (s, 1H), 4.93-5.00 (m, 2H), 5.34 (s, 1H), 5.35 (s, 1H), 5.90-5.91 (m, 1H); 13C NMR (coaoo, 125 MHz) 3 14.74, 14.77, 15.33, 21.05, 22.53, 24.59, 34.54, 35.05, 33.93, 42.93, 44.55, 54.93, 55.33, 74.43, 113.99, 123.39, 129.22, 137.91, 144.53, 145.05, 171.33, 200.34. IR (neat) 2923, 1734, 1590, 1237 cm"; mass spectrum m/z (% rel intensity) 315 (M-42)" (5), 255 (5), 201 (15), 147 (100), 133 (13), 119 (21), 91 (24), 79 (20). HRMS (FAB) calcd for (C22H3004+Na)+ m/z 381.2042, meas 381.2051. Colorless oil; Rr = 0.43 (2:1 hexanes/EtOAC). Cleavage of Acetate 378a rt, 45 min A solution of acetate 378a (6.5 mg, 0.018 mmol) in 1.0 mL of 1:4 mixture Of THF/MeOH containing NaOH (8.4 mg, 0.21 mmol) was stirred at room 262 temperature for 45 minutes. The reaction was quenched with saturated aqueous NH4CI (10 mL). The aqueous layer was extracted with 320 (3 * 5 mL). The combined organic layer was washed with brine (10 mL) and dried over Na2804. Filtration and concentration followed by flash chromatography using 1:1 hexanes/EtOAC containing 1% Et3N as eluent provided 5.4 mg of phomactin B2 306 (0.017 mmol, 94%) as a colorless oil. The following spectral match those reported for the natural product.80b 1H NMR (CDCI3, 500 MHz) 3 0.31 (d, 3H, J = 7.3 Hz), 1.05 (s, 3H), 1.14 (s, 3H), 1.30-1.35 (m, 1H), 1.48-1.52 (m, 1H), 1.55 (s, 3H), 1.69-1.72 (m, 1H), 1.80 (br, 1H), 1.85-1.89 (m, 1H), 2.06-2.19 (m, 4H), 2.27-2.31 (m, 1H), 4.04 (s, 1H), 4.06 (s, 1H), 5.00 (t, 1H, J = 6.4 Hz), 5.26 (s, 1H), 5.27 (d, 1H, J = 1.5 Hz), 6.06 (d, 1H, J =3.9 Hz); 13C NMR (CDCI3, 125 MHz) 6 14.45, 14.95, 16.48, 23.00, 23.65, 33.55, 34.15, 37.61, 41.35, 45.44, 63.54, 64.68, 71.57, 116.74, 122.23, 131.92, 136.67, 141.47, 144.73, 199.61. 1H NMR (C0300, 500 MHz) 6 0.76 (d, 3H, J = 7.3 Hz), 1.02 (s, 3H), 1.05 (s, 3H), 1.26-1.32 (m, 1H), 1.46-1.50 (m, 1H), 1.52 (s, 3H), 1.64-1.67 (m, 1H), 1.85-1.89 (m, 1H), 1.98-2.15 (m, 4H), 2.10-2.30 (m, 1H), 3.92 (t, 1H, J = 3.0 Hz), 4.06 (s, 1H), 5.01 (tq, 1H, J = 6.8 1.2 Hz), 5.19 (s, 1H), 5.27 (d, 1H, J = 1.6 Hz), 5.93 (d, 1H, J = 4.0 Hz); 13C NMR (C0300, 125 MHz) 3 14.52, 15.35, 15.53, 23.70, 24.51, 34.66, 35.34, 38.34, 42.45, 45.90, 64.75, 66.14, 71.98, 117.04, 123.66, 134.28, 137.93, 142.42, 146.62, 201.82. IR (neat) 3477, 2919, 1688, 1381, 1217, 1009 cm"; mass spectrum m/z (% rel intensity) 316 M+ (0.4), 301 (2), 273 (3), 189 (16), 175 (17), 165 (71), 164 (28), 163 (24), 161 (20), 159 (17), 149 (55), 147 (34), 145 (20), 137 (20), 135 (45), 133 (35), 121 (56), 119 (38), 109 (43), 107 263 (41), 105 (49), 93 (53), 91 (81), 81 (56), 77 (48), 69 (26), 67 (48), 55 (74), 53 (48), 43 (100). HRMS (Cl) calcd for (C20H2303+Na)+ m/z 339.1936, meas 339.1945. Colorless oil; R; = 0.31 (1:1 hexanes/EtOAc). Mitsunobu reaction of C13-epimer 380 o PNBOH, DEAD K2003, EtZO/MeOH rt, 45 min To a solution of para-nitrobenzoic acid (6.2 mg, 0.037 mmol), C13-epimer 330 (5.9 mg, 0.0137 mmol) and PPh3 (9.3 mg, 0.037 mmol) in 0.9 mL of toluene at 0 °C was added DEAD (5.9 (1L, 0.037mmol) dropwise. The reaction mixture was stirred at 0 °C for 15 minutes, and then quenched with saturated aqueous NaHC03 (5 mL). The aqueous layer was extracted with 320 (3 * 5 mL). The combined organic layer was washed with brine (10 mL) and dried over Na2SO4. Filtration and concentration followed by flash chromatography using 3:1 hexanes/EtOAC as eluent provided ester 419 (7.0 mg, 0.015 mmol, 81%) as a yellow oil. 1H NMR (CDCI3, 500 MHz) 6 0.92 (d, 3H, J = 7.3 Hz), 1.11 (s, 3H), 1.12 (s, 3H), 1.21-1.25 (m, 1H), 1.37-1.44 (m, 1H), 1.59 (s, 3H), 1.86-1.92 (m, 2H), 2.15-2.22 (m, 4H), 2.38-2.41 (m, 1H), 4.07 (s, 1H), 5.04-5.05 (m, 1H), 5.36 (d, 1H, J = 4.7 Hz), 5.33 (s, 1H), 5.43 (s, 1H), 6.11(d, 1H, J = 4.5 Hz), 3.15 (d, 2H, J = 9.0 Hz), 8.29 (d, 2H, J = 9.0 Hz); 130 NMR (CDCI3, 125 MHz) 6 14.41, 14.61, 16.41, 22.01, 23.88, 33.31, 33.94, 38.19, 41.58, 43.83, 63.83, 64.80, 264 74.49, 118.73, 122.14, 123.72, 126.83, 130.62, 135.45, 136.50, 143.26, 143.86, 150.65, 163.66, 198.61; IR (neat) 2926, 1722, 1690, 15530, 1271, 1101, 720 cm' 1; mass spectrum m/z (% rel intensity) 300 (M-OPNB)+ (3), 299 (4), 151 (73), 150 (63), 148 (91), 146 (100), 133 (26), 120 (80), 119 (100), 115 (25), 105 (91), 103 (36), 94 (16), 93 (33), 91 (91), 81 (49), 79 (21), 77 (25), 69 (21), 67 (22), 55 (73), 53 (25). HRMS (Cl) calcd for (C27H31N05+H)+ m/z 466.2243, meas 466.2237. Colorless oil; Rr = 0.41 (33% EtOAC in hexanes). Cleavage of PNB ester 419 To a solution of PNB-ester 419 (5.0 mg, 0.0108 mmol) in 0.5 mL of MeOH/Et20 (2:1) at room temperature was added K2C03 (7.4 mg, 0.054 mmol) as a powder. The reaction mixture was stirred at room temperature until all of the starting material was consumed, and then quenched with saturated aqueous NH4CI (5 mL). The aqueous layer was extracted with 320 (3 * 5 mL). The combined organic layer was washed with brine (10 mL) and dried over Na2SO4. Filtration and concentration followed by flash chromatography using 1:1 hexanes/EtOAC as eluent provided phomactin 32 306 (2.9 mg, 0.0092 mmol, 85%) as a colorless Oil. 265 Preparation of alcohol 383 O (IHPS TBAF,THF m12h To a solution of 360 (72 mg, 0.157 mmol) in 2.0 mL of THF at room temperature was added TBAF (0.31 mL, 1.0 M in THF). The reaction mixture was stirred overnight and then quenched with 5 mL of water. The aqueous layer was extracted with 320 (3 * 5 mL). The combined organic layer was washed with brine (5 mL), and then dried over MgSO4, concentrated and chromatographed on silica gel using 9:1 hexanes/EtOAc as eluent to afford a 83% yield of the alcohol 383 (39.5 mg, 0.131 mmol). 1H NMR (CDCI3, 500 MHz) 6 1.13 (s, 3H), 1.38- 1.42 (m, 2H), 1.52 (s, 3H), 1.57 (br s, 1H), 1.69 (s, 3H), 1.70-1.75 (m, 1H), 1.86- 1.89 (m, 1H), 1.92-1.98 (m, 2H), 2.25-2.36 (m, 2H), 3.63 (s, 3H), 4.49 (d, 1H, J = 11.3 Hz), 4.67 (d, 1H, J = 9.3 Hz), 4.90 (d, 1H, J = 3.2 Hz), 5.46 (d, 1H, J = 9.3 Hz), 6.99 (d, 1H, J = 3.2 Hz); 13C NMR (CDCI3, 125 MHz) 6 15.32, 15.79, 25.42, 29.62, 35.95, 38.10, 39.21, 49.64, 54.77, 64.44, 110.65, 124.51, 128.33, 134.51, 134.58, 137.36, 140.51, 150.86, 202.29; IR (neat) 3443br m, 2917m, 16455, 1597m, 1383s, 1129m, 1043m, 733m cm"; mass spectrum m/z (% rel intensity) 302 M” (4), 274 (16), 205 (18), 203 (21), 191 (17), 189 (73), 175 (26), 168 (42), 165 (17), 150 (18), 121 (16), 105 (15), 91 (26), 86 (62), 84 (100), 77 (24), 67 (18), 55 (25). HRMS (FAB) calcd for (C19H2503+H)*m/z 303.1959, meas 303.1960. Light yellow needle, mp. 130-132 °C; R; = 0.45 (3:1 hexanes/EtOAC). 266 Preparation of MOM other 362 from alcohol 383 O OH O OMOM 0 MOMCI, DIPEA ‘ O CH2C12, rt, 2 d / / 333 362 To a solution of 383 (166 mg, 0.55 mmol) in 10 mL of CH2CI2 at room temperature was added DIPEA (0.287 mL, 1.65 mmol) and MOMCI (0.083 mL, 1.10 mmol). The resulting solution was stirred for 2 days, and then quenched with saturated aqueous NaHC03 (10 mL). The aqueous layer was extracted with B20 (2 * 10 mL). The combined organic layer was washed with brine (10 mL), dried over Na2804, filtered and concentrated in vacuo. The crude product was purified by Chromatography on silica gel with 9:1 hexanes/EtOAc as eluent to give an 88% yield of MOM ether 362 (167 mg, 0.0484 mmol). The spectral data for this compound matched that for a product obtained from the thermolysis of compound 359 (vide supra). 267 Preparation of TES-ether 384 TESOTf, TEA CHQCIQ, I1, 1h To a solution of 383 (2.2 mg, 0.0073 mmol) in 0.2 mL of CH2CI2 at room temperature was added TEA (10 uL, 0.036 mmol) and TESOTf (3.3 uL, 0.014 mmol). The resulting solution was stirred for 1 hours, and then quenched with saturated aqueous NaHCO3 (2 mL). The aqueous layer was extracted with 820 (2 * 5 mL). The combined organic layer was washed with brine (10 mL), and then dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography on silica gel with 9:1 hexanes/EtOAc as eluent to give a 92% yield of 384 (2.8 mg, 0.0067 mmol). 1H NMR (CDCI3, 500 MHz) 6 0.56 (qd, 6H, J = 7.8, 1.4 Hz), 0.91 (t, 9H, J = 7.8 Hz), 1.12 (s, 3H), 1.38-1.41 (m, 1H), 1.52 (d, 3H, J = 1.0 Hz), 1.66 (d, 3H, J = 1.1 Hz), 1.69-1.75 (m, 1H), 1.84-1.87 (m, 1H), 1.90-1.96 (m, 2H), 2.04-2.08 (m, 1H), 2.23-2.36 (m, 2H), 3.63 (s, 3H), 4.48 (d, 1H, J = 10.0 Hz), 4.63 (dd, 1H, J = 9.3, 1.2 Hz), 4.89 (d, 1H, J = 3.2 Hz), 5.37 (dd, 1H, J = 9.3, 1.0 Hz), 5.95 (dd, 1H, J = 3.2, 1.1 Hz); 1“’C NMR (CDCI3, 125 MHz) 6 4.90, 6.78, 15.34, 15.59, 25.45, 29.75, 36.06, 37.95, 39.20, 49.66, 54.72, 64.70, 110.40, 124.62, 129.59, 134.42, 134.70, 134.78, 141.45, 151.04, 202.29; IR (neat) 2953, 2915, 2876, 1647, 1383, 1086, 843, 747 cm"; mass spectrum m/z (% rel intensity) 416 M+ (7), 319 (23), 227 (24), 282 (57), 269 (17), 200 (21), 251 (41), 241 (71), 203 (23), 139 (94), 137 (22), 175 (21), 173 (20), 115 (45), 103 268 (26), 91 (30), 87 (100), 81 (40), 79 (24), 77 (24), 75 (58), 67 (21), 59 (73). HRMS (FAB) calcd for (C2,=,H4002,Si+H)+ m/z 417.2825, meas 417.2828. colorless oil. Preparation of MEM other 385 O OH O OAON \ O 0 MEMCI, DIPEA O CH20I2, ft, 24 h / / 383 385 TO a solution of 383 (10.9 mg, 0.036 mmol) in 0.5 mL of CH2CI2 at room temperature was added DIPEA (12 (1L, 0.072 mmol) and MEMCI (6.2 (1L, 0.054 mmol). The resulting solution was stirred for 24 hours, and then quenched with 2 mL of saturated aqueous NaHCOa. The aqueous layer was extracted with 320 (2 * 5 mL). The combined organic layer was washed with brine (10 mL), dried over Na2804, filtered and concentrated. The crude product was purified by chromatography on silica gel with 9:1 hexanes/EtOAC as eluent to give a 71% yield of 385 (10.0 mg, 0.0256 mmol). 1H NMR (CDCI3, 500 MHz) 6 1.13 (s, 3H), 1.37-1.42 (m, 1H), 1.51 (s, 3H), 1.69 (s, 3H), 1.70-1.75 (m, 1H), 1.86-1.89 (m, 1H), 1.93-2.00 (m, 2H), 2.07-2.11 (m, 1H), 2.24-2.36 (m, 2H), 3.46 (s, 3H), 3.50 (td, 2H, J = 4.1, 1.2 Hz), 3.62 (s, 3H), 3.63-3.70 (m, 2H), 4.49 (d, 1H, J = 11.2 Hz), 4.56 (d, 1H, J = 9.5 Hz), 4.65 (d, 1H, J = 6.6 Hz), 4.77(dd, 1H, J = 6.6, 1.1 Hz), 4.90 (d, 1H, J = 2.9 Hz), 5.39 (dd, 1H, J = 9.5, 1.0 Hz), 6.90 (dd, 1H, J = 3.2, 1.0 Hz); 130 NMR (CDCI3, 125 MHz) 6 15.36, 15.74, 25.41, 29.60, 35.94, 38.15, 39.33, 49.55, 54.76, 58.97, 66.98, 67.62, 71.82, 92.64, 110.63, 124.56, 126.42, 269 134.58, 135.05, 138.77, 138.88, 150.80, 202.06; IR (neat) 2919, 1647, 1599, 1451, 1382, 1129. 1038 cm”; mass spectrum m/z (% rel intensity) 390 M+ (1), 362 (4), 284 (13), 203 (27), 189 (79), 175 (20), 167 (16) 151 (29), 144 (15), 135 (22), 115 (15), 105 (21), 89 (100), 81 (58), 79 (270, 77 (22), 67 (21), 59 (100), 55 (20), 53 (21). HRMS (FAB) calcd for (C23H3405+H)+ m/z 391.2484, meas 391.2471. Light yellow oil; R; = 0.30 (3:1 hexanes/EtOAC). Preparation of SEM other 386 | / O OH O OAO/VSK O SEMCI, DIPEA O / / 383 386 To a solution of 383 (11.1 mg, 0.0368 mmol) in 0.5 mL of CH2CI2 at room temperature was added DIPEA (12.8 uL, 0.0736 mmol), SEMCI (10 uL, 0.0552 mmol) and Bu4NI (16.3 mg, 0.044 mmol). The resulting solution was stirred for 2 hours, and then quenched with 2 mL of saturated aqueous NaHCOa. The aqueous layer was extracted with 820 (2 * 5 mL). The combined organic layer was washed with brine (10 mL), dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel with 9:1 hexanes/EtOAc as eluent to give a 63% yield of 386 (10.0 mg, 0.0231 mmol). 1H NMR (CDCI3, 500 MHz) 6 -0.03 (s, 9H), 0.89 (t, 2H, J = 8.5 Hz), 1.13 (s, 3H), 1.37-1.42 (m, 1H), 1.52 (s, 3H), 1.69 (s, 3H), 1.71-1.76 (m, 1H), 1.86-1.89 (m, 270 1H), 1.93-2.00 (m, 2H), 2.08-2.12 (m, 1H), 2.24-2.37 (m, 2H), 3.53-3.61 (m, 2H), 3.62 (s, 3H), 4.50 (d, 1H, J = 11.3 Hz), 4.57 (d, 1H, J = 9.8 Hz), 4.61 (d, 1H, J = 6.6 Hz), 4.73 (d, 1H, J = 6.6 Hz), 4.90 (d, 1H, J = 3.2 Hz), 5.38 (d, 1H, J = 9.5 Hz), 5.91 (dd, 1H, J = 3.2 Hz, 1.0 Hz); 13C NMR (CDCI3, 125 MHz) 3 -1.43, 15.35, 15.74, 18.17, 25.43, 29.61, 35.96, 38.15, 39.33, 49.54, 54.74, 65.25, 67.60, 92.14, 110.57, 124.58, 126.64, 134.58, 135.06, 138.59, 138.93, 150.83, 202.09; IR (neat) 2951, 2918, 1649, 1383, 1055, 1028, 835 cm'1; mass spectrum m/z (% rel intensity) 432 M+ (0.4), 284 (10), 189 (44), 82 (22), 73 (100). HRMS (FAB) calcd for (C25H4oO4Si)* m/z 432.2696, meas 432.2699. Colorless oil; Rf = 0.32 (9:1 hexanes/EtOAC). Preparation of dienone 388 O OMOM 1) LICHZTMS, THF, rt, 15 min 0 2) KHMDS, 0 °C to rt, 1.5 h 3) HCl, MeOH/E120, 5 min / 362 Trimethylsilylmethyllithium (1.0 M in THF, 0.12 mL) was added dropwise to a solution of compound 362 (20.7 mg, 0.0598 mmol) in 0.3 mL of THF at 0 °C. The solution was stirred for 15 minutes at 0 °C, and then KHMDS (0.24 mL, 0.12 mmol, 0.5 M in toluene) was added. The reaction mixture was stirred for 1.5 hours at room temperature before quenching with H20 (5 mL). The aqueous phase was separated and extracted with 320 (3 * 10 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated in 271 vacuo to give an unstable enol ether intermediate. The crude enol ether was dissolved in 1 mL of MeOH, and then treated with 1 mL of 1% aqueous HCI and stirred at room temperature for 5 minutes. The mixture was diluted with 320 (5 mL) and neutralized with saturated aqueous NaHCOa (10 mL). The aqueous phase was separated and then extracted with 320 (2 * 10 mL). The combined organic layer was washed with brine (10 mL), dried over Na2804 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a 9:1 hexanes/Et20 as eluent to give ketone 388 (14.6 mg, 0.0442 mmol, 74%). 1H NMR (CDCI3, 500 MHz) 6 1.18 (s, 3H), 1.35-1.41 (m, 1H), 1.44 (s, 3H), 1.67 (d, 3H, J = 1.2 Hz), 1.69-1.80 (m, 2H), 2.02-2.13 (m, 5H), 2.23 (d, 1H, J = 16.0 Hz), 2.46 (d, 1H, J = 16.0 Hz), 3.35 (s, 3H), 4.53 (d, 1H, J = 6.8 Hz), 4.63-4.67 (m, 2H), 4.69 (d, 1H, J = 6.8 Hz), 5.27 (dd, 1H, J = 9.8, 1.1 Hz), 5.30 (d, 1H, J = 1.5 Hz), 5.42 (s, 1H), 6.28 (s, 1H); 13C NMR (CDCI3, 125 MHz) 6 16.33, 16.74, 24.34, 24.84, 34.23, 35.59, 38.43, 42.81, 54.21, 55.46, 68.86, 93.23, 114.90, 122.99, 124.46, 124.63, 135.80, 140.37, 146.42, 157.38, 199.45; IR (neat) 2923, 1671, 1583, 1150, 1036, 916 cm"; mass spectrum m/z (% rel intensity) 330 M‘ (0.8), 285 (2), 269(3), 247(3), 105 (15), 91 (24), 81 (15), 66 (18), 45 (100). HRMS (FAB) calcd for (C21H3002,+H)+ m/z 331.2271, meas 331.2273. Light yellow oil; Rr = 0.40 (3:1 hexanes/EtOAC). Compound 389 was isolated when KOtBu was used in Peterson elimination (0 to 46% in different runs). 1H NMR (CDCI3, 500 MHz) 6 1.21 (s, 272 3H), 1.25 (s, 3H), 1.79-2.11 (m, 6H), 2.30-2.33 (m, 2H), 2.34-2.35 (m, 2H), 4.93 (s, 1H), 5.01 (d, 1H, J = 8.3 Hz), 5.17 (s, 1H), 5.37 (s, 1H), 5.41 (s, 1H), 5.86 (s, 1H), 6.23 (d, 1H, J = 16.1 Hz), 6.83 (d, 1H, J = 16.1 Hz); 13C NMR (CDCI3, 125 MHz) 6 15.17, 24.40, 29.47, 34.52, 34.84, 36.20, 43.91, 54.26, 111.57, 115.33, 123.56, 125.25, 126.97, 136.91, 141.93, 147.10, 147.60, 155.79, 199.28; IR (neat) 2938, 1655, 1553, 1260, 901, 733 cm"; mass spectrum m/z (% rel intensity) 268 M“ (25), 253 (16), 240 (18), 226 (20), 224 (21), 209 (19), 198 (16), 196 (20), 185 (16), 183 (34), 171 (19), 169 (41), 159 (25), 155 (39), 145 (33), 141 (47), 133 (29), 128 (67), 121 (75), 115 (69), 105 (66), 91 (100), 77 (28), 65 (24), HRMS (FAB) calcd for (C19H2403+H)+ m/z 269.1906, meas 269.1906. Light yellow oil; Rr = 0.48 (4:1 hexanes/EtOAC). Methylation of dienone 388 1) LHMDS, THF, -78 °C, 1 h 2) Mel, -73 °C to rt, 12 h A solution of ketone 388 (9.7 mg, 0.0292 mmol) in 0.50 mL of THF was added to a solution of LHMDS (1.0 M in THF, 0.050 mL, 0.050 mmol) in THF at -78 °C. After stirring for 1 hour, iodomethane (4 uL, 0.07 mmol) was added. The cooling bath was removed immediately and the reaction mixture was allowed to warm to room temperature. After stirring for 11 hours, 2 mL of saturated aqueous NH4CI was added to the flask. The aqueous layer was extracted with 820 (2 * 10 273 mL). The combined organic layer was washed with brine (10 mL), and then dried over MgSOa. The residue was purified by flash column chromatography on silica gel with 9:1 hexanes/Et2O as eluent to give ketone 390 (9.0 mg, 0.0261 mmol, 96%). 1H NMR (CDCI3, 500 MHz) 6 0.96 (d, 3H, J = 7.3 Hz), 1.09 (s, 3H), 1.35- 1.41 (m, 1H), 1.53 (s, 3H), 1.67 (d, 3H, J = 1.2 Hz), 1.69-1.74 (m, 1H), 1.78-1.83 (m, 1H), 2.01-2.16 (m, 6H), 3.35 (s, 3H), 4.53 (d, 1H, J = 6.5 Hz), 4.64-4.66 (m, 2H), 4.68 (d, 1H, J = 6.5 Hz), 5.26-5.28 (m, 2H), 5.51 (s, 1H), 6.17 (s, 1H); 13C NMR (CDCI3, 125 MHz) 6 13.95, 16.48, 16.58, 21.07, 24.33, 34.50, 36.41, 38.21, 45.65, 55.48, 55.51, 68.82, 93.34, 116.94, 120.98, 124.56, 124.80, 135.84, 140.14, 144.69, 156.08, 204.60; IR (neat) 2934, 1671s, 1587, 1150, 1036, 916 cm'1; mass spectrum m/z (% rel intensity) 344 M+ (1), 329 (0.4), 135 (13), 119 (15), 107 (16), 95 (12), 91 (15), 81 (22), 79 (17), 55 (24), 45 (100); HRMS (FAB) calcd for (C22H32031-H)+ m/z 345.2430, meas 345.2430. Colorless oil; R; = 0.38 (3:1 hexanes/EtOAC). Reduction of ketone 390 NaBH4 MeOH, 45 °C, 2 h ‘ 391 a 391 b To a solution of ketone 390 (32.5 mg, 0.094 mmol) in 0.2 mL of MeOH at room temperature was added sodium borohydride (63.9 mg, 1.88 mmol) as a powder. The reaction mixture was heated at 45 °C until 390 was all consumed 274 (monitored by TLC). The reaction was cooled to room temperature and diluted with 320 (5 mL), and then quenched with water (5 mL). The aqueous layer was extracted with E120 (3 * 5 mL). The combined organic layer was washed with brine (5 mL), dried over MgSO4, concentrated and carefully chromatographed on silica gel (15% EtOAC in hexanes as eluent) to afford alcohol 391a (10.0 mg, contaminated by ~ 3:1 over-reduction product, 0.0216 mmol, 23%) and 391b (15.2 mg, 0.0437 mmol, 46%, contaminated by over-reduction product, the ratio was not determined). The two isomers of 391 (2:1 dr) could be separated by careful Chromatography. However, each isomer was contaminated by an impurity (~30% of impurity), which was tentatively identified as a 1,6-over-reduction product. Major isomer 391b 1H NMR (CDCI3, 500 MHz) 6 0.91 (d, 3H, J = 6.9 Hz), 0.92 (s, 3H), 1.48 (s, 3H), 1.64 (d, 3H, J = 1.2 Hz), 1.74 (d, 1H, J = 1.4 Hz), 1.81-1.86 (m, 2H), 1.98-2.15 (m, 6H), 3.36 (s, 3H), 3.99-4.01 (m, 1H), 4.57 (d, 1H, J = 6.5 Hz), 4.68-4.70 (m, 3H), 4.97 (d, 1H, J = 1.4 Hz), 4.99 (s, 1H), 5.12- 5.15 (m, 1H), 6.00 (s, 1H); 13C NMR (CDCI3, 125 MHz) 6 11.91, 15.75, 16.18, 25.28, 25.40, 34.47, 34.71, 39.17, 40.32, 42.48, 55.35, 68.77, 70.87, 93.27, 109.09, 125.01, 125.34, 127.45, 134.93, 137.86, 138.20, 147.10; IR (neat) 3409, 2922, 1452, 1148. 1200, 1038 cm”; mass spectrum m/z (% rel intensity) 346 M+ (0.08), 284 (5), 269 (4), 203 (10), 175 (15), 161 (18), 159 (18), 149 (18), 147 (20), 145 (20), 135 (25), 133 (23), 121 (34), 119 (21), 107 (30), 105 (30), 95 (27), 93 (21), 91 (33), 81 (37), 79 (24), 67 (29), 55 (36), 45 (100); HRMS (FAB) calcd 275 for (C22H3403-H)" m/z 345.2430, meas 345.2431. Colorless oil; R; = 0.20 (4:1 hexanes/EtOAc). Minor isomer 391a 1H NMR (CDCI3, 500 MHz) 6 0.73 (d, 3H, J = 6.8 Hz), 1.06 (s, 3H), 1.36-1.41 (m, 2H), 1.47 (s, 3H), 1.64 (d, 3H, J = 2.3 Hz), 1.67- 1.74 (m, 2H), 1.84-1.89 (m, 1H), 1.99-2.09 (m, 4H), 3.36 (s, 3H), 4.56 (d, 1H, J = 6.6 Hz), 4.64-4.65 (m, 3H), 4.67 (d, 1H, J =6.5 Hz), 4.86 (s, 1H), 5.13 (s, 1H), 5.13 (d, 1H, J = 9.6 Hz), 5.78 (s, 1H);13C NMR (CDCI3, 125 MHz) 6 8.36, 16.19, 17.00, 21.96, 24.44, 33.66, 35.44, 38.51, 44.78, 46.22, 55.32, 68.62, 68.79, 93.32, 110.26, 123.45, 124.75, 127.11, 136.08, 137.81, 138.79, 145.05; IR (neat) 3428, 2936, 1439, 1148, 1098, 1037 cm"; mass spectrum m/z (% rel intensity) 346 M+ (0.3), 301 (3), 284 (9), 203 (18), 187 (17), 175 (20), 173 (24), 161 (25), 159 (33), 15), 131 (23), 127 (25), 147 (27), 145 (38), 143 (20), 135 (32), 133 (36), 131 (23), 121 (39), 119 (51), 115 (17), 107 (36), 105 (46), 91 (47), 81 (55), 79 (32), 67 (35), 55 (44), 45 (100). ); HRMS (FAB) calcd for (C22H3403)+ m/z 346.2508, meas 346.2509. Colorless oil; R; = 0.16 (4:1 hexanes/EtOAC). Acetylation of alcohol 391a A053 391a 3926 To a solution of alcohol 391a (10.7 mg, 0.0307 mmol) in pyridine (1.0 mL) was added acetic anhydride (0.2 mL). The mixture was stirred at room 276 temperature for 4 hours and then the solvent was evaporated to dryness. The residue was subjected to silica gel column chromatography (9:1 hexanes/EtOAC as eluent) to give 392a (4.4 mg, 0.011 mmol, 37%). 1H NMR (CDCI3, 500 MHz) 6 0.71 (d, 3H, J = 6.8 Hz), 0.82-0.87 (m, 1H), 1.04 (s, 3H), 1.48 (s, 3H), 1.64 (d, 3H, J = 1.2 Hz), 1.73-1.78 (m, 1H), 1.83-1.90 (m, 2H), 2.01-2.10 (m, 5H), 2.06 (s, 3H), 3.36 (s, 3H), 4.56 (d, 1H, J: 6.5 Hz), 4.64 (d, 1H, J = 1.1 Hz), 4.67 (d, 1H, J = 6.5 Hz), 4.68 (br, 1H), 4.89 (s, 1H), 5.10 (s, 1H), 5.14 (d, 1H, J = 9.8 Hz), 5.70 (s, 1H), 5.73 (d, 1H, J = 5.5 Hz); 13C NMR (CDCI3, 125 MHz) 3 9.32, 15.15, 17.05, 21.35, 21.68, 24.44, 33.67, 35.58, 38.56, 43.44, 44.86, 55.33, 68.83, 72.28, 93.31, 110.74, 119.74, 124.70, 126.99, 136.11, 138.02, 139.97, 144.72, 170.80; IR (neat) 2924, 2851, 1837, 1240, 1038 cm-1; mass spectrum m/z (% rel intensity) 326 (M-62)+ (1), 284 (5), 203 (18), 201 (19), 187 (26), 185 (19), 173 (44), 171 (40), 159 (28), 157 (21), 147 (30), 106 (34), 133 (28), 107 (29), 91 (21), 82 (37), 57 (26), 46 (100). Colorless oil; R; = 0.43 (15% EtOAC in hexanes). Acetylation of alcohol 391 b ACZO pyridine, rt, 4 h 391 134-391 6 392b 3926 To a solution of alcohol 391b (18.2 mg, 0.0523 mmol) in pyridine (1.0 mL) was added acetic anhydride (0.2 mL). The mixture was stirred at room temperature for 4 hours and then the solvent was evaporated to dryness. The 277 residue was subjected to silica gel column chromatography (9:1 hexanes/EtOAC as eluent) to give 392b (13.7 mg, 0.035 mmol, 67%) and 1.6-over-reduction product 392C in (3.4 mg, 0.0087 mmol, 18%). Compound 392b 1H NMR (CDCI3, 500 MHz) 6 0.83 (d, 3H, J = 7.1 Hz), 0.97 (s, 3H), 1.48 (s, 3H), 1.59-1.64 (m, 1H), 1.65 (d, 3H, J = 1.2 Hz), 1.72-1.76 (m, 1H), 1.79-1.85 (m, 2H), 2.07 (s, 3H), 2.00-2.25 (m, 5H), 3.35 (s, 3H), 4.54 (d, 1H, J = 6.5 Hz), 4.67 (d, 1H, J = 6.5 Hz), 4.68-4.71 (m, 2H), 4.99 (d, 1H, J = 1.7 Hz), 5.05 (s, 1H), 5.13-5.15 (m, 2H), 5.86 (s, 1H); 13C NMR (CDCI3, 125 MHz) 6 12.83, 15.87, 16.25, 21.42, 24.18, 24.97, 29.69, 34.72, 38.78, 40.58, 40.84, 55.35, 68.83, 73.41, 93.30, 110.33, 120.25, 124.85, 127.04, 135.38, 138.04. 139.80, 146.08, 170.77; mass spectrum m/z (% rel intensity) 388 M“ (0.14), 284 (12), 266 (30), 252 (22), 213 (19), 211 (19), 209 (28), 203 (35), 201 (34), 197 (22), 195 (30), 187 (40), 185 (40), 183 (31), 175 (17), 173 (70), 171 (100), 169 (35), 165 (19), 159 (44), 157 (48), 147 (44), 145 (46), 133 (45), 119 (54), 105 (38), 91 (43), 81 (60), 79 (33), 55 (40). Colorless oil; R; = 0.43 (15% EtOAC in hexanes) Compound 392C was tentatively assigned to the above structure based on the NMR analysis. 1H NMR (CDCI3, 500 MHz) 6 0.90 (d, 3H, J = 7.1 Hz), 0.94 (s, 3H), 1.33-1.38 (m, 1H), 1.39-1.41 (m, 3H), 1.53 (s, 3H), 1.58-1.66 (m, 1H), 1.73 (m, 3H), 1.86-1.89 (m, 1H), 1.91-2.03 (m, 2H), 2.00 (s, 3H), 2.06-2.12 (m, 3H), 2.25-2.45 (m, 3H), 3.32 (s, 3H), 4.42 (d, 1H, J = 6.4 Hz), 4.54 (d, 1H, J = 6.4 Hz), 4.77 (d, 1H, J = 11.0 Hz), 5.03 (d, 1H,J=1.2 Hz), 5.13 (d, 1H, J= 10.6 Hz), 5.24-5.25 (m, 1H); 13C NMR (CDCI3, 125 MHz) 3 12.95, 14.30, 15.59, 15.57, 278 21.39, 23.03, 26.59, 28.07, 32.91, 35.36, 36.03, 38.74, 40.99, 55.15, 70.71, 73.27, 93.01, 123.67, 126.22, 128.12, 132.93, 133.83, 137.02, 171.12; IR (neat) 2924, 2851, 1736, 1250, 1036 cm"; mass spectrum m/z (% rel intensity) 330 (M- 60)+ (2), 268 (20), 253 (16), 239 (15), 197 (15), 187 (19), 186 (20), 185 (26), 175 (24), 173 (33), 171 (100), 159 (27), 157 (26), 147 (32), 145 (31), 133 (43), 128 (31), 121 (31), 119 (54), 109 (26), 107 (29), 105 (49), 98 (58), 95 (28), 91 (53), 83 (23), 81 (41), 79 (39), 67 (31), 55 (38). HRMS (FAB) calcd for (022H3302 (M- OMOM))+ m/z 329.2481, meas 329.2480. Light yellow oil; Rf = 0.41 (15% EtOAc in Hexanes). Cleavage of MOM group in 390 6 N HCI, MeOH 50°C,12h To a solution of MOM ether 390 (25 mg, 0.0727 mmol) in 3.7 mL of MeOH at room temperature was added 6 N HCI (0.024 mL). The reaction mixture was heated at 50 °C for 12 hours, and then cooled to room temperature. The mixture was diluted with 820 (5 mL) and neutralized with saturated aqueous NaHCOs (10 mL). The aqueous phase was separated and then extracted with 320 (2 * 10 mL). The combined organic layer was washed with brine (10 mL), and then dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 7:3 hexanes/Et2O as eluent to give 279 alcohol 394 (20.2 mg, 0.0672 mmol, 93%). 1H NMR (CDCI3, 500 MHz) 6 0.95 (d, 3H, J = 7.2 Hz), 1.08 (s, 3H), 1.35-1.41 (m, 1H), 1.43 (s, 3H), 1.67 (d, 3H, J = 1.4 Hz), 1.71-1.72 (m, 1H), 1.78-1.83 (m, 1H), 2.02-2.14 (m, 6H), 4.64 (t, 1H, J= 6.5 Hz), 4.76 (dd, 1H, J = 9.5, 1.0 Hz), 5.24 (d, 1H, J = 1.6 Hz), 5.35 (d, 1H, J = 9.6 Hz), 5.47 (s, 1H), 6.24 (s, 1H); 13C NMR (CDCI3, 125 MHz) 6 13.89, 16.59, 16.37, 21.00, 24.29, 34.48, 36.43, 38.07, 45.72, 55.60, 66.50, 116.75, 120.28, 124.87, 126.74, 135.86, 128.98, 144.45, 157.73, 204.63; IR (neat) 3405 brs, 2932, 1653, 1385 cm"; mass spectrum m/z (% rel intensity) 300 M+ (11), 189 (22), 187 (18), 176 (20), 173 (23), 169 (15), 161 (25), 159 (26), 148 (20), 145 (21), 141 (23), 135 (61), 128 (26), 121 (29) 105 (35), 91 (63), 81 (98), 77 (71), 67 (52), 55 (80), 53 (42), 41 (100); HRMS (FAB) calcd for (C2oH2302+H)" m/z 301.2168, meas 301.2166. Colorless oil; Rf = 0.11 (3:1 hexanes/EtOAc). Preparation of compound 395 TIPSOTI, DIPEA CHZCI2, rt, 2 h To a solution of allylic alcohol 394 (10.4 mg, 0.0347 mmol) in CH20I2 (1.7 mL) was added DIEPA (0.024 mL, 0.139 mmol) followed by the addition of triisopropylsilyl triflate (0.019 mL, 0.069 mmol). The reaction mixture was stirred at room temperature for 2 hours and quenched with H20 (10 mL). Diethyl ether (3 * 10 mL) was added to extract the product from the aqueous layer. The combined 280 organic layer was washed with brine (15 mL), and then dried over Na2SO4. Removal of the solvent under reduced pressure followed by flash chromatography on silica gel (9:1 hexanes/EtOAc as eluent) provided the desired product 395 (15.4 mg, 0.0337 mmol, 97%) as a colorless oil. 1H NMR (CDCI3, 500 MHz) 6 0.93 (d, 3H, J = 7.2 Hz), 1.00-1.07 (m, 21H), 1.08 (s, 3H), 1.35-1.40 (m, 1H), 1.44 (s, 3H), 1.59 (d, 3H, J = 2.4 Hz), 1.67-1.71 (m, 1H), 1.76-1.81 (m, 1H), 2.03-2.10 (m, 6H), 4.67-4.69 (m, 1H), 4.81 (d, 1H, J= 8.8 Hz), 5.24 (d, 1H, J = 1.5 Hz), 5.30 (dd, 1H, J = 9.0, 1.1 Hz), 5.45 (s, 1H), 6.30 (s, 1H); 13C NMR (CDCI3, 125 MHz) 6 12.15, 13.74, 16.40, 16.76, 17.87, 17.98, 20.99, 24.39, 34.34, 36.85, 38.60, 45.70, 55.87, 67.00, 116.42, 121.10, 124.50, 127.67, 135.75, 136.75, 144.67, 158.72, 205.07; IR (neat) 2944, 2857, 1671, 1462, 1109, 1096, 884 cm"; mass spectrum m/z (% rel intensity) 456 M+ (7), 413 (42), 171 (17), 157 (16), 143 (18), 141 (18), 131 (51), 128 (42), 119 (30), 103 (86), 95 (36), 91 (28), 81 (45), 79 (38), 76 (58), 75 (100), 73 (29), 61 (81), 59 (58), 55 (40), 43 (37); HRMS (FAB) calcd for (C29H4302Si+H)+ m/z 457.3489, meas 457.3484. White solid; R; = 0.29 (9:1 hexanes/EtOAc). 281 Reduction and acetylation of dienone 396 1) NaBH4, EtOH/EtZO rt, 2 d 2) Ac20, Py., rt, 4 h To a solution of dienone 395 (71.2 mg, 0.156 mmol) in 3.0 mL of 1:1 mixture of EtOH/Et20 was added NaBH4 (53 mg, 1.56 mmol) at room temperature. The reaction mixture was stirred at room temperature until all of the ketone was consumed (monitored by TLC, ~ 2 days). The reaction was quenched with H20, and the aqueous layer was extracted with 320 (3 * 20 mL). The combined organic layer was washed with brine (20 mL) and dried over Na2804. After filtration and concentration, the residue was dissolved in 4 mL of pyridine, and then 1.0 mL of acetic anhydride was added. The mixture was stirred at room temperature for 4 hours and then was evaporated to dryness. The residue was purified by column Chromatography on silica gel using 9:1 hexanes/EtOAc as eluent to give inseparable acetate 396 as a 2:1 Inseparable mixture of isomers (65.5 mg, 0.131 mmol, 84%) as a colorless oil. 282 Desilylation of TIPS-ether 396 TBAF THF, rt, 12h 7 To a solution of the above mixture of acetated 396 (65.5 mg, 0.131 mmol) in 6.5 mL of dry THF at room temperature was added TBAF (0.26 mL, 0.26 mmol, 1.0 M in THF) dropwise. The mixture was stirred overnight and then quenched with H20 (15 mL). The aqueous layer was extracted with 320 (3 * 20 mL). The combined organic layer was washed with brine (20 mL) and dried over Na2SO4. Filtration and concentration followed by flash chromatography on silica gel using 4:1 hexanes/EtOAc as eluent provided a ratio of 1:2 allylic alcohols 393a (10.1 mg) and 393b (20.0 mg) and 5.4 mg of mixture of the two products (0.103 mmol, 79% overall yield) as a colorless oil. Major isomer 393b 1H NMR (CDCI3, 500 MHz) 6 0.71 (d, 3H, J = 6.8 Hz), 1.04 (s, 3H), 1.48 (s, 3H), 1.49-1.51 (m, 1H), 1.64 (s, 3H, J = 1.2 Hz), 1.71- 1.76 (m, 1H), 1.84-1.89 (m, 2H), 2.06 (s, 3H), 2.01-2.10 (m, 5H), 4.65-4.68 (m, 1H), 4.75 (d, 1H, J = 9.5 Hz), 4.89 (s, 1H), 5.07 (s, 1H), 5.21-5.23 (m, 1H), 5.73 (d, 1H, J = 5.6 Hz), 5.78 (s, 1H); 13C NMR (CDCI3, 125 MHz) 6 9.31, 16.35, 17.03, 21.31, 21.62, 24.43, 33.71, 35.57, 38.40, 43.49, 44.92, 66.37, 72.19, 110.72, 118.91, 124.86, 128.96, 136.04, 136.84, 141.96, 144.49, 170.79; IR (neat) 3445, 2936, 1734, 1719, 1242, 1022 cm"; mass spectrum m/z (% rel intensity) 344 M“ (1), 302 (1), 203 (16), 187 (19), 185 (17), 173 (34), 171 (25), 283 161 (16), 159 (30), 157 (19), 147 (34), 145 (31), 137 (25), 135 (36), 133 (36), 121 (45), 119 (67), 115 (23), 107 (44), 105 (61), 95 (36), 93 (49), 91 (69), 84 (43), 81 (100), 79 (43), 77 (33), 67 (32), 556 (32), 55 (27); HRMS (CI) calcd for (C22H3102)+ (M-H2O+H) m/z 327.2324, meas 327.2313. Colorless oil; Rr = 0.31 (3:1 hexanes/EtOAC). Minor isomer 393a 1H NMR (CDCI3, 500 MHz) 6 0.83 (d, 3H, J = 6.8 Hz), 0.97 (s, 3H), 1.48 (s, 3H), 1.49 (d, 1H, J = 2.4 Hz), 1.65 (d, 3H, J = 1.5 Hz), 1.73-1.75 (m, 1H), 1.81-1.85 (m, 2H), 2.01-2.06 (m, 4H), 2.08 (s, 3H), 2.11-2.15 (m, 1H), 4.68-4.70 (m, 1H), 4.78 (d, 1H, J = 9.6 Hz), 4.99 (d, 1H, J = 1.5 Hz), 5.04 (s, 1H), 5.11-5.14 (m, 1H), 5.23 (d, 1H, J = 9.3 Hz), 5.92-5.93 (m, 1H); 13C NMR (CDCI3, 125 MHz) 6 12.92, 15.91, 16.42, 21.42, 24.04, 24.91, 34.68, 34.81, 38.64, 40.61, 41.03, 66.41, 73.35, 110.39, 119.46, 124.89, 128.94, 135.40, 136.79, 141.93, 145.82, 170.78; IR (neat) 3438br, 2922, 1732, 1242,1022 cm'1; mass spectrum m/z (% rel intensity) 344 M+ (1), 266 (17), 251 (16), 209 (17), 195 (20), 185 (32), 183 (22), 173 (52), 171 (64), 159 (39), 157 (64), 147 (29), 143 (38), 134 (32), 128 (67), 119 (49), 105 (43), 95 (32), 93 (32), 91 (50), 81 (91), 77 (55), 69 (29), 67 (37), 60 (22), 55 (51), 53 (28), 45 (34), 43 (100); HRMS (Cl) calcd for (C22H31O2)+ (M-H2O+H) m/z 327.2324, meas 327.2325. Colorless oil; Rf = 0.29 (3:1 hexanes/EtOAc). 284 Epoxidation of allylic alcohol 393b VO(acac)2, TBP Benzene, rt, 1h A solution of new tert-butyl hydroperoxide (75% WNV) in H2O (1.8 (1L) was added to a stirred solution of vanadyl acetylacetonate (1.0 mg, 0.0038 mmol) and the allylic alcohol 393b (5.0 mg, 0.0145 mmol) in 0.72 mL of benzene at room temperature. After 15 minutes, another 0.9 uL of tert-butyl hydroperoxide was added to the solution. The light green solution turned yellow brown, and was stirred at room temperature for 60 minutes before quenching with 2 mL of saturated aqueous Na2S203. The aqueous layer was extracted with 320 (3 * 10 mL). The combined organic layer was washed with brine (15 mL) and dried over Na2SO4. Filtration and concentration followed by flash Chromatography on silica gel using 2:1 hexanes/EtOAc as eluent provided epoxy alcohol 398b (4.6 mg, 0.0128 mmol, 88%) as a colorless oil. 1H NMR (CDCI3, 500 MHz) 6 0.72 (d, 3H, J = 7.0 Hz), 1.03 (d, 3H, J = 0.5 Hz), 1.04-1.12 (m, 1H), 1.26 (s, 3H), 1.52 (s, 3H), 1.55-1.59 (m, 1H), 1.65-1.69 (m, 1H), 1.78-1.82 (m, 1H), 1.95-2.04 (m, 3H), 2.05 (s, 3H), 2.06-2.09 (m, 2H), 2.64 (s, 1H), 3.11 (d, 1H, J= 1.5 Hz), 4.79 (t, 1H, J = 6.8 Hz), 4.99 (s, 1H), 5.13-5.14 (m, 1H), 5.26 (s, 1H), 5.78-5.79 (rn, 1H), 5.82-5.83 (m, 1H); 130 NMR (CDCI3, 125 MHz) 6 9.05, 14.82, 16.51, 21.25, 22.52, 23.43, 32.65, 34.25, 39.04, 43.04, 45.32, 62.59, 64.37, 65.02, 71.69, 111.29, 121.26, 121.57, 135.56, 137.14, 144.18,170.74; IR (neat) 3497br, 2924, 285 1738, 1373, 1242, 1024 cm'l; mass spectrum m/z (% rel intensity) 318 (M-42)+ (3), 167 (39), 162 (23), 150 (89), 149 (94), 135 (43), 124 (47), 121 (100), 119 (48), 105 (87), 91 (72), 81 (95); HRMS (Cl) calcd for (C22H3103)+ (M-H2O+H) m/z 343.2273, meas 343.2281. Colorless oil; Rr = 0.30 (3:1 hexanes/EtOAC). Epoxidation of allylic alcohol 393a VO(acac)2, TBP Benzene, rt, 1h A solution of new tert-butyl hydroperoxide (75% WNV) in H2O (2.2 (1L) was added to a stirred solution of vanadyl acetylacetonate (1.1 mg, 0.0041 mmol) and the allylic alcohol 393a (6.0 mg, 0.0174 mmol) in 0.87 mL of benzene at room temperature. After 15 minutes, another 1.1 uL of tert—butyl hydroperoxide was added to the solution. The light green solution turned yellow brown, and was stirred at room temperature for 60 minutes before quenching with 2 mL of saturated aqueous Na2S203. The aqueous layer was extracted with 320 (3 * 10 mL). The combined organic layer was washed with brine (15 mL) and dried over Na2SO4. Filtration and concentration followed by flash Chromatography on silica gel using 2:1 hexanes/ EtOAc as eluent provided epoxy alcohol 398a (7.6 mg, 0.0211 mmol, 93%) as a colorless oil. 1H NMR (CDCI3, 500 MHz) 6 0.84 (d, 3H, J = 7.3 Hz), 0.99 (s, 3H), 1.31 (s, 3H), 1.33-1.42 (m, 2H), 1.52 (s, 3H), 1.68-1.73 (m, 2H), 1.98-2.02 (m, 1H), 2.03 (s, 3H), 2.05-2.13 (m, 3H), 2.63 (s, 1H), 3.08 (d, 286 1H, J = 4.4 Hz), 4.33435 (m, 1H), 5.05-5.03 (m, 2H), 5.15-5.17 (m, 1H), 5.33 (s, 1H), 5.95-5.97 (m, 1H); 13C NMR(CDC13, 125 MHz) 3 14.53, 15.14, 15.21, 21.42, 23.02, 23.42, 33.93, 35.13, 39.09.4195, 42.92, 52.53, 54.23, 55.31, 73.25, 112.02, 113.92, 121.13, 135.37, 137.05, 144.51, 170.45; lR (neat) 3495br, 2924, 1730, 1335, 1240 cm"; colorless oil; R; = 0.25 (3:1 hexanes/EtOAC). Oxidation of epoxy alcohol 398b DMP, NaHCOa ‘ CH2CI2, 0 °C 10 I1, 2.5 h Freshly prepared DMP93 (0.047 mmol, 20 mg) was added to a mixture of NaHCO:; (0.189 mmol, 16 mg) and the epoxy alcohol 398b (8.5 mg, 0.0236 mmol) in 1 mL of dry CH2CI2 at 0 °C. The mixture was stirred at 0 °C for 30 minutes, and then allowed to warm to room temperature over 2.5 hours. The reaction was quenched with saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with 320 (3 * 10 mL). The combined organic layer was washed with brine (15 mL) and dried over Na2SO4. Filtration and concentration followed by flash chromatography on silica gel using 3:1 hexanes/EtOAC containing 1% Eth as eluent provided epoxy ketone 378b (7.5 mg, 0.021 mmol, 89%). The data for this product matched that obtained from the oxidation of 376b (vide infra). 287 Oxidation of epoxy alcohol 398a DMP, NaHCO3 ‘ CH2CI2, 0 0C10 11, 2.5 h Freshly prepared DMP93 (0.032 mmol, 13.4 mg) was added to a mixture of NaHCOa (10.6vmg, 0.126 mmol) and the epoxy alcohol 398a (5.7 mg, 0.0158 mmol) in 1 mL of dry CH2CI2 at 0 °C. The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature over 2.5 hours. The reaction was quenched with saturated aqueous NaHCOa (5 mL). The aqueous layer was extracted with 820 (3 * 10 mL). The combined organic layer was washed with brine (15 mL) and dried over Na2SOa. Filtration and concentration followed by flash Chromatography on silica gel using 3:1 hexanes/EtOAC containing 1% EtaN as eluent provided epoxy ketone 378a (5.0 mg, 0.014 mmol, 88%). The data for this product matched that obtained from the oxidation of 376a (vide supra). 288 Oxidation of alcohol 383 DMP, NaHC03 CH2C12, 0 0C10 l1, 2 I1 Freshly prepared DMP93 (138 mg, 0.325 mmol) was added to a mixture of NaHC03 (137 mg, 1.63 mmol) and alcohol 383 (49.3 mg, 0.163 mmol) in 5 mL of dry CH2CI2 at 0 °C. The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature over a period of 1.5 hours. The reaction was quenched with saturated aqueous NaHCO;; (5 mL). The aqueous layer was extracted with 320 (3 * 5 mL). The combined organic layer was washed with brine (10 mL) and dried over Na2SOa. Filtration and concentration followed by flash Chromatography using 3:1 hexanes/EtOAc as eluent provided dione 417 (43.1 mg, 0.144 mmol, 33%) as a yellow solid. 1H NMR (CDCla, 500 MHz) 3 1.27 (s, 3H), 1.28 (s, 3H), 1.52-1.57 (m, 1H), 1.76 (d, 3H, J = 1.1 Hz), 1.75-1.80 (m, 1H), 1.97-2.03 (m, 1H), 2.09-2.22 (m, 5H), 3.56 (s, 3H), 4.79-4.82 (m, 1H), 5.22 (d, 1H, J = 3.4 Hz), 6.72 (s, 1H), 7.44 (d, 1H, J = 3.4 Hz); 13C NMR (CDCI3, 125 MHz) 6 15.11, 17.79, 20.29, 26.31, 33.16, 37.36, 38.94, 51.62, 55.03, 117.02, 126.62, 128.22, 134.82, 134.97, 141.64, 148.73, 149.89, 188.90, 203.52; IR (neat) 2919, 2851, 1678, 1662, 1632, 1563, 1383, 1370, 1250, 1212, 1020 cm"; mass spectrum m/z (% rel intensity) 300 M+ (2), 285 (4), 205 (26), 175 (21), 165 (19), 135 (19), 124 (27), 123 (55), 12 (29), 109 (100), 107 (34), 105 (19), 91 (52), 82 (43), 81 (38), 79 (39), 77 (38), 67 (21), 55 (28), 54 (30). HRMS (Cl) calcd 289 for (C19H2403+H)+ m/z 301.1799, meas 301.1804. Yellow solid, mp. 130-132 °C; R; = 0.39 (3:1 hexanes/EtOAC). Reduction of ketone 417 with NaBHJCeCIa NaBH4, C8CI3'7H20 MeOH/CH2C12, -78 °C, 15 min To a solution of dione 417 (17.2 mg, 0.057 mmol) in 4 mL of 1:1 mixture of MeOH/CH2CI2 at —78 °C was added NaBH4 (3.9 mg, 0.114 mmol) and CeCl3-7H2O (32 mg, 0.086 mmol). The reaction mixture was stirred at —78 °C for 15 minutes, and then diluted with 320 (5 mL) and quenched with water (5 mL). The aqueous layer was extracted with 320 (2 * 5 mL). The combined organic layer was washed with brine (10 mL), and then dried over Na2SOa, filtered and concentrated. The crude product was purified by Chromatography on silica gel using 3:1 hexanes/EtOAC as eluent to give a 96% yield of B-alcohol 383 (16.5 mg, 0.0547 mmol). The spectral data for this compound matched that for a product obtained from the deprotection of compound 360 (vide supra). 290 Preparation of a-alcohol 404 O OTIPS TBAF, THF 2 h, rt To a solution of 361 (19.1 mg, 0.042 mmol) in THF (1.0 mL) at room temperature was added TBAF (1.0 M solution in THF, 0.084 mL, 0.084 mmol). The reaction mixture was stirred for 2 hours and then quenched with water (5 mL). The aqueous layer was extracted with 320 (3 * 5 mL). The combined organic layer was washed with brine (5 mL), and then dried over MgSO4, concentrated and chromatographed on silica gel (9:1 hexanes/EtOAc) to afford a 98% yield of alcohol 404 (12.4 mg, 0.041 mmol). 1H NMR (CDCI3, 500 MHz) 6 1.17 (s, 3H), 1.45 (s, 3H), 1.41-1.49 (m, 1H), 1.52 (s, 3H), 1.84-1.99 (m, 4H), 2.16-2.21 (m, 2H), 2.32-2.37 (m, 1H), 3.61 (s, 3H), 3.77 (d, 1H, J = 11.0 Hz), 4.55 (t, 1H, J = 6.9 Hz), 4.76 (dd, 1H, J = 11.0, 8.5 Hz), 4.95 (d, 1H, J = 3.2 Hz), 5.36 (d, 1H, J = 8.5 Hz), 6.50 (d, 1H, J = 2.9 Hz); 13C NMR (CDCI3, 125 MHz) 6 15.55, 16.66, 25.19, 28.85, 36.20, 37.16, 39.62, 50.20, 54.87, 72.30, 110.96, 124.47, 129.31, 134.11, 134.90, 136.22, 137.14, 149.93, 206.07; IR (neat) 3514 br, 2917, 2851, 1636, 1391, 1251, 1017 cm'1; mass spectrum m/z (% rel intensity) 302 M” (3), 287 (13), 274 (79), 205 (33), 203 (22), 191 (35), 189 (91), 176 (26), 175 (100), 165 (44), 163 (26), 159 (20), 151 (47), 138 (29), 123 (34), 121 (31), 114 (24), 109 (31), 107 (331), 105 (37), 93 (31), 91 (87), 81 (42), 79 (52), 77 (67), 67 (43). 291 HRMS (FAB) calcd for (C19H2503)+ m/z 302.1882, meas 302.1880. Colorless Oil; R; = 0.40 (3:1 hexanes/EtOAc). Oxidation of alcohol 404 DMP CHQCI2, I1, 45 min Freshly prepared DMP93 (17 mg, 0.040 mmol) was added to a solution of alcohol 404 (6.1 mg, 0.0202 mmol) in 0.5 mL of dry CH2CI2 at room temperature. The mixture was stirred at room temperature for 45 minutes, and then quenched with 5% NaOH solution (2 mL). The aqueous layer was extracted with B20 (3 * 5 mL). The combined organic layer was washed with brine (10 mL) and dried over Na2SO4. Filtration and concentration followed by flash Chromatography using 3:1 hexanes/EtOAC as eluent provided dione 417 (4.6 mg, 0.0153 mmol, 76%) as yellow solid. Preparation of carbene complex 329 1) Cr(CO)6, THF, -73 °C OMe M 2) n-BuLi. -73°c to rt (OC)5Cr=&‘<——>= / | > _ 3) Me OBF4, 1Z1 CH20l2/l-l20. I1 3 329 435 To a flame dried round bottom flask under Ar was added vinyl iodine 435 (755 mg, 3.20 mmol), Cr(CO)5 (739 mg, 3.36 mmol) and THF (32 mL). The 292 solution was cooled to —78 °C, and n-butyl lithium (1.6 mL, 3.2 mmol, 2.0 M in hexanes) was added dropwise. The solution was stirred at —78 °C for 30 minutes, and then allowed to warm up to room temperature during 2 hours. The resulting carbene lithium acylate solution was concentrated in vacuo, and allowed to stand under high vacuum for 10 minutes. The acylate was dissolved in 20 mL of 1:1 CH2CI2/H2O, and then Me303F4 (947 mg, 6.40 mmol) was added to the solution and keep stirring for 30 minutes at room temperature under Ar. The reaction was quenched by pouring into a separatory funnel with saturated aqueous NaHCOa and hexanes. The aqueous layer was extracted with pentane until no red color was seen in the aqueous layer. The combined organic layer was washed with brine twice, and then dried over M9804, The dried solution was filtered through a fritted funnel dry packed with Celite 503. The crude product was purified by silica gel chromatography on silica gel using pure pentane as eluent to provide carbene complex 329 (825 mg, 2.40 mmol, 75%) as a red oil. 1H NMR (CDCI3, 500 MHz) 6 1.73 (s, 3H), 1.83 (s, 3H), 2.20-2.26 (m, 4H), 4.70 (s, 4H), 4.74 (s, 1H), 7.21 (s, 1H); 13C NMR (CDCI3, 125 MHz) 3 20.43, 22.30, 35.35, 39.09. 66.18, 110.82, 140.97, 142.02, 144.36, 216.76, 224.00, 340.25; IR (neat) 3079, 2957, 2058, 1917, 1651, 1586, 1455, 1377, 1250, 1094, 1042, 982, 891 cm"; mass spectrum m/z (% rel intensity) 344 M1 (2), 288 (8), 260 (6), 232 (22), 204 (42), 172 (95), 148 (95), 107 (60), 91 (81). Anal calcd for C15H16Cr05: C. 52.33; H, 4.68. Found: C, 52.68; H, 4.76. Red oil; R; = 0.19 (hexanes). 293 Preparation of propargyl alcohol 437 o _ OH N ngBr M \ = \ \ H § THF, -30 °C, 1h 436 437 To a solution of aldehyde 436 (0.167 g, 1.33 mmol) in THF (4 mL) at —30 °C under an argon atmosphere was added ethynyl magnesium bromide (0.5 M solution in THF, 4.0 mL, 2.0 mmol) dropwise. The reaction mixture was stirred at -30 °C for 1 hour and quenched with saturated aqueous NH4CI (8 mL). The aqueous layer was extracted with 820 (3 * 10 mL). The combined organic layer was washed with brine (15 mL) and dried over MgSO4. Flash chromatography on a silica gel column (eluent: 10% EtOAc in hexanes) provided the desired propargyl alcohol 437 as a colorless oil (0.141 g, 0.94 mmol, 71%). 1H NMR (CDCI3, 500 MHz) 6 1.72 (d, 3H, J = 1.2 Hz), 1.73 (d, 1H, J = 5.1 Hz), 2.09-2.12 (m, 2H), 2.16-2.19 (m, 2H), 2.47 (d, 1H, J = 2.2 Hz), 4.94-4.96 (m, 1H), 5.01 (dq, 1H, J = 17.1, 2.0 Hz), 5.06 (ddd, 1H, J = 8.3, 6.1, 2.2 Hz), 5.38 (dq, 1H, J = 8.3, 1.2 Hz), 5.73 (ddt, 1H, J = 15.5, 10.0.5.4 Hz); 13C NMR (CDCI3, 125 MHz) 15.55, 31.70, 38.51, 58.89, 72.52, 84.40, 114.83, 124.37, 137.91, 140.46; IR (neat) 3300br, 1079, 2934, 2116, 1641, 1449, 1005, 914, 639 cm"; mass spectrum m/z (% rel intensity) 150 M+ (9), 149 (100), 104 (5), 71 (9), 70(9), 57 (11). Anal calcd for C10H14O: C, 79.96; H, 9.39. Found: C, 79.98; H, 9.46. Coclorless oil; R; = 0.29 (CH2CI2). 294 Preparation of trityl other 330 \ ’ A \ Q — M 437 CH2CI2, 1 d, 11 33° To a solution of alcohol 437 (46.1 mg, 0.307 mmol) and TrCl (171 mg, 0.614 mmol) in 1 mL of CH2CI2 was added DBU (0.10 mL, 0.614 mmol) dropwise. The solution was stirred at room temperature for 1 day, and then poured slowly into ice-cold water. The aqueous layer was extracted with CH2CI2 (2 * 10 mL). The combined organic layer was washed with saturated aqueous NaHCOa (10 mL), brine (10 mL), and dried over MgSO4. Filtration and concentration followed by flash Chromatography on silica gel using 9:1 hexanes/EtOAC as eluent provided trityl ether 330 (118 mg, 0.301 mmol, 98%) as a colorless oil, which was crystallized in freezer after 1 week. 1H NMR (CDCI3, 500 MHz) 6 1.28 (d, 3H, J = 1.2 Hz), 1.84-1.90 (m, 2H), 1.96-2.02 (m, 2H), 2.04 (d, 1H, J = 2.1 Hz), 4.67 (dd, 1H, J = 8.1, 2.1 Hz), 4.86-4.97 (m, 2H), 5.17-5.21 (m, 1H), 5.63-5.77 (m, 1H), 7.11-7.24 (m, 9H), 7.42-7.48 (m, 6H); 13C NMR (CDCI3, 125 MHz) 6 16.70, 31.74.3835, 61.95, 72.10, 83.27, 88.25, 114.56, 124.34, 127.02, 127.71, 128.98, 136.34, 138.24, 144.34. IR (neat) 3291, 3059, 2930, 1637m 1491, 1449, 1026, 708, 631 cm"; mass spectrum m/z (% rel intensity) 244 (35), 243 (CPh3)+ (100). Anal calcd for C29H2aO: C. 88.73; H, 7.19. Found: C, 88.60; H, 7.08. Colorless needle, mp 47-48 °C; R; - 0.60 (9:1 hexanes/Et20). 295 Preparation of TIPS-ether 431 b M): TIPSCI, DMAP OTIPS \ \ \ 7 W \ Q CH2CI2, I1, 20 h 437 4311) To a solution of propargyl alcohol 437 (149 mg, 0.99 mmol) in CH2CI2 (10 mL) was added DMAP (366 mg, 3.00 mmol) followed by the addition of triisopropylsilyl Chloride (0.428 mL, 2.00 mmol). The reaction mixture was stirred at room temperature for 20 hours and then quenched with saturated aqueous NaHCO3 (10 mL). Diethyl ether (3 * 20 mL) was added to extract the product from the aqueous layer. The combined organic layer was washed with brine (25 mL), and then dried over MgSO4. Removal of the solvent under reduced pressure followed by flash chromatography on silica gel (19:1 hexanes/EtOAC as eluent) provided the desired product 431b (258 mg, 0.84 mmol, 84%) as colorless oil. 1H NMR (CDCI3, 500 MHz) 6 1.03-1.09 (m, 21H), 1.66 (d, 3H, J = 1.3 Hz), 2.06-2.09 (m, 2H), 2.14-2.19 (m, 2H), 2.40 (d, 1H, J = 2.2 Hz), 4.91-4.94 (m, 1H), 4.98-5.02 (m, 1H), 5.10 (dd, 1H, J = 8.0, 2.2 Hz), 5.34 (dq, 1H, J = 7.9, 1.3 Hz), 5.74-5.82 (m, 1H); 13C NMR (CDCI3, 125 MHz) 6 12.17, 16.66, 17.85, 17.90, 31.78. 38.46, 59.91, 71.47, 85.00, 114.66, 126.39, 136.21, 138.11; IR (neat) 3312, 3081, 2946, 2866, 1641, 1464, 1063, 883, 684, 654 cm"; mass spectrum m/z (% rel intensity) 263 (M-43)+ (46), 131 (62), 130 (43), 103 (73), 91 (18), 77 (17), 75 (89), 61 (100). Anal calcd for C19H340$iz C. 74.44; H, 11.18. Found: C, 74.33; H, 11.47. Colorless oil; R; = 0.15 (hexanes). 296 Preparation of triphenylsilyl-ether 431C OH Ph3SiCI, DMAP OSiPha M = M 437 CH2C12, rt, 12 h 431,: TO a solution of propargyl alcohol 437 (0.737 g, 4.91 mmol) in CH2CI2 (10 mL) was added DMAP (1.20 g, 9.82 mmol) and triphenylsilyl chloride (2.17 g, 7.36 mmol) respectively. The reaction mixture was stirred at room temperature for 12 hours and quenched with saturated aqueous NaHCOa (10 mL). Diethyl ether (3 * 10 mL) was added to extract the product from the aqueous layer. The combined organic layer was washed with saturated aqueous NH4CI (25 mL), brine (25 mL), and then dried oVer M9804. Removal of the solvent under reduced pressure followed by flash chromatography on silica gel (19:1 hexanes/EtOAc as eluent) provided the desired product 431C (1.88 g, 4.60 mmol, 94%) as a colorless oil. 1H NMR (CDCI3, 500 MHz) 6 1.28 (d, 3H, J = 1.4 Hz), 1.97-2.00 (m, 2H), 2.03-2.09 (m, 2H), 2.38 (d, 1H, J = 2.2 Hz),,4.90-4.92 (m, 1H), 4.95-5.00 (m, 1H), 5.14 (dd, 1H, J = 8.6, 2.2 Hz), 5.42 (dq, 1H, J = 8.6, 1.4 Hz), 5.72 (ddt, 1H, J = 16.6, 10.3, 6.4 Hz), 7.34-7.37 (m, 6H), 7.39-7.41 (m, 3H), 7.64- 7.66 (m, 6H); 13C NMR (CDCI3, 125 MHz) 6 16.27, 31.63, 38.44, 60.78, 72.38, 84.33, 114.65, 125.07, 127.75, 130.02, 134.03, 135.55, 137.88, 138.07; IR (neat) 3291, 3071, 2934, 2116 w, 1590, 1429, 1117, 1053, 712 cm"; mass spectrum m/z (% rel intensity) 408 M“ (2), 289 (13), 259 (96), 210 (17), 199 (79), 197 (100), 181 (38), 180 (58), 105 (47), 91 (40), 79 (17), 77 (69). HRMS (Cl) calcd for (C23H230+H)" m/z 409.1988, meas 409.1998. Colorless oil; R; = 0.41 (9:1 hexanes/EtOAC). 297 Preparation of TES-ether 431d \ \ 7 M § CH2CI2 o “C to rt. 1 h Q 437 431d To a solution of propargyl alcohol 437 (0.217 g, 1.45 mmol) in CH2CI2 (10 mL) at 0 °C was added TEA (1.0 mL, 7.17 mmol) followed by the addition of triethylsilyl triflate (0.654 mL, 2.89 mmol). The reaction mixture was allowed to warm to room temperature and stirred until all of the propargyl alcohol was consumed. The reaction was then quenched with saturated aqueous NaHC03 (10 mL). Diethyl ether (3 * 10 mL) was added to extract the product from the aqueous layer. The combined organic layer was washed with saturated aqueous NH4CI (15 mL), brine (15 mL), and then dried over MgSO4. Removal of the solvent under reduced pressure followed by flash chromatography on silica gel (49:1 hexanes/EtOAC as eluent) provided the desired product 431d (278 mg, 1.05 mmol, 73%) as a colorless Oil. 1H NMR (CDCI3, 500 MHz) 6 0.63 (qd, 6H, J = 7.8, 2.0 Hz), 0.95 (t, 9H, J = 7.8 Hz), 1.67 (d, 3H, J = 1.2 Hz), 2.06-2.09 (m, 2H), 2.15-2.19 (m, 2H), 2.41 (d, 1H, J= 2.2 Hz), 4.92-4.95 (m, 1H), 4.98-5.02 (m, 1H), 5.04 (dd, 1H, J = 8.1, 2.2 Hz), 5.34 (dq, 1H, J = 8.3, 1.2 Hz), 5.79 (ddt, 1H, J = 16.6, 10.0, 6.3 Hz); 13C NMR (CDCI3, 125 MHz) 6 4.79, 6.67, 16.48, 31.71, 38.51, 59.41, 71.64, 84.87, 114.66, 125.76, 137.16, 138.06; IR (neat) 3312, 2955, 2876, 1641, 1458, 1063, 1005, 749, 628 cm"; mass spectrum m/z (% rel intensity) 235 (M-29)+ (4), 115 (14), 103 (100), 91 (18), 87 (27), 75 (70), 57 (23). 298 HRMS (CI) calcd for (C15H280+H)" m/z 265.1988, meas 265.1991. Colorless oil; R; = 0.35 (49:1 hexanes/EtOAc). Preparation of MOM-ether 431e OH M M W MOMCI' DIPEA MK Q t \ \ Q CH I,rt, 20h 437 202 4315 To a solution of 437 (119 mg, 0.793 mmol) in CH2CI2 (5 mL) at room temperature was added DIPEA (0.415 mL, 2.38 mmol) and MOMCI (0.12 mL, 1.59 mmol). The above solution was stirred for 20 hours, and then quenched with saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with 320 (2 * 10 mL). The combined organic layer was washed with brine (15 mL), and then dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography on silica gel using 9:1 hexanes/EtOAc as eluent to give a 86% yield of 4313 (133 mg, 0.696 mmol). 1H NMR (CDCI3, 500 MHz) 6 1.70 (d, 3H, J = 1.2 Hz), 2.09-2.12 (m, 2H), 2.15-2.20 (m, 2H), 2.42 (d, 1H, J = 2.0 Hz), 3.36 (s, 3H), 4.59 (d, 1H, J = 6.8 Hz), 4.81 (d, 1H, J = 6.8 Hz), 4.93 (d, 1H, J = 10.3 Hz), 4.99 (d, 1H, J = 17.0 Hz), 5.03 (dd, 1H, J = 8.8, 2.2 Hz), 5.30 (dd, 1H, J = 3.3, 1.0 Hz), 5.73-5.30 (m, 1H); 13C NMR (CDCI3, 125 MHz) 3 15.51, 31.69, 38.57, 55.57, 61.45, 73,13, 82.12, 93.14, 114.77, 121.88, 137.90, 141.11; IR (neat) 3297, 3079, 2936, 1641, 1152, 1094, 1030, 942 cm“. Anal calcd for C;2H;gO2: C. 74.19; H, 9.34. Found: C, 74.22; H, 9.72. Colorless oil; R; = 0.36 (9:1 hexanes/EtOAc). 299 General procedure for the thermolysis of carbene complex 329 and alkynes The carbene complex 329 and alkyne (1.2 equiv.) was dissolved in acetonitrile (0.02 M) and transferred to a schlenk flask equipped with a threaded Teflon high vacuum stopcock. The reaction was deoxygenated by the freeze- thaw procedure with 3 cycles. The flask was filled with an argon atmosphere at room temperature, sealed and heated at 55 °C. After the reaction was completed (indicated by the color of the carbene complex), the reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was dissolved in 1:1 mixture of CH2CI2/Et2O and stirred in air at room temperature. After stirring 12 hours, the solution was passed through Celite 503, concentrated, and then purified by chromatography on silica gel (30:1:1 hexanes/ CH2CI2/Et2O) to afford the cyclized products. Thermolysis of carbene complex 329 with alkyne 330 OMe OTr (OC)5Cr + M 55 °C. CHacN,121; — \ § 329 330 The thermolysis was performed with carbene complex 329 (68.8 mg, 0.20 mmol) and alkyne 330 (94 mg, 0.24 mmol) in 10 mL of CH30N according to the general procedure to afford 328 (97.4 mg, 0.167 mmol, 83%) and 430a (98:2 dr) as yellow oil. 300 Major isomer 328 1H NMR (CDCI3, 500 MHz) 6 0.93 (s, 3H), 1.26-1.35 (m, 3H), 1.52 (s, 3H), 1.55 (d, 3H, J = 1.4 Hz), 1.75-1.31 (m, 1H), 1.93-2.02 (m, 2H), 2.03-2.12 (m, 2H), 3.50 (s, 3H), 4.45 (s, 1H), 4.54 (s, 1H), 4.59 (d, 1H, J = 3.2 Hz), 4.92 (dq, 1H, J = 10.1.2.0 Hz), 5.00 (dq, 1H, J = 17.0.2.1 Hz), 5.04-5.05 (m, 1H), 5.30 (dd, 1H, J = 9.0, 0.7 Hz), 5.73-5.30 (m, 1H), 5.55 (dd, 1H, J = 3.1, 1.0 Hz), 7.11-7.14 (m, 3H), 7.13-7.21 (m, 6H), 7.43-7.43 (m, 6H); 13C NMR (CDCI3, 125 MHz) 3 15.93, 22.33, 27.02, 32.23, 32.37, 33.93, 41.25, 43.57, 54.54, 55.93, 37.79, 109.33, 109.47, 114.42, 125.33, 125.75, 127.50, 123.34, 135.02, 135.24, 133.29, 133.53, 144.53, 145.43, 150.44, 202.30; IR (neat) mass spectrum m/z (% rel intensity) 312 (4), 244 (Ph3C+1) (33), 243 (95), 189 (24), 155 (19), 155 (100), 123 (79), 105 (32), 95 (14), 91 (17). Anal calcd for C40H4403: C. 83.88; H, 7.74. Found: C, 84.04; H, 8.09. Light yellow solid, mp. 109-111 °C; R; = 0.24 (30:1:1 hexanes/ CH2CI2/ 820). Minor isomer 430a 1H NMR (CDCI3, 500 MHz) 3 0.94 (s, 3H), 1.22- 1.32 (m, 2H), 1.43 (d, 3H, J = 1.2 Hz), 1.51-1.53 (m, 2H), 1.70 (s, 3H), 1.37-1.95 (m, 2H), 2.00-2.03 (m, 2H), 3.53 (s, 3H), 4.52453 (m, 1H), 4.55457 (m, 1H), 4.79 (d, 1H, J = 3.2 Hz), 4.37 (dq, 1H, J = 10.3, 2.0 Hz), 4.95 (dq, 1H, J = 17.2, 2.0 Hz), 4.93-5.01 (m, 1H), 5.29 (dd, 1H, J = 3.3, 0.9 Hz), 5.53-5.75 (m, 1H), 5.74 (dd, 1H, J = 3.1, 0.9 Hz), 7.12-7.15 (m, 3H), 7.13-7.22 (m, 6H), 7.44-7.43 (m, 6H); 13C NMR (CDCIa, 125 MHz) 3 15.97, 22.57, 27.41, 32.17, 33.71, 33.54, 39.05, 49.37, 54.53, 57.59, 37.97, 109.47, 109.52, 114.34, 125.52, 125.30, 127.52, 123.90, 135.52, 135.99, 133.33, 133.43, 144.73, 145.94, 150.31, 202.57; IR (neat) 3063, 2921, 1647, 1449, 1046, 704 cm"; mass spectrum m/z (% rel 301 intensity) 244 (Ph30+H)+ (84), 243 (100), 189 (13), 166 934), 165 (51), 123 (24), 105 (16). HRMS (Cl) calcd for (C40H4403+H)+ m/z 573.3369, meas 573.3361. Yellow oil. Thermolysis of carbene complex 329 with alkyne 431b O OTIPS OMB OTIPS (OC)50r + M 55 °C, CH30N, 12 1; 5° — \ Q 329 431b The thermolysis was performed with carbene complex 329 (68.8 mg, 0.20 mmol) and alkyne 431b (74 mg, 0.24 mmol) in 10 mL of CH3CN according to the general procedure to afford 83% of 429b (81.2 mg, 0.167 mmol, >98:2 dr) as a yellow oil. 1H NMR (CDCI3, 500 MHz) 6 0.99-1.01 (m, 21H), 1.16 (s, 3H), 1.45 (td, 1H, J= 12.3, 3.9 Hz), 1.51-1.54 (m, 1H), 1.58 (s, 3H), 1.73-1.77 (m, 1H), 1.78 (d, 3H, J = 1.3 Hz), 1.95-2.01 (m, 3H), 2.04-2.10 (m, 2H), 3.61 (s, 3H), 4.52 (s, 1H), 4.58 (s, 1H), 4.86(dq, 1H, J = 10.3, 2.0 Hz), 4.91- 4.96 (m, 3H), 5.47 (dd, 1H, J = 8.8, 1.1 Hz), 5.68-5.74 (m, 1H), 7.00 (dd, 1H, J = 3.2, 1.1 Hz); 13C NMR (CDCI3, 125 MHz) 6 12.17, 16.95, 17.93, 18.01, 22.50, 26.88, 32.16, 32.73, 38.97, 40.87, 49.34, 54.73, 65.11, 109.67, 109.96, 114.35, 127.44, 135.76, 136.20, 138.40, 141.24, 145.53, 150.73, 203.63; IR (neat) 3077, 2946, 2869, 1649, 1601, 1385, 1047, 884, 689 cm"; mass spectrum m/z (% rel intensity) 443 (M - 43)+ (14), 387 (15), 321 (20), 319 (16), 312 (43), 279 (22), 277 (19), 263 (15), 257 (23), 244 (48), 235 (26), 221 (27), 189 (66), 188 (51), 157 (16), 115 302 (29), 109 (20), 103 (23), 102 (20), 91 (15), 37 (24), 31 (17), 75 (45), 73 (37), 59 (50), 57 (24), 51 (27), 59 (31), 41 (100). HRMS (Cl) calcd for (C30H5003+H)+ m/z 487.3607, meas 487.3606. Yellow oil; R; = 0.30 (30:1:1 hexanes lCH2Cl2/Et20). Thermolysis of carbene complex 329 with alkyne 431C 0 OSiPh3 (N09 - . OSIPh3 55 °C, 0.02 M (OC)5CF — + W 7 S“ Q CH3CN, 5 h We / 329 4296 431e The thermolysis was performed with carbene complex 329 (62.5 mg, 0.182 mmol) and alkyne 431C (89.2 mg, 0.218 mmol) in 9.1 mL of CH3CN according to general procedure to afford major isomer 429c (45.9 mg, 0.078 mmol) in 43% yield and minor isomer 430C (21.5 mg, 0.036) in 20% yield. The ratio of diastereomers determined by crude 1H NMR was 2:1. Major 429C 1H NMR (CDCI3, 500 MHz) 6 1.08 (s, 3H), 1.37 (cl, 3H, J = 1.1 Hz), 1.43 (td, 1H, J= 12.2, 4.0 Hz), 1.50-1.55 (m, 1H), 1.57 (s, 3H), 1.70-1.76 (m, 1H), 1.87-1.90 (m, 2H), 1.92-2.00 (m, 3H), 3.61 (s, 3H), 4.52 (s, 1H), 4.58 (s, 1H), 4.84-4.86 (m, 1H), 4.90-4.97 (m, 2H), 5.01-5.03 (m, 1H), 5.61 (d, 1H, J= 9.0 Hz), 5.67 (ddt, 1H, J = 16.4, 10.1, 6.2 Hz), 7.14 (dd, 1H, J = 3.1, 0.9 Hz), 7.32- 7.35 (m, 6H), 7.37-7.40 (m, 3H), 7.53-7.52 (m, 6H); 13C NMR (CDCI3, 125 MHz) 3 16.47, 22.46, 26.89, 31.96, 32.75, 38.88, 40.73, 49.25, 54.73, 66.42, 109.68, 110.12, 114.31, 125.91, 127.70, 129.85, 134.44, 135.48, 136.41, 137.49, 138.34, 140.09, 145.48, 150.57, 203.21; IR, (neat) 3071, 2832, 1647, 1429, 1110, 1046, 303 711 cm'l; mass spectrum m/z (% rel intensity) 560 (M-28)+ 312 (20), 260 (21), 259 (89), 258 (64), 257 (15), 244 (23), 199 (28), 198 (34), 189 (100), 181 (22), 180 (20), 121 (19). HRMS (Cl) calcd for (C39H4403+H)+ m/z 589.3138, meas 589.3149. Yellow oil; R; = 0.15 (30:1:1 hexanes/CH2CI2/Et20). Minor 430C 1H NMR (CDCI3, 500 MHz) 6 1.07 (s, 3H), 1.32 (d, 3H, J = 1.3 Hz), 1.40 (td, 1H, J: 12.5, 4.0 Hz), 1.54-1.60 (m, 1H), 1.64 (s, 3H), 1.67-1.73 (m, 1H), 1.85-1.89 (m, 2H), 1.94-1.99 (m, 2H), 2.03 (td, 1H, J = 12.3, 5.1 Hz), 3.61 (5, 3H), 4.57-4.58 (m, 1H), 4.63 (s, 1H), 4.80-4.85 (m, 1H), 4.89-4.93 (m, 1H), 4.95 (d, 1H, J = 3.2 Hz), 4.99-5.02 (m, 1H), 5.59 (dd, 1H, J = 9.0, 1.2 Hz), 5.64 (ddt, 1H, J = 16.9, 10.3, 6.7 Hz), 7.14 (dd, 1H, J = 3.2, 1.1 Hz), 7.30-7.33 (m, 6H), 7.36-7.40 (m, 3H), 7.57-7.61 (m, 6H), 13C NMR (CDCI3, 125 MHz) 6 16.42, 22.59, 27.16, 31.86, 33.19, 38.89, 39.87, 49.57, 54.75, 66.52, 109.77, 110.12, 114.31, 125.87, 127.70, 129.86, 134.45, 135.48, 136.22, 137.46, 138.35, 140.01, 145.72, 150.49, 203.01; IR (neat) 3071m 2930, 1647, 1429, 1117, 711 cm"; mass spectrum m/z (% rel intensity) 560 (M-28)+ (4), 312 (20), 261 (28), 259 (97), 258 (78), 243 (22), 206 (76), 199 (33), 198 (38), 189 (100), 181 (27), 180 (24), 177 (29), 11 (20), 105 (17), 55 (18). HRMS (CI) calcd for (C2,;9Htr403+H)+ m/z 589.3138, meas 589.3135. Yellow oil; R; = 0.19 (30:1:1 hexanes/CH2CI2/Et20). 304 Thermolysis of carbene complex 329 with alkyne 431d O OTES 0 OTES (OC)50rW77 +\/\J\)OT\ES 55 DC 002M ‘6‘... \ CH3CN, 7h 77L O 329 431 d 429d 430d The thermolysis was performed with carbene complex 329 (42.2 mg, 0.123 mmol) and alkyne 431d (38.9 mg, 0.147 mmol) in 6.2 mL of CH30N according to general procedure to afford 2:1 ratio of inseparable diastereomers 429d and 430d (34.9 mg in total, 0.0786 mmol, 64%) as yellow oil. IR (neat) 2955, 2878, 1647, 1383, 1047, 747 cm'1; mass spectrum m/z (% rel intensity) 416 (M-28)+ (3), 312 (7), 244 (18), 189 (49), 188 (82), 115 (55), 103 (24), 87 (100), 75 (20), 60 (22), 59 (22). Yellow oil; R; = 0.21 (30:1:1 hexanes/CH2CI2/Et20). General procedure for the thermolysis of carbene complex 329 with alkyne 431e (OC)5Cr w varies conditions k ‘3‘“ (MMe / 4313 4293 The carbene complex 329 and alkyne 431e (1.2 equiv.) was dissolved in the certain amount of solvent and transferred to a schlenk flask equipped with a threaded Teflon high vacuum stopcock. The reaction was deoxygenated by the 305 freeze-thaw procedure with 3 cycles. The flask was filled with an argon atmosphere at room temperature, sealed and heated at the specific temperatures. After the reaction was completed (indicated by the color of the carbene complex), the reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was dissolved in 1:1 mixture of CH2CI2/Et20 and stirred in air at room temperature. After stirring 12 hours, the solution was passed through Celite 503, concentrated, and then purified by Chromatography on silica gel (30:1:1 hexanes/ CH2CI2/Et2O) to afford the cyclized products 429e and 430e as yellow oil. The ratio of 429e to 4305 was determined on the crude reaction mixture by 1H NMR based on the integral of the following peaks: 6 6.94 for 429e and 6.92 for 430s. Annulation reaction in CH3CN at 55 °C at a concentration of 0.02 M The thermolysis was performed with carbene complex 329 (90 mg, 0.26 mmol) and alkyne 431e (60.9 mg, 0.314 mmol) in 13 mL of CH3CN at 55 °C for 12 hours according to general procedure to afford 48% of 429e (46.3 mg, 0.124 mmol) and 15% of 4305 (14.6 mg, 0.039 mmol). 1H NMR determined ratio 429e/430e = 3:1. Annulation reaction in benzene at 55 °C at a concentration of 0.02 M The thermolysis was performed with carbene complex 329 (66 mg, 0.192 mmol) and alkyne 431e (44.7 mg, 0.230 mmol) in 9.6 mL of benzene at 55 °C for 306 28 hours according to general procedure to afford 50% of 429e and 4296 (36.0 mg in total, 0.096 mmol). 1H NMR determined ratio 429e/430e = 3:1. Annulation reaction in THF at 55 °C at a concentration of 0.02 M The thermolysis was performed with carbene complex 329 (66.2 mg, 0.192 mmol) and alkyne 431e (44.7 mg, 0.230 mmol) in 9.6 mL of THF at 55 °C for 28 hours according to general procedure to afford 33% of 429e (23.4 mg, 0.0626 mmol) and 10% of 4305 (7.0 mg, 0.0187 mmol). 1H NMR determined ratio 4299/4309 = 3:1. Annulation reaction in CH3CN at 40 °C at a concentration of 0.02 M The thermolysis was performed with carbene complex 329 (53.9 mg, 0.157 mmol) and alkyne 431e (36.5 mg, 0.188 mmol) in 6.9 mL of CH2,CN at 40 °C for 60 hours according to general procedure to afford 27% of 4296 (16.0 mg, 0.043 mmol) and 18% of 430e (10.5 mg, 0.028 mmol). 1H NMR determined ratio 429e/430e = 3:2. Annulation reaction in CH3CN at 55 °C at a concentration of 0.005 M The thermolysis was performed with carbene complex 329 (40.2 mg, 0.117 mmol) and alkyne 4316 (27.2 mg, 0.140 mmol) in 23.4 mL of CH3CN at 55 °C for 12 hours according to general procedure to afford 24% of 429e (10.4 mg, 0.028 mmol) and 17% of 430e (7.5 mg, 0.020 mmol). 1H NMR determined ratio 429e/430e = 4:3. 307 Annulation reaction in CH3CN at 55 °C at a concentration of 0.1 M The thermolysis was performed with carbene complex 329 (41 mg, 0.119 mmol) and alkyne 4316 (27.7 mg, 0.142 mmol) in 1.2 mL of CH3CN at 55 °C for 24 hours according to general procedure to afford 43% of 429e (19.0 mg, 0.051 mmol) and 16% of 4303 (7.3 mg, 0.020 mmol). 1H NMR determined ratio 429e/430e = 2:1. Major isomer 429e . 1H NMR (CDCI3, 500 MHz) 6 1.19 (s, 3H), 1.47 (td, 1H, J = 12.4, 3.0 Hz), 1.60 (q, 3H, J = 0.8 Hz), 1.73-1.79 (m, 1H), 1.79 (d, 3H, J = 1.4 Hz), 1.98-2.14 (m, 6H), 3.32 (s, 3H), 3.61 (s, 3H), 4.52 (d, 1H, J = 6.5 Hz), 4.53-4.54 (m, 1H), 4.59-4.60 (m, 1H), 4.67 (d, 1H, J = 6.5 Hz), 4.87-4.97 (m, 3H), 5.00 (d, 1H, J = 3.2 Hz), 5.37 (dd, 1H, J = 9.2, 1.0 Hz), 5.68-5.75 (tdd, 1H, J = 16.9, 9.9, 6.5 Hz), 6.94 (dd, 1H, J = 3.2, 1.1 Hz); 13C NMR (CDCI3, 125 MHz) 6 16.68, 22.51, 26.85, 32.06, 32.79, 38.99, 40.84, 49.35, 54.80, 55.40, 67.36, 93.47, 109.76, 110.42, 114.61, 123.11, 136.91, 138.15, 138.20, 140.89, 145.48, 150.37, 203.55; IR (neat) 2932, 1649, 1385, 1034 cm'1; mass spectrum m/z (% rel intensity) 374 M+ (1), 346 (2), 312 (5), 244 (17), 189 (100), 95 (33), 69 (16), 67 (16), 55 (21). Anal calcd for C23H3404: C. 73.76; H, 9.15. Found: C, 73.40; H, 8.90. Yellow oil; R; = 0.36 (9:1 hexanes/EtOAC). Minor isomer 4306 1H NMR (CDCI3, 500 MHz) 6 1.14 (s, 3H), 1.49 (td, 1H, J = 11.6, 4.2 Hz), 1.64 (s, 3H), 1.69-1.73 (m, 1H), 1.78 (d, 3H, J = 1.2 Hz), 2.05-2.14 (m, 6H), 3.31 (s, 3H), 3.61 (s, 3H), 4.52 (d, 1H, J = 6.6 Hz), 4.58-4.59 308 (m, 1H), 4.61-4.62 (m, 1H), 4.66 (d, 1H, J = 6.6 Hz), 4.88 (dq, 1H, J = 10.3, 1.1 Hz), 4.94 (dq, 1H, J = 6.0, 1.5 Hz), 4.96-4.97 (m, 1H), 5.00 (d, 1H, J = 3.2 Hz), 5.36 (dd, 1H, J = 9.2 Hz, 1.0 Hz), 5.67-5.74 (m, 1H), 6.92 (dd, 1H, J = 3.1, 1.0 Hz); 13C NMR (CDCI3, 125 MHz) 6 16.64, 22.58, 27.13, 31.95, 33.12, 39.00, 40.05, 49.56, 54.80, 55.38, 67.42, 93.54, 109.75, 110.45, 114.60, 123.13, 136.89, 138.08, 138.16, 140.74, 145. 65, 150.29, 203.38; IR (neat) 2930, 1649, 1385, 1034 cm"; mass spectrum m/z (% rel intensity) 312 (M-62)+ (4), 189 (78), 91 (20), 55 (20), 45 (100). HRMS (Cl) calcd for (C23,H2,4O.;+H)+ m/z 375.2535, meas 375.2539. Yellow oil; R; = 0.31 (9:1 hexanes/EtOAC). Preparation of propargyl TIPS-ether 447 /l\/\/I\/\ 1) DMP. CHZCIZ' rt. 30 min W \ T \ \ OH \ Q 2) —:—MgBr ,THF, -30 °C,1h 3) TIPSCI, DMAP, CH20l2, rt 446 447 To a solution of geraniol 446 (0.879 g, 5.7 mmol) in CH2CI2 (10 mL) under an argon atmosphere was added freshly prepared DMP93 (3.60 g, 8.5 mmol) as powder. The reaction mixture was stirred at room temperature for 30 minutes before it was quenched with 10% aqueous NaOH (10 mL). The stirring was continued for another 5 minutes and then 320 (3 * 10 mL) was added to extract the product from the reaction mixture. The combined organic layer was dried over MgSO4. Removal of the solvent under reduced pressure followed by flash Chromatography on a silica gel column (9:1 hexanes/EtOAC as eluent) provided the desired aldehyde as a colorless oil, which was used immediately. 309 TO the above aldehyde in THF (20 mL) at to -30 °C under an argon atmosphere was added ethynyl magnesium bromide (0.5 M solution in THF, 20 mL, 10 mmol) dropwise. The reaction mixture was stirred at —30 °C for 1 hour and quenched with saturated aqueous NH4CI (10 mL). The aqueous layer was extracted with B20 (3 * 15 mL). The combined organic layer was washed with brine (25 mL) and dried with MgSO4. Flash chromatography on a silica gel column (4:1 hexanes/EtOAc as eluent) provided the desired propargylic alcohol as a colorless oil (790 mg, 4.44 mmol, 78%). The alcohol was used immediately to prepare the corresponding TIPS-ether. To a solution of the above propargyl alcohol (537 mg, 3.02 mmol) in CH2CI2 (10 mL) was added DMAP (737 mg, 6.4 mmol) followed by the addition of triisopropylsilyl Chloride (0.65 mL, 3.04 mmol). The reaction mixture was stirred at room temperature for 12 hours and quenched with water (10 mL). Diethyl ether (3 * 20 mL) was added to extract the product from the aqueous layer. The combined organic layer was washed with saturated aqueous NH4CI (25 mL), brine (25 mL), and then dried over MgSOa. Removal of the solvent under reduced pressure followed by flash chromatography on silica gel (19:1 hexanes/EtOAC as eluent) provided the desired product 447 as a colorless oil (773 mg, 2.32 mmol, 77%). 1H NMR (CDCI3, 500 MHz) 6 1.04-1.11 (m, 21H), 1.58 (s, 3H), 1.650 (s, 3H), 1.652 (s, 3H), 1.99-2.01 (m, 2H), 2.06-2.09 (m, 2H), 2.40 (d, 1H, J = 2.1 Hz), 5.07 (ft, 1H, J = 7.0, 1.3 Hz), 5.11 (dd, 1H, J = 7.9, 2.2 Hz), 5.33 (dq, 1H, J = 7.9, 1.2 Hz); 13C NMR (CDCI3, 125 MHz) 6 12.18, 16.64, 17.67, 17.85, 17.91, 25.67, 26.10, 39.18, 59.97, 71.39, 85.09, 123.81, 126.13, 310 131.70, 136.66; IR (neat) 3312, 2944, 2888, 1671, 1464, 1060, 883, 685, 650 cm’1; mass spectrum m/z (% rel intensity) 334 M“ (0.2), 291 (16), 131 (66), 103 (100), 91 (25), 89 (18), 76 (37), 75 (74), 70 (52), 69 (46), 61 (37). Colorless oil; R; = 0.52 (19:1 hexanes/EtOAC) Thermolysis of carbene complex 329 and alkyne 447 OMe OTIPS o (OC)5Cr + W 55 C. CH3CN,12h> — \ § OMe / 329 447 The thermolysis was performed with carbene complex 329 (45.8 mg, 0.133 mmol) and alkyne 447 (53.0 mg, 0.159 mmol) in 6.2 mL of CH3CN according to general procedure to afford 63% of 444 (43.2 mg, 0.084 mmol) as a single isomer. 1H NMR (CDCI3, 500 MHz) 6 0.99-1.00 (m, 21H), 1.17 (s, 3H), 1.43-1.51 (m, 1H), 1.54 (s, 3H), 1.57 (s, 3H), 1.61-1.63 (m, 3H), 1.70-1.75 (m, 2H), 1.77 (d, 3H, J = 1.2 Hz), 1.87-1.92 (m, 2H), 1.95-2.02 (m, 3H), 3.61 (s, 3H), 4.51 -4.52 (m, 1H), 4.56-4.58 (m, 1H), 4.91-4.93 (m, 1H), 4.96 (d, 1H, J = 3.2 Hz), 5.01-5.04 (m, 1H), 5.47 (d, 1H, J = 8.7 Hz), 7.00 (dd, 1H, J = 3.2, 1.1 Hz); 13C NMR (CDCI3, 125 MHz) 6 12.16, 16.94, 17.60, 17.93, 18.01, 22.47, 25.64, 26.49, 26.91, 32.75, 39.67, 40.94, 49.32, 54.73, 65.10, 109.73, 109.89, 124.12, 127.11, 131.42, 136.15, 136.21, 141.31, 145.53, 150.73, 203.66. IR (neat) 2944, 2888, 1647, 1383, 883 cm'1; Mass spectrum m/z (°/o rel intensity) 471 (M - 43)+ (2), 340 (15), 272 (26), 271 (38), 189 (41), 135 (28), 115 (19), 107 (15), 93 (18), 311 87 (18), 75 (32), 70 (96), 69 (100), 59 (66). HRMS (Cl) calcd for (C32H5.;O3+H)+ m/z 515.3920, meas 515.3923. Yellow oil; R; = 0.31 (30:1:1 Hexanes/CH2Cl2/Et20). General procedure for ring-closing metathesis Diene was dissolved in a certain amount of solvent (toluene or CH2CI2), and transferred to a schlenk flask equipped with a threaded TeflOn high-vacuum stopcock under an argon atmosphere. To this solution was added Grubbs 2nd gerneration catalyst or Hoveda catalyst (5 mol% to 25 mol%) and the stopcock was Closed. The solution was heated in an oil bath at a specific temperature and time. Then the reaction was cooled to room temperature and the solvent was removed in vacuo. Crude 1H NMR was taken to determine the ratio of products. RCM of diene 328 5 mol% Grubbs ll Tol,110°C,1mM,3 h 327 RCM of diene 328 (20.0 mg, 0.035 mmol) was carried out in 35 mL of toluene at 110 °C for 3 hours with 5 mol% loading of Grubbs ll catalyst according to the general procedure. The crude product was purified by chromatography on silica gel (30:1:1 hexanes/CH2Cl2/Et20) to give bicyclic compound 327 (18.0 mg, 0.033 mmol) in 94% yield. 1H NMR (CDCI3, 500 MHZ) 6 0.79 (s, 3H), 1.43 (s, 312 3H), 1.45 (s, 3H), 1.55-1.57 (m, 2H), 1.31-1.35 (m, 2H), 2.00 (td, 1H, J = 12.5, 4.3 Hz), 2.12-2.23 (m, 3H), 3.51 (s, 3H), 4.41 (d, 1H, J = 11.5 Hz), 4.52 (d, 1H, J = 3.2 Hz), 4.34 (d, 1H, J = 9.4 Hz), 5.23 (d, 1H, J = 3.5 Hz), 5.54 (dd, 1H, J = 3.2, 0.5 Hz), 7.10-7.14 (m, 3H), 7.17-7.22 (m, 5H), 7.42-7.47 (m, 6H); 13C NMR (CDCI3, 125 MHz) 3 15.03, 15.53, 25.54, 30.43, 35.17, 37.93, 39.37, 49.12, 54.52, 55.92, 37.72, 109.39, 124.52, 125.73, 127.29, 127.55, 123.35, 134.39, 134.33, 135.32, 139.23, 144.75, 150.73, 201.57. IR (neat) 2913, 1545, 1443, 1335, 1045, 704 cm"; mass spectrum m/z (% rel intensity) 301 (M-Ph3C)+ (3), 244 (23), 243 (100), 155 (53). HRMS (Cl) calcd for (C38H4003+H)+ m/z 545.3055, meas 545.3071. Light yellow solid, mp 209-212 °C; R; = 0.27 (30:1:1 hexanes/ CH2CI2/ E1120). RCM of diene 429b O OTIPS 5 mol% Grubbs ll Tol, 100 °C, 0.2 mM, 8 h 429b RCM of diene 429b (9.2 mg, 0.019 mmol) was carried out in 95 mL of toluene at 100 °C for 8 hours with 5 mol% loading of Grubbs lI catalyst according to the general procedure. The crude product was purified by Chromatography on silica gel (30:1:1 hexanes/CH2Cl2/Et20) to give bicyclic compound 360 (8.0 mg, 0.0175 mmol) in 93% yield. The spectral data for this compound matched that for a product obtained from the thermolysis of compound 349 (vide supra). 313 RCM of diene 429C 5 mol% Grubbs II ~ Tol, 100 °C, 1 mM, 8 h OMe / 4296 RCM of diene 429C (5.4 mg, 0.0092 mmol) was carried out in 9.2 mL of toluene at 100 °C for 8 hours with 5 mol% loading of Grubbs ll catalyst according to the general procedure. The crude product was purified by chromatography on silica gel (30:1 :1 hexanes/CH2Cl2/Et20) to give bicyclic compound 331C (3.8 mg, 0.0068 mmol) in 74% yield. 1H NMR (CDCI3, 500 MHz) 6 0.97 (s, 3H), 1.31 (d, 3H, J: 1.0 Hz), 1.32-1.38 (m, 1H), 1.52 (s, 3H), 1.65-1.70 (m, 1H), 1.80-1.92 (m, 3H), 1.96-2.00 (m, 1H), 2.17-2.29 (m, 2H), 3.61 (s, 3H), 4.44 (d, 1H, J = 1.2 Hz), 4.75 (m, 1H), 4.83 (d, 1H, J = 3.2 Hz), 5.57 (dd, 1H, J = 9.2, 1.0 Hz), 7.08 (dd, 1H, J = 3.2, 1.1 Hz), 7.29-7.32 (m, 5H), 7.35-7.33 (m, 3H), 7.57-7.52 (m, 6H); 13C NMR (CDCI3, 125 MHz) 6 15.21, 15.32, 25.45, 29.80, 36.12, 37.90, 39.17, 49.51, 54.70, 66.10, 110.44, 124.61, 127.71, 128.79, 129.84, 134.38, 134.40, 134.96, 135.45, 135.61, 140.70, 150.92, 201.82; IR (neat) 3071, 2919, 2851, 1647, 1599, 1429, 1383, 1117, 1044, 712, 700 cm“; mass spectrum m/z (% rel intensity) 560 M+ (5), 426 (15), 347 (16), 259 (100), 241 (26), 199 (40), 189 (42), 181 (32), 105 (21), 91 (18), 77 (22). HRMS (FAB) calcd for (C37H4003Si+H)+ m/z 561.2825, meas 561.2821. Colorless oil; R; = 0.20 (30:1:1 hexanes/CH2CI2/Et20). 314 RCM of mixtures of 429d/430d o OTES O OTES OMe OMe 7: / S: / 429d 2:1 dr 430d 10 mol% Grubbs ll ‘ Tol, 100 °C, 1 mM, 8 h RCM of mixtures of diene 429d and 430d (5.2 mg, 0.0117 mmol, 2:1 dr) was carried out in 11.7 mL of toluene at 100 °C for 8 hours with 10 mol% loading of Grubbs ll catalyst according to the general procedure. The crude product was purified by Chromatography on silica gel (30:1:1 hexanes/CH2Cl2/Et20) to give 3.7 mg of bicyclic compound 384 together with inseperable dimer (3:1 ratio based on crude 1H NMR). No RCM product from diene 430d was detected. The spectral data for this compound matched that for a product obtained from compound 383 (vide supra). RCM of diene 429e O OMOM OMe / 4296 10 mol% Grubbs ll y Tol, 100 °C, 1 mM, 14 h RCM of diene 429e (24.7 mg, 0.066 mmol) was carried out in 66 mL of toluene at 100 °C for 14 hours with 10 mol% loading of Grubbs ll catalyst according to the general procedure. The crude product was purified by Chromatography on silica gel (30:1:1 hexanes/CH2CI2/Et20) to give a 76% yield 315 of bicyclic compound 362 (17.3 mg, 0.050 mmol) and 2.9 mg of unreacted 4295. The spectral data for this compound matched that for a product obtained from the thermolysis of compound 359 (vide supra). Peterson olefination of compound 429b O OTIPS 1) LICHZTMS, THF, rt, 30 min 2) KHMDS, THF, rt, 1 h 3) HCI, MeOH, rt, 5 min 429b Trimethylsilylmethyllithium (0.142 mmol, 0.237 mL, 0.6 M in THF) was added dropwise to a solution of compound 429b (23.1 mg, 0.0475 mmol) in 5.0 mL of THF at room temperature. The solution was stirred for 30 minutes, and then quenched with H2O. The aqueous phase was separated and extracted with B20 (3 * 10 mL). The combined organic layer was washed with brine (15 mL), dried over Na2SO4 and concentrated in vacuo to give an silyl alcohol. The residue was dissolved in 5 mL of THF, and then KHMDS (0.12 mL, 0.060 mmol, 0.5 M in toluene) was added dropwise. The reaction mixture was stirred for 1.5 hours at room temperature, and then quenched with H20 (5 mL). The aqueous phase was separated and extracted with 320 (3 * 10 mL). The combined organic layer was washed with brine (15 mL), dried over Na2SO4 and concentrated in vacuo to give an unstable enol ether. The residue was dissolved in 1 mL of methanol, and then treated with 1 mL of 1% HCI and stirred at room temperature for 5 minutes. The mixture was 316 diluted with 320 (5 mL) and neutralized with saturated aqueous NaHCOa (5 mL), and the aqueous phase was separated and then extracted with 320 (3 * 10 mL). The combined organic layer was washed with brine (15 mL), dried over MgSO.; and concentrated in vacuo. The residue was purified by flash column Chromatography on silica gel using 9:1 hexanes/Et20 as eluent to give (20.9 mg, 0.0444 mmol, 94%) ketone 449. 1H NMR (CDCI3, 500 MHz) 6 1.01-1.09 (m, 21H), 1.17 (s, 3H), 1.33-1.41 (m, 1H), 1.55-1.64 (m, 2H), 1.61 (s, 3H), 1.68 (d, 3H, J = 1.0 Hz), 1.78-1.84 (m, 1H), 1.96-2.02 (m, 2H), 2.06-2.10 (m, 2H), 2.34- 2.42 (m, 2H), 4.54 (s, 1H), 4.61 (s, 1H), 4.89-4.91 (m, 1H), 4.94-4.98 (m, 1H), 5.04-5.06 (m, 1H), 5.26 (d, 1H, J = 1.5 Hz), 5.37 (d, 1H, J = 9.0 Hz), 5.52 (s, 1H), 5.72 (ddt, 1H, J = 16.6, 10.0, 6.3 Hz), 6.33 (s, 1H); 13’C NMR (CDCI3, 125 MHz) 6 12.27, 17.33, 17.92, 18.02, 22.73, 25.06, 31.81, 32.51, 36.51, 38.88, 42.24, 51.73, 68.43, 109.51, 114.48, 114.66, 123.72, 127.27, 136.42, 138.04, 145.46, 147.04, 159.72, 199.63; IR (neat) 2944, 2867, 1671, 1093, 883 cm"; mass spectrum m/z (% rel intensity) 470 M+ (0.1), 427 (24), 131 (28), 105 (35), 103 (100), 95 (25), 91 (21), 81 (24), 75 (65), 73 (20), 62 (27), 61 (39), 58 (25). HRMS (CI) calcd for (C30H5002,+H)+ m/z 471.3658, meas 471.3676. Light yellow oil; R; = 0.59 (9:1 hexanes/EtOAC). 317 Peterson olefination of compound 328 O OTr 1) LiCHQTMS, THF, rt, 30 min 2) KHMDS, THF, rt, 1 h 3) HCI, MeOH, rt, 5 min 328 Trimethylsilylmethyllithium (0.210 mmol, 0.35 mL, 0.6 M in THF) was added dropwise to a solution of compound 328 (40.9 mg, 0.070 mmol) in 5.0 mL of THF at room temperature. The solution was stirred for 30 minutes, and then quenched with H20 (5 mL). The aqueous phase was separated and extracted with 320 (3 * 10 mL). The combined organic layer was washed with brine (15 mL), dried over Na2SO4 and concentrated in vacuo to give a silyl alcohol. The residue was dissolved in 5 mL of THF, and then KHMDS (0.21 mL, 0.105 mmol, 0.5 M in toluene) was added dropwise. The reaction mixture was stirred for 1.5 hours at room temperature before quenching with H20 (5 mL). The aqueous phase was separated and extracted with 320 (3 * 10 mL). The combined organic layer was washed with brine (15 mL), dried over Na2804 and concentrated in vacuo to give an enol ether. The residue was dissolved in 1 mL of MeOH, and then treated with 1 mL of 1% HCI and stirred at room temperature for 5 minutes. The mixture was diluted with 820 (5 mL) and neutralized with a saturated aqueous NaHCOa (5 mL), and the aqueous phase was separated and then extracted with B20 (3 "' 10 mL). The combined organic layer was washed with brine (15 mL), dried over M9804 and concentrated in vacuo. The residue was purified by flash column 318 chromatography on silica gel using 9:1 hexanes/Et2O as eluent to give ketone 448 (35.0 mg, 0.0626 mmol) in 89% yield. 1H NMR (CDCI3, 500 MHz) 6 1.00 (s, 3H), 1.19-1.25 (m, 2H), 1.42 (s, 3H), 1.43-1.49 (m, 2H), 1.55 (s, 3H), 1.665-1.72 (m, 1H), 1.94-2.00 (m, 3H), 2.07-2.13 (m, 2H), 4.48 (s, 1H), 4.57 (s, 1H), 4.93- 4.96 (m, 1H), 4.99-5.03 (m, 2H), 5.14 (s, 2H), 5.19 (s, 1H), 5.76 (ddt, 1H, J = 15.5, 10.2, 5.5 Hz), 5.02 (s, 1H), 7.15-7.31 (m, 9H), 7.43-7.43 (m, 6H); 13C NMR (CDCI3, 125 MHz) 6 17.62, 22.68, 25.08, 31.89, 32.45, 36.36, 38.83, 41.72, 51.17, 70.18, 88.47, 109.42, 114.73, 114.98, 124.90, 125.09, 127.00, 127.77, 127.91, 136.94, 138.03, 144.39, 145.44, 145.91, 157.38.199.34; IR (neat) 3061, 2922, 1669, 1449, 1026, 706 cm"; mass spectrum m/z (% rel intensity) 243 (CPh3)" (100), 227 (22), 166 (99), 164 (94), 105 (83), 95 (18), 91 (33), 77 (19), 55 (24). HRMS (Cl) calcd for (C40H44O2+H)” m/z 557.3420, meas 557.3434. Light yellow solid, mp. 50-52 °C; R; = 0.19 (9:1 hexanes/EtOAc). RCM of diene 449 10 mol% Grubbs lI Tol, 100°C, 1 mM, 24 h RCM of diene 449 (4.5 mg, 0.0093 mmol) was carried out in 9.3 mL of toluene at 100 °C for 24 hours with 10 mol% loading of Grubbs ll catalyst according to the general procedure. The crude product was purified by Chromatography on silica gel (9:1 hexanes/EtOAC) to give 1:0.8 mixture of E- and 319 Z- bicyclic compound 451 (3.5 mg in total, 0.0076 mmol) in 82% yield. The spectra of 4512 was extracted from the mixture of E- and 2-451. 1H NMR (CDCI3, 500 MHz) 6 1.01-1.03 (m, 21H), 1.13 (s, 3H), 1.38-1.44 (m, 1H), 1.53 (s, 3H), 1.69 (d, 3H, J = 1.0 Hz), 1.80-1.97 (m, 2H), 2.00-2.08 (m, 5H), 2.32 (d, 1H, J = 16.4 Hz), 2.42 (d, 1H, J = 16.4 Hz), 4.96 (d, 1H, J = 8.2 Hz), 5.04-5.07 (m, 1H), 5.24 (d, 1H, J = 1.4 Hz), 5.32 (dd, 1H, J = 15.3, 1.1 Hz), 5.41 (s, 1H), 6.29 (s, 1H); 13C NMR (CDCI3, 125 MHz) 6 12.15, 17.87, 18.00, 18.78, 22.57, 23.33, 25.65, 26.01, 35.52, 39.07, 43.05, 54.25, 68.60, 113.97, 121.83, 123.81, 126.00. 138.01, 147.43, 160.71, 199.54 (1 sp2 carbon was not located). Colorless oil, R; = 0.45 (9:1 hexanes/EtOAc). Preparation of TIPS-ether 451 from MOM-ether 388 1) 6 N HCI/MeOH, 55 °C, 20 h 2) TIPSCI, DMAP CH2CI2, rt, 4 d To a solution of MOM ether 388 (11 mg, 0.033 mmol) in 1.0 mL of MeOH was added 6 N HCI (0.011 mL) at room temperature. Thereaction mixture was heated at 55 °C for 20 hours, and then cooled to room temperature. The mixture was diluted with B20 (5 mL) and neutralized with saturated aqueous NaHC03 (10 mL). The aqueous phase was separated and then extracted with B20 (2 * 10 mL). The combined organic layer was washed with brine (10 mL), dried over 320 Na2SO4 and concentrated in vacuo. The crude product was passed through a short silica gel column in pipette, concentrated and went directly to the next step. To the solution of the above alcohol in CH20|2 (1 mL) was added DMAP (12.2 mg, 0.10 mmol) followed by the addition of TIPSCI (0.014 mL, 0.066 mmol). The reaction mixture was stirred at room temperature for 4 days and quenched with water (5 mL). Diethyl ether (3 * 10 mL) was added to extract the product from the aqueous layer. The combined organic layer was washed with saturated aqueous NaHCOa (15 mL), brine (15 mL), and then dried over MgSO4. Removal of the solvent under reduced pressure followed by flash chromatography on silica gel (9:1 hexanes/EtOAC as eluent) provided the desired product 451 as a colorless Oil (13.3 mg, 0.030 mmol, 91%). 1H NMR (CDCI3, 500 MHz) 6 1.00- 1.03 (m, 21H), 1.18 (s, 3H), 1.36-1.41 (m, 1H), 1.45 (s, 3H), 1.58 (d, 3H, J = 1.4 Hz), 1.71-1.80 (m, 2H), 2.01-2.07 (m, 5H), 2.22 (d, 1H, J= 15.6 Hz), 2.44 (d, 1H, J = 15.6 Hz), 4.68-4.70 (m, 1H), 4.79 (d, 1H, J = 9.3 Hz), 5.26 (d, 1H, J = 1.6 Hz), 5.32 (dd, 1H, J = 9.3, 1.2 Hz), 5.35 (s, 1H), 6.41 (s, 1H); 13C NMR (CDCI3, 125 MHZ) 6 12.24, 16.39, 17.02, 17.92, 18.04, 24.42, 24.85, 34.10, 36.02, 38.71, 42.96, 54.77, 67.22, 114.23, 123.11, 124.43, 127.88, 135.68, 136.01, 146.54, 160.05, 199.88; IR (neat) 2942, 2867, 1671, 1464, 1094, 1044, 884 cm"; mass spectrum m/z (% rel intensity) 442 Mi (7), 399 (43), 135 (21), 131 (28), 105 (22), 103 (27), 102 (27), 95 (28), 91 (23), 81 (38), 77 (22), 75 (100), 61 (46), 59 (19). HRMS (CI) calcd for (C2;;H.;;302+H)+ m/z 443.3345, meas 443.3331. Colorless oil; R; = 0.45 (9:1 hexanes/EtOAC). 321 RCM of diene 450 OTr 5 mol% Grubbs ll ‘2 Tol, 100 °C, 1 mM, 8 h 5:0 448 1) LHMDS THF, ~78 °C > HCI, MeOH 2) Mel -78 °C to rt rt, 6 h RCM of diene 448 (21.3 mg, 0.0372 mmol) was carried out in 34.2 mL of toluene at 100 °C for 8 hours with 5 mol% loading of Grubbs II catalyst according to the general procedure. The crude product was purified by Chromatography on silica gel (10% EtOAC in hexanes) to give a 2:1 mixture of inseparable E- and Z- bicyclic compounds 450E and 4502 (14.2 mg, 0.0260 mmol) in 70% yield. To a solution of the above mixture in THF (1.0 mL) at —78 °C was added LHMDS (0.052 mL, 0.052 mmol, 1.0 M solution in THF) dropwise. After stirring for 1 hour at —78 °C, iodomethane (6.5 uL, 0.104 mmol) was added. The cooling bath was removed immediately and the reaction mixture was allowed to warm to room temperature. After stirring 11 hours, 5 mL of saturated aqueous NH4CI was added to the flask. The aqueous layer was extracted with 320 (2 * 10 mL). The combined organic layer was washed with brine (10 mL), and then dried over MgSO4. The residue was purified by flash column chromatography on silica gel using 9:1 hexanes/5120 as eluent to give a 2:1 mixture of ketones 4525 and 4522 (13.2 mg in total, 0.0236 mmol, 91%). 322 The resulting ketones were treated with 2 equivalent of 6 N HCI in 1 mL of MeOH at room temperature until the trityl group was totally cleaved (monitored by TLC). Then 5 mL of saturated aqueous NH4CI was added to the flask to quench the reaction. The aqueous layer was extracted with 320 (2 * 10 mL). The combined organic layer was washed with brine (10 mL), and then dried over MgSOa. The residue was purified by flash column Chromatography on silica gel using 9:1 hexanes/Et20 as eluent to give inseparable mixture of E- and Z- alcohols 394 and 3942 (5.6 mg in total, 0.0187 mmol, 2:1 dr, 79%). The spectra for Z-isomer 3942 was extracted from the mixture of E- and Z-394. 1H NMR (CDCI3, 500 MHz) 6 0.97 (d, 3H, J = 7.2 Hz), 1.04 (s, 3H), 1.35- 1.41 (m, 1H), 1.53 (s, 3H), 1.76 (d, 3H, J = 1.2 Hz), 1.92-1.95 (m, 2H), 2.06-2.18 (m, 6H), 4.98 (d, 1H, J = 8.5 Hz), 5.03 (t, 1H, J = 8.2 Hz), 5.22 (d, 1H, J = 1.5 Hz), 5.39 (d, 1H, J = 9.0 Hz), 5.58 (s, 1H), 6.15 (s, 1H); 130 NMR (CDCI3, 125 MHz) 6 13.28, 18.76, 19.67, 22.57, 25.97, 36.30, 38.91, 46.02, 54.89, 67.88, 116.40, 119.49, 123.74, 124.52, 136.04, 141.10, 145.22, 158.11, 204.03 (1 sp3 carbon was not located). 323 Methylation of dienone 448 OCPh3 1) LHMDS or KHMDS, THF, ~78 °C, 1 h 2) Mel, -78 °C to rt, 11 h .. Q ‘ ‘\ \ ¢¥ 448 To a solution of ketone 448 (4.1 mg, 0.00716 mmol) in THF (0.2 mL) at —78 °C was added KHMDS (0.029 mL, 0.0145 mmol, 0.5 M solution in toluene) dropwise. After stirring for 1 hour at -78 °C, iodomethane (4.5 uL, 0.0716 mmol) was added. The cooling bath was removed immediately, and the reaction mixture was allowed to warm to room temperature. After stirring 5 hours, 5 mL of aqueous saturated NH4CI was added to the flask. The aqueous layer was extracted with 320 (2 * 10 mL). The combined organic layer was washed with brine (10 mL), and then dried over MgSO4. The residue was purified by flash column chromatography on silica gel using 9:1 hexanes/Et2O as eluent to give 5: 1 of ketone 454 and starting material 448 (3.7 mg in total, 0.0053 mmol of 454, 74%). 1H NMR (CDCI3, 500 MHz) 6 0.63 (d, 3H, J = 7.3 Hz), 0.92 (s, 3H), 1.37 (s, 3H), 1.46-1.58 (m, 3H), 1.56 (s, 3H), 1.68-1.71 (m, 1H), 1.92-2.05 (m, 3H), 2.09-2.11 (m, 2H), 4.48 (s, 1H), 4.57 (s, 1H), 4.95 (m, 2H), 5.02 (dq, 1H, J= 16.1, 1.8 Hz), 5.15 (br, 3H), 5.77 (ddt, 1H, J = 169,102, 6.5 Hz), 6.09 (s, 1H), 7.15- 7.30 (m, 9H), 7.45-7.47 (m, 6H); 13C NMR (CDCI3, 125 MHz) 3 13.45, 17.53, 21.14, 22.71, 31.85, 32.31, 37.13, 38.90, 44.88, 53.09, 70.17, 88.66, 109.39, 114.74, 116.60, 123.07, 125.66, 127.05, 127.73, 127.93, 128.99, 136.99, 138.08, 144.57, 145.53, 157.11, 204.04; IR (neat) 3059, 2924, 1667, 1449, 1026, 706 324 cm'i; mass spectrum m/z (% rel intensity) 243 (CPh3)" (100), 165 (25), HRMS (Cl) calcd for (C.;;H.;;3O2+H)+ m/z 571.3576, meas 571.3551. Light yellow oil; R; = 0.35 (9:1 hexanes/EtOAC). RCM of diene 454 10 mol% Grubbs ll Tol, 100 °C, 1 mM, 7 h RCM of diene 454 (3.6 mg, 0.0061 mmol) was carried out in 6.1 mL of toluene at 100 °C for 7 hours with 10 mol% loading of Grubbs II catalyst according to the general procedure. The crude product was purified by Chromatography on silica gel (9:1 hexanes/EtOAC) to give 0.6:1 mixture of E- and Z- bicyclic compounds 452 (2.8 mg in total, 0.0050 mmol) in 82% yield. Colorless oil; R; = 0.35 (9:1 hexanes/EtOAC). 325 APPENDICES Figure A-1 ORTEP Drawing of the Structure of Compound 370 OTIPS O 6071 ‘131. ‘7 0115 0 0115 ’1" ' . 0 01321 01141 "“01131 ‘F; . )3 7 . I '251 01131 - 7 CB) 910(4) Cl 1 9 " I O “-3) .3 I \' \\' 01301 ‘3 f: 0121 “ C‘ o 0111 - (ts/‘5‘ At 0 ‘ 3' Cl o ‘6 9 (1,5. 511231,. 0‘12“ 01191 ' J 5) 01251 9 (3,24, '-' 0(2) f’w ° (0513,3111. - - (7 "01201 15;: 01291 01111:) /:7 ’ ‘5') ' C(27) "' o 2:? 0121’ '0 cm 01101 .- .QT—O [191 5’ . 1231 0:7) 0131 . 326 Table 1. Crystal data and structure refinement for wf021005 Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size Theta range for data collection lndexranges Reflections collected / unique Completeness to theta = 28.23 Refinement method Data / restraints / parameters Goodness-of-fit on F"2 Final R indices [l>2sigma(l)] R indices (all data) Absolute structure parameter Largest diff. peak and hole p21 C58 H93 04 Si2 910.50 173(2) K 0.71073 A Monoclinic P2(1) a = 10.600(2) A b = 22.885(5) A c = 12.657(3) A alpha = 90 deg. beta = 108.01(3) deg. gamma = 90 deg. 2919.9(10) A"3 2 1.036 Mg/m"3 0.101 mm"-1 1002 06x04x02mm 1.69 to 28.23 deg. -14<=h<=14, -29<=k<=30, -16<=l<=16 35046 I 13757 [R(int) = 0.0940] 97.8% Full-matrix least-squares on F"2 13757 / 1 /593 0.245 R1 = 0.0449, wR2 = 0.1101 R1 = 0.1004, wR2 = 0.1236 0.5(3) 0.259 and -0.217 e.A"-3 327 Table 2. Atomic coordinates ( x 10‘4), equivalent isotropic displacement parameters (A02 x 10‘3), and occupancies for M021005 x y z U(eq) Occ. C(1) -656(6) 3708(3) 2393(5) 24(2) 1 C(2) -562(7) 4046(3) 3455(5) 26(2) 1 C(3) -1606(6) 4496(3) 3374(5) 28(2) 1 0(4) -1379(7) 5061 (3) 2697(6) 37(2) 1 C(5) -105(7) 5368(3) 3197(6) 49(2) 1 C(6) 799(8) 5403(3) 2435(7) 42(2) 1 0(7) 1934(8) 5135(3) 2665(6) 37(2) 1 0(8) 2807(8) 5031(3) 1972(7) 51(2) 1 C(9) 3186(7) 4413(3) 1874(6) 37(2) 1 C(10) 1956(7) 3997(3) 1589(6) 35(2) 1 C(1 1) 1699(7) 3686(3) 2397(6) 26(2) 1 C(12) 430(6) 3340(3) 2260(5) 28(2) 1 Q(13) -1802(6) 3752(3) 1520(5) 27(2) 1 C(14) -3021 (7) 4059(3) 1560(6) 32(2) 1 C(15) -3935(5) 4133(2) 742(4) 44(1) 1 C(16) -2999(7) 4259(3) 2729(6) 37(2) 1 C(17) -3465(7) 3746(3) 3327(6) 40(2) 1 C(18) -1631(7) 4718(3) 4555(5) 40(2) 1 C(19) 408(8) 3915(3) 4367(6) 40(2) 1 C(20) 223(7) 5742(4) 1378(6) 62(2) 1 C(21) 1056(7) 4073(3) 440(6) 57(2) 1 0(22) 706(4) 2864(2) 3051 (4) 30(1) 1 Si(23) 588(2) 2159(1) 2770(2) 29(1) 1 C(24) 966(8) 1863(3) 4175(6) 52(2) 1 C(25) -78(9) 2004(4) 4780(7) 66(2) 1 C(26) 1001 (10) 1 187(4) 4265(6) 109(4) 1 C(27) 1945(7) 1916(3) 2189(6) 37(2) 1 C(28) 3348(7) 21 15(4) 2975(7) 50(2) 1 C(29) 1745(7) 2122(3) 1022(6) 44(2) 1 C(30) -1060(7) 1996(3) 1733(6) 41(2) 1 C(31) -1 142(8) 1335(3) 1312(7) 58(2) 1 C(32) -2307(7) 2120(4) 2085(7) 61(3) 1 C(33) 571 0(6) 3297(3) 7578(6) 26(2) 1 C(34) 5569(6) 2998(3) 6553(6) 27(2) 1 C(35) 661 5(6) 2502(3) 6608(6) 32(2) 1 C(36) 6357(7) 1980(3) 7231 (6) 36(2) 1 C(37) 4980(6) 1643(3) 6761(6) 32(2) 1 C(38) 4228(8) 1622(3) 7564(6) 34(2) 1 C(39) 3055(7) 1919(3) 7323(6) 39(2) 1 C(40) 2171(7) 1978(3) 8070(6) 37(2) 1 C(41) 1798(7) 2658(3) 8049(6) 41(2) 1 328 Table 2 (cont’d) 0(42) 0(43) C(44) C(45) 0145) 0(47) C(48) 0(49) 0(50) 0(51) 0(52) 0(53) C(54) 51155) 0(55) 0(57) C(58) 0(59) 0(50) 0(51) 0(52) 0(53) C(64) 3003(7) 3309(7) 4537(5) 6787(7) 7954(7) 8934(5) 7989(5) 8438(7) 5554(7) 4508(7) 4849(8) 3925(5) 4295(4) 4412(2) 5051(7) 5157(8) 7277(8) 3055(7) 3235(7) 1720(7) 4103(7) 3700(8) 5097(8) 3018(3) 3330(3) 3578(3) 3288(3) 2958(3) 2884(2) 2753(3) 3305(3) 2328(3) 31 1 1(3) 1258(3) 3003(3) 4152(2) 4854(1) 5040(3) 5551(4) 4855(4) 5098(3) 4873(3) 4925(3) 5172(3) 5825(3) 4943(4) 8375(5) 7507(5) 7745(5) 8430(5) 8405(5) 9253(5) 7294(5) 5732(5) 5492(5) 5595(5) 8508(5) 9579(5) 5957(4) 7233(2) 8305(5) 8720(8) 7955(8) 7808(5) 9009(5) 7092(5) 5754(4) 5545(5) 5209(5) 32(2) 36(2) 28(2) 36(2) 33(2) 48(2) 30(2) 44(2) 47(2) 36(2) 66(2) 49(2) 32(1) 29(1) 41(2) 73(3) 64(3) 31(2) 49(2) 52(2) 30(2) 61(2) 62(2) U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. 329 Table 3. C(1)-Q(13) C(1)-C(12) C(1)-C(2) C(2)-C(19) C(2)-C(3) C(3)-C(16) C(3)-C(18) C(3)-C(4) 0(4)-0(5) C(5)-C(6) C(6)-C(7) C(6)-C(20) C(7)-C(8) C(8)-C(9) C(9)-C(10) 0(10)-0(1 1) 0(10)-0(21) 0(1 1)-0(12) C(12)-O(22) Q(13)-C(14) 0(14)-0(15) 0(14)-0(15) 0(15)-0(17) O(22)-Si(23) Si(23)-C(24) Si(23)-C(30) Si(23)-C(27) C(24)-C(26) C(24)-C(25) C(27)-C(29) C(27)-C(28) C(30)-C(32) C(30)-C(31) C(33)-C(45) C(33)-C(34) C(33)-C(44) C(34)-C(51) C(34)-C(35) C(35)-C(50) C(35)-C(36) C(35)-C(48) C(36)-C(37) C(37)-C(38) C(38)-C(39) 1 370(9) 1 .477(8) 1 528(8) 1 .321 (9) 1.492(9) 1 548(9) 1 .586(8) 1.510(9) 1 .480(9) 1.557(9) 1 .302(10) 1 .502(10) 1 .478(10) 1 .485(10) 1 554(9) 1 342(9) 1 .482(10) 1 524(8) 1 445(8) 1 .486(9) 1 .191 (8) 1.541 (1 0) 1 .558(10) 1.549(5) 1 829(7) 1 859(7) 1 890(7) 1 .551 (10) 1 .552(10) 1 .502(9) 1 .579(10) 1.545(9) 1.597(9) 1.307(9) 1.432(9) 1.585(8) 1.345(9) 1.574(8) 1.484(9) 1 503(9) 1 555(9) 1 594(8) 1.474(9) 1.355(9) 330 Bond lengths [A] and angles [deg] for wf021005 C(38)-C(52) C(39)-C(40) C(40)-C(41) C(41)-C(42) C(42)—C(43) C(42)—C(53) C(43)-C(44) C(44)—O(54) C(45)-C(46) C(46)-O(47) C(46)-C(48) C(48)-C(49) O(54)-Si(55) Si(55)-C(59) Si(55)-C(56) Si(55)-C(62) C(56)-C(57) C(56)-C(58) C(59)-C(61) C(59)-C(60) C(62)-C(64) C(62)-C(63) Q(13)-C(1)—C(12) Q(13)—C(1)-C(2) C(12)-C(1)-C(2) C(19)-C(2)-C(3) C(19)-C(2)-C(1) C(3)-C(2)—C(1) C(2)-C(3)—C(16) C(2)-C(3)-C(18) C(16)-C(3)-C(18) C(2)-C(3)-C(4) C(16)-C(3)-C(4) C(18)-C(3)-C(4) C(5)-C(4)-C(3) C(4)-C(5)-C(6) C(7)-C(6)-C(20) C(7)-C(6)-C(5) C(20)-C(6)-C(5) C(6)-C(7)-C(8) C(7)-C(8)—C(9) C(8)-C(9)-C(10) C(11)-C(10)-C(21) C(11)-C(10)—C(9) Table 3 (cont’d) 1 .527(10) 1.529(9) 1.503(9) 1.458(9) 1.325(9) 1.535(9) 1.489(9) 1.443(7) 1.458(9) 1.251(8) 1 .487(9) 1.577(10) 1.552(5) 1.878(7) 1.889(7) 1.920(5) 1 .485(10) 1 .549(10) 1 .480(10) 1 .55019) 1.529(9) 1.551(9) 1 18.6(6) 1 18.2(5) 123.2(5) 125.3(5) 1 18.3(6) 1 15.4(5) 1 1 1 .1(5) 1 12.5(5) 108.6(5) 1 1 1.2(5) 105.1(5) 107.1(5) 1 14.9(5) 1 14.5(5) 122.3(7) 122.7(7) 1 14.8(7) 130.5(8) 1 15.0(5) 1 1 1 7(5) 125.1(5) 1 19.9(7) C(21)-C(10)-C(9) 0(10)-0(11)-0(12) 0(22)-0(12)-0(1) O(22)-C(12)-C(1 1) C(1)-C(12)-C(11) C(1)-Q(13)-C(14) 0(15)-0(14)-o(13) 0(15)-0(14)-0(15) Q(13)-C(14)-C(16) 0(14)-0(15)-0(3) 0(14)-0(15)-0(17) C(3)-C(16)-C(17) C(12)-O(22)-Si(23) 0(22)-51(23)-0(24) O(22)-Si(23)—C(30) C(24)-Si(23)-C(30) 0(22)-51(23)-0(27) C(24)-Si(23)-C(27) C(30)-Si(23)-C(27) C(26)-C(24)-C(25) C(26)-C(24)-Si(23) C(25)-C(24)—Si(23) C(29)-C(27)-C(28) C(29)-C(27)-Si(23) C(28)-C(27)-Si(23) 0(32)-0(30)-0(31) C(32)-C(30)-Si(23) C(31)-C(30)-Si(23) 0(45)-0(33)-0(34) 0(45)-0(33)-0(44) C(34)-C(33)-C(44) 0(51)-0(34)-0(33) 0(51)-0134)-0(35) 0(33)-0(34)-0(35) 0(50)-0(35)-0(35) C(50)-C(35)-C(48) C(36)-C(35)-C(48) 0(50)-0(35)-0(34) C(36)-C(35)-C(34) 113.2(5) 124.7(5) 110.4(5) 109.3(5) 112.5(5) 124.8(6) 121.3(7) 124.0(7) 114.7(5) 109.8(5) 109.3(5) 113.7(5) 127.0(4) 100.0(3) 109.8(3) 119.0(4) 110.8(3) 107.7(3) 109.1(3) 100.0(5) 115.8(5) 115.1(5) 110.4(5) 113.4(5) 110.5(5) 107.8(5) 117.3(5) 111.5(5) 124.1(5) 114.8(6) 121 .215) 124.1(5) 120.4(5) 115.5(5) 110.5(5) 109.2(5) 107.5(5) 112.5(5) 110.9(5) C(48)-C(35)-C(34) C(35)-C(36)-C(37) C(38)-C(37)-C(36) C(39)-C(38)-C(37) C(39)-C(38)-C(52) C(37)-C(38)-C(52) C(38)-C(39)-C(40) C(39)-C(40)-C(41) 0(42)-0(41)-0(40) 0(43)-0(42)-0(41) 0(43)-0(42)-0(53) C(41)-C(42)-C(53) 0(42)-0(43)-0(44) 0(54)-0(44)-0143) O(54)-C(44)-C(33) 0(43)-0(44)-0(33) C(33)-C(45)-C(46) 0(47)-0(45)-0(45) O(47)-C(46)—C(48) C(45)-C(46)-C(48) C(46)-C(48)-C(35) C(46)-C(48)-C(49) C(35)-C(48)-C(49) C(44)-O(54)-Si(55) O(54)-Si(55)—C(59) O(54)-Si(55)-C(56) 0(59)-51(55)-0(55) 0(54)-51(55)-0(52) C(59)-Si(55)-C(62) 0(55)-s1(55)-0(52) C(57)-C(56)-C(58) 0(57)-0(55)-51(55) C(58)-C(56)-Si(55) 0(51)-0(59)-0(50) 0(51)-0(59)-51(55) 0(50)-0(59)-51(55) 0(54)-0(52)-0(53) 0(54)-0(52)-51155) 0(53)-0(52)-51(55) 105.7(5) 118.9(6) 112.8(5) 118.5(5) 125.7(7) 115.7(5) 125.5(7) 105.7(5) 110.5(5) 119.0(7) 121.0(7) 119.9(5) 127.2(7) 111.0(5) 107.4(5) 1 12.515) 121.4(7) 121.9(7) 121.3(7) 115.5(5) 110.4(5) 105.8(5) 114.2(5) 127.3(4) 110.2(3) 110.7(3) 107.7(3) 100.2(3) 110.4(3) 117.5(3) 111.0(5) 114.4(5) 114.0(5) 108.3(5) 112.9(5) 1 14.015) 119.5(5) 1 12.515) 114.1(4) Symmetry transformations used to generate equivalent atoms: Table 4. Anisotropic displacement parameters (A"2 x 10‘3) for wf021005 U11 U22 U33 U23 U13 U12 C(1) 30(4) 20(3) 20(3) -8(3) 6(3) -9(3) C(2) 40(4) 25(3) 9(3) 2(2) 4(3) -7(3) C(3) 36(4) 27(3) 21(3) -6(3) 9(3) 1 1(3) C(4) 38(4) 26(4) 43(4) 17(3) 5(3) 12(3) C(5) 88(6) 34(4) 36(4) -1 1(3) 33(4) -1(4) C(6) 48(5) 38(4) 49(5) -3(4) 26(4) -1 1(4) C(7) 50(5) 21(3) 38(4) 5(3) 10(4) -12(3) C(8) 62(6) 39(5) 47(5) 0(4) 1 1(4) -22(4) C(9) 27(4) 43(4) 33(3) -2(3) 0(3) -7(3) C(10) 21(4) 26(4) 57(5) -6(3) 13(3) -3(3) C(1 1) 30(4) 20(4) 24(4) 3(3) 4(3) 3(3) C(12) 27(4) 29(4) 18(3) -7(3) -8(3) -7(3) Q(13) 34(4) 34(4) 4(2) 2(2) -5(3) 5(3) C(14) 21(4) 34(4) 41(4) 8(3) 9(3) 2(3) 0(15) 28(3) 56(4) 39(3) -1(3) -3(3) 8(3) C(16) 41 (5) 31(4) 39(4) 2(3) 13(4) 8(3) C(17) 26(4) 54(5) 34(4) -1(3) 0(3) -4(3) C(18) 59(5) 48(4) 26(3) -8(3) 30(3) 9(4) C(19) 48(5) 38(5) 28(4) -12(3) 5(4) 4(4) C(20) 45(4) 67(5) 81(6) 48(4) 30(4) 30(4) C(21) 74(5) 48(4) 36(4) -7(3) —1(4) -39(4) 0(22) 37(3) 24(3) 31(3) 2(2) 14(2) 7(2) Si(23) 35(1) 27(1) 26(1) -1(1) 11(1) -2(1) C(24) 79(5) 25(4) 67(5) 1(3) 44(4) 4(3) C(25) 71(5) 75(5) 59(5) 28(4) 28(4) 30(4) C(26) 231 (1 1) 68(6) 49(4) 25(4) 74(6) 41(6) C(27) 46(5) 20(4) 45(5) 1(3) 15(4) 6(3) C(28) 29(4) 62(5) 58(5) -16(4) 13(3) -1 1(3) C(29) 50(5) 42(4) 52(5) -16(3) 33(4) -1(3) C(30) 55(5) 35(4) 36(4) 1(3) 16(4) -9(4) C(31) 72(6) 26(3) 70(6) -25(4) 13(5) -21(3) C(32) 23(4) 77(6) 79(6) -2(5) 8(4) 3(4) C(33) 23(4) 20(3) 35(4) 10(3) 9(3) 7(3) C(34) 16(3) 21(3) 43(4) -4(3) 7(3) 2(3) C(35) 26(4) 29(4) 38(4) 5(3) 9(3) 18(3) C(36) 34(4) ' 33(4) 37(4) —4(3) 5(3) -9(3) C(37) 18(3) 22(3) 52(4) -4(3) 5(3) -7(2) C(38) 49(5) 15(3) 34(4) -2(3) 5(4) 4(3) C(39) 39(4) 43(4) 36(4) —17(3) 14(4) -12(3) C(40) 31(4) 37(4) 47(5) -4(3) 20(4) -4(3) C(41) 39(4) 35(4) 63(5) 1(3) 34(3) 1(3) C(42) 37(4) 37(4) 23(3) -4(3) 13(3) 2(3) 332 Table 4 (cont’d) C(43) C(44) C(45) C(46) 0(47) C(48) C(49) C(50) C(51) C(52) C(53) 0(54) Si(55) C(55) C(57) C(58) C(59) C(60) C(61) C(62) C(63) C(64) 21(4) 36(4) 28(4) 32(4) 36(3) 16(4) 43(4) 36(4) 36(4) 99(7) 52(4) 37(3) 34(1) 26(4) 50(6) 56(6) 40(5) 57(5) 51(5) 47(4) 83(4) 76(5) 38(4) 17(3) 27(4) 27(4) 51(4) 35(4) 43(4) 31(4) 33(4) 45(4) 51(4) 18(2) 19(1) 32(4) 95(5) 53(5) 29(4) 50(5) 48(5) 30(4) 23(3) 91(5) 43(5) 35(4) 53(4) 31 (4) 47(4) 38(4) 55(5) 71(5) 31 (4) 63(5) 43(4) 32(3) 34(1) 60(5) 73(7) 84(7) 25(4) 35(4) 54(5) 1 3(3) 67(4) 36(4) -7(4) 6(3) -5(3) 0(3) 7(3) 0(3) -4(3) -7(3) -2(3) -3(4) 12(3) 3(2) 2(1) -10(4) -14(5) 43(5) -7(3) 23(3) -5(4) 1 1(2) 13(3) -1 1(3) 2(3) 20(3) 15(3) 4(3) -3(3) 5(3) 29(4) 14(4) 4(3) 40(5) 29(4) 0(2) 10(1) 6(3) 19(5) 23(5) 12(3) 19(4) 1 1(4) 10(3) 9(3) 40(4) 5(3) 1 1(3) -1 (3) -5(3) 5(3) 6(3) 9(3) -1 (3) 8(3) 3(4) 0(3) 0(2) 2(1) -8(3) -21(5) -22(4) -1 (3) 5(4) 22(4) 1(3) -1 (3) -28(4) The anisotropic displacement factor exponent takes the form: -2 pi"2[h"2 a*"2 U11 + + 2 h ka* b* U12] 333 Table 5. Hydrogen coordinates ( x 10"4), isotropic displacement parameters (A"2 x 10‘3), and occupancies for wf021005 x y z U(eq) Occ. H(4A) -1428 4940 1950 45 1 H(4B) -2097 5334 2635 45 1 H(5A) 378 5169 3879 59 1 H(SB) -291 5762 3390 59 1 H(7A) 2247 4984 3381 44 1 H(8A) 361 1 5257 2275 61 1 H(8B) 2365 5178 1231 61 1 H(9A) 3823 4291 2569 44 1 H(9B) 3610 4383 1298 44 1 H(11A) 2341 3681 3091 31 1 H(12A) 142 3173 1511 34 1 H(13A) -1817 3578 852 32 1 H(16A) -3636 4579 2641 44 1 H(17A) -4326 3616 2881 60 1 H(17B) -3509 3876 4036 60 1 H(17C) -2846 3428 3434 60 1 H(18A) -775 4872 4960 61 1 H(188) —1844 4398 4959 61 1 H(18C) 2288 5019 4459 61 1 H(19A) 370(30) 4099(14) 51 10(30) 9(9) 1 H(19B) 1230(50) 3620(30) 4380(50) 70(20) 1 H(20A) 817 5723 940 93 1 H(20B) 102 6142 1553 93 1 H(20C) -617 5576 967 93 1 H(21A) 320 3809 314 85 1 H(21 B) 1530 3991 -78 85 1 H(21 C) 735 4468 341 85 1 H(24A) 1829 2016 4624 63 1 H(25A) 229 1855 5526 99 1 H(25B) -908 1823 4388 99 1 H(25C) -195 2419 4799 99 1 H(26A) 1279 1075 5034 164 1 H(26B) 1613 1034 3913 164 1 H(26C) 131 1033 3905 164 1 H(27A) 1939 1488 2176 44 1 H(28A) 4025 1982 2676 75 1 H(28B) 3495 1951 3701 75 1 H(28C) 3375 2534 3027 75 1 H(29A) 2460 1983 773 66 1 H(29B) 1728 2542 1003 66 1 H(ZQC) 920 1973 543 66 1 334 I Table 5 (cont’d) H(30A) H(31A) H(31 B) H(31C) H(32A) H(328) H(32C) H(36A) H(37A) H(37B) H(39A) H(40A) H(408) H(41A) H(41 B) H(43A) H(44A) H(45A) H(48A) H(49A) H(498) H(490) H(50A) H(50B) H(50C) H(51A) H(51 B) H(52A) H(52B) H(52C) H(53A) H(538) H(53C) H(57A) H(57B) H(57C) H(58A) H(588) H(58C) H(59A) H(60A) H(508) H(6OC) -1130 -1968 -1088 -420 -3088 -2307 -2301 6989 4446 5150 2765 2642 1377 1253 1289 2688 4826 6810 8663 8465 9303 7818 6817 5837 7371 4250(50) 4050(30) 4288 5705 4944 4683 4212 3457 7036 5513 6026 8071 7241 7280 3074 2523 4065 3227 2243 1274 1076 1257 2041 2522 1873 1855 1835 1247 2103 1854 1743 2766 2728 3332 3842 3496 2457 3200 3430 3620 2668 2152 2053 2860(20) 3455(15) 1270 1414 861 3247 2609 3145 5712 5720 5916 4980 5060 4451 5526 5017 5010 4453 335 1085 737 1921 1025 1472 2301 2700 7879 6089 6568 6636 8821 7789 7307 8555 6903 8498 9067 7399 6006 7179 6669 5102 5081 5570 4950(50) 5530(30) 9075 9003 8400 9645 9777 10067 9234 9087 8106 8526 7274 7850 7840 9256 9500 9011 50 87 87 87 92 92 92 43 38 38 47 44 44 50 50 43 33 43 35 55 55 55 70 70 70 80(20) 5(8) 99 99 99 73 73 73 1 10 1 10 1 10 95 95 95 38 74 74 74 Table 5 (cont’d) H(61A) H(61 B) H(61C) H(63A) H(63B) H(530) H(64A) H(64B) H(64C) 1066 1675 1550 3624 4364 2863 4935 4999 5982 5057 4508 5100 5957 6053 5874 5126 4528 5032 7421 7020 6372 4907 6174 5779 4497 5114 5667 78 78 78 91 91 91 94 94 94 336 Figure A-2 ORTEP Drawing of the Structure of Compound 383 O OH 1‘: . ‘49 337 Table 1. Crystal data and structure refinement for wf072805 Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size Theta range for data collection lndexranges Reflections collected / unique Completeness to theta = 28.31 Refinement method Data / restraints / parameters Goodness-of-fit on F"2 Final R indices [l>25igma(|)] R indices (all data) Largest diff. peak and hole p-1 C19 H26 03 302.40 173(2) K 0.71073 A Triclinic P-1 a = 6.4091(13) A b = 14.590(3) A 0 = 18.406(4) A alpha = 9037(3) deg. beta = 9469(3) deg. gamma = 100.75(3) deg. 1684.9(6) A"3 4 1.192 Mg/m"3 0.079 mm"-1 656 14x12x05mm 1.78 to 28.31 deg. -8<=h<=8, -19<=k<=19, -24<=l<=23 20386 / 7977 [R(int) = 0.0315] 94.9% Full-matrix least-squares on F"2 7977 / 0 I405 1.093 R1 = 0.0514, wR2 = 0.1508 R1 = 0.0620, wR2 = 0.1559 0.556 and -0.311 e.A"-3 338 Table 2. Atomic coordinates ( x 10"4), equivalent isotropic displacement parameters (A02 x 10‘3), and occupancies for wf072805 x y z U(eq) Occ. C(1) 2902(2) 4041(1) 294(1) 22(1) 1 C(2) 2480(2) 4148(1) -485(1) 22(1) 1 C(3) 3210(2) 3642(1) -983(1) 20(1) 1 C(4) 4546(2) 2961(1) -746(1) 21(1) 1 C(5) 5065(2) 2839(1) 69(1) 22(1) 1 C(6) 4041(2) 3420(1) 557(1) 24(1) 1 0(7) 1991(2) 4634(1) 691(1) 28(1) 1 C(8) 2241(3) 4553(1) 1462(1) 37(1) 1 0(9) 5300(2) 2517(1) -1191(1) 32(1) 1 C(10) 7507(2) 3150(1) 206(1) 30(1) 1 C(11) 4479(2) 1793(1) 255(1) 26(1) 1 C(12) 2113(2) 1329(1) 124(1) 29(1) 1 C(13) 1398(2) 889(1) -625(1) 26(1) 1 C(14) 2684(3) 194(1) -862(1) 42(1) 1 C(15) -329(2) 1069(1) -1006(1) 26(1) 1 C(16) -1290(2) 666(1) -1740(1) 32(1) 1 C(17) -1575(2) 1439(1) -2286(1) 32(1) 1 C(18) 484(2) 2139(1) -2301(1) 27(1) 1 C(19) 2306(2) 1781(1) -2597(1) 33(1) 1 C(20) 641(2) 2977(1) -1981(1) 25(1) 1 C(21) 2620(2) 3700(1) -1793(1) 23(1) 1 0(22) 2234(2) 4620(1) -1936(1) 31(1) 1 C(1A) 2206(2) 6079(1) -5577(1) 22(1) 1 C(2A) 2426(2) 5816(1) -4817(1) 22(1) 1 C(3A) 1598(2) 6227(1) -4287(1) 20(1) 1 C(4A) 396(2) 6980(1) ~4461 ( 1) 22(1) 1 C(5A) 100(2) 7267(1) -5256(1) 24(1) 1 C(6A) 1199(2) 6770(1) -5784(1) 25( 1) 1 O(7A) 3147(2) 5539(1) -6014(1) 28(1) 1 C(8A) 3201(2) 5785(1) -6763(1) 36(1) 1 O(9A) -420(2) 7349(1) -3989(1) 33(1) 1 C(10A) -2329(2) 7017(1) -5471(1) 33(1) 1 C(11A) 787(2) 8338(1) -5312(1) 30(1) 1 C(12A) 3135(2) 8752(1) -5082(1) 32(1) 1 C(13A) 3691(2) 9002(1) 4280(1) 31(1) 1 C(14A) 2366(3) 9635(1) -3967(1) 51(1) 1 C(15A) 5329(2) 8724(1) -3909(1) 30(1) 1 C(16A) 6145(3) 8942(1) -3123(1) 37(1) 1 C(17A) 6284(2) 8051(1) -2686(1) 37(1) 1 C(18A) 4179(2) 7376(1) -2768(1) 30(1) 1 C(19A) 2357(3) 7676(1) -2420(1) 41(1) 1 339 Table 2 (cont’d) C(20A) 3987(2) 5523(1) -3198(1) 25(1) 1 C(21A) 1959(2) 5994(1) 3491(1) 24(1) 1 0(22A) 2252(2) 5041(1) -3418(1) 29(1) 1 U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. 340 Table 3. Bond lengths [A] and angles [deg] for wf072805 C(1)-C(6) C(1)-0(7) C(1)-C(2) C(2)-C(3) C(3)-C(4) C(3)-C(21) C(4)-0(9) C(4)-C(5) C(5)-C(6) C(5)-C(10) C(5)-C(1 1) C(7)-C(8) C(1 1)-C(12) C(12)-C(13) C(13)-C(15) C(13)-C(14) C(15)-C(16) C(16)-C(17) C(17)-C(18) C(18)-C(20) C(18)-C(19) C(20)-C(21) C(21)-o122) C(1A)-C(6A) C(1A)-O(7A) C(1A)-C(2A) C(2A)-C(3A) C(3A)-C(4A) C(3A)-C(21A) C(4A)-O(9A) C(4A)-C(5A) C(5A)-C(6A) C(5A)-C(1 1A) C(5A)-C(10A) O(7A)-C(8A) 011 1A)-C(12A) C(12A)-C(13A) C(13A)-C(15A) C(13A)-C(14A) C(15A)-C(16A) C(16A)-C(17A) C(17A)-C(18A) C(18A)-C(20A) C(18A)-C(19A) 1.3345119) 1 .3687(15) 1 .4529117) 1.3392117) 1 .4734117) 1.5159117) 1.2238(16) 1 .5282117) 1.500511 8) 1.5455119) 1 .549511 8) 1 4232117) 1 .54012) 1 .51512) 1.331 (2) 1.503(2) 1.505(2) 1 .54112) 1.513(2) 1 .3351 (1 9) 1 .50512) 1 .5047119) 1 4330115) 1 3345119) 1.370811 5) 1 .4555117) 1.337511 8) 1.478811 8) 1 .5154117) 1.2214115) 1 .531011 8) 1 .502511 8) 1 .5489(19) 1 .5490119) 1.4290117) 1.537(2) 1 .51512) 1.33412) 1.50712) 1.50812) 1.545(2) 1.510(2) 1 331(2) 1 .50812) 341 Table 3 (cont’d) C(20A)-C(21A) C(21A)-0(22A) C(6)-C(1)-O(7) C(6)-C(1)-C(2) O(7)-C(1)—C(2) C(3)-C(2)-C(1) C(2)-C(3)-C(4) C(2)-C(3)-C(21) C(4)-C(3)-C(21) O(9)-C(4)-C(3) O(9)-C(4)-C(5) C(3)-C(4)-C(5) C(6)-C(5)-C(4) C(6)-C(5)-C(10) C(6)-C(5)-C(1 1) C(4)-C(5)-C(1 1) C(10)-C(5)-C(11) C(1)-C(6)—C(5) C(1)-O(7)-C(8) C(1 2)-011 1)-c15) C(13)-C(12)-C(11) C(15)—C(13)-C(14) C(15)-C(13)-C(12) C(14)-C(13)-C(12) C(13)-C(15)-C(16) C(15)-C(16)—C(17) C(18)-C(17)-C(16) C(20)-C(18)-C(19) C(20)-C(18)-C(17) C(19)-C(18)-C(17) C(18)-C(20)-C(21) O(22)-C(21)-C(20) o122)-c121)-013) C(20)-C(21)-C(3) C(6A)-C(1A)—O(7A) C(6A)-C(1A)-C(2A) O(7A)-C(1A)-C(2A) C(3A)-C(2A)-C(1A) C(2A)-C(3A)-C(4A) C(2A)-C(3A)-C(21A) C(4A)-C(3A)-C(21A) O(9A)-C(4A)-C(3A) O(9A)-C(4A)-C(5A) 1.49712) 1.4433115) 12572112) 12143112) 111.8511 1) 12257112) 119.88(12) 122.4811 1) 11755111) 12104112) 11971111) 11921111) 11453110) 10575111) 11048111) 109.52111) 108.30(11) 12213112) 11501111) 115.7811 1) 11534112) 123.95113) 12113113) 11475113) 12774113) 11155112) 11033112) 12459114) 11902113) 115.82(12) 12809113) 111.08(11) 10804110) 10727110) 12723112) 12145112) 11132111) 12270112) 12012112) 12223111) 11752111) 12122112) 12003111) 342 Table 3 (cont’d) C(3A)-C(4A)-C(5A) C(6A)-C(5A)-C(4A) C(6A)-C(5A)-C(1 1A) C(4A)-C(5A)-C(1 1A) C(6A)-C(5A)-C(10A) C(4A)-C(5A)-C(10A) C(1 1A)-C(5A)-C(10A) C(1A)-C(6A)-C(5A) C(1A)-O(7A)-C(8A) C(12A)-C(11A)-C(5A) C(13A)-C(12A)-C(11A) C(15A)-C(13A)-C(14A) C(15A)-C(13A)-C(12A) C(14A)-C(13A)-C(12A) C(13A)-C(15A)-C(16A) C(15A)-C(16A)—C(17A) C(18A)-C(17A)-C(16A) C(20A)-C(18A)-C(19A) C(20A)-C(18A)-C(17A) C(19A)-C(18A)-C(17A) C(18A)-C(20A)-C(21A) O(22A)-C(21A)-C(20A) O(22A)-C(21A)-C(3A) C(20A)-C(21A)-C(3A) 118.70(11) 11491111) 11050111) 109.88(11) 10795111) 10552111) 10759111) 12193112) 115.55111) 11557112) 11552113) 12393114) 12115113) 11477114) 127.86(14) 11229112) 11057113) 124.45114) 11901113) 11512113) 12740113) 108.20(11) 110.72110) 105.7811 1) Symmetry transformations used to generate equivalent atoms: 343 Table 4. Anisotropic displacement parameters (AA2 x 10"3) for wa72805 U11 U22 033 U23 U13 U12 0(1) 22(1) 21(1) 20(1) 411) 3(1) 111) C(2) 2411) 19(1) 21(1) 1(1) 1(1) 4(1) 0(3) 2211) 1711) 18(1) 3(1) 311) 211) C(4) 22(1) 1911) 22(1) 111) 2(1) 3(1) 0(5) 2511) 2111) 21(1) 0(1) -211) 511) 0(5) 28(1) 2511) 17(1) -111) -111) 311) 0(7) 3111) 33(1) 2111) -8(1) 2(1) 11(1) C(8) 41(1) 54(1) 19(1) -9(1) 211) 1311) o19) 3811) 35(1) 25(1) -211) 411) 1811) C(10) 2511) 3011) 3411) 4(1) -311) 4(1) C(11) 3411) 21(1) 24(1) 4(1) -5(1) 5(1) C(12) 35(1) 2411 ) 23(1) 511 ) 1(1) 0(1) 0113) 3211) 18(1) 28(1) 111) 3(1) 011) 0114) 45(1) 3411) 48(1) -1011) -8(1) 15(1) C(15) 3111) 21(1) 2511) -211) 3(1) 111) C(16) 3511) 28(1) 31(1) -511) -211) 1(1) 0117) 34(1) 34(1) 27(1) -7(1) -711) 5(1) C(18) 35(1) 31(1) 15(1) 1(1) -211) 911) 0119) 4311) 3311 ) 23(1) -5(1) 4(1) 11(1) C(20) 3011) 2911 ) 15(1) 4(1) 011) 1011) C(21) 33(1) 22(1) 1711) 4(1) 5(1) 8(1) 0122) 5011) 2311) 2111) 711) 5(1) 12(1) C(1A) 2111) 2311) 18(1) 411) 211) 1(1) C(2A) 24(1) 20(1) 2111) 211) 111) 311) C(3A) 2111) 20(1) 18(1) 311) 111) 1(1) 014A) 22(1) 22(1) 2211) 011) 111) 3(1) C(5A) 2711) 2311) 2211) 011) -2(1) 5(1) C(6A) 28(1) 2711) 1711) 211) 011) 211) O(7A) 3211) 35(1) 20(1) 4(1) 511) 9(1) C(8A) 33(1) 5511 ) 18(1) -311) 511 ) 10(1) O(9A) 3811) 38(1) 27(1) -311) 5(1) 1711) C(10A) 28(1) 35(1) 3511) -311) -511) 8(1) C(11A) 38(1) 2311) 3011) 4(1) -511) 8(1) C112A) 38(1) 2311) 3211) 5(1) 211) 211) C(13A) 35(1) 19(1) 35(1) 4(1) 311) 1(1) C(14A) 55(1) 4211) 5011 ) -1911) -5(1) 23(1) C(15A) 3311) 24(1) 31(1) -511) 3(1) 011) C(16A) 38(1) 34(1) 35(1) -1211) -211) -111) C(17A) 37(1) 4411) 2511) -1011) -5(1) 3(1) C(18A) 3411) 38(1) 1711) 0(1) -211) 511) C(19A) 4211) 53(1) 2511) -1411) 411) 5(1) C(20A) 29(1) 32(1) 18(1) 411) 1(1) 711) 344 Table 4 (cont’d) c121A) 31(1) 2411) 1511) 4(1) 411) 511) 0122A) 39(1) 24(1) 22(1) 711) 1(1) 511 ) The anisotropic displacement factor exponent takes the form: -2 pi"2 [1142 a*"2 U11 + + 2 h ka* 5* U12] 345 Table 5. Hydrogen coordinates ( x 10"4), isotropic displacement parameters (A"2 x 1003), and occupancies for M072805 x y z U(eq) Occ. H(2A) 1669 4585 -645 26 1 H(6A) 4205 3345 1058 29 1 H(8A) 1554 4998 1689 56 1 H(88) 3731 4673 1625 56 1 H(8C) 1607 3934 1594 56 1 H(10A) 7901 3798 93 45 1 H(108) 8201 2784 -98 45 1 H(1OC) 7937 3062 709 45 1 H(1 1A) 5299 1450 -29 32 1 H(1 1 B) 4930 1727 765 32 1 H(12A) 1807 851 484 34 1 H(128) 1257 1796 209 34 1 H(14A) 2129 -52 -1339 63 1 H(148) 2600 -305 -523 63 1 H(14C) 4144 497 -877 63 1 H(15A) -1025 1494 -794 32 1 H(16A) -2666 275 -1686 38 1 H(168) -376 278 -1930 38 1 H(17A) -1995 1 163 -2770 39 1 H(17B) -2694 1753 -2147 39 1 H(19A) 3531 2275 -2584 49 1 H(198) 1909 1562 -3091 49 1 H(19C) 2642 1277 -2305 49 1 H(20A) -631 3133 -1860 30 1 H(2 1 A) 3782 3573 -2070 28 1 H(22A) 2290(30) 4731 (14) -2432(1 1) 47(5) 1 H(2AA) 3173 5342 -4695 26 1 H(6AA) 1 177 6948 -6268 30 1 H(8AA) 3887 5362 -7016 53 1 H(8AB) 3982 6410 -6797 53 1 H(8AC) 1773 5748 -6979 53 1 H(1 OD) -2804 6356 -5439 49 1 H(10E) -2625 7206 -5961 49 1 H(10F) -3065 7335 -5145 49 1 H(11C) 480 8505 -5813 36 1 H(1 1 D) -92 8633 -5015 36 1 H(12C) 3994 8307 -521 8 38 1 H(12D) 3543 9310 -5359 38 1 H(14D) 2820 9760 -3461 77 1 H(14E) 893 9337 -4017 77 1 H(14F) 2543 10211 -4225 77 .1 346 Table 5 (cont’d) H(15B) H1150) H1150) H(17C) H(17D) H(19D) H(19E) H(19F) H1208) H1218) H1228) 6056 5205 7548 7390 6661 1101 2093 2719 5250 774 1120140) 8350 9287 9335 7755 8218 7201 8249 7768 6469 6100 4529117) -4166 -2898 -3105 -2859 -2175 ~2504 -2628 -1904 -3331 -3222 -3697(14) 35 44 44 44 44 51 51 51 31 28 77(7) 347 1O REFERENCE Fischer, E. 0.; Maasbbl, A. 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