a: Outta! .1... k... .2. A! .v. : gaff; we. . 1 a _ . l'p 1. :1. . a... K»... In; 7.. 1 augmwuwmwfifl . . z . 1. .t 1 . ! 11 6 1:. v .1, .b ,t 1.1., a 32:? “My?! ‘viil‘. D d- ). m .2. of . a 33.?» 1 3:3 . 35.....- figs. . . . “a”... This is to certify that the dissertation entitled Synthetic Studies Toward Phomactins: The Application of lntramolecular Cyclohexadienone Annulations of Fischer Carbene Complexes presented by Jie Huang has been accepted towards fulfillment of the requirements for the Ph.D. degree in Chemistry Major Professor’s Signature .lhxfl ;2§ 2005/ ‘ / (Bate MSU is an Affirmative Action/Equal Opportunity Institution LIBRARY Michigan State University ---o-o-o-o--o-oo.- - —¢'-.-O-.-.-— -. 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. DATE DUE DATE DUE DATE DUE 2/05 p:/CIRC/DateDue.indd-p.1 SYNTHETIC STUDIES TOWARD THE PHOMACT INS: THE APPLICATION OF THE INTRAMOLECULAR CYCLOHEXADIENONE ANNULATIONS OF FISCHER CARBENE COMPLEXES By Jie Huang A DISSERTATION Submitted to Michigan State University In partial fulfillment of the requirements For the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 2005 ABSTRACT SYNTHETIC STUDIES TOWARD THE PHOMACT INS: THE APPLICATION OF THE INTRAMOLECULAR CYCLOHEXADIENONE ANNULATIONS OF FISCHER CARBENE COMPLEXES By Jie Huang A unique strategy for the total synthesis of phomactins is proposed and pursued in this thesis. The key step to construct the skeleton of phomactins is a novel intramolecular cyclohexadienone annulation of a Fischer carbene complex. To probe the feasibility of this strategy, model studies based on simplified Fischer carbene complexes are initially carried out. By thermolysis of these compounds, the effect of olefin geometry, reaction solvent and the tether length are investigated. The extent of the chiral relay in the key step is also determined. The synthesis of the key bicyclic intermediate for the total synthesis of phomactins is successfully achieved by the intramolecular cyclohexadienone annulation of a Fischer carbene complex that is synthesized from geraniol. The structure of the key intermediate is confirmed by X-ray crystallography analysis. Efforts focusing on functional group manipulations after the macrocyclic ring- closure are described. Reactions based on model compounds before they are carried out on the fully functionalized system. In synthetic efforts towards phomactin B2, a Peterson olefination is followed by a-methylation of a ketone, which provide the desired key intermediate whose structure is also confirmed by X-ray crystallography. Synthesis of the targets such as phomactin D, Bz, B, B,, E and F can all be envisioned from this versatile key intermediate in the near future. To my dearest parents, husband and children ACKNOWLEDGEMENTS Writing an acknowledgement is undoubtedly the most pleasant part of writing this thesis. The only hard thing here is I cannot mention all the names of those who deserve my heartfelt thanks. First and foremost, I would like to thank my advisor, Professor Wulff for his guidance and patience through all these years. He gave me the opportunity to work on this exciting project and provided countless suggestions for this research. I owe my thanks to him not only for the knowledge he taught me, but also for the way he taught. His generous and humorous personality makes the tough life in graduate school easier. I would like to thank the other members of my committee, Babak Borhan, James Geiger and David Weliky. Dr. Borhan, in particular, provided insightful feedback that added greatly to the clarity of the dissertation. Special thanks are given to Chunrui Wu, who worked together with me on this project during my last several months of stay and will carry along with this project after I leave. I appreciate her efforts on all the achievements we made together and I wish her luck in the future synthesis. I would like to thank all my colleagues in Wulff’s research group for creating a friendly and stimulating working environment. First of all, I owe my thanks to Zhenjie Lu for being an excellent benchmate, chatmate and shoppingmate. I will never forget her help on arranging all my spectrum data until 1:00 am on my last day in MSU. I regret no one will make tea in the lab and remind me to drink anymore. I would like to thank Yu Zhang who spent lots of time go over my thesis and slides and gave valuable suggestions iv for modification. Thank him for taking pictures for me in the commencement free of charge, and also thank him for all the help on computer work. Thank Yiqian for proofread Chapter 1 of this thesis. Thank him and Victor for discussions and sharing their profound knowledge with me. Thank Gang Hu for providing music in the lab. Thank Ding for the jokes. Thank Glenn for his blessing in Chinese before my defense ...... Especially, I would like to give my best wishes to Cory Newman and Vijay who will become happy grooms soon. Wish them happy ever after. I would also like to thank former group member Ying Liu, Huan Wang and Richard Hsung for their pioneer research work which laid the theoretical foundation for this project. Thank Aliya, a visiting scholar from Turkey, for being an excellent work partner during her three-month stay in our group and being a good friend for life. I wish her successful in her future career as a professor in chemistry. Thank undergraduate Nick Simon who helped in preparing the starting material for the total synthesis. I would like to thank Rui Huang for GC-Mass analysis, elemental analysis and X- ray analysis. In spite of his busy schedule, he is always willing to help on time. I feel guilty pushing him too much during the last period of my thesis by sending him piles of samples day and night. I would also like to acknowledge Lijun Chen and Beverly Chamberlin of MSU Mass spectrometry team for doing HRMS. Thank Daniel Holmes and Kermit Johnson for their help on N MR analysis. The social aspects of graduate school made my life colorful. I enjoyed the moments I spent with families of Zheng Wang, Zhang Rong, Yiqian Lian and Dongming Xie. Thank them for being good friends and offering help when needed. I will remember the happiness their lovely kids- Mengmeng, Lanxing, Qingqing and Xiaoke brought to us after work. I wish Amanda Ao will give birth to a wonderful baby as Mengmeng’s sibling next January. Finally I would like to extend my thanks to my family. First of all I would like to thank my husband Tao Wu for being always there for me. I cannot imagine how mess my life will be without him. I would like to thank my parents and my brother for their years of support and encouragement. Particularly, I would like to thank my sons: Jason Wu and William Wu, who are the wonderful by-products of my 6 years of research. I feel so blessed to have them! vi TABLE OF CONTENTS LIST OF SCHEMES ....................................................................................................... x LIST OF TABLES ....................................................................................................... xiv LIST OF FIGURES ....................................................................................................... xv ABBREVIATIONS ...................................................................................................... xvi CHAPTER 1 INTRODUCTION ........................................................................................................... 1 1.1 Isolation and Biological Activities of the Phomactins ........................................... 1 1.2 Previous Approaches to the Synthesis of the Phomactins ..................................... 3 1.2.1 Total Synthesis of Phomactin D .................................................................. 4 1.2.2 Total Synthesis of Phomacin A and G ......................................................... 6 1.2.3 Recent Partial Syntheses of the Phomactins: Macrocyclization Strategies... 9 1.3 Synthetic Strategies of Phomactins Based on Cyclohexadienone Annulation of Fischer Carbene Complex .................................................................................. 12 1.3.1 Introduction: Benzannulation and Cyclohexadienone Annulation .............. 12 1.3.2 Intermolecular Approach ........................................................................... 14 1.3.3 lntramolecular Approach ........................................................................... 17 1.4 An Overview of the Key Reaction: Mechanism and Related Reactions .............. 20 1.4.1 Mechanisms of Cyclohexadienone Annulation .......................................... 20 1.4.2 Asymmetric Cyclohexadienone Annulation ............................................... 22 1.4.3 Previous Studies of lntramolecular Cyclizations of Fischer Carbene Complexes ................................................................................................ 25 1.4.3.1 lntramolecular Benzannulations ........................................................ 25 1.4.3.1a Type A Benzannulations ................................................................. 26 1.4.3.1b Type B Benzannulations ................................................................. 29 1.4.3.2 lntramolecular Cyclohexadienone Annulation .................................. 32 1.4.4 Applications of Cyclohexadienone Annulation in Natural Compound Synthesis ................................................................................................... 34 vii CHAPTER 2 INTRAMOLECULAR CY CLOHEXADIENONE ANN ULATIONS ON MODEL SYSTEMS .................................................................................................................... 37 2.1 Specific Aims .................................................................................................... 37 2.2 Model System with Carbene Complexes Containing Alkyne Fraction at the End of an All Methylene Tether (Model I) ......................................................... 40 2.2.1 Preparation of the Model I Fischer Carbene Complexes 153 ...................... 41 2.2.1.1 Synthesis of Carbene Complexes Z-153c .......................................... 41 2.2.1.2 Synthesis of Carbene Complexes E-153c .......................................... 46 2.2.2 Effect of Olefin Geometry ......................................................................... 47 2.2.3 Effect of Tether length and the Reaction Solvents ..................................... 48 2.3 Modified Model System with Carbene Complexes Containing Propargylic Tertiary Center (Model II) ................................................................................. 52 2.3.1 Preparation of the Model 11 Fischer Carbene Complexes ........................... 53 2.3.2 Cyclization of Carbene Complexes lSSa-d ................................................ 55 2.3.3 Cyclization of Carbene Complexes 192 ..................................................... 57 2.4 Mechanistic Consideration ................................................................................. 58 2.5 Summary ........................................................................................................... 61 CHAPTER 3 SYNTHESIS OF THE KEY INTERMEDIATE OF THE PHOMACT IN S .................... 62 3.1 Specific Aims .................................................................................................... 62 3.2 Retrosynthetic Study of the key intermediate 58 ................................................ 64 3.3 Preparation of the Cyclization Precursor: Fischer Carbene Complex 70 ............. 65 3.4 Synthesis of the Key Intermediate by Cyclohexadienone Annulation ................. 69 3.5 An Alternative Route toward Compound 215/221: Olefin Cross Metathesis ....... 73 3.5.1 Selectivity of Olefin Cross Metathesis (CM) ............................................. 74 3.5.2 Optimization of CM Conditions ................................................................ 76 3.6 Summary ........................................................................................................... 77 viii CHAPTER 4 FUNCTIONAL GROUP MANIPULATION S AFTER THE CYCLIZATION .............. 79 4.1 Specific Aims .................................................................................................... 79 4.2 Synthesis toward Phomactin D ........................................................................... 79 4.2.1 Planned Synthetic Strategy ........................................................................ 79 4.2.2 Attempted Direct a-Methylation via Ketone Enolate ................................. 80 4.2.3 Attempted ot-Methylation via Ketal Formation .......................................... 81 4.2.4 Attempted Methylation via Ring Opening of Cyclopropane ...................... 84 4.2.4.1 General Information about Simmons-Smith Reaction ....................... 84 4.2.4.2 Simmons-Smith Reaction on Model Systems .................................... 85 4.2.4.3 B-Elimination of Key Intermediates 227/228 .................................... 88 4.2.5 Attempted a-Methylation via Reduced Intermediates 227/228 .................. 91 4.3 Synthesis Toward Phomactin 32 ........................................................................ 94 4.3.1 Proposed Synthetic Strategy ...................................................................... 95 4.3.2 Synthesis of Phomactin B2 analogs ............................................................ 97 4.4 Prospective Synthetic Plans to Phomactin B, B], E and F from 227/228 ............. 99 4.5 Comparison of the Reactivity of Key Intermediates 227 and 228 in 1,4— or 1,2- Nucleophilic Addition ...................................................................................... 100 4.6 Summary ......................................................................................................... 103 EXPERIMENTAL SECTION ..................................................................................... 105 REFERENCES ............................................................................................................ 210 APPENDICES ............................................................................................................ 214 ix LIST OF SCHEMES Scheme 1.1 Yamada’s Total Synthesis of Phomactin D ................................................... 4 Scheme 1.2 Halcomb’s Total Synthesis of (+)-Phomactin D ............................................ 6 Scheme 1.3a Pattenden’s Total Synthesis of Phomactin A ............................................... 7 Scheme 1.3b NHK Coupling in the Total Synthesis of Phomactin G ................................ 8 Scheme 1.4 Suzuki Coupling in Halcmb’s Total Synthesis of Phomactin A ..................... 9 Scheme 1.5 Maleczka’s NHK Macrocyclization Strategy ................................................ 9 Scheme 1.6 Rawal’s Macrocyclization Strategy ............................................................. 10 Scheme 1.7 Hsung’s Synthesis Using lntramolecular oxa—[3+3] Cycloaddition ............. 11 Scheme 1.8 Thomas’s Strategy Using 2,3-Wittig Rearrangement .................................. 12 Scheme 1.9 Benzannualation and Cyclohexadienone Annulations ................................. 13 Scheme 1.10 Retrosynthesis of Phomactin D Using Intermolecular Annulation ............. 15 Scheme 1.11 RCM of Compound 59 ............................................................................. 16 Scheme 1.12 Intermolecular Cyclohexadienone Annulation of 64 and 65 ...................... 17 Scheme 1.13 lntramolecular Cyclohexadienone Annulation Strategy ............................. 18 Scheme 1.14 Asymmetric Cyclohexadienone Annulation of Carbene 78/79 .................. 23 Scheme 1.15 Type A and Type B lntramolecular Benzannulations ................................ 26 Scheme 1.16 Semmelhack’s Synthesis of Deoxyfrenolicin ............................................ 27 Scheme 1.17 Synthesis of Furanocoumarins .................................................................. 28 Scheme 1.18 lntramolecular Benzannulation of Amino Carbene Complexes ................. 29 Scheme 1.19 lntramolecular Benzannulation of Complexes 112 .................................... 30 Scheme 1.201ntramolecular Benzannulation of Carbene 123 ....................................... 32 Scheme 1.21 Ddtz’s Synthesis of Metacyclopane .......................................................... 32 Scheme 1.22 Bos’s lntramolecular Cyclohexadienone Annulation ................................. 33 Scheme 1.23 The Preparation and lntramolecular Cyclohexadienone Annulation of Carbene Complex 140 ............................................................................. 34 Scheme 1.24 Total Synthesis of (-)-Acorenone .............................................................. 35 Scheme 1.25 Study toward the Synthesis of Taxodione ................................................. 36 Scheme 2.1 lntramolecular Cyclohexadione Annulation Strategy to Synthesize Phomactins and Corresponding Model Systems .......................................... 38 Scheme 2.2 lntramolecular Cyclohexadione Annulation of Model I Fischer Carbene Complexes .................................................................................................. 41 Scheme 2.3 Strategies to Synthesize Z— Vinyl Iodide ..................................................... 42 Scheme 2.4 Synthesis of Iodide 168 .............................................................................. 42 Scheme 2.5 Planned Synthesis of Z-153c via Normant Reagent ..................................... 43 Scheme 2.6 Synthesis of Model Compound 176 via Normant Reagent .......................... 44 Scheme 2.7 Synthesis of Z-l71c Using Negishi’s Carboalumination ............................. 45 Scheme 2.8 The Dianion Approach to Alkenyl Carbene Complex 187 .......................... 45 Scheme 2.9 Synthesis of Z- Carbene Complexes Z-153c ............................................... 46 Scheme 2.10 Synthesis of Vinyl Iodide E-17la-d .......................................................... 47 Scheme 2.11 Synthesis of Fischer Carbene Complex E-153c ......................................... 47 Scheme 2.12 lntramolecular Cyclohexadienone Annulation of Z-153c/ E-153c ............. 48 Scheme 2.13 Preparation of Fischer Carbene Complexes E-153a, b and d ..................... 49 Scheme 2.14 Cyclization of Model 11 Carbene Complexes 155 and 192 ........................ 53 Scheme 2.15 Preparation of Model Fischer Carbene Complexes 155 ............................. 54 Scheme 2.16 Preparation of Model Fischer Carbene Complexes 192 ............................. 55 xi Scheme 3.1 Comparison of the lntramolecular Cyclohexadienone Annulation of the Carbene Complex 155 and Carbene Complex 70 ........................................ 63 Scheme 3.2 Retrosynthetic Strategy for Key Intermediate 58 ......................................... 64 Scheme 3.3 Synthesis of Intermediate 209 from Geraniol .............................................. 65 Scheme 3.4 Major By-products of the Coupling Reaction between 216 and 217 ............ 66 Scheme 3.5 Synthesis of Intermediate 209 from Geranyl Acetate .................................. 67 Scheme 3.6 Synthesis of Cyclization Precursor 226 ....................................................... 68 Scheme 3.7 lntramolecular Cyclohexadienone Annulation of 226 ................................. 70 Scheme 3.8 Selenium Oxidation to Obtain Allylic Alcohols 221 and 215 ...................... 73 Scheme 3.9 CM Reaction of Methacrolein 234 and Olefin 233 ...................................... 75 Scheme 4.1 Planned Total Synthesis of Phomactin D from 227/228 .............................. 80 Scheme 4.2 Hydrolysis of 227 and Failed Methylation of 2403 ..................................... 81 Scheme 4.3 Possible Mechanism of Failed Methylation ................................................. 81 Scheme 4.4 Weyerstahl’s Strategy of a—Methylation via Ketal Formation ..................... 82 Scheme 4.5 Planned Methylation Following Weyerstahl’s Strategy ............................... 83 Scheme 4.6 Ketal Formation of Compound 227 ............................................................. 83 Scheme 4.7 Simmons—Smith Reaction ........................................................................... 84 Scheme 4.8 a-Methylation of Keto Compounds via Simmons-Smith Reaction .............. 85 Scheme 4.9 Unexpected Product from Simmons-Smith Reaction of 262 ........................ 86 Scheme 4.10 Attempted Simmons-Smith Reaction on Model Vinyl Ether ..................... 87 Scheme 4.11 Simmons-Smith Reaction of Alcohol 269 and 272 .................................... 88 Scheme 4.12 Planned Methylation of 227/228 via Cyclopropane Intermediate .............. 89 Scheme 4.13 Unexpected B-Elimination Process During the Reduction of 227/228 ....... 90 Scheme 4.14 Strategy of Direct a-Methylation after Reduction ..................................... 92 xii Scheme 4.15 NaBH4 Reduction of Dione 2403 .............................................................. 92 Scheme 4.16 Unexpected Product of LAH Reduction on 228 ........................................ 94 Scheme 4.17 Planned Total Synthesis of Phomactin B2 from 227/228 ........................... 95 Scheme 4.18 Witti g Reaction and Peterson Olefination ................................................. 96 Scheme 4.19 Conversion of 228 to 307 via Peterson Olefination ................................... 97 Scheme 4.20 Synthesis of Phomactin 82 Analogs from Intermediate 307 ....................... 98 Scheme 4.21 Envisions of Possible Target Molecules .................................................. 100 Scheme 4.22 1,2-Addition of TMSCHzLi or CH3Li to 227 and 228 ............................. 101 Scheme 4.23 Comparison of LAH Reduction of 227 and 228 ...................................... 103 xiii LIST OF TABLES Table 1.1 Biological Activities of Phomactins ................................................................. 2 Table 1.2 Intermolecular Cyclohexadienone Annulation of 60 and 61 ........................... 16 Table 1.3 Asymmetric Cyclohexadienone Annulation Reaction of Carbene 82 with Chiral Propargyl Ethers 83 ....................................................................................... 23 Table 2.1 Cyclization of E-153a-d in Different Reaction Solvents ................................. 50 Table 2.2 Cyclization of Carbene Complexes 155a-d .................................................... 55 Table 2.3 Cyclization of Carbene Complexes 1923-c ..................................................... 58 Table 3.1 Conditions to Convert Complex 226 to Key Intermediates 227/228 ............... 71 Table 3.2 Concentration Effect on Cyclization of Carbene Complex 229 ....................... 72 Table 3.3 CM Reaction between Compound 250 and Olefin 251 ................................... 77 Table 4.1 Attempted Conditions to Convert Compound 228 to 280 ............................... 91 Table 4.2 Attempted Conversion of Key Intermediate 227 to 281 .................................. 93 xiv LIST OF FIGURES Figure 1.1 Structures of Naturally Occurring Phomactins ................................................ 1 Figure 1.2 Structure of PAF (Platelet Activating Factor) .................................................. 2 Figure 1.3 Fragments of Phomactin D Subjected to Investigation .................................... 3 Figure 1.4 Comparison of Ring Construction Strategies ................................................. 19 Figure 1.5 Mechanism of the Benzannulation Reaction and the Cyclohexadienone Annulation ................................................................................................... 21 Figure 1.6 Regioselectivity of Cyclohexadienone Annulation ........................................ 22 Figure 1.7 Proposed Mechanism for Asymmetric Introduction in the Cyclohexadienone Annulation of Carbene 82 with Alkyne 83 ..................................................... 25 Figure 2.1 Mechanism of “Zipper Reaction” .................................................................. 42 Figure 2.2 X-ray Crystallography of Compound 1903 ................................................... 51 Figure 2.3 X-ray Crystallography of Compound 156b ................................................... 57 Figure 2.4 Proposed Mechanism for the Diastereoselectivity ......................................... 60 Figure 3.1 X-ray Structure of Key Intermediate 228 ...................................................... 70 Figure 4.1 X-ray Structure of Key Intermediate 307 ...................................................... 97 Figure 4.2 Explanation of Greater Reactivity of 228 over 227 ..................................... 102 Figure 4.3 Possible Explanation ................................................................................... 103 XV Ac Acac APA 9-BBN CAN CM DDQ DIBAL DMAP DMF DMPU DMSO El FAB GC HMPA HRMS IR KAPA KHMDS LAH LDA LHMDS MS NaHMDS N IS NMR NOE PAF RCM TBAF TBDMS Tf TFA THF TIPS TMSCl Ts ABBREVIATIONS acetyl acetyl acetonyl aminopropylamine 9-borabicyclo[3.3.1]nonane cerium ammonium nitrate cross metathesis 2,3-dichloro-5,6—dieyanoquinone diisobutylaluminum hydride 4—(dimethylamino)pyridine N, N-dimethylformamide 1,3-dimethyl 3 ,4,5,6-tetrahydro-2( 1H)-pyrimidinone dimethyl sulfoxide electron ionization fast atom bombardment gass chromatography hexamethylphosphoramide high resolution mass spectrometry infrared spectroscopy potassium 3-amino-propylamine potassium hexamethyldisilazide lithium aluminum hydride lithium diisopropylamide lithium hexamethyldisilazide mass spectrometry sodium bis(trimethylsilyl)amide N-iodosuccinimide nuclear magnetic resonance nuclear overhauser enhancement platelet activating factor ring closing metathesis tetrabutylammonium fluoride tert-butyl dimethyl silyl trifluoromethanesulfonyl trifluoroacetic acid tetrahydrofuran triisopropylsilyl trimethylsilyl chloride 4—toluenesulfonyl xvi CHAPTER 1 INTRODUCTION 1.1 Isolation and Biological Activities of the Phomactins The phomactins (Figure 1.1) are a group of macrocyclic compounds discovered in the early to mid 1990’s. Phomactin A, B, BI, 82, D, E, F and G were discovered by Japanese scientists Sugano and coworkers from a culture broth of marine fungus Phoma sp.1 The fungus was isolated from the shell of a crab, Chinoecetes opilio, collected off the coast of Fukui prefecture, Japan. Phomactin C, however, was first discovered by US scientists from the Phoma 5p. isolated from a leaf litter sample of mixed Quercus species, which was collected in a second growth mixed hardwood lot in Baton Rouge, Louisiana.2 Recently, a new compound phomactin H which was isolated by Koyama from cultures of an unidentified marine fungus, was added to the family.3 The absolute configuration of phomactin A, B, B1 and B2 could be ascertained while those of phomactin C, D, E, F, G, and H still remain undetermined. Figure 1.1 Structures of Naturally Occurring Phomactins O Phomactln A Phomactin a Cl-QO Phomactin B, Phomactln c O OH 9H 0 Phomactin D Phomactin E Phomactin F Phomactin G Phomactin H l Phomactins have demonstrated marked biological activity as PAF (platelet activating factor, Figure 1.2) antagonist. PAF causes platelet aggregation, chemotaxis, degranulation of polymorphonuclear leukocytes, smooth muscle contraction, vascular permeability, and hypotension.4 Recent studies have shown that PAF may be involved in many inflammatory, respiratory, and cardiovascular diseases? Hence PAF antagonists have definite potential as lead compounds for pharmaceutical drugs. Figure 1.2 Structure of PAF (Platelet Activating Factor) \ PAF (platelet activating factor) I -O-alkyl-2(R)-(acetyl-glyceryl)-3-phosphorylcholine The PAF antagonistic activities of the phomactins are listed in Table 1.1. Phomactin D has been shown to possess 10-100 times the activity of the other phomactins. It inhibited the binding of PAF to its receptors and PAF-induced platelet aggregation with IC50 of 2.8 x 10‘7M and 8.0 x 10'7M, respectively. Table 1.1 Biological Activities of Phomactins Phomactins Platelet aggregation PAF binding 1C50(mM) IC50(mM) A 10.0 2.3 B 17.0 > 47.9 BI 9.8 20.0 B, 1.6 > 22.1 C 6.4 63.0 D 0.80 0.12 E 2.3 5.19 F 3.9 35.9 G 3.2 0.38 A paper concerning the structure-activity relationships of several phomactin derivatives as PAF antagonist was also published by Sugano and coworkers soon after the discovery of phomactin D.6 By modifying the structure in fragments A, B and C of phomactin D (Figure 1.3), they found that the lipophilicity at C(7)-C(8), acetoxy, (methoxycarbonyl)oxy, and 3-isoxazolyloxy at C(20), and the 2-B-OH configuration at C(2) all enhance the inhibitory activity over that of phomactin D. The information obtained in this study provided useful information for the interaction between the PAF receptor and its ligands. Figure 1.3 Fragments of Phomactin D Subjected to Investigation 1.2 Previous Approaches to the Synthesis of the Phomactins The structures of phomactins share a common bicyclo[9.3.1]pentadecane ring system (Figure 1.1). Their unusual carbon skeleton combined with their biological activity has prompted much interest among synthetic organic chemists. In 1996, Yamada published the first total synthesis of phomactin D.7 The second total synthesis of this molecule was accomplished by Kallan in Halcomb’s research group six years later, but can only be found in his Ph.D. thesis.8 In addition, two total syntheses of phomactin A9 and one total synthesis of phomactin Glo have also been reported recently. An overview 3 of these total syntheses and other partial syntheses are presented below, highlighting the two main synthetic challenges: the construction of the highly substituted cyclohexane core, and the formation of the macrocycle. 1.2.1 Total Synthesis of Phomactin D The key steps of the first total synthesis of phomactin D by Yamada7 involved the use of bicyclo[2.2.2]octane derivative 3 as the chiral building block to generate the highly substituted cyclohexane core, and the intramolecular cyclization of sulfone 8 to obtain the macrocycle (Scheme 1. 1). Scheme 1.] Yamada’s Total Synthesis of Phomactin D H3C CH3 . /~., 2. steps 0 MsCl 10 Phomactln D As summarized in Scheme 1.1, the kinetic enolate of 2-cyclohexene-l-one 1 was reacted with enoate 2 (prepared from L-ascorbic acid) in a double Michael addition sequence to provide bicyclo[2.2.2]octane derivative 3. Cleavage of the C(2)-C(19) bond in 3 provided pentasubstituted cyclohexane 4 in good diastereoselectivity after several steps. The aldehyde in 4 was epimerized and reduced to a methyl group in 5. A nine- carbon side chain was then installed for use in the macrocyclization reaction. Intramolecular coupling between the sulfone anion generated with potassium hexamethyldisilazide (KHMDS) and the allylic chloride in 8 furnished bicycle 9 in 39% yield for two steps. This total synthesis of phomactin D was accomplished in 36 steps and in 0.5% overall yield. The second total synthesis of phomactin D was accomplished six years later by Nicholas Kallan in Halcomb’s research group, and is documented in his Ph.D thesis (Scheme 1.2).8 Phomactin D was synthesized in both racemic and enantioselective forms. An intramolecular B-alkyl Suzuki coupling was utilized as the key step in the construction of the macrocycle contained in the phomactin architecture. The total synthesis of phomactin D accomplished by Halcomb and Kallan is illustrated in Scheme 1.2. The chiral cyclohexanone derivative 12 can be converted to the vinylogous thiolester 13. An alkylation of 13 installed the quaternary stereocenter C(11) in the cyclohexane unit. After a series of functional group transformations, a, [3- unsaturated aldehyde 15 was generated in a straightforward manner. Conjugate addition of cyanide at C(15) occurred through an axial addition, but was later epimerized by base to the desired equatorial position in compound 17 under thermodynamic conditions. Compound 17 contained the required stereochemistry in the cyclohexane core and the appropriate functionalities for the pivotal Suzuki macrocyclization. Regioselective hydroborartion of 17 with 9-BBN at 40 °C, followed by coupling under high dilution in the presence of leCO3, furnished bicycle 18 in 37% yield. Compound 18 was readily transformed to the desired target molecule (+)—phomactin D. The total synthesis took 29 steps with an overall yield of 0.23% from commercially available (+)-pulegone 11. Scheme 1.2 Halcomb’s Total Synthesis of (+)-Phomactin D O KHMDS fixfl Steps )§_> steps fisTOI/V —Er /\\“ / STol 14 (+)- pulegone o ‘5 1. NaCN steps H 2. sidechain add r: ' 15 cm 9H m 9-BBN/ H20 steps f / Pdtdppocu ' 1., Tl2C03l AsPh3 / 37% 18 (+)-Phomactln D 1.2.2 Total Synthesis of Phomacin A and G Pattenden and coworkers recently published a synthesis of racemic phomactin A33" In their approach (Scheme 1.3 a), the quaternary C(11) stereocenter was established by a sequential alkylation of the dioxin 19 with methyl iodide followed by homoallylic iodide 20 to give 21. After manipulation of the functionality of 21, the key aldehyde vinyl iodide intermediate 22 was produced. Macrocyclization of 22 was accomplished by a 6 Nozaki-Hiyama-Kishi (NHK) coupling in the presence of CrCIZ/ NiCl2 to furnish the desired bicycle 23 in 36% yield. Intermediate 23 was then carried on to afford phomactin A (24) (Scheme 1.3a, equation 1). It was noteworthy that when the MOM protected epimer 25 at the secondary center C(14) was used as precursor, the NHK cyclization generated the macrocycle in a higher yield of 52% (Scheme 1.3a, equation 2). Scheme 1.3a Pattenden’s Total Synthesis of Phomactin A O 11 O t > \‘ (1) J 0 o 1 1° W 21 steps PMBO fiCHO CrCI2I NiCl ~‘ 1.‘g'oema 2 I 36% _ —- / 22 24 Phomactin A PMBO CHO CrCIzl NICIZ (2) ‘ 14 OMOM 52% I 25 Using the same strategy, Pattenden and coworkers also accomplished the total synthesis of racemic phomactin G,l0 a central intermediate in the biosynthesis of phomactin A in phoma Sp. The key step is the macrocyclization of compound 27 7 mediated by CrClzl NiCl2 to prepare the bicycl[9.3.l]pentadecane 28 (Scheme 1.3 b). The yield of this step is 47%. Reduced product 29, which resulted from the cleavage of C-1 bond was produced concurrently in 20% yield. Scheme 1.3b NHK Coupling in the Total Synthesis of Phomactin G PMBO fiCHO 29 (20%) PMBO Phomactin G Almost at the same time, Halcomb’s group completed the total synthesis of (+)- phomactin A using a related strategy to that they employed in the synthesis of phomactin D9" The key step to construct the macrocycle was a intramolecular thallium mediated Suzuki coupling of intermediate 30 to give 31. The optimized yield of this step is 37% (Scheme 1.4). Scheme 1.4 Suzuki Coupling in Halcomb’s Total Synthesis of Phomactin A OTES \s‘ 9-BBN/ H20 deprotection O a" H O I —-——-> H Pd(dppI)C|2 I / T123303/ ASPh3 / / "/1: 3O 31 24 Phomactin A 1.2.3 Recent Partial Syntheses of Phomactins: Macrocyclization Strategies The NHK macrocyclization strategy was also utilized by Maleczka and coworkers in their studies toward the synthesis of phomactins.ll The Julia olefination product 32, which contains a mixture of olefin diastereomers, undergoes the desired intramolecular NHK coupling to afford bicyclic alcohols 33 and 34 in a combined yield of 60% (Scheme 1.5). Scheme 1.5 Maleczka’s NHK Macrocyclization Strategy _..CH0 :0 Crew... "'oras 32 33 (33%) 34 (27%) Rawal and coworkers reported the assembly of the phomactin skeleton using two macrocyclization strategies.” The first strategy was carbonylative cyclization of enol tiflate 35 in the presence of a Pd catalyst under a CO atmostphere. The unoptimized yield of this reaction is 36% (Scheme 1.6). The second macrocyclization strategy involves acetylide addition to an aldehyde. The alkyne-aldehyde 37 was treated with NaHMDS at —10°C to afford a mixture of diastereomeric alcohols 38 in 54% yield. Treatment of the alcohols with manganese dioxide provided the alkynyl enone 36, which was identical to that obtained by the carbonylative cyclization procedure, but with a higher overall yield (46%). Scheme 1.6 Rawal’s Macrocyclization Strategies Hsung and coworkers recently published the construction of the phomactin A skeleton using an formal intramolecular oxa-[3+3] cycloaddition method developed in his research group.13 The a, 1.3-unsaturated iminium salt 40 was generated in-situ from the corresponding aldehyde 39. The cyclization was believed to proceed through a Knoevenagel condensation (process described in the brackets) followed by a 67c electrocyclic ring closure of l-oxatriene 41. A mixture of regio- and stereoisomers of compound 42, 43 and 44 were generated in a combined yield of 76% (Scheme 1.7). They claimed that this formal 0xa-[3+3] cycloaddition had never been employed in an intramolecular manner. This synthetic approach to phomactin A is unique in that the 12- 10 membered macrocycle was formed simultaneously with the 1-oxadecane ring. Unfortunately, the major products did not have the carbon skeleton of phomactin A. Scheme 1.7 Hsung’s Synthesis Using Intramolecular oxa-[3+3] Cycloaddition ' O filflzc-(DDAC piperidinium acetate 76% 1. 1.2-addition —————p 2. elimination V Gar-electron electrocyclic ring-closure 434-44 (42:43+44=1:2.5) Thomas and coworkers synthesized the skeleton of phomactins using the 2,3- Wittig rearrangement as the key step which occurs before the macrocyclization.l4 As shown in Scheme 1.8, the 2, 3-Witti g rearrangement of propargylic ether 45 was carried out using 2.5 equivalents of n-butyllithium and gave a mixture of diastereomers 47 and 48 (47: 48 = 82: 18) in a combined yield of 72%. Both compounds 47 and 48 contain the required configuration of the sidechain at C(1), and both were carried on in the synthesis. After several functionality transformations, the final macrocyclization was performed following Yamada’s method7 employing a sulfone to give intermediate 49. 11 Scheme 1.8 Thomas’s Strategy Using 2,3-Wittig Rearrangement — .1 \ \ Omoraops (.OWOTBDPS , fl”. , ‘) .4) ___. PhOgS/ 72% PhOQS/ OSEM OSEM 45 - 45 _ HR‘ R2 /~ ..~ '- ste s OSEM 47 31:011. R2=H as R1=H.R2=OH 1.3 Our Strategies for the Synthesis of Phomactins Based on the Cyclohexadienone Annulation of Fischer Carbene Complexes 1.3.1 Introduction: Benzannulation and Cyclohexadienone Annulation The reaction of a Fischer carbene complex 50 and an alkyne 51 to generate a phenol derivative 52 is a benzannulation reaction (Scheme 1.9, equation 1).15 Formally, it incorporates an alkyne, the organic portion of the carbene complex, and a CO ligand from the metal into the phenol derivative 52. The formal assembly of the pieces is indicated as 53 in Scheme 1.9.The mechanism of this reaction is quite complicated and will be discussed in detail in section 1.4.1. 12 Scheme 1.9 Benzannualation and Cyclohexadienone Annulations OH 2 9 OCH3 RL 92 R R C RI. (1) (OC)5Cr benzannulation L i I 1_ 2 + II 1 ,1 .. R R R R RS S RS OCH3 OCH3 50 51 52 53 OCH RL R30 3 Cyclohexadienone 2 (2) (OC)5Cr _ Ra + Ill annulation R R'- 1 2 1 F1 F1 Rs R R3 00143 54 51 55 lntramolecular OCHa 2 RS Cyclohexadlenone (3) (OC)5Cr R H annulation O - R1 R1 RS H 56 oc 3 57 The cyclohexadienone annulation is an important variation of the benzannulation reaction. When the (:3 carbon of a Fischer carbene complex is disubstituted, as in the case of compound 54, the reaction with alkyne 51 will provide cyclohexadienone 55 instead of the phenol product 52 (Scheme 1.9, equation 2).16 The regioselectivity is the same as that observed for the benzannulation reaction, which has the larger substituent on the triple bond incorporated adjacent to the newly inserted carbonyl functionality. Although the intermolecular version of the cyclohexadieneone reaction has been extensively studied, only one example of the intramolecular variation of this reaction is known.17 This example has the alkyne moiety tethered to the B-carbon of a carbene complex as is shown in compound 56 (Scheme 1.9, equation 3). The intramolecular cyclohexadienone annulation of 56 takes place to give the meta cyclohexadienone derivative 57 as the dominant product. Strategies to construct the skeleton of phomactins based on both inter- or intramolecular cyclohexadienone annulations of Fischer carbene complexes are presented 13 in the following sections (1.3.2 and 1.3.3). The intramolecular strategy will be the subject of this thesis. 1.3.2 Intermolecular Approach The project involving the synthesis of phomactins began in Wulff’s group in 1996.18 The original goal was to synthesize phomactin D. The first version of the strategy employed an intermolecular cyclohexadienone annulation of a Fischer carbene complex as the key reaction to construct the highly substituted six-membered core (Scheme 1.10). Two retrosynthetic routes A and B were devised. In route A, the key step was the cyclohexadienone annulation of Fischer carbene complex 60 with dienyne 61 followed by closure of the macrocycle with a ring closing metathesis (RCM) of the cyclohexadienone 59. In route B, sulfone 63 would be synthesized using the cyclohexadienone annulation of the sulfide containing carbene complex 64 with dienyne 65. The formation of the advanced intermediate 62 would follow Yamada’s macrocyclization strategy (Scheme 1.1).7 14 Scheme 1.10 Retrosynthesis of Phomactin D Using Intermolecular Annulation OMB (OC)5CT I OTBS as The intermolecular cyclohexadienone annulation of Fischer carbene complex 60 with 61 proved to be a complete success (Table 1.2). Optimization of the reaction conditions provided the annulated product 59 in 88% yield and with a diastereoselectivity of 98:2. The high stereoselectivity at C(11) resulted from an efficient 1,4-relay of stereochemical information from the propargylic center at C(2).19 A detailed mechanism suggesting a possible source of this 1,4-relay will be discussed later in section 1.4.2. Despite the success of this annulation, the ring closing metathesis unfortunately failed. Only the dimerized product 66 was obtained and none of the desired macrocyclic compound 58 was observed even at very low concentration (Scheme 1.11). This failure may be due to the steric hindrance in generating a trisubstituted double bond since Grubb’s generation 1 catalyst was used. It also could be due to the strain in 58, which may be higher than can be overcome by the ring closing metathesis reaction.20 15 Table 1.2 Intermolecular Cyclohexadienone Annulation of 60 and 61 O OTr OMe OTr j “’95“sz Cfi\> L: + I -—> 60 61 59 Solvent Temperature ( °C) Yield (%) Diastereoselectivity heptane 9O 60 94:6 CH3CN 90 72 95:5 CH3CN 55 88 98:2 Scheme 1.11 RCM of Compound 59 catalyst 67 70% The cyclohexadienone annulation in route B also worked well (Scheme 1.12). Starting from a 1:10 (Z:E) mixture of the sulfide carbene complex 64 and dienyne 65, the cyclohexadienone derivatives 68 and 69 were generated in a combined yield of 65%. The diastereoselectivity (68:69: 8:1) was a little lower than that in route A, but still remarkable. The transformation of sulfide 68 to sulfone 63 was also successful. However, further studies on the cyclization of 63 were not performed since Ying Liu left the graduate program. 16 Scheme 1.12 Intermolecular Cyclohexadienone Annulation of 64 and 65 0M8 OTr 0 R152 (00)50r=<=<‘ + — __ OTBS 65% .. SPh PhS-4§ 64 65 TBSO 68R1=OTr,R2=H 69R1=H,R2=0Tr 88:69:811 1.3.3 Intramolecular Approach Despite the accomplishments made using the intermolecular cyclohexadienone annulation, this strategy was abandoned at this time due to the emergence of a more efficient pathway: the intramolecular annulation pathway. As shown in Scheme 1.13, Fischer carbene complex 70, which was proposed to be derived from geraniol, contains an alkyne function at the end of a 12-carbon diene tether. The intramolecular cyclohexadienone annulation of 70 could lead to the macrocyclic compound 58. In this way, both the six-membered core and the macrocycle could be constructed in a single step. The configuration of the chiral center at C(11) was hoped to be controlled by a 1,4— relay from the propargylic center at C(2) as in the intermolecular case. Elaboration of the structure of the key intermediate 58 will allow access to several members of the phomactin family as well as their analogs. 17 Scheme 1.13 Intramolecular Cyclohexadienone Annulation Strategy geranlol derivative geranlol By comparison to the numerous strategies for the synthesis of phomactins that have been described previously, our new strategy has some advantages which are summarized as follows: 1. It is more efficient due to the fact that the 12-membered macrocycle and the six- memebered core structure can be constructed simultaneously in the key annulation step (Figure 1.4b). All the previous strategies, including the intermolecular cyclohexadienone annulation strategy (Scheme 1.10), involved the installation of the cyclohexane core first and then realize the macrocyclization using different coupling methods in the subsequent steps (Figure 1.4a). Since the cyclohexane core is densely equipped with stereogenic centers, the construction of the six-membered ring is long and tedious in all syntheses to date. Furthermore, the coupling reactions which join the sidechains into the macrocycle sometimes provided low to moderate yields and poor stereoselectivity. Considering that the formation of the highly substituted cyclohexane core and the formation of the macrocycle are the most formidable 18 challenges in the synthesis of phomactins, the possibility of constructing them simultaneously would undoubtedly make the new strategy efficient and elegant . Figure 1.4 Comparison of Ring Construction Strategies a. Previous strategies (OJ—*0 b. lntramolecular cyclohexadienone annulation strategy 2. Another notable feature of this new strategy is that the configuration at the stereogenic center C(2) in carbene complex 70 could be used for the relay of stereochemical information to all the other chiral centers formed in all subsequent steps in the synthesis. Hence, stereocontrol in this new strategy would be straightforward. Furthermore, the olefin geometries of the two tri-substituted double bonds between C(3)-C(4) and C(7)—C(8) are either derived from the starting material (geraniol), or from a straightforward functionalized geraniol (Scheme 1.13) and thus do not need to be addressed during the synthesis. 3. This new strategy also expands the application of Fischer carbene complexes in organic synthesis. A large number of reactions of Fischer carbene complexes have 19 been examined for their application in organic synthesis.21 Among them, the benzannulation reaction has been the most widely used in the synthesis of natural products. However, the applications of cyclohexadienone annulations are very limited. The only known examples are the total synthesis of (—)-acorenone and the synthetic studies toward taxodione done by Gilberson and Wulff (see section 1.4.4 for details).22 The synthetic strategy presented in this thesis on the intramolecular cyclohexadienone approach to the phomactins will provide a new perspective on the synthetic value of this chemistry. 1.4 An Overview of the Key Reaction: Mechanism and Related Reactions 1.4.1 Mechanisms of Cyclohexadienone Annulations The cyclohexadienone annulation differs from the benzannulation only in the last step of the reaction mechanism. A summary of current understanding of the reaction of a, B-unsaturated Fischer carbene complexes with alkynes is presented in Figure 1.5. 2‘ The first and rate-limiting step is carbon monoxide dissociation from the starting carbene complex 54 to give the 16-electron unsaturated species 71.21 Then the alkyne coordinates and inserts into the carbene-metal bond to form the 111-713 carbene complexed intermediate 73. A CO insertion takes place to give the vinyl ketene complex 74, which is normally formed in an irreversible process. Electrocyclic ring closure (ERC) of 74 provides cyclohexadienone chromium tricarbonyl complex 75. If R3 is H, tautomerization occurs quickly to generate the phenol chromium tricarbonyl complex 76. The metal moiety is usually lost to air oxidation during the workup to yield the free phenol 77. This process is known as the benzannulation reaction. If R3 and R2 are alkyl or any other group 20 of low migratory propensity relative to hydrogen, then the tautomerization will be blocked and cyclohexadienone 55 will be generated as the final product after demetallation. This process is referred to as the cyclohexadienone annulation. Figure 1.5 Mechanism of the Benzannulation Reaction and the Cyclohexadienone Annulation RL : RS OCHa OCH3 . . g (OC)5CT R3 'CO (OChcrigqa aIKYne COOfdlnaIIBH (QC)4C|:'_ OCH% 3 R1 R2 R1 R2 — 54 alkyne insertion O R2 R L Ra tautomerization L loss of metal R RL 1 R OCH RS R3 = H R1 \RS R1 R3 3 Cr(CO)a °CH3 Cr(CO)3 OCHa 75 76 77 R2 or R3 "°I H Benzennuletlon loss of metal ‘32 Rn R Cyclohexadienone annulation 9‘ Rs OCH3 55 When an unsymmetric alkyne is used, the regioselectivity of the reaction is determined in the alkyne coordination and insertion steps. As shown in Figure 1.6, intermediate 73 should be more favored than 73’ due to less steric hindrance between the larger substitution on the alkyne and the CO ligand. Consequently, the major product is 21 55, which has the larger group adjacent to the newly formed carbonyl functionality. In the cyclohexadienone annulation, the regioisomer 55 is usually exclusively formed (2 100 :1) when a terminal alkyne is used, while internal unsymmetrical alkynes usually give less regioselectivity and result in a mixture of isomers. Figure 1.6 Regioselectivity of Cyclohexadienone Annulation 0 R2 R3 RL 1 OCH3 55 2 <3 R ____. R3 RS R‘ RL OCH3 55 less favored 1.4.2 Asymmetric Cyclohexadienone Annulation One important feature of the cyclohexadienone annulation of Fischer carbene complexes is the formation of a quaternary center. Development of an asymmetric version of this reaction would be of great significance for extending its applications. Before Hsung’s reaserch on chiral propargyl ethers,l9 the only known examples of diastereoselective cyclohexadienone annulation reactions involved chiral carbene complexes such as 78 and 79 as shown in Scheme 1.14.23 Complex 78 having a chiral center at C(6) yielded mixtures of 80 : 81 in greater than 9 : 1 diastereoselectivity and 44- 22 78% combined yield depending on the nature of R. However, complex 79 with a chiral center at C(3) provided no induction under the same conditions.16a Scheme 1.14 Asymmetric Cyclohexadienone Annulation of Carbene 78/79 OMe Hz_ 0 R2 0 (0&5er _ ; a : H E n R R, S a? THF, 45°C R‘ OMe R‘ OMe trans cis 78: R‘: CH3; R2 = H 80: Yield: 44-78%; trans/cis 9:1 to 19:1 79: R1: H; R2 = CH3 8": Yield: 79%; trans/cis 52248 The diastereoselective cyclohexadienone annulations mentioned earlier in this thesis (section 1.3.2, Table 1.2) involved stereochemical relay from chiral propargyl ethers and is based on the pioneering studies by Hsung.19 He studied the asymmetric reaction of B,B-disubstituted Fischer carbene complexes 82 with chiral prop-2-ynyl ethers 83 (Table 1.3). The reaction was found to be both stereoselective and stereospecific. In each case, the substituent Rl syn to the carbene unit was selectively incorporated syn to the alkoxy substituent R3. If R3 was changed from trityl (CPh3) to tert-butyl dimethyl silyl (T BDMS), the selectivity of 84 : 85 dropped from 90:10 to 82:18. This appears to be due to electronics rather than sterics.24 23 Table 1.3 Asymmetric Cyclohexadienone Annulation Reaction of Carbenes 82 with Chiral Propargyl Ethers 83 0R3 0 0R3 0 0R3 OMe Z w ‘53 “tr “15* 92 32 OMe OMe 84 65 Entry R1 R2 R3 Yield 84 : 85 (%) 1 Me Et CPh3 73 92: 8 2 Et Me CPh3 66 91 : 9 3 Me Ph CPh3 72 90: 10 4 Me Ph TBDS 73 82: 18 A working model to explain the diastereoselectivity has been proposed and is presented in Figure 1.7.19 The alkyne insertion product carbene intermediate 86a and 86b are in equilibrium. There is a stereoelectronic preference for an alignment of the propargyl oxygen in a direction approximately anti to the chromium as shown in intermediate 86a and 861).25 Due to the allylic strain, intermediate 86h has a higher stability over 86a. After CO insertion takes place, vinyl ketene complex 87 will be obtained. Pathway a and pathway b indicated the possible direction of the subsequent eletrocyclic ring closure. The favored direction is pathway b, with the rotation of the substituent R1 up and away from the metal center 87 to give the cyclohexadienone metal complex 88b. Downward rotation of R1 (pathway a) is apparently disfavored since it would lead to severe close contact with metal and its ligands. In this example, an elegant chiral relay from propargyl alcohols to the final cyclohexandienone products was accomplished. The presence of the chromium moiety is vital for this relay to take place. As mentioned earlier (Scheme 1.10 and 1.13), the strategies 24 developed in our group to construct the skeleton of phomactins stereoselectively are based on the success of this highly stereoselective reaction of Fischer carbene complex. Figure 1.7 Proposed Mechanism for Asymmetric Introduction in the Cyclohexadienone Annulation of Carbene 82 with Alkyne 83 n? H1" _ 0M6 3 m 3 OR m on ,\ :_< H3C-1- ‘I H 83 06, “00-95-00 «'8‘ oc Co OMe (OC)5Cr=$_ 10), the expected para-cyclophane 114 was generated in moderate yield (11 = 10, 58%; n = 13, 65%). A shorter tether length (n = 8) resulted in the 31 appearance of the dimer 124 as a minor product (114 43%, 124 15%). When the tether length was shortened to 6 methylenes, only dimer 124 and trimer 125 were generated as products. Scheme 1.201ntramolecular Benzannulation 0f Carbene 123 3 OCH 00113 CH2) O H3CO (0C)5C'=<=\'—' OH I : + ( ) + n n 123 OCHa 0 114 OCH3 124 Besides Wulff’s work, Dbtz also reported a benzannulation of this type in 1999 (Scheme 1.21).3| Metacyclophane 127 was obtained as the final product of benzannulation reaction of the Fischer carbene complex 126 after oxidative demetallation with CAN, which also oxidized the p-methoxy phenol ring to a quinone. Scheme 1.21 Diitz’s Synthesis of Metacyclophane OMe 1. 31.120. 90°C : 2. CAN, 40% O C O 127 (OC)5CT 126 1.4.3.21ntramolecu1ar Cyclohexadienone Annulation As an important variant of the benzannulation reaction, the cyclohexadienone annulation has received much less attention in the literature. The only published example 32 of an intramolecular cyclohexadienone annulation was reported by Wulff and 808 (Scheme 1.22).32 Carbene complexes 128 and 131, which had the alkyne tethered to oxygen, were cyclized in benzene. Despite the fact that no CO insertion product was observed in the intermolecular reaction between alkynes and 2,6-disubstituted aryl carbene complexes, the intramolecular reaction of 128 and 131 led to the CO-inserted products 130 and 133, respectively. Compound 130 came from the tautomerization of the initial product 134, while compound 133 arose from 135 via a 1,5-methyl migration. It should be noted that these are isolated products. Minor changes in the tether led to significantly reduced yields of the CO-inserted products for these complexes.‘7 Scheme 1.22 Bos’s Intramolecular Cyclohexadienone Annulation o—/ _ o (OC)5CT 0 O benzene, 60°C + O O 1211 OH 129 (20%) 130 (51%) R 0 O-’ — o 0 (0950i: ; OH 134 R = OH benzene, 110°C W 0’ 135 F! = H 0 O 131 132 (17%) 133 (37%) The only example of an intramolecular cyclohexadienone annulation of a carbene complex with an alkyne that is tethered to the alkenyl functionality is described by H.Wang in his Ph. D. thesis.l7 Carbene complex 140 with the tether on the B-carbon of the alkenyl group was synthesized using an aldol reaction (Scheme 1.23). As a result, a 33 mixture of isomers (E:Z = 71:29) of 140 was obtained as the cyclization precusor. The thermolysis of precusor 140 led to a mixture of products. The expected bicyclic cyclohexadienone 141 was generated in 37% yield, and dimeric product 142 was generated in 14% yield as a 1:1 mixture of syn— and anti- stereoisomers. Scheme 1.23 The Preparation and Intramolecular Cyclohexadienone Annulation of Carbene Complex 140 OMe (OC)5Cr=( OMe ;(CH) \ a = : ’CH) E(CH2)10‘€ A; (0050' _ 28 OH 1 28\' c,d _ 138 137 OMe 138 140 (10.: CH2)10 O O (CH2)100 (CH2)10 OMe 37% OMe 141 142 14%, ~1:1 mixture a. MsCI. Et3N. then Nal, 100%; b. methyl acetoacetate, NaH. then LiCl, DMSO, H20, 66%; c. BFgEtZO. anion of 138 (0.5 eq). quench with H20. 54%: d. pyridine (ZOeq), 70%; e. THF, 0.005M, 100 °C, 18h, 1.4.4 Applications of the Cyclohexadienone Annulation in Natural Product Synthesis Gilberson and Wulff accomplished the total synthesis of (—)-Acorenone and studied on the synthesis of the skeleton of taxodinone and related diterpenes. These are the only known applications of the cyclohexadienone annulation in the synthesis of natural compounds.22 The enantioselective synthesis of (-)-Acorenone began with the easily prepared aldehyde 143 (Scheme 1.24). It was converted to the Fischer carbene complex 144 in a 34 few steps. The reaction of carbene complex 144 with trimethylsilylacetylene 145 proceeded at 55°C in THF to give the expected spirocyclic dienone 146 in 80% yield as a mixture of four diastereomers in a ratio of 85.7 : 7.5 : 4.9 : 1.8. The major isomer 146 was then transformed to the final target molecule after minor modifications. This example demonstrated that the cyclohexadienone annulation of a B, B-blocked Fischer carbene complex and an acetylene can be used to synthesize naturally occurring compounds that contain spiro cyclic carbons with a high degree of stereoselectivity. Scheme 1.24 Total Synthesis of (-)-Ac0renone CHO OMe k (OC)5CT :— TMS ,,,,, —. — __15§__. TH F . 55 °C, 80% 143 144 M63811:6 —\ OMe n — H n 0 OR 12 OMe (3) 00 Cr ( )5 . OR ' OMe 9 \ \ (CH2) 155 158 The first issue to be addressed is how the geometry of the olefin in conjugation with the carbene complex 70 will affect the efficiency of the intramolecular cyclohexadienone annulation. In the only known example (Scheme 1.23),l7 carbene complex 140 was prepared by an aldol reaction and was used as a mixture of isomers (E: Z = 71:29). Thermolysis of this isomeric mixture generated the intramolecular cyclohexadienone annulation product 141 in only 37% of yield. This is considerably lower than the yield (58%) of the related intramolecular benzannulation with the same tether length (Complex 123, n = 10, Scheme 1.20). It is possible that one of the isomers of 140 cyclizes more efficiently than the other one. If this is true, then the yield of the annulation could be improved by starting with the Fischer carbene complex of the correct olefin geometry. 38 Secondly, it was known that the reactions of Fischer carbene complexes with alkynes are sensitive to the nature of the reaction solvent.l7 In some cases, not only the yield, but also the product distribution can be effected by different reaction solvents. Thus it is expected that there will be some solvent effect on the intramolecular cyclohexadienone annulation as well. The effect of both the olefin geometry and the nature of the solvent will be explored first on model carbene complexes 153 (Scheme 2.1, equation 2.) rather than on the fully functionalized carbene complex 70. The third issue is the tether length and this is anticipated to be a critical issue. As shown by Wang’s work,30 the product distribution among monomeric, dimeric and trimeric products from the intramolecular benzannulation of Fischer carbene complex 123 is highly dependent on the tether length (Scheme 1.20). No monomeric product was observed with n = 6, a 43% yield was observed with n = 8, and a 58% yield was observed with n = 10. The tether length required in the key annulation of the carbene complex 70 for the synthesis of the phomactins contains a tether of nine carbons bridging the alkyne and the alkenyl carbene complex. A straightforward comparison of tether length may not have a significant prediction value. The tether in complex 70 has five sp3 carbons and four sp2 carbons. The carbene complex 123 has 10 sp’ carbons. Thus introduction of sp2 carbons in the tether might be expected to increase the strain in the macrocycle 58 (Scheme 2.1) and thus reduce the efficiency of its formation. On the other hand, the benzannulated product 114 (Scheme 1.20) has the tether anchored through two spz carbons while the macrocycle 58 (Scheme 2.11) has it tethered through one sp2 and one sp3 carbon, and this would be expected to decrease the strain in 58. 39 The final issue to be addressed with the model systems is the stereoselectivity of the reaction. The intermolecular cyclohexadienone annulation was shown to be highly stereoselective and stereospecific (Table 1.2).‘8'19 However, the stereoselectivety of the intramolecular cyclohexadienone annulation is unknown. A second model system (Scheme 2.1, equation 3) will be devised to determine the extent of the chiral relay from the exiting propargylic trisubstituted carbon in carbene complex 155 to the newly generated stereocenter C(12) of cyclohexadienone product 156. This is also a critical issue since the propargylic chiral center in the carbene complex 70 is expected to be used to set all the stereochemistry in the target via this relay. 2.2 Model System with Carbene Complexes Containing the Alkyne Function at the End of an All Methylene Tether (Model I) First the simplified model system (Model I) (Scheme 2.1, equation 2) was devised to determine the effect of the olefin geometry, solvent and tether length on the efficiency of the intramolecular cyclohexadienone annulation. Model carbene complexe lS3c with tether length of 10 were prepared with both E- and Z- olefin geometry so that the effect of olefin geometry on the cyclization can be evaluated (Scheme 2.2, equation 1). Once the optimum geometry is determined, then additional carbene complexes 153a-d will be prepared with different tether lengths (n = 6, 8, 10,13), and thermolized in three different solvents: THF, benzene and acetonitrile (Scheme 2.2, equation 2). Scheme 2.2 Intramolecular Cyclohexadienone Annulation of Model I Fischer Carbene Complexes 153 o OMe OMe (1) (OC)5Cr (OC)5Cr 1o: _TH_F- _ __ 0' — 100°C OMe 1o “'— 5453:: 2453:: H 10 154a o OMe 153a. 154: n: 6 (2) (OC)50r solvent 153b.154b n=8 —- 0M6 153c,154c n=10 :— 100°c 153d,154cl n=13 n 153m H n 154m n: 6,8,10,13 2.2.1 Preparation of the Model I Fischer Carbene Complexes 153 2.2.1.1 Synthesis of Carbene Complexes Z-lS3c To address the issue of the effect of olefin geometry of the alkenyl Fischer carbene complex on the intramolecular cyclohexadienone annulation, both E- and Z- carbene complexes needed to be prepared. The Z- alkenyl Fischer carbene complexes will be derived from the corresponding Z- vinyl iodides. Two strategies were designed for the synthesis of the Z- vinyl iodides. (Scheme 2.3). The first strategy features the syn addition of a Normant reagent 157 containing the long chain tether to propyne (Scheme 2.3, equation 1).33 The second strategy involves the carbometallation of a trimethysilyl acetylene function in a bis- silyated diyne 160 to obtain 161 followed by the hydrolysis of the metal—carbon bond and iodination of the silyl group (Scheme 2.3, equation 2). 3“ 41 Scheme 2.3 Strategies to Synthesize Z- Vinyl Iodide (1) TMS : (CH2)1o-'Cu' — Cu/— —H3M TM:—> m(<,_ 2 1‘ —5::1—=—(TMS TMS TMS (2)|2 160 M. metal center Scheme 2.4 outlines the synthesis of intermediate 168 required for the synthesis of Z-vinyl iodide 159 (Scheme 2.3). Simultaneous deprotonation of the terminal alkyne and the hydroxyl group in compound 162 with two equivalents of LiNHZ/NH3 followed by refluxing the resultant dianion with bromononane 163 in liquid ammonia afforded alcohol 164 in essentially quantitative yield. 35 The next reaction has been termed the acetylenic zipper reaction36 since the triple bond migrates down the chain over nine carbons to the terminal position via a successive isomerization process as illustrated in Figure 2.1. The potassium 3-amino-propylamide (KAPA)/3-aminopropylamine (APA) system proved exceptionally active for this reaction. When all was zipped up, the terminal alkyne 165 was obtained in 77% yield. Scheme 2.4 Synthesis of Iodide 168 klaBr __ 2 eq UNHlei'lg 153 J’F—Zfl KAPA/APA .——-. _ ‘OH -78'c.1h reflux, 31? 8 OH Tilh—‘r. .. .Nl'é'" 5““ 162 164 H 9970 3 C4 1.26qn-BuLi,THF ’l ' :_—-—-—(CH2)10°OH '78 6:") 0'1'5 h HC' (2” TMS I (CH2)1oOH Fig. 2.1 165 o 'C-rt. 2.511 166 77% "’q "'BUL' 73°" T”; ms (CH2)1o-OTs NMTMS : (CH2)1o-I LL 5h reflux, 167 168 92% (2 steps trom 165) 81% 42 Two equivalents of base was used to deprotonate the terminal alkyne and the hydroxyl group in compound 165 (Scheme 2.4). Sequential treatment of the dianion with trimethylsilyl chloride (TMSCl) and HCI provided the TMS protected alkyne alcohol 166. This was converted to tosylate 167 in greater than 90% overall yield from 165. Iodination of tosylate 167 afforded iodide 168 in 81% yield. Now the stage was set for the key reaction involving the in situ generation of Normant reagent 170 followed by syn addition of 170 to propyne (Scheme 2.5).33 Since three air and moisture sensitive steps will be involved in the overall transformation from 168 to Z-17lc, this sequence was first performed on model compound as indicated in Scheme 2.6. The model system will involve the conversion of l-iododecane 172 to the 2-vinyliode Z-176. Scheme 2.5 Planned Synthesis of Z-153c via Normant Reagent o CuBr-Me TMS : (CH2)10| "Mg” TMS : (CH2)10'MQI “nu-"2?» TMS Z (CH2)100U°MQBTI 168 189 170 «ST... _ — ----- 9 (OC) Cr=< ( I _ 2.12 ' ‘ 16— 5 0MB "7— As can be seen from Scheme 2.6, the generation of Normant reagent 174 and the subsequent carbometallation of propyne proceeded smoothly. However, a two component mixture was obtained after iodination of cuprate 175 which could not be separated by column chromatography on silica gel. Gratifyingly, it was possible to isolate the desired Z- vinyl iodide 176 from the mixture by distillation which gave a 30% yield with a high stereoselectivity (> 20:1 Z- to E- as determined by 1H NMR). The major by-product was 43 determined to be 177 on the basis of NMR and GC-Mass spectrum analysis and would be expected from the dimerization of vinyl cuprate 175.37 Scheme 2.6 Synthesis of Model Compound 176 via Norman Reagent Mgo CuBr-Mezs CH3-(CH2)9-| m CH3(CH2)9'M9| -30 °C 30min CH3(CH2)9-CU'MQBFI 172 173 ’ 174 —_——> — I2, -50 °C-10 °C _ ) _ -30 °C~-20 °C- 3" Wrfit W I/—(<-¢ + 3- 1 9 175 2476 177 'Cu' = Cu. MgBrl 30% 20% Although the result of the model reaction was encouraging, unfortunately this method failed on the desired substrate 168. When using the same reagent and following the same procedure as in the model synthesis, white sediment was observed during the preparation of the Grignard reagent 169. The detailed reason for the failure is not clear. At this point, the second strategy (Scheme 2.3, equation 2) was evaluated as a synthetic route to Z-vinyl iodide Z-171c. This strategy involved Negishi’s titanium catalyzed carboalumination reaction as the key step.34 The synthesis started from the commercially available trimethylsilyl acetylene 178 (Scheme 2.7). Deprotonation of 178 using n-BuLi followed by coupling of the resulting anion with diiodide 179c produced 180c in good yield (88%). In this reaction, hexamethylphosphoramide (HMPA) was used to activate the organolithium, otherwise the yield was extremely low. Diyne 180c was treated with one equivalent of TiCp2Cl2 and AlMeZCl. The Z- olefin 181 was isolated from a statistic mixture of diene, enyne and unreacted diyne in about 40% of yield. No regioisomers were observed. After iodination with N-iodosuccinimide (NIS) and desilylation with tertrabutylammonium fluoride (TBAF), the desired vinyl iodide Z- 171c was isolated in moderate yield (45%) and with good stereoselectivity (Z : E = 13:1). Scheme 2.7 Synthesis of Z- 17 1c Using Negishi’s Carboalumination 1%: 1. 1eq. szTICI2 /1 eq. Me3AI : TMS nBuLI,THF,HMPA¢ 1129 ¢ 10% CH2012,8hrs ; ~78°C—0°C. 1h . ., "a rt 12h TMS 180° TMS 2.1420 88% TMS _ TMS NIS I 0: TMS TBAF I 0: ‘_ 0 EtCN, r.t, 30min: _ 131 132 Z-171c(Z:E=13:1) ~40°/o 45% over 2 steps Next the vinyl iodide Z-171c needed to be converted into the corresponding carbene complex. The routine procedure for making alkenyl Fischer carbene complexes involves the addition of an alkenyl lithium, generated in situ by lithium-halogen exchange, to Cr(CO)6 followed by methylation of the resultant metal acylate. However, due to the presence of an alkynyl proton in compound Z-l71c that would be acidic enough to quench the newly generated alkenyl lithium, it was necessary to deprotonate the alkyne before the iodine-lithium exchange took place. To this end, the dianinon approach developed by Huan Wang was followed (Scheme 2.8).17 Scheme 2.8 The Dianion Approach to Alkenyl Carbene Complex 187 x _ PhLi _ tauu Li_ Cr(CO)s (0%ch mags—[:4 (OC)5Cr RHZO/CHZCIZ m \\ 1.. \\ Li 45 The extension of Wang’s dianion approach to the synthesis of alkenyl complex 187 is shown in Scheme 2.8. When compound 183 is treated with one equivalent of PhLi and then two equivalents of t-BuLi, sequential deprotonation of the terminal alkyne and halogen-lithium exchange will take place, affording the desired dianion 185. One equivalent of Cr(CO)6 is added at this time and will preferentially react with the more nucleophilic spz carbon to give vinyl carbene acylate 186. Methylation using Meerwein’s salt (Me3OBF4) in the presence of water will yield the desired carbene complex 187. Under these conditions, the acetylide is initially protonated but not the metal acylate. When the substrate Z-l71c is used as the starting material, this dianion approach provided the desired alkenyl carbene complex Z-153c in 37% yield (Scheme 2.9). Scheme 2.9 Synthesis of Z- Carbene Complexes Z-153c OMe ' 10: 1 eq. PhLi = 1 eq. t-BuLi ‘ 1 eq. Cr(CO)Q 2 eq. Me3O*BFfi‘ (OC)5Cr 10: THF. -78 °C THF, -78 °C THF, -78 0041 01-1202] H20 7 24 716 1.5 h 0.5 h 2 h r.t. 30 min Z-153c- 37 3% (25 5‘13”) (2: 5:13:11 2.2.1.2 Synthesis of Carbene Complexes E-153c Model I carbene complex 153c was also synthesized as isomerically pure compounds with E- olefin geometry. The general procedure starting from compound 180c was described in Scheme 2.10. Desilylaticn of 180c with TBAF provided dialkyne 188c in 80% yield. A regioselective zirconium mediated syn addition of one equivalent of AlMe3 to the alkyne function in 188 produced a statistical mixture of monoiodide E-l7lc, diiodide 189c and unreacted dialkyne 45 188c after the reaction was quenched with iodine.38 Pure monoiodide E-l7lc was readily separated from the mixture by chromatography in 42% yield with greater than 20:1 E-: Z- stereoselectivity. Scheme 2.10 Synthesis of Vinyl Iodide E-l71a-d 1*}01 _ n-BuLi, THF, HMPA 179g / \ TBAF _—TMS 4 A, / 10\ ——-> / \ -78°cc°c. 1h r.t., 12h TMS TMS r.t..6h / ‘°\ 178 1801: 133g 88°/o 80%: 1. ZGC2C|21AIMe3 | I I ft . 12h t — + \__.<_ >—J_ 2. '2 (Ll—n—1 0: 1o E-171c 1896 42% With the E- vinyl iodides E-171c in hand, the synthesis of carbene complexes E- 153c was carried out following the dianion procedure described in Scheme 2.8. The yield for the preparation of E-153c was 49% (Scheme 2.11). Scheme 2.11 Synthesis of Fischer Carbene Complex E-153c OMe ' _ 1.1eq.PhLi,THF,-78°L 1eq-Cr(CO)6_ 2°9~M93°BF4~ (OC)5Cr ( — 2-1eQ-t-BuLi.THF. -78°C-r.t. CH2CI2/H20 ‘( _ 1°.— ‘78 °C'° °C r.t.. 10'— E-171c E-153c 49% 2.2.2 Effect of Olefin Geometry The stage is now set for the crucial intramolecular cyclohexadienone annulation of Model I Fischer carbene complexes 153c. The first issue to be addressed is the effect of olefin geometry on the efficiency of the cyclization. The isomeric carbene complexes 47 Z-153c and E-153c were each thermolized in THF at a concentration 0.005 M (Scheme 2.12). When the reaction was heated to 100 °C overnight, compound E-153c was found to cyclize to give bicyclic compound 154c in higher yield (37.6%) than its Z- isomer (14.8%). Thus the conclusion was drawn that the Fischer carbene complex with E- olefin geometry is a better cyclization precursor in the intramolecular cyclohexadienone annulation. A complex mixture of compounds was obtained from the thermolysis of the Z- isomer of 153e, from which the desired product 154 was isolated in low yield. The complication in the case might be attributed to stability of the Z- carbene complex, which may lead to its decomposition during the reaction. In addition, considerable amount of dimerized product 142 was also observed in the product mixture. Scheme 2.121ntramolecular Cyclohexadienone Annulation of Z-153c/E-153c O OMe (OC)5Cr : IHL. __ 10 100 °C OMe 24536 or 51536 H 10 1546 from Z-153c: 14.8% from 5'15“: 37.6%: 2.2.3 Effect of Tether Length and the Reaction Solvents Knowing that E-153c was a better cyclization precursor than its Z- isomer, more E- carbene complexes were synthesized with different tether length (n = 6, 8 and 13) and thermolyzed to find out the effect of tether length and reaction solvents. The preparation of the carbene complexes was summarized in Scheme 2.13. Scheme 2.13 Preparation of Fischer Carbene Complexes E-153a, b and d 1*}! _ n43uLi, THF, HMPA 179 / \ TBAF =—TMS = ; / "\ ——> / \ -78 06-0 °C, 1h r.t., 12h TMS TMS r.t. 6-12h A 178 180 133 n = 6 54% Zsteps from 179 n = 8 57% 2steps from 179 n=13 67% Zsteps from 179 1. ZGC2CI2IAlMea 1. 1 eq. PhLi, THF OMe r.t., 12h v ' _ -78 °C, 1h 1 eq. Cr(C0)s_ M6303F4 ‘ (OC)5Cr 2- '2 ( : 2. 1 eq. t-BuLi. THF. -78 °C-r.t., 2n CH2c12/ H20 — __ n ~78 °C, 10 min ”- 0.5,, 1 n — 5.171 ' 5153 n = 6 35% n = 6 38% n = 8 39% n = a 13% n=13 43% n=13 35% In the light of dramatic solvent effects and the dominant role of the tether size that was observed in the intramolecular benzannulation reactions,1730 both variables were also examined for the intramolecular cyclohexadienone annulation (Table 2.1). With the (1, [3— unsaturated carbene complexes E-153a-d of various tether lengths (n = 6, 8, 10 and 13) in hand, the cyclizations were performed in CH3CN, benzene and THF. These three solvents were chosen because of their differing coordinating ability to the metal center: CH3CN has the strongest coordinating ability while benzene has the weakest. The results of the twelve reactions are summarized in Table 2.1. 49 Table 2.1 Cyclization of E-153a-d in Different Reaction Solvents OMe (OC)5Cr / ARV—('3‘- + ( / overnlg t OMe n E-153a-d H n o 154 OMe 190 Entry Complex Solvent Yield (%)” 154 190 191 l 153 a (n = 6) THF -b 13" 6 CH3CN° - 22 4 benzenec ' 46 13 2 153 b (n = 8) THF 45 - - CH3CN 45 31 - benzene 10 - - 3 153 c (n = 10) THF 43 - - CH3CN 64 - - benzene 36 - - 4 153 d (n = 13) THF 64 - - CH3CN 51 - - benzene 32 - - a.The yield listed are those after separation by column chromatography on silica gel unless otherwise annotated; b. “-“ means products not detectable; 6. yields were calculated from the weight of crude mixture and HPLC analysis; (1. The structure of the dimer with higher Rf value was confirmed by X-ray analysis. When the tether length was as short as 6 carbons (Table 2.1, entry 1), only intermolecular reactions took place in all three solvents. As a result, only dimers and trimers were obtained as the products. The yields and product distribution in THF or CH3CN were quite similar. Curiously benzene promoted dimer and trimer formation in this case, giving much higher total yield. The two diastereomers (1:1) of the dimer 190 were seperated after flash chromatography on silica gel. Dimer 190a with the higher R{ value is crystalline and the structure was confirmed by X-ray analysis (Figure 2.2). However, all diastereomers of the trimer 191 were obtained as an inseparable mixture. 50 Figure 2.2 X-ray structure of Dimer 190 M60 The cyclization of E-153b (n = 8) generated monomer 154 as the major product (Table 2.1, entry 2). No detectable trimers 191 could be isolated, and the dimer 190 was only observed and isolated in the coordinating solvent CH3CN (31% yield). The monomer 154b was produced with the same yield (45%) in both THF and in acetonitrile. However, only 10% of desired products were isolated when nonpolar solvent benzene was used, and the reason is unclear. This trend in the dependence of the yield with the solvent is similar to that seen for the corresponding intramolecular benzannulation reactions, but is opposite to that observed for intermolecular annulations where the hi ghtest yields are seen in non-polar solvents.39 When the tether length reached 10 and 13 (Table 2.1, entry 3&4), only intramolecular annulations products were observed which led to the formation of desired cyclohexadienone product 154. Again the trend of lower yields in more poorly coordinating solvent was observed. The formation of 154c (n = 10) was achieved with yields of 43% and 64% in THF and CH3CN, but dropped to 36% in benzene. Similarly, 51 the yield of 154d (n = 13) was 64% in THF and 51% in CH3CN, but was only 32% when benzene was used as the reaction solvent. 2.3 Modified Model System with Carbene Complexes Containing Propargylic Tertiary Center (Model 11) The carbene complexes 155 and 192 of Model II system (Scheme 2.14) were selected for a study of the stereoinduction from the existing tertiary center on the tether of the carbene complex to the newly generated quaternary center C(12) in the cyclohexadienone annulated products 156 and 193. Carbene complex 155 contains a propargyl ether at the end of the tether, while carbene complex 192 has alkyl or aryl substitution at the tertiary propargylic position. In the intermolecular cyclohexadienone annulation a strong stereoelectronic effect of the propargylic oxygen was observed. ”'25 Therefore, it was expected that by comparing the stereochemical outcome of the annulation of these two types of carbene complexes, the electronic effect of the propargylic oxygen substitution can be explored. It was also anticipated here that the variation of the R substituent on carbene complexes 155 or 192 could change the diastereoselectivity of the annulations due to differences in electronic properties or differences in the size of the substitution. 52 Scheme 2.14 Cyclization of Model 11 Carbene Complexes 155 and 192 0 on 12 OMe 2 (1) OC Cr ( )5 — 2 OR 912\ —* 0M6 R=MOM,CH3,Tips,CPh3 155 \ (CH2) 156 O R 12 OMe 2 (2) (OC)5Cr R 2 12 ——r OMe R=CH3.t-Bu,Ph 9 192 \\ (CH2) 193 2.3.1 Preparation of the Model 11 Fischer Carbene Complexes The synthesis of carbene complex 155 which contains a propargyl ether function at the end of the methylene tether is shown in Scheme 2.15. First, the terminal alkyne 162 was transformed to E- vinyl iodide 194 using Negishi’s carboalumination method.38 The hydroxyl group survived the reaction in the form of an anion when an extra equivalent of trimethyl aluminum was used. Swem oxidation readily converted the primary alcohol 194 to aldehyde 195. The addition of ethynyl magnesium bromide to the aldehyde 195 installed the alkyne function and the secondary propargyl alcohol 196. This alcohol was transformed to various propargyl ethers 197a-d in good yields (67%-95%). Finally, carbene complexes 155a-d were synthesized from the corresponding vinyl iodides 197a- (I using the dianion approach described earlier in this chapter (Scheme 2.8). 53 Scheme 2.15 Preparation of Model Fischer Carbene Complexes 155 “$3” 162 196 196 196 196 ZGCQCIZIAIMea 12 CH2C|2 , r.t. r 736/; 194 Ph3CC|lDMAP 'fl CH2C12, r.t. 9 Q 67% 1976 TlPSCl/DMAP ' _ OT'PS CH2C12, r.t. \ 9595 9 \\ 197D CHallNaH '% CHzclz, [.1. 90% 9 Q 1976 MOMBr/NaH | OMOM CH2C12, r.t. % 670/0 9 \\ 197d '\_{+— (COC"’“°MS°= 'Lg- MQB' E1 N H °/o 1C? 7 °/o 9GHQ 86 195 1. PhLi: Cr(CO)s ‘ M630+BF' ‘(OC)5CI‘ 196 OMe 2. t-BuLi -78 °C-r.t.' CH2C12/H207rt THF, -78 °C Same as above 51 % Same as above 33% Same as above 1 9% 1 558 57% OMe 1555 9 Q OMe (OC)5Cf OCH3 155:: 9 Q OMe (OC)5Cr OMOM 9 Q 155d 9% OTr % The process used to synthesize model carbene complexes 19Za-c is described in Scheme 2.16. The action of various Grignard reagents on aldehyde 195 resulted in the formation of secondary alcohols 198a-c. The Grignard reagents chosen for this addition included those with a bulky tert-butyl group, a small methyl group and the rt—electron ladden phenyl group. The resultant alcohols 198a-c were converted by Jones’ oxidation to ketones 199a-c. Then the terminal alkyne function was introduced by another Grignard reaction which gave the propargyl alcohols 200a-c in good yields. Gratifyingly, the reductive removal of the propargylic hydroxyl group at the tetrasubstituted carbon of 200 proceeded smoothly on their dicobalt hexacarbonyl complexes upon treatment with borane-dimethyl sulfide complex in the presence of trifluoroacetic acid to provide the desired vinyl iodides 201a-c in good yields (68% to 90%)“). Preparation of carbene 54 complexes l92a-c from the vinyl iodides 201a-c via the dianion of 201 was achieved in modest yield. Scheme 2.16 Preparation of Model Fischer Carbene Complexes 192 '\=<+ RMgBr '\=__(Mj:H Jones'oxidation_ K‘fl E—MgBr '% R 195 QCHO 9 R 9 9R § 196: R = t-Bu. 33% 1998-6 1966 R = CH3 69% 1966 R = Phenyl 67% 1. C02(CO)8 I R . + . 2. BHa-MeZSICFLQOOH: — Phu > Cr(CO)6 > M930 BF4= (OC)50r 3.CAN Q t-BuLi 9 201. R = t—Bu. 70% 2015 R = CH3 90% 2016 R = Phenyl 68% 2.3.2 Cyclization of Carbene Complexes 155a-d 2006 87% (2 steps) 2006 56% (2 steps) 2006 86% (2 steps) OMe 2'6 // 1928 31% 1921) 27% 1926 13% The annulation reactions of complexes 155a-d were carried out in THF at a concentration of 0.005M (Table 2.2). For each compound, the annulation was performed at 55 °C and 100 °C. As shown by the table, the reaction temperature did not make a significant difference on the yields. However, the temperature did have a slight effect on the diastereoselectivity. 55 Table 2.2 Cyclization of Carbene Complexes 155a-d 0 OR c on OMe 12 1 _ 0.005M \ 9 \ OMe 1556-d (CH2)9 (CH2) 1566-1! 1558'-d' Entry Complex R T(°C) 111616070)a 156a-d: 156a’-d’b'° 1 155a cm 55 65 1.0: 1.1 100 52 1.2: 1.0 2 155b Tips 55 45 3.0: 1.0cl 100 47 2.0: 1.0 3 155c CH3 55 66 2.1: 1.0 100 69 16:10 4 155d MOM 55 44 1.0: 1.1 100 36 1.01.0 a. All the yields are isolated yields after chromatography on silica gel; b. Ratios are determined by 1H NMR; c. Diastereochemical assignment for isomers were made based on the known X-ray structure of 156b; d. X-ray diffraction analysis was obtained for the major isomer of 156b. Compared to the high selectivity (>90: 10) observed for intermolecular cyclohexadienone annulations (Table 1.2),19 the stereoselectivity of the intramolecular reactions dropped dramatically. The highest selectivity was observed when the triisopropyl silyl group (Tips) was used as the protecting group and the complex was cyclized at 55 °C (T able 2.2, entry2). In this case, a ratio of 3:1 was obtained for isomers 156b and 156b’. The major isomer 156b was crystalline and its relative configuration was confirmed by X-ray diffraction analysis (Figure 2.3). 56 Figure 2.3 X-ray Crystallography of Compound 156b 0M6 H 156b (Shown as the 2R, 12R enantiomer) 2.3.3 Cyclization of Carbene Complexes 192 The original goal to introduce a methyl or a t—butyl group at the propargylic position of carbene complexes 192 was to probe the effects of sterics alone on the stereoselectivity of the intramolecular cyclohexadienone annulation. Unlike propargyl ethers 155, there should be no electronic effect due to the absence of an oxygen atom in the cyclization step. As the role of the electronic effect in the intramolecular reaction has not been previously examined, removing the propargyl oxygen may be revealing. In addition, since a t-butyl group is much bulkier than a methyl group, the effect of sterics may also be revealed in the stereoselectivities recorded for the cyclizations of complexes 192a and l92b. The results of the cyclizations were listed in Table 2.3. 57 Table 2.3 Cyclization of Carbene Complexes l92a-c O R 12 1 OMe (005wa THF _ 0.005M 9 \\ 100°C 0M6 H 1926-6 (C 2)9 1933-6 193a'-6' Entry Complex R Time (h) Yield (%) 193a-c: 193a’-c’a 1 192a tBu 15 66 l: 1.0 2 192b C113 10 94 1: 1.2 3 192c Ph 10 S4 1:1.0 a. ratio determined by 1H NMR analysis To our surprise, almost no stereoselectivity was observed when complexes 192a-c were cyclized (Table 2.3). In each case, the cyclization products were obtained as a nearly equal mixture of diastereomers. This result demonstrates that the oxygen must have some electronic effect on the cyclization, albeit small for the methoxy and siloxy complexes 155b and 1556. The MOM ether complex 155d (Table 2.2) had reduced selectivity which may be due to the electron-withdrawing nature of the methoxymethyl group. The reduced selectivity for the trityloxy complex 155c is not understood in terms of electronic effects. Its low selectivity compared to methoxy is also not understood in terms of steric effect given the lack of steric effctes of observed for l92a-c. 2.4 Mechanistic Consideration Based on the above results, the following mechanism was proposed to explain the stereochemical outcome of the intramolecular cyclohexadienone annulation of carbene complexes 155 (Figure 2.3). After the CO dissociation, insertion of the alkyne into the Cr-C double bond gives the 11', 113-vinyl carbene complex intermediates 203 and 204. 58 Intermediate 203 has the OR group at a pseudo-equatorial position, while 199 has the OR group at a pseudo-axial position. The dissociation of the double-bond in 203 and 204 to give the l6e' complex 202 is expected to be facile based on theoretical and experimental observations.“ Thus it is fully expected that 203 and 204 be in rapid equilibrium. After CO insertion and the subsequent electrocyclic ring closure (ERC), intermediate 203 would lead to the cyclohexadienone with (2R, 12S or ZS, 12R) configuration, and 204 would lead to the product with (2R, 12R or ZS, 12S) configuration. The rotation of the double bonds in the electrocyclic ring closure of 205 and 206 is expected to occur in the direction shown by the arrow (Figure 2.4), because this can avoid close contacts of methyl group with the CO ligands of the chromium. This direction of ring-closure has been proposed for intermolecular cyclohexadione annulations before.19 When R is a triisopropylsilyl or methyl group, the propargylic oxygen prefers to exist in a direction approximately anti to the chromium”25 and thus the equilibrium is slightly in favor of intermediate 203. This type of stereoelectronic effect has been documented in the intermolecular cyclohexadienone annulation and was used to explain the remarkable stereoselectivity.l9 However, this stereoelectronic effect is much smaller in the intramolecular reaction. Furthermore, when the energy difference between 203 and 204 was negligible, no diastereoselectivity was observed. Negligible steric effect was also seen in the intermolecular reaction.19 59 Figure 2.4 Proposed Mechanism for the Diastereoselectivity OMe 9 Q 155 (1) -CO (2) Alkyne insertion 05 \co CO Insertion CO insertion 0M6 OMe CH2 CH2) 156 minor 156 major (28,123 or 23, 128) (2R.12Fi or 28,125) 2.5 Summary The model studies have demonstrated that the intramolecular cyclohexadienone annulation of Fischer carbene complexes containing an alkyne function at the end of a polymethylene tether (n = 8—13) can be successfully cyclized to give bicyclic products in moderate to good yields. Carbene complexes 153 of Model 1 contain an all methylene tether. By thermolysis of these compounds, the effects of olefin geometry, reaction solvent and the tether length were investigated. It was found that the E-vinyl carbene complex cyclized more efficiently than the Z- isomer. The reaction solvent was found to play an important role, and good coordinating solvents such as CH3CN and THF provided better yields of annulation products than the non-coordinating solvent benzene. A dependence was found between the tether length and the product distribution. Complexes with short tether lengths give dimer or even trimer products, while complexes with longer tether lengths give predominantly the monomeric product. Modified model carbene complexes 155 and 192 were devised to determine the extent of the chiral relay from the existing propargylic tertiary carbon in the tether to the newly. generated stereocenter C(12) of the cyclohexadienone product. A mechanistic model was developed to provide an explanation of the diastereoselective outcome of the cyclizations. The result of these studies is that the presence of a propargylic oxygen is essential for any stereoinduction. 61 CHAPTER 3 SYNTHESIS OF THE KEY INTERMEDIATE OF PHOMACTINS 3.1 Specific Aims The model studies presented in Chapter 2 have demonstrated that the intramolecular cyclohexadienone annulation of Fischer carbene complexes containing an alkyne function at the end of a long tether can be used to construct bicyclic ring systems similar to that found in the skeleton of phomactins (Scheme 2.1). The cyclization of carbene complexes 155 utilized in the model study 11 and the carbene complex intermediate 70 required in the total synthesis of phomactins are shown in Scheme 3.1. The success that was observed for the model compound 155 has set the stage for the investigation of whether the intramolecular annulation of carbene complex 70 can provide for access the bicyclic compound 58 as an advanced intermediate for the total synthesis of phomactins. It was anticipated that the key intermediate 58 could be converted to the natural compounds in phomactin family including phomactin D and phomactin B2 (Scheme 3.1). Compared to all the other published strategies (see Chapter 1), the elegance of this strategy is that both the six-membered core structure and the macrocycle connecting C(1) and C(11) can be constructed simultaneously in the key annulation step (Scheme 3.1, equation 2). 62 Scheme 3.1 Comparison of the Intramolecular Cyclohexadienone Annulation of the Carbene Complex 155 and Carbene Complex 70 0 OR 0M8 12 1 (1) (0050' OR 55 °C 2 . — -—> R = TIpS 45% 9 Q THF 3:1 (dr) 155 Phomactin D Phomactin 32 With the strategy set, the main issues to be addressed are now reduced to the synthetic problems. One concern is whether the fully functionalized long chain carbene complex 70 can be synthesized using the routine dianion method (Scheme 2.8).17 The other concern is whether the carbene complex 70 can be converted to the desired key intermediate 58 smoothly. Considering the reduced number of carbons (n = 9) and the presence of two tri-substituted double bonds (C3-C4 and C7-C8) in the tether of carbene complex 70, the success of key annulation step is far from certain. The increased strain in the tether compared to the model system may also be expected to affect the diastereoselectivity outcome of the key intramolecular cyclohexadienone annulation reaction. 63 3.2 Retrosynthetic study of the key intermediate 58 The retrosynthetic strategy for the key intermediate 58 is summarized in Scheme 3.2. As indicated in Scheme 3.2, the bicyclo[9.3.1]pentadecane core of 58 can be anticipated from the intramolecular cyclohexadienone annulation reaction of Fischer carbene complex 70 in a single step. Hopefully, carbene complex 70 can be prepared from the corresponding vinyl iodide 207 following the dianion method (Scheme 2.8). Propargyl alkyne 207 derives from the protected alcohol 208 in a straightforward manner. The E-vinyl iodide function in 208 will be a direct product of Negishi’s carbometallation- iodination reaction from terminal alkyne 209. Intermediate 209 arises from the carbon chain enlongation of compound 210. Finally, the synthesis of allylic alcohol 210 can be traced back to the commercially available compound geraniol 212 or genranyl acetate 211 through stereoselective and chemoselective allylic oxidation reaction. Scheme 3.2 Retrosynthetic Strategy for Key Intermediate 58 211 212 geranyl acct-to geraniol 3.3 Preparation of the cyclization precursor: Fischer carbene complex 70 One of the key intermediates in the retrosynthetic analysis for phomactins is the Fischer carbene complex 70, which contains the alkyne function at the end of a long chain tether. A close look into the structure of the tether revealed the presence of the carbon skeleton of geraniol (C2-C9) (Scheme 3.2). So the synthesis of carbene complex 70 commenced with geraniol 212 (Scheme 3.3). Scheme 3.3 Synthesis of Intermediate 209 from Geraniol 3602/ f-BUOOH _ 0” BzCI >_=\—>.=/—-OBz CHZCIZ, 10°C. 5h= — Py 0 °C 20h 212 21 3 99% NaBH4, 0 °C, 5 min 052 0.4 eq.PBr3/ 0.059q. PY Br OBz HOW E120. 0 °C, 35 h : _>—:\—>—=/> 215 216 57% 86% TMS 3.0 -5.0eq Li TMS———/: \\ \\ 217 : OH TBAF _ OH -20°C-0°C. 6h — _ ' — 218 209 78% (2 steps) The conversion of geraniol 212 to allylic bromide 216 followed known procedures.42 First the free alcohol was protected with benzoyl group in almost quantitative yield. Then the protected geraniol 213 was subjected to allylic oxidation with a catalytic amount (0.5 equiv.) of selenium dioxide and 70% tert-butyl hydroperoxide at 10 °C.43 The product mixture was briefly treated with NaBH4 to convert a small amount of the over-oxidized 65 aldehyde 214 back to alcohol 215. The desired compound 215 was obtained in 57% overall yield for the above two steps. Treatment of alcohol 215 with phosphorus tribromide and a catalytic amount of pyridine led to allylic bromide 216 in 86% yield. The coupling step between TMS propargyl lithium 217 and the allylic bromide 216 was found to be tricky. After several failed attempts, the reaction finally worked when 3.0 to 5.0 equivalents of organo lithium 217 was used. Compound 217 was generated in situ from l-trimethylsilyl propyne and n-butyllithium. The coupling reaction proceeded smoothly with an excess amount of 217 at 0 °C, not only accomplishing the desired coupling, but also concommitantly deprotecting the benzoyl group, providing free alcohol 218. When less than 3 equivalents of compound 217 was used, a complex mixture was generated, which contained the desired deprotected coupling product 218 together with undesired benzoyl protected coupling product 219 (Scheme 3.4), deprotected bromide 220 and the unreacted starting material 216. Compound 218 was desilylated to terminal alkyne 209 in 78% overall yield from 218 (3 steps). Scheme 3.4 Major By-products of the Coupling Reaction between 216 and 217 TMS \\ OBZ Br—>__\_—>_—/rOH 219 220 Other protecting groups for geraniol were prepared, such as the triisopropylsilyl (TIPS) and trimethylsilyl (T MS) ether. But complications were observed in both cases in the selenium oxidation step. However, the commercially available geranyl acetate 211 was found 66 to be almost as equally efficient as benzoyl geraniol 213 in holding up to the oxidation step (Scheme 3.5). The procedures used to prepare compound 209 were similar to those described in Scheme 3.3, except that the allylic oxidation step was performed with a stoichiometric amount of selenium dioxide.44 The yield of the oxidation step was slightly lower with the acetate (45%) than that with the benzoate (52%). Gratifyingly, the acetate protecting group was also be concommitantly cleaved in the presence of excess amount of organolithium 217 during the coupling reaction to furnish compound 218 directly. Scheme 3.5 Synthesis of Intermediate 209 from Geranyl Acetate 1) 8902/ EtOH(95%) HO 0.4 eq.PBr3 / 0.056q. Py OAc - OAc 2) NaBH4, 0 °C, 5 min ' 211 221 45% 3. 0 -.5 0 eq Br OAc TMS—=U W m _ -2o C°-0 °C 6 h 222 74% 88% (2 steps) Deprotection of 218 gave 209 which was subjected to the Negishi’s carbometallation reaction (Scheme 3.6). Because of the presence of the free alcohol, the carbometallation was performed with 3.0 equivalents of trimethyl aluminum instead of the 2.0 equivalent that is otherwise used. The reaction was stirred at 0 °C overnight and produced the desired E- vinyl iodide 208 in 47% of yield after iodination. Temperature control in this reaction was vital. At room temperature, the only product was the allylic chloride that results from replacement of the allylic alcohol with chlorine. The free allylic hydroxyl group in compound 208 was readily oxidized to the corresponding aldehyde 67 223 using Dess-Martin periodinane.45 Swern oxidation did not work well in this case and only led to conversion of the allylic alcohol to the corresponding allylic chloride as the major product. Alkynylation of aldehyde 223 with ethynyl magnesium bromide was followed by converting the newly generated alcohol to a triisopropylsilyl ether. This completed the synthesis of intermediate 225 which was obtained in an overall yield of 90% for the last three steps. The choice of the triisopropyl group as the protecting group for the tertiary propargyl alcohol in compound 225 was based on the previous model study (Table 2.2), which showed the Tips-protected carbene complex 155b could cyclize with the best diastereoselectivity (3:1) and in satisfactory yield (45%-47%). Scheme 3.6 Synthesis of Cyclization Precursor 226 1) 1 eq. ZGC2C12I3 eq AlMe3 Bess-Martin OH CH2012 0 ".C overnight oxidation 2) 12 47% _CHo : MgBrA IIDMAP THF, -30°C, 307111 OTr-12012 overnight OMe 1 — \\ 11 13111.1 THF (0050' OTips 7-8 °,C 1.511 Cr(CO)6 THF M6308F4 _ — _ 21143111.) 1141: -78 °c rt 21: CH202/15120 (11) ' rt. 40 min -78 °C. 30 mm 90% (3 steps) To our great pleasure, the preparation of fully functionalized Fischer carbene complex 226 did not met with too much trouble (Scheme 3.6). The dianion procedure was followed as described in the previous chapter (Scheme 2.8).17 After successive 68 treatment of compound 225 with one equivalent of phenyllithium and two equivalent of :- butyllithium, the resultant dianion was added to Cr(CO)6 and then methylated with Meerwein’s salt or methyl triflate in a two-phase mixture of CH2C12 and water. Carbene complex 226 was obtained as a red oil. For some unknown reason, the reaction was very sensitive and the yield can vary from 0%-54% depending on the quality of the reagent and the purity of the starting vinyl iodide. The nature of the methylating reagent, however, did not affect the yield too much as methyl triflate and trimethyloxonium tetrafluoroborate gave similar yields. 3.4 Synthesis of the key intermediate by cyclohexadienone annulation With the cyclization precursor 226 in hand, the stage was now set for the key intramolecular cyclohexadienone annulation (Scheme 3.7). Since the tether length of the carbene complex 226 contained only 9 carbons, four of which were spz hybridized, there was a concern about the feasibility of the cyclization although the parallel annulation of the similar model carbene complexes 155a-d succeeded (Table 2.2). Luckily, the increased strain in the real system did not complicate the reaction. The cyclohexadienone annulation was completed in only 2 hours when performed in T HF at 100 °C (Scheme 3.7). The desired bicyclic products 227/228 was obtained in a combined yield of 63%. The diasteromeric ratio of 227 and 228 for the stereogenic centers C(2) and C(11) was 2:1 in favor of the stereochemistry (2R, 11R or 2S, 11S). The two isomers could be separated by silica gel column chromatography, and the compound with a lower Rf value was the minor isomer which could be crystallized from hexanes. The relative stereochemistry was established by the X-ray analysis (Figure 3.1). 69 Scheme 3.7 lntramolecular Cyclohexadienone Annulation of 226 O OTips O OTips THF 100 °C, 2 h OTips 226 63% (2: 1) Figure 3.1 X-ray Structure of Key Intermediate 228 (shown as the enantiomer) It is instructive to note that the diastereomeric ratio of key intermediates 227:228 is not very important in the racemic total synthesis since the hydroxyl group at C(2) will be oxidized to the carbonyl functionality at a later stage in the total synthesis. To optimize the yield of the annulation key step, the reaction was carried out at different temperatures, in different reaction solvents and at different concentrations. The results of the optimization studies of the intramolecular annulation of carbene complex 226 is summarized in Table 3.1. 70 Table 3.1 Conditions to Convert Complex 226 to key intermediates 227/228 OMe 0 01198 O OTips OTips solvent 226 Entry Solvents Concentration Temperature Time (h) 227+228 227:228"-C (M) ( °C) (%)“ l THF 0.005 60 40 60 4: 1 2 THF 0.005 80 10 50 3: l 3 THF 0.005 100 2 63 2: l 4 CH3CN 0.005 80 l 42 2: 1 5 benzene 0.005 80 l < 28 - 6 THF 0.001 80 10 55 3: 1 7 THF 0.05 80 15 41 3: 1 8 THF 0. 14 80 13 31 3: 1 a. isolation yield; b. diastereomeric ratio was determined by crude 1H NMR based on vinyl proton on C( 12); c. configuration of 228 was confirmed by X-ray analysis. First, the temperature effect was investigated. The intramolecular annulation was carried out at 60 °C, 80 °C and 100 °C, respectively in THF at the concentration of 0.005 M (Table 3.1, entry 1-3). All the reactions gave approximately the same yield (50-63%). However, the rate of the reaction increased as the temperature increased. At 60 °C it took 40 hours for the reaction to go to completion, but it only took about 10 hours when the temperature was increased to 80 °C. At 100 °C, the color of the carbene complex faded within 2 hours indicating the complete consumption of the starting carbene complex. The ratio of the isomers was also slightly affected by different reaction temperature. The preferrence for the major to the minor isomer was 4:1, 3:1 and 2:1 at 60 °C, 80 °C and 100°C, respectively, as determined by 1H NMR analysis of the crude reaction mixture. The solvent effect was also studied by performing the reaction in three different solvents at a concentration of 0.005 M and at 80 °C (Table 3.1, entry 2, 4, 5). Comparable 71 yields and diastereoselectivity of the desired products were obtained in THF and acetonitrile. Benzene only provided complex mixure of products from which the desired compounds were obtained in less than 28% of yield. The ratio of 227: 228 can not be determined due to the presence of inseperable impurities. It is well established that the product distribution from the reaction of Fischer carbene complexes can be hightly sensitive to the reaction media.”21 The reason for this is not completely understood, and may not even be the same in every case. But it may be related to the ability of the solvents to coordinate with the metal center. The reactions between the Fischer carbene complexes and alkynes are also known to be sensitive to the reaction concentration. The following example is from the work of Huan Wang who showed that the cyclization of substrate 229 was best carried out at 0.005 M.17 Higher concentration (0.025 M) leads to a diminished yield of the dimer product 230 (Table 3.2). Table 3.2 Concentration Effect on Cyclization of Carbene Complex 229 OMe (0%ch THF ““0 O O 0” ' _ —’ 8 + trimer ( 6— 231 230 Entry Concentration of 229 Temperature Time (h) Yield (%) (M) (° C) 230 231 1 0.025 60 18 19 9 2 0.005 60 14 35 9 However, in the present case of the intramolecular cyclohexadienone annulation of Fischer carbene complex 226, the concentration of the substrate 226 in THF did not 72 affect the yield of the cyclization nearly as much (Table 3.1, entry 2, 6-8). Even at 0.14 M, the cyclization still gave decent yield of the desired product. This result is significant as it will allow for much easier scaling up of the reaction during the total synthesis. 3.5 An alternative route toward compound 215/221: olefin cross metathesis Optimization of the conversion of geranyl acetate 211 or geraniol benzoate 213 to the corresponding allylic alcohols 225 or 215 is necessary (Scheme 3.8). Although the stereoselective allylic oxidation by selenium dioxide gave the desired products with excellent diastereoselectivity, the process suffers from unsatisfactory yield and the need for the toxic selenium dioxide. Recently, Grubbs and co-workers published their work on the stereoselective olefin cross metathesis (CM) to afford functionalized trisubstituted olefins.“ It was anticipated that trisubstituted olefins 215 and 221 could also be obtained using this methodology. Scheme 3.8 Selenium Oxidation to Obtain Allylic Alcohols 221 and 215 >_\—>=/‘OFI $602 OHC)—_\_—>=/—OR NaBH4 H0—>-=\—>:/-OR yield (2 steps) R = AC 211 232 221 450/0 R = 82 213 214 215 57% 73 3.5.1 Selectivity of olefin cross metathesis (CM) As we know, olefin cross metathesis (CM) is a convenient route to functionalized olefins from simple alkene precursors. However, the limited application of CM compared to ring-closing metathesis (RCM) and ring-opening metathesis polymerizations (ROMP) has been a result of its unpredictable selectivity, namely the regioselectivity and chemoselectivity of the olefin product. Therefore, Grubbs and co-workers developed a general empirical model for olefin reactivity to predict the outcome of CM reactions. Olefins were categorized into four types by their relative ability to undergo homodimerization in CM and the susceptibility of their homodimers toward secondary metathesis reaction. When an olefin of high reactivity is reacted with an olefin of lower reactivity (sterically bulky, electron-deficient, etc.), selective cross metathesis can be achieved. The olefin categorization and rules for selectivity in CM reaction is summarized as follows: Type 1 — Rapid homodimerization; homodimers consumable Type II — Slow homodimerization; homodimers sparingly consumable Type III — No homodimerization Type IV — Olefin inert to CM, but do not deactivate catalyst (spectator) Reaction between two olefins of Type I = Statistical CM Reaction between two olefins of same type (non-Type I) = Non-selective CM Reaction between olefins of two different types = selective CM This empirical model was used to explain the chemo- and diastereoselectivity in a series of CM reactions in Grubb’s paper. One related example was shown in Scheme 3.9. 74 Methacrolein 234 will react with trisubstituted prenyl olefin 233 under the catalysis of ruthenium alkylidene 235 to generate allylic aldehyde 236 in good yield and excellent diastereomeric selectivity. In this case, 1,1-disubstituted olefin methacrolein 234 is a type III olefin, while compound 233 can be regarded as a practical substitute for propene, and thus was a type I olefin.47 The highly active catalyst 235 was shown to perform a metathesis on the trisubsubstituted prenyl olefin 233, which was equivalent to a regio- and stereoselective formal allylic oxidation of one of the terminal methyl group. This example also demonstrates that even functionalized 1,1-disubstituted olefins such as methacrolein are excellent substrates for CM reaction. Scheme 3.9 CM Reaction of Methacrolein 234 and Olefin 233 (ROOM A Grubb's catalyst 235 N / 6.3 mol% AcO / 3 + CHO 4 CH0 233 234 CH Cl ,40°C.1211 3 2 2 236 97% ) (E/Z>20:1) NTN—g >— 3:11“— PCy_3\=‘< 235 r 75 3.5.2 Optimization of CM conditions Based on the success of the reaction in Scheme 3.9, it was anticipated that allylic oxidation product of geraniol 238 should be accessible via the CM reaction of methacrolein or methyl methacrylate 237 and geraniol derivatives 236 (Table 3.3). Although there are two double bonds present in compound 236, the prenyl double bond ‘ (type I olefin) should be much more reactive than the other trisubstituted double bond which has any allylic ether function and is classified as the inert Type IV olefin in CM reactions when catalyst 235 was used. Therefore high chemoselectivity would be expected. The experimental results are listed in Table 3.3. Acetyl, benzoyl and Tips were used as the protecting groups in compound 236. The CM of 236 with 237 was carried and then either followed by an in situ reduction to achieve allylic alcohol 239, or without reduction to give compound 238. All reactions using methacrolein as the starting material resulted in high stereoselectivity (E: Z > 20:1) (entry 1-9). However, when methyl acrylate was used, the selectivity dropped to 4:1 (E: Z) (entry 10-11). It was also found that the one-pot reductions using NaBH4 were not very successful (entry 1-3 and 6). Some unknown impurity in the crude mixture after the CM diminished the yield of the following reduction step. Without the reduction step, the isolated yield of product 238 was much better. Since the pure allylic aldehydes 238 can be easily converted to the corresponding alcohols 239 with quantitative yield, the overall yield from 236 to 239 was still good. This research demonstrated that CM could be envisioned as a substitute method for the selenium allylic oxidations to generate functionalized olefins. 76 Table 3.3 CM Reaction between Compound 236 and Olefin 237 Catalyzed by 235 1 1 _ + A ——" fly —_"* ‘- 238 236 239 1 237 2363 R‘ = Ac 237. a? = (2140 236. R‘ = A6, 132 = CHO 239. n1 = Ac 2366 R‘ = 82 2371, F12 = (:0on3 2366 R‘ = 82, R2 = CHO 2366 R‘ =Tips 2386 R‘ = Bz. R2 = COZCH3 238d 9‘ =Tips, a? = 0026113 R1 R2 Entries 236:237 Reaction One-pot Yield of Yield of (E:Z)b time (h) reduction 233 (%)“ 239 (%)a Ac CH0 1 2.6:1 2 h Yes - 34 E only 2 2.621 18 h Yes - 22 E only 3 2.6:1 24 h Yes - 8.6 E only 4 1:1 12 h no 39 - E only 5 1:2 12 h no 46 E only 6 1:2 12 h yes - 26 E only 7 1:3 12 h no 64 E only 82 CH0 8 1:3 14 h no 70 - E only 9° 1:3 19 h no 48 - E only 82 COZCH3 10 1:3 15 h no 33 - 4:1 Tips COzCl-I3 ll 2.6:1 12 h no 30 - 4:1 a.Isolation yield from flash column chromatography; b. ratio determined based on 'H NMR analysis of crude product mixture; c. Four folds higher concentration (0.4 M) 3.6 Summary In summary, key bicyclic intermediate 227/228 for the total synthesis of phomactins can be obtained using the intramolecular cyclohexadienone annulation of Fischer carbene complex 226. The yield of this key step was good (~ 60%) and the diastereoselectivity ranged from 2:1 to 4:1 depending on the reaction temperature. THF was found to be the best solvent for the cyclization. Fortunately, it was found that the effect of concentration on the key annulation step was not dramatic, which facilitates the scaling up of the reaction for the total synthesis. 77 Diastereomers 227 and 228 were obtained in a 3:1 ratio at 80 °C in THF. The minor isomer 228 was crystallized from hexanes and X-ray crystallography analysis was used to determine its relative configuration (2R, llS; 2S, 11R) The synthesis of precursor carbene complex 226 from geranyl acetate was accomplished in 10 steps with an overall yield of 12.4%. Olefin cross metathesis (CM) was also studied as an alternative to the selenium dioxide mediated regio- and stereoselective allylic oxidation to obtain compound 215 or 221. Good yield (70%) and excellent diastereoselectivity were achieved when mathacrolein reacted with benzoyl geraniol under the catalysis of Grubb’s generation two catalyst 235. 78 CHAPTER 4 FUNCTIONAL GROUP MANIPULATIONS AFTER THE CYCLIZATION 4.1 Specific aims With the advanced intermediates 227/228 in hand, attention is now focused on their conversion to the final natural products via functional group manipulations. Our original goal was to synthesize phomactin D, which possesses the best bioactivity. Additionally, phomactin B2 will be another important target since its structure is seemingly more straightforward from 227/228. A general vision toward the total synthesis of other phomactins, such as phomactin B, B,, C, E and F will also be formulated in this chapter. 4.2 Synthesis toward phomactin D 4.2.1 Planned synthetic strategy The plan to accomplish the total synthesis of phomactin D is outlined in Scheme 4.1. Once the macrocycle is constructed, the hydrolysis of methyl enol ether at C(13) will provide ketone 240. Methylation at the ct-position of the ketone should occur at the less hindered 6 face of the molecular as can be predicted from the X-ray crystallography of intermediate 228 (Figure 3.1). The carbonyl function at C(13) in 241 will be removed in two steps via reduced intermediate 242.48 Then 1,4-reduction of the a,B-unsaturated ketone 243 will afford intermediate 244. Transformation of 244 to the final product will involve steps including one carbon extension from the carbonyl at C(15),49 deprotection of C(2) silyl ether, hydroxy group assisted epoxidation of the double bond between C(3) 79 and C(4), and finally oxidation of the C(2) hydroxyl group. It is anticipated that the epoxide moiety can be introduced in a stereoselective manner. The required configuration of the epoxide should arise naturally considering the hindrance posed by the macrocycle on the a face of the molecules.“ Scheme 4.1 Planned Total Synthesis of Phomactin D from 227/228 O OTips o OTips O OTips 1,2-reduction of less hindered ketone 1,4-reduction o1 ‘ (1.8-unsaturated “ ketone ......... - ......... - ---------- deoxygenation .- ......... .. Phomactln 0 According to the plan in Scheme 4.1, the first key step encountered during the synthesis of phomactin D is the preparation of the (Jr-methylated product 241. Efforts devoted to this goal are documented in section 2 of this chapter. 4.2.2 Attempted direct a-methylation via ketone enolate The most straightforward way to introduce an a-methyl group is through the formation of a ketone enolate. Hydrolysis of the vinyl methyl ether 227 using 10% aqueous HCI in THF (Scheme 4.2) provided the desired ketone 240a in 60% yield together with a small amount of the deprotected by-product 245. Unfortunately, treatment of 240a with either LDA/Mel or KH/MeOTf failed to afford the desired (Jr-methylation 80 product. Unreacted 240a was recovered in good yield in both cases. One possible explanation for the failed methylation may be due to the intramolecular attack of the enolate on the hindered ketone in intermediate 246 (Scheme 4.3). As a result, the cyclopropane compound 247 would be generated, which could readily be converted back to the starting ketone 240a upon protonation. Scheme 4.2 Hydrolysis of 227 and Failed Methylation of 240a O OTips O OTips 11291191.. ... THF, rt, 2.5 h 2406 ~ 60% LDA/Mel KH/MeOTt 0°C. 31: / \ -30°C-RT, 211 Recovered SM Recovered SM Scheme 4.3 Possible Mechanism of Failed Methylation _ O O OTips (O OTips O OTips 4.2.3 Attempted a-methylation via ketal formation This failure to introduce an a-methyl group to a cyclohexen-l,4—dione via enolate formation is not unprecedented. Weyerstahl found it difficult to methylate the diketone 248 directly using LDA/Mel (Scheme 4.4).50 In his case, the desired methylation product 253 was isolated in poor yield (25%-40%) from a complex reaction mixture upon direct 81 methylation of 248. Switching to different bases such as NaNH2 or KOtBu did not give improved results. However, compound 250 which has its more hindered carbonyl function protected with a 1,2—dioxolane was readily methylated in high yield (90%). The resultant tetramethyl acetate 252 was subsequently hydrolyzed and converted to the desired ketone 253. Although this methylation procedure via ketal formation involved several steps and the conversion to compound 250 was poor due to the formation of undesired monoketal 249 and diketal 251, this example suggested one possible solution to the a—methylation problem encountered for the related diketone 240a. Scheme 4.4 Weyerstahl’s Strategy of a-Methylation via Ketal Formation U U U U U U benzene reflux 249 251 35% 45% 1 5% 54% 34% l 1) LDA HCOOH 1) LDA 2) M61 2) M81 2576-4076 900/0 :53 Considering the similarity of diketone 2403 to Weyerstahl’substrate, his strategy involving ketal formation was attempted on the key intermediate 227. The planned transformation from 227 to the methylated compound 241a is presented on Scheme 4.5. Hopefully in situ generation of the diketone intermediate 240a under acidic conditions followed by the selective protection of the more hindered carbonyl group using Weyerstahl’s strategy will provide monoketal 254, which upon methylation should furnish 255. After hydrolysis, the desired methylated diketone 241a would be realized. 82 Scheme 4.5 Planned Methylation Following Weyerstahl’s Strategy . 0’ 0‘ OTips O OTips r- 0 OTIps - Unfortunately, ketal formation only took place at the less hindered carbonyl of 227 as shown in Scheme 4.6. After refluxing 227 with 1,2-dihydroxyl ethane in benzene in the presence of catalytic amount of TsOH for 21 hours, only the undesired monoketal 256 was generated in moderate yield together with a 30% recovery of the starting material. No desired monoketal 254 was observed. Therefore, this strategy was not further pursued. Scheme 4.6 Ketal Formation of Compound 227 O OTips O OTips HO, ,OH TsOH benzene reflux, 21 h 25% 83 4.2.4 Attempted a-methylation via ring opening of an alkoxy cyclopropane 4.2.4.1 General information about Simmons-Smith reaction The next strategy considered was methylation via ring opening of a cyclopropane. The reaction of the organozinc reagent prepared from methylene iodide and zinc-copper couple with unsaturated compounds has been used for the synthesis of cyclopropanes for about half a century and is known as the Simmons-Smith reaction (Scheme 4.7, equation a).48 The structure of the organozinc intermediate was proposed to resemble that of a Grignard reagent. Two useful variations of this cyclopropanation reaction involving the same or a similar organozinc intermediates are: (1) diazomethane reaction with zinc iodide in ether to form a reagent which converts unsaturated compounds to cyclopropanes (Scheme 4.7, equation b); (2) 1,1-diiodoalkane reaction with diethylzinc in ether in the presence of unsaturated compounds to yield the corresponding cyclopropanes (Scheme 4.7, equation c). The mechanism of the reaction is believed to be a one-step methylene- transfer in which the quasi-trigonal methylene group of iodomethylzinc iodide intermediate adds to an olefin n—bond as shown in transition state 257 such that both new carbon-carbon bonds are formed essentially simultaneously.48 Scheme 4.7 Simmons-Smith Reaction \/ \/ C\ (a) 'C'; + CH2|2 + Zn(Cu) —’ ',CH2 + Zl'llz + (Cu) \C/ /C\ /C\ “ r'z'“ ’23:, 5 \C/ \C/ C" 2 ‘I (b) b + CH2N2+ an2 ——> (33‘3”2 + an2 + N2 / \ / \ / \ 257 \C/ \C/ (C) a + RCHIZ + (C2H5)22n ———D C':CHR + [CZH5ZnI + Cszl] 84 Enol ethers have been found to be highly active toward organozinc reagents. Therefore, the transformation of keto compounds 258 into a-methylketo substances 261 can be realized by way of oxycyclopropane intermediate 260 (Scheme 4.8).51 The cyclopropane is usually unravelled under acidic conditions. This whole process would be viewed as a useful alternative to the classical a-alkylation of keto systems via enolate formation. Scheme 4.8 a-Methylation of Keto Compounds via Simmons-Smith Reaction if H Simmons— Smith I cyclopropanation O on 258 259 4.2.4.2 Simmons-Smith reaction on model systems Before applying this methodology to the enol ether 227 or 228, a model study was chosen involving the simple molecule cyclohexadienone 262 (Scheme 4.9) which contains the same substitution pattern as the cyclohexadienone core of 227. The model cyclohexadienone 262 was prepared from the commercially available compound 248. Although a-methylation of ketone 248 was found to be difficult, (Scheme 4.4), its oxygen methylation was quite successful under the condition presented in Scheme 4.9 and provided the model enol ether 262 with 78% yield.52 Then the Simmons-Smith reaction was attempted on 262 employing a combination of 2 equivalent of Ean and CH212 (Scheme 4.7, method c).50 The reaction was complete in only 15 minutes in toluene at 0 °C. However, after detailed analysis, the structure of the new product was determined to be 263 instead of the desired 265. Only one diastereomer was 85 observed. Although the relative stereochemistry of the compound was not determined, it was assigned as indicated in Scheme 4.9 based on the proposed mechanism. The possible mechanism for the formation of 263 could be the unexpected addition of an ethyl group from EQZn to the carbonyl to generate a tertiary alcohol 264, followed by a hydroxyl group directed cyclopropanation. The IR spectrum indicated the disappearance of the ketone functionality. The introduction of the ethyl group was confirmed by 1H-NMR, 13C- NMR and GC-Mass analysis (MW m/z 210). An NOE study indicated that the vinyl proton Hd (6 4.2 ppm) was close in proximity to both methyl protons H, (6 1.16 ppm) and H, (6 1.21 ppm), which precluded the structure of 265 and further confirmed the position of the cyclopropane ring. Consistent with this structure is the fact that the cyclopropane ring was found intact after the treatment of 263 with HCl while the enol ether function was converted to a ketone as shown in compound 266. Scheme 4.9 Unexpected Product from Simmons-Smith Reaction of 262 0 O __ _ 1)KHMDS 20” a Zn/CHI ”0 H0 ,. 2 DMPU ~ - 2 22 " ) Toluene, 0°C, 15 m .LCL. 3) MeOTf 36% o THF, -7e°co°c We 0 243 262 263 266 OMe 78% HO i Ho ‘ 6 Ha HC Hb [ ] Ha 0M8 0M9 OMe 254 263 265 To avoid the regioselectivity problem, the double bond adjacent to the carbonyl functionality was removed by treating 262 with L-selectride. Conjugate 1,4-reduction occurred cleanly to provide 267 in 93% yield (Scheme 4.10). 86 Scheme 4.10 Attempted Simmons-Smith Reaction on Model Vinyl Ether O o O L-selectride Conditions .= ----- x ----- - 3 THF, -78°C, 30 min OMe 93% We OMe 262 267 268 To our disappointment, direct cyclopropanation of enol ether 267 failed (Scheme 4.10). The addition of 267 to the preformed organozinc reagent (2 equiv.) made from 13an and CH2]2 in THF gave only recovered starting material after the reaction mixture was stirred at room temperature for 30 minutes.53 The same result was observed using CH2C1253 or toluene54 as the solvent. Switching the sequence of addition of CHZI2 and 267 did not make any difference either. An alternative procedure for making the organozinc reagent employing the classic Zn-Cu couple was attempted.55 Although the Zn-Cu couple was freshly prepared and the reaction was refluxed in ether for 8 hours, most of the starting material was recovered after the reaction. The exact reasons for the above failures were not clear but may be attributed to the presence of the carbonyl group. To circumvent this problem, ketone 267 was treated with LAH (Scheme 4.11), and the resultant alcohol 269, which was obtained as a mixture of diastereomers (3:1), was exposed to Simmons-Smith reaction. It is known that an appropriately positioned hydroxy group will direct the Simmons-Smith reaction.S6 Therefore, as expected the cyclopropanation of a 4:1 mixture of diastereomers of 269 occurred readily in the presence of Et2Zn/CH212 providing compound 270 in excellent yield (96%) and also as a 4:1 mixture of diastereomers. The relative stereochemistry of hydroxyl group and the cyclopropane in this molecular was not determined but was 87 assumed to be cis considering the directing effect the hydroxyl group during the Simmons-Smith reaction. Acid-catalyzed ring opening of the cyclopropane was also attempted on the major isomer of 270. Although harsh reaction condition was necessary for complete conversion (12 hours in hot HCl solution), the desired a-methyl ketone 271 could be obtained in good yield (85%). A parallel cyclopropanation on the related tertiary alcohol 272 was also successful (Scheme 4.11). Addition of methylmagnesium bromide to ketone 267 afforded 272 with good yield (76%) and excellent diastereoselectivity (>10:1). Cyclopropanation was then executed following the same procedure and provided 273 in good yield (60%). Scheme 4.11 Simmons-Smith Reaction of Alcohol 269 and 272 0 OH Etzzn/CHzlg HCI/ CH30H etheeqr, 0°C- rt, Benzene 0°C, 1 h 100°C 12 h 58%(4: 1) 629%(4 1) 85% OMe O 271 MeMg Br EtZZn/CHZIZ I ether.g 0°C, 3h Benzene. 0°C 1 h 76% (> 10:1) 60% 4.2.4.3 fi-Elimination of key intermediate 227/228 With the key cyclopropanation of the enolate successfully achieved on the model compound, effort could now be directed toward the goal of methylation of the key intermediate 227 or 228 via a cyclopropane intermediate. As depicted in Scheme 4.12, this strategy would involve a sequential 1,4— and 1,2-reduction of intermediate 227/228 88 followed by application of Simmons-Smith reaction on the resultant alcohol 274, then ring-opening under acidic condition. Scheme 4.12 Planned Methylation of 227/228 via Cyclopropane Intermediate 275 O OTips OH OTips 1 ,2-reduction cyclopropanation ......... . 275 276 First the 1,4-reduction was performed on the major key intermediate 227 using L- selectride. Since the reduction was extremely sluggish, excess amount (4 equiv.) of L- selectride was added to a highly concentrated solution and stirred overnight. The reaction was clean, affording one new compound. Unfortunately, this product was not the desired 273 since the Tips group was missing according to NMR analysis. Furthermore, no methine proton adjacent to oxygen at C(2) position was detected which precluded the simple desilylation product. The IR spectrum of the compound also confirmed the absence of hydroxyl group. GC-Mass analysis showed the molecular weight of the new compound to be (m/z) 288. Application of the same reaction condition on isomer 228 led to the same product and the reaction was much faster (completed within one hour). The structure of the new compound was finally determined to be 277 (Scheme 4.13). This surprising result can be rationalized by the mechanism described in Scheme 4.13. Upon 89 addition of the first equivalent of L-selectride, anionic intermediate 278 would be generated, which could undergo a B-elimination reaction spontaneously to afford intermediate 279. Reaction of 279 with L-selectride that is in excess leads to a second 1,4-reduction process and would afford compound 277 as the final product. Scheme 4.13 Unexpected B-Elimination Process During the Reduction of 227/228 — 0 OTips O OTips \J excess L-selectride 227/228 278 An attempt to optimize the reduction conditions was performed on 228 to find out whether the transformation could be stopped after first conjugate reduction to produce the desired compound 280. Unfortunately, with reduced amounts of L-selectride, no reaction took place (Table 4.1, entry 1 to 3). A lowered temperature also failed to give any significant conversion even in the presence of 3 equivalent of L—selectride (Table 4.1 entry 4). Under these latter conditions, most of the starting material was recovered unreacted after 12 hours. Table 4.1 Attempted Conditions to Convert Compound 228 to 280 O QTipS O QTipS - [8999??? 228 280 Entry L-selectride (equiv.) T (°C) Time (h) Result 1 1.5 -78 to -30 24 recovered SM 2 1.2 O 18 recovered SM 3 1.2 it 4.5 recovered SM 4 3.0 0 12 recovered SM + unknown product 4.2.5 Attempted a-methylation via reduced intermediate 281/282 The strategy employing Simmons-Smith reaction to introduce the a-methyl group was suspended due to the [ES-elimination problem. So the direct methylation via ketone enolate formation was revised. As opposed to strategy described in Chapter 4, section 4.2.3, the hindered carbonyl at C (15) would be converted to a protected hydroxyl group instead of ketal functionality (Scheme 4.14, equation 1) before the methylation step. To test the feasibility of the strategy, enedione 248 was again used in the model study (Scheme 4.14, equation 2). First the hindered carbonyl group of compound 248 was reduced with 0.25 equivalent of NaBH4 following the reported procedures7 Attempted direct methylation of 285 using excess amount of base failed. So the free hydroxyl group was protected with TMS to give compound 286. The subsequent methylation gave the desired product 287 as a mixture of equimolar amounts of diastereomers in 70% combined yield. 91 Scheme 4.14 Strategy of Direct a-Methylation after Reduction 0 OTips OH OTips OP OTips 1) O OTMS OTMS 0.25 eq. NaBH4 MeOH, 0°C. 30 min TMSCIIEtaN LHMDS” Me' 72% n 21 h -30°C-I'1. 12 h o 740/ O 70% (1 :1 ) O Encouraged by this result, this strategy was executed on dione 2403 starting with the 1.2-reduction of the hindered carbonyl group at C(15). Curiously, direct reduction with NaBH4 at 0 °C as in the model study failed to provide the desired monoketone 281. Either both carbonyls got reduced with excess amount of NaBH4 (~10 eq.), or only the less hindered carbonyl at C(13) was reduced selectively with stoichiometric amount of NaBH4 (Scheme 4.15). Scheme 4.15 NaBH4 Reduction of Dione 240a O OTIpS o OTips OH OTips To circumvent this regioselectivity problem, the reduction was performed directly on the enol ether 227 (Table 4.2). Reducing reagents that were screened for the conversion of 227 to 290 included superhydride, DIBAL, NaBH4/CeCl3 and NaBH4 but 92 unfortunately all failed (Table 4.2, entry 1 to 4). Gratifyingly, when 227 was exposed to 4 equivalent of LAH in THF at room temperature, the desired alcohol 290 was obtained as a single diastereomer (Table 2, entry 5). Compound 290 was not stable and has a very close Rf value to that of the starting enol ether 227, therefore could not be isolated in pure form. Fortunately, treatment of 290 in—situ with dilute aqueous HCl (1%) in MeOH instantly hydrolyzed the enol ether to afford ketone 281 as a stable white, crystalline solid which can be easily separated from the starting material 227 with an overall yield of 75%. As outlined in Scheme 4.14, the selective reduction and hydrolysis to 281 in good yield sets the stage for the desired alkylation to give 283. The transformation, however, will not be pursued in this thesis. Table 4.2 Attempted Conversion of Key Intermediate 227 to 281 OH OTips OH OTips Conditions 1% HCI MeOH,1 min 281 Not stable Stable Close R, value as 227 Can be easily seperated from 227 Entries Reducing Amount (eq.) Temperature Reaction time Result reagent 1 superhydride 2 rt 2 h recovered SM 2 rt 16 h recovered SM 4 rt 30 h messy 2 NaBH4 2 rt 3 d messy 3 NaBHJCeCl3 10 rt 3 d recovered SM 4 DIBAL 1 0 °C 6 h recovered SM 5 LAH 4 rt 17 h 290:227 > 10:] The LAH reduction was also tried on the minor isomer 228 of the key intermediate (Scheme 4.16). The starting material was consumed within 30 minutes. 93 However, the structure of the resultant product was different from what would be expected for a diastereomer of 290. Although the structure of the product was not determined, it was observed that the triisopropyl silyl group was lost. The molecular weight before hydrolysis was found to be (m/z) 288. In combination with the NMR analysis, the structure of the new compound is tentatively assigned as 291. Treatment of 291 under acidic condition provided compound 292 with an overall yield of 32% from intermediate 228. Scheme 4.16 Unexpected Product of LAH Reduction on 228 HCI MeOH, 3 min 32% (2 steps) 4.3 Synthesis toward phomactin B2 At this stage, the total synthesis of phomactin D was suspended yielding the way to another target molecule: phomactin B2. Unique from other family members, this molecule features a methylene moiety at C(15) (Figure 1.1). Although the bioactivity of phomactin B2 is relatively low (Table 1.1), its synthesis may provide valuable information for the future studies toward the syntheses of other phomactins. 94 4.3.1 Proposed synthetic strategy The proposed synthetic strategy for phomactin B2 is outlined in Scheme 4.17. Olefination of the carbonyl group at C(15) will transform the key intermediates 227/228 to 293.55 Then hydrolysis followed by a-methylation will afford compound 295. The carbonyl group at C(13) of 295 will be reduced and protected to give in compound 296. Subsequent desilyation of the silyl ether in this intermediate should free the hydroxyl group at C(2) which will be used to assist the epoxidation of allylic double bond between C(3) and C(4). The installation of the epoxide is expected to occur stereoselectively as indicated in compound 297 considering the steric hindrance of the a-face of the molecule. Finally oxidation of the hydroxy group at C(2) and then removal of the protection group would complete the total synthesis of phomactin B2 in a straightforward way. Scheme 4.17 Planned Total Synthesis of Phomactin B2 from 227/228 0 OTips OTips OTips 1. reduction 1, desilyllation 1. oxidation —‘—> —————> ——h-- 2. protection 2. epoxidation 2. deprotection Phomactln a, The Peterson olefination is the silicon analog of the Wittig reaction (Scheme 4.18),56 and involves the addition of a-heteroatom stabilized carbanion 298 to aldehydes 95 or ketones. The B-hydroxysilyl intermediate can be treated with either acid or base to afford the desired olefins 302. One advantage of the Peterson olefination is that it can be used to methylenate sterically hindered ketones.58 Furthermore, the disiloxane (R3SiOSiR3) by-product is usually volatile and thus can be readily removed which is in contrast to the difficulty associated with removing the triphenylphosphine oxide by- product of the Witti g reaction. Scheme 4.18 Wittig Reaction and Peterson Olefmation X 0 J\ 1L X 0. X-O' R2R1C3CR394 Fl' 32 R3 4 ' ' and! or ' ' e R RZR1C—CR3R4 82610-08384 302 + 293 299 300 301 xo‘ 303 X = P83 Wittig Reaction X = 8023 Peterson Olefination The total synthesis of phomactin B2 from the advanced intermediate 227 or 228 commenced with the Peterson olefination. First the reaction was effected on the minor isomer 228 as described in Scheme 4.19. Addition of trimethylsilyl methyl lithium to 228 in THF was complete in 10 minutes at room temperature and the crude product 304 was converted to the olefin 305 with both KH and KO’Bu. KH worked better in this case, providing a clean sample of 305, which upon hydrolysis with dilute aqueous HCl solution afforded the desired ketone 306 in good yield. Although the (Jr-methylation of dione 240a was found to be difficult (Scheme 4.2), this process was quite successful on the olefinated substrate 306. Compound 307 was obtained as a single diastereomer upon methylation of 306. This methylated intermediate was crystalline and its structure was confirmed by X- ray crystallography (Figure 4.1). Once this encouraging result was obtained, the Peterson olefination of the major intermediate 227 was attempted using the same reagents. Unfortunately only recovered starting material was observed even after 3 days at room temperature. Increased reaction temperature (40 °C) led to the formation of an unknown elimination product. Scheme 4.19 Conversion of 228 to 307 via Peterson Olefination o gnps TMSHZC 0H QTips grips TMSCH2U KH or KO'Bu 1% HCI — —> ‘5 .___. C THF, RT MeOH, RT 10min 10 min Mel/ LHMDS THF, ~78 °C-FlT 18 h Figure 4.1 X-ray Structure of Intermediate 307 4.3.2 Synthesis of phomactin B2 analogs After the methyl group at C(12) was installed in 307, the following steps leading to analogs of phomactin B2 were accomplished by Chunrui Wu (Scheme 4.20).59 Reduction of the carbonyl group in 307 with NaBH4 gave a 3:1 mixture of diastereomers 308 and 309, which could not be separated by column chromatography. Treatment of the mixture with Ac20 and pyridine followed by desilylation with TBAF resulted in the 97 quantitative formation of alcohols 310 and 311, which can be separated using column chromatography and each was taken on to further manipulations. Treatment of 310 or 311 with VO(acac)2 led to the products 312 or 313. After Dess-Martin oxidation of C(2) hydroxyl group, compounds 314 or 315 was obtained. Although the subsequent hydrolysis proceeded smoothly, none of the final products 316 or 317 agreed with the known structure of phomactin 82 according to the NMR analysis. As the C(12) methyl group of compound 307 was confirmed to be of the right stereochemistry (B face) by X- ray crystallography (Figure 4.1), the difference thus must result from the unexpected stereoselectivity when installing the epoxide functionality. Further investigation to solve these problems is still underway. Scheme 4.20 Synthesis of Phomactin B2 Analogs from Intermediate 307 QTips OH NaBH4 1. Ac2O/ Pyridine _.__. ————> \ 5120 IEIOH 2. TBAF RT 100% 73% ”7 310131 1 310:311 (3:1) OH O '30 Dess-Martin ' oxidation 3100r 311 312:" 313 314or315 NaOH THF/MeOH Phomactln 32 98 4.4 Prospective synthetic plans to phomactin B, B,, E and F from 227/228 Other target molecules of this research project in the future may include phomactin B, B], E, F and their analogs (Scheme 4.21). If a methyl function can be introduced to the hindered carbonyl group in the key intermediate 227/228, the synthesis of these compounds, or at least their epimers, will be possible. To probe the possibility of introducing a nucleophile to the quite hindered C(15) carbonyl, methylation was explored by treating both 227 and 228 with CH3MgBr. It seems the Grignard reagent was either too sterically hindered or not reactive enough. Only the starting materials were recovered even after 24 hours at room temperature from reaction with both 227 and 228. Gratifyingly, smaller CH3Li added to the more reactive diastereomer 228 easily and led to the quaternary alcohol 318 as a single diastereomer in about 60% yield. The relative stereochemistry of the newly introduced methyl group was not determined but was assumed to be that resulting from attack at the less hindered B-face. Hydrolysis of 318 with 1% aqueous HCI afforded ketone 319, which should be useful in the synthesis of phomactin analogs via further functional group manipulations. The addition of CH3Li to 227 failed due to the severe steric hindrance posed by the bulky Tips protecting group. Most 227 was recovered unreacted with the same reaction conditions as was used for 228. Although preliminary, these investigations suggest that efficient syntheses of a number of phomactins and phomactin analogs should be possible from the key intermediate 227/228. Scheme 4.21 Envisions of Possible Target Molecules HO (QTips HO gTipS 1 °/oHCl MeOH, 1 min ~ 40% Phomactin B Phomactln 31 Phomactin E Phomactln F 4.5 Comparison of the reactivity of key intermediates 227 and 228 in nucleophilic addition reactions During the investigation of different synthetic routes to phomactins from the key intermediates 227 and 228, a difference in the reactivity of these two isomers was observed in nucleophilic addition reactions. Scheme 4.22 summarized the results of 1,2- addition of organolithium to the carbonyl group of 227 and 228. Although the nucleophilic attack of either TMSCHzLi or CH3Li on intermediate 228 (equation a and c) could be successfully accomplished, these additions failed on intermediate 227 (equation b and d). 100 Scheme 4.22 1,2-Addition of TMSCHzLi or CH3Li to 227 and 228 TMSCHgLi TMSCH2U No Reaction 228 c d . CH Li CH3LI .__.3 No Reaction 228 318 A possible explanation for the greater reactivity of 228 over 227 can be found in Figure 4.2. According to the X-ray structure of 228, the conformations about the C(2)- C(14) bond in 228 is as shown in Figure 4.2. The hydrogen at C(2) in 228 is anti to the carbonyl and C(15). It is thus expected that in the C(2) epimer 227 the H will be syn to the carbonyl. Thus, the approach of the nucleophile at the Burgi-Dunitz angle will be more subject to close contacts with the bulky trimethylsilyloxy group at C(2) in 227 than in 228. 101 Figure 4.2 Explanation of Greater Reactivity of 228 over 227 X-ray structure of 228 R'Li Fl'Ll \ R3Sl-o,' 1 2 o - 0:1), 01%;) H _. 12 ; H -— c C conformation in 227 conformation in 228 R' = TMS or CH3 Another interesting difference that can be explained using this model is described in Scheme 4.23 and Figure 4.3. In this case, treatment of 227 and 228 with LAH produced completely different products. Reduction of 227 with LAH provided alcohol 290 which is the expected 1,2-addition product (equation 3). However when 228 was treated with LAH (equation b), compound 291 was generated which appears to be the product of sequential 1,4—reduction, B-elimination and 1,2-reudtion. A possible explanation for the above result is given in Figure 4.3. As both C(15) and C(13) in compound 227 are equally hindered, the hydride will attack the carbonyl since LAH normally actes as a 1,2-reductant. In compound 228, the approach of hydride to C(13) is much easier than to C(15) due to less steric hindrance, therefore 1,4-addition takes place first. The following B-elimination process is similar to that observed in L- selectride reduction (Scheme 4.13). Excess amount of LAH will then convert the carbonyl of C(15) to a hydroxyl group. 102 Scheme 4.23 Comparison of LAH Reduction of 227 and 228 O OTips OH OTips a LAH H’ “’ THF, 11. 17 h , ,' Fl 3‘ R Si " \ 3 ‘0 04$? on? H _. '-, 5 H C C b conformation in 227 conformation in 228 LAH THF, rt, 30 min Figure 4.3 Possible Explanation 1 4.6 Summary In this chapter, efforts focusing on functional group manipulations after the macrocyclic ring-closure were described. The original target of our synthesis was phomactin D but approaches to phomactin B2 were also considered and investigated. Sythesis of targets such as phomactin B, B,, E, F can also be envisioned from the versatile key intermediates 227 and 228. The difficulties encountered during the synthesis of phomactin D mainly lie in the (ii-methylation at C(12). Several strategies were attempted to obtain this goal, including direct a-methylation via ketone enolate formation, indirect (at-methylation after ketal protection or reduction of C(15) carbonyl group, and Simmon-Smith reaction of the enol ether double bond followed by cyclopropane unraveling. Reactions based on model compounds were carried out to test the feasibility of each strategy. However, execution of the strategies to the fully functionalized system led to some unexpected results despite the success of the model studies. 103 The synthetic approach to phomactin B2 utilizes a Peterson olefination as the key step to convert C(15) carbonyl into a methylene. Another important achievement was the successful (ii-methylation of the ketone intermediate 306 to provide the desired compound 307 as a single diastereomer, whose structure was confirmed by X-ray crystallography. During the synthesis, an interesting difference in the reactivity of key intermediates 227 and 228 in nucleophilic addition reactions was observed. A working model is proposed to explain the difference. The success synthesis of advanced intermediates in this chapter holds the promise that the development in this thesis might eventually culminate in the synthesis of most phomactin family of natural products in the near future. 104 EXPERIMENTAL SECTION Preparation of 1, n-Bis(trimethylsilyl)-diyne 180 i’l’Z‘i 179a-d Ems —’ TMS é n \ TMS 178 180a-d General Procedure I: Trimethylsilyl acetylene 178 (3.0—4.0 equiv.) was dissolved in THF at a concentration of 0.7 M and precooled to -78 °C. To this solution n-BuLi (3.0-4.0 equiv.) was added dropwise. The reaction mixture was stirred at —78 °C for 30 minutes and then raised to 0 °C for 50 minutes. The anion obtained was transferred by cannula to a solution of diiodode 179 (1 equiv.) (0.5 M in THF) at room temperature. Freshly distilled HMPA (16 equiv.) was then added and the brown mixture was stirred at room temperature for 12 hours before it was quenched with 3N HCI. The aqueous layer was extracted with ether and the organic layer was separated and washed sequentially with saturated NaHCO3 and brine. Then the ether layer was dried with MgSO4 and concentrated. The diyne products 180a-d were either purified by flash chromatography on silica gel using hexanes as the eluant, or used directly without further purification. Diiodide 179a (n=6) and 179b (n=8) were bought from Adrich company and used directly. Diiodide 179c (n=10) and 179d (n=13) were prepared from the corresponding diols following the procedure described in Wang’s Ph.D. thesis.17 105 Preparation of 1,10-Bis(trimethylsilyl)deca-l, 9-diyne 180a (n = 6): Compound 180a was prepared according to the general procedure I. Trimethylsilyl acetylene 178 (4.33 mL, 30.0 mmol) was dissolved in dry THF (20 mL) and reacted with n-BuLi (12 mL, 2.5 M in hexanes). Then it was transferred to a solution of diiodide 179a (1.7 mL, 10.0 mmol) in THF (40 mL) followed by addition of 30 mL HMPA to the reaction mixture. The crude product was taken on to the next step. A small portion of the product was purified using flash column chromatography on silica gel (eluant: pure hexanes) to give a colorless liquid for characterization. Rf: 0.12 (hexanes); 1H NMR (CDCl3) 6 0.11 (s, 18H), 1.35-1.37 (m, 4H), 1.47-1.50 (m, 4H), 2,18 (t, 4H, J = 4.5 Hz); l3C NMR (CDCI3) 6 0.15, 19.75, 28.18, 28.41, 84.31, 107.48; IR (neat) 2930, 2860, 2176, 1250, 841 cm"; MS (EI) m/z (% rel intensity) 278 M" (1), 263 (7), 250 (4), 235 (6), 221 (3), 189 (27), 175 (31), 73(100). Anal calcd for C16H3OSi2: C 68.98, H 10.85. Found: C 69.42, H 11.13. Preparation of 1,l2-Bis(trimethylsilyl)dodeca-l, ll-diyne 180b (n = 8): Compound 180b was prepared according to the general procedure I. Trimethylsilyl acetylene 178 (4.33 mL, 30.0 mmol) was dissolved in dry THF (20 mL) and reacted with n-BuLi (12 mL, 2.5 M in hexanes). Then it was transferred to a solution of diiodide 179b (2.0 mL, 10.0 mmol) in THF (40 mL) and HMPA (30 mL) was added. The product was purified using flash column chromatography on silica gel (eluant: pure hexanes) to give a colorless liquid (2.2 g, 7.4 mmol, 74%). R, = 0.11 (hexanes); 1H NMR (CDCl3) 6 0.12 (s, 18H), 1.26—1.30 (m, 4H), 1.32-1.38 (m, 4H), 1.44-1.52 (m, 4H), 2.17— 106 2.20 (m, 4H); 13C NMR (CDCI3) 6 0.17, 19.83, 28.59, 28.71, 28.90, 84.26, 107.69; IR (neat) 2959, 2934, 2859, 2176, 1250, 841 cm]; Preparation of l,14-Bis(trimethylsilyl)tetradeca-l, l3-diyne 180c (n = 10) Compound 180c was prepared according to the general procedure I. Trimethylsilyl acetylene 178 (2.5 mL, 17.7 mmol) was dissolved in dry THF (25 mL) and reacted with n-BuLi (10 mL, 1.6 M in hexanes). Then it was transferred to a solution of diiodide 179c (1.55 g, 3.7 mmol) in THF (25 mL) followed by addition of 12.5 mL HMPA. Flash column chromatography (eluant: pure hexanes) on silica gel provided the purified compound 180c as a colorless liquid (1.09 g, 3.3 mmol, 88%). Rf = 0.32 (hexanes); 1H NMR (CDCI3) 6 0.12 (s, 18H), 1.26 (br, s, 8H), 1.30-1.38 (m, 4H), 1.46- 1.51 (m, 4H), 2.19 (t, 4H, J = 7.2 Hz); 13C NMR (CDC13) 6 0.16, 19.83, 28.62, 28.77. 29.04, 29.39, 84.21, 107.75; IR (neat) 2930, 2857, 2175, 1250 cm". Anal calcd for CZOH33812: C 71.77, H 11.44. Found: C 72.17, H 11.77. Preparation of l,l7-Bis(trimethylsilyl)heptadeca-1,16-diyne 180d (11 =13) Compound 180d was prepared according to the general procedure I. Trimethylsilyl acetylene 178 (2.6 mL, 18.4 mmol) was dissolved in dry THF (40 mL) and reacted with n-BuLi (7.2 mL, 2.5 M in hexanes). Then it was transferred to a solution of diiodide 179d (2.0 g, 4.6 mmol) in THF (20 mL) followed by addition of 12.7 mL of HMPA. Flash column chromatography (eluant: pure hexanes) provided the purified compound 180d as a colorless liquid (1.4 g, 3.9 mmol, 84%). R{ = 0.35 (hexanes); 1H NMR (CDCI3) 6 0.12 (s, 18H), 1.25 (s, ]4H), 1.30-1.40 (m, 4H), 1.46-1.54 (m, 4H), 2.17- 107 2.20 (m, 4H); 13C NMR (CDCl3) 6 0.18, 19.85, 28.64, 28.79, 29.08, 29.49, 29.59, 84.21, 107.79 (one aliphatic carbon not located); IR (neat): 2928, 2855, 2176, 1466, 1250 cm“. Preparation of l, n-Diyne 188a-d / \ / fl \ / \ TMS TMS A 1800-d 188a-d General Procedure II To a solution of 180a-d in THF (0.2 M) was added TBAF (1.0 M in THF) (3.0 - 4.0 equiv.) at room temperature. The mixture was stirred for 6 to 12 hours and quenched with brine. Ether was added. Then the organic layer was separated and dried over MgSO4. Concentration followed by flash chromatography on silica gel (eluant: hexanes) provided diacetylene 188a-d. Preparation of Deca-l, 9-diyne 188a (n = 6) Compound 188a was obtained as colorless oil (0.72 g, 5.4 mmol, 54% over two steps from 179a) following the general procedure 11 starting with 1.7 mL (10.0 mmol) of diiodide 179a and treating the resultant crude 180a with 30 mL of TBAF (1.0 M solution in T HF). Rf = 0.19 (hexanes); 1H NMR (CDC13) 6 1.22-1.42 (m, 4H), 1.49-1.54 (m, 4H), 1.92 (t, 2H, J = 2.4 Hz), 2.16 (td, 4H, J = 6.9, 2.4 Hz); l3C NMR(CDC13) 6 18.31, 28.16, 28.26; 68.16, 84.55; IR (neat) 3301, 2937, 2860, 2118 cm"; 108 Preparation of Dodeca-l, ll-diyne 188b (n = 8) Compound 188b was obtained as a colorless liquid (0.92 g, 5.7 mmol, 57% for 2 steps from 179b) following the general procedure 11 starting with 2.0 mL (10.0 mmol) of diiodide 179b and treating the resultant crude 180b with 30 mL of TBAF (1.0 M solution in THF). Rf = 0.20 (hexanes); ‘H NMR (CDC13) 6 1.28-1.30 (m, 4H), 1,33-1.40 (m, 4H), 1.45-1.55 (m, 4H), 1.92 (t, 2H, J = 2.7 Hz), 2.16 (td, 4H, J = 6.9, 2.7 Hz); 13C NMR (CDC13) 6 18.38, 28.44, 28.67, 28.94, 68.07, 84.71; IR (neat) 3300, 2934, 2859, 2117 cm' 1 Preparation of Tetradeca-l, l3-diyne 188c (n = 10) Compound 188c was obtained as a white solid (0.4 g, 2.1 mmol, 80%) by treating the bis-silyldiyne 180c (0.9 g, 2.7 mmol) with TBAF (11.0 mL, 1.0 M solution in THF) following the general procedure 11. Rf = 0.25 (hexanes); mp 30-32 °C; 'H NMR (CDCI3) 6 1.10-1.30 (s, 8H), 1.30-1.40 (m, 4H), 1.50 (m, 4H), 1.92 (t, 2H, J = 2.7 Hz), 2.15 (td, 4H, J = 6.9, 3.0 Hz); 13C NMR (CDC13) 6 18.3, 28.5, 28.9, 29.1, 29.5, 68.0, 84.5; IR (neat) 3287, 2936, 2918, 2851, 2120, 1471 cm“. Anal calcd for C14H223 C 88.35, H 11.65. Found: C 88.59, H 12.15. Preparation of Heptadeca-l,l6-diyne 188d (11 =13) Compound 188d was obtained as a white solid (0.22 g, 1.0 mmol, 80%) by treating compound 180d (0.45 g, 1.2 mmol) with TBAF (5.0 mL, 4.8 mmol) following the general procedure 11. Rf = 0.28 (hexanes); mp 30-32 °C; 1H NMR(CDC13) 6 1.20-1.44 (m, 18 H), 1.50 (m, 4H), 1.92 (t, 2H, J = 2.4 Hz), 2.16 (td, 4H, J = 7.2, 2.4 Hz); 13C NMR (CDCI3) 6 18.38, 28.47, 28.75, 29.10, 29.48, 29.57, 29.59, 68.01, 84.80; IR (neat) 3279, 109 2924, 2851, 2105, 1462 cm“. Anal calcd for CnHZB: C 87.86, H 12.14. Found: C 87.61, H 12.40. Preparation of E- Monovinyliodide l7la-d I _ I _ __ I Ha: 904,, //"’\n\\ n 188a-d E4 71 a-d 189a-d General Procedure 11138 To a suspension of CIZZGC2 (1.0 equiv) in methylene chloride was added Me3Al (1.0 eq) under an argon atmosphere at 0°C. A lemon-yellow solution was obtained. After 10 minutes, diyne 188 (1.0 equiv) in CHzCl2 was added to the above mixture and the lemon-yellow solution turned orange. After the mixture was stirred at room temperature for 12 hours, it was quenched by a solution of 12 (1.2—5.0 eq) in THF at 0 °C. The reaction was warmed to room temperature again and stirred for 30 minutes. Then it was slowly poured into ice water. The sediment was removed by filtration through Celite. After thorough extraction with ether, the combined organic layer was washed with NaQSZO3 and brine, dried over MgSO4, and concentrated. Flash chromatography on silica gel column (eluant: hexanes) provided E-171a-d as colorless liquids. Statistical amounts of diiodides 189a-d were obtained as the major by-products and can be easily separated from the monoiodides E-171a-d. 110 Preparation of E-l-Iodo-2-methyldec-1-en-9-yne E-17la (n = 6) Trimethyl aluminum (2.0 M solution in hexanes) (1.60 mL, 3.20 mmol) was added to zirconocene dichloride (0.93 g, 3.13 mmol) in methylene chloride (10 mL) and reacted with 188a (0.42 g, 3.13 mmol) in methylene chloride (7 mL) following the general procedure 111. 12 (4.0 g, 15.7 mmol) was dissolved in THF (5 mL) and used to quench the reaction. The vinyl iodide E-l71a was obtained as a colorless liquid (0.30 g, 1.1 mmol, 35%) as a single diastereomer. Compound E-171a: Rr = 0.35 (hexanes); 1H NMR (CDCI3) 6 1.22-1.54 (m, 8H), 1.80 (s, 3H), 1.92 (t, 1H, J = 2.7 Hz), 2.15-2.25 (m, 4H), 5.84 (s, 1H); 13C NMR (CDCI3) 6 18.00, 23.45, 27.17, 27.97, 28.08, 28.11, 39.13, 67.84, 74.11, 84.23, 147.78; IR (neat) 3303, 2934, 2857, 2100 cm". Anal calcd for CHHHI: C 47.84, H 6.20. Found: C 48.37, H 6.29. Preparation of E-l-Iodo-Z-methyldodec-l-en-1l-yne E-17lb (n = 8) Zirconocene dichloride (1.29 g, 4.32 mmol) was reacted with trimethyl aluminum (2.0 M solution in hexanes) (2.20 mL, 4.40 mmol) in methylene chloride (10 mL) and 188b (0.70 g, 4.32 mmol) in methylene chloride (7 mL) following the general procedure 111. 12 (5.49 g, 21.6 mmol) was dissolved in THF (5 mL) and used to quench the reaction. Compound E-l7lb was obtained as a colorless liquid (0.50 g, 1.7 mmol, 39%) and as a single diastereomer. Compound l89b (0.3 g, 0.7 mmol, 16%) was isolated as the by- product. Compound E-17lb: R, = 0.25 (hexanes); 1H NMR(CDC13) 6 1.26-1.29 (m, 6H), 1.35—1.42 (m, 4H), 1.47-1.52 (m, 2H), 1.80 (s, 3H), 1.91 (t, 1H, J = 2.7 Hz), 2.17 (m, 4H), 5.83 (s, 1H); 13C NMR (CDC13) 6 18.36, 23.79, 27.63, 28.41, 28.66, 28.93, 28.95, 111 29.19, 39.53, 68.07, 74.30, 84.68, 148.21; IR (neat) 3304, 2930, 2855, 2] 18, 1464, 1271, 1143 cm“. Preparation of E-l-Iodo-Z-methyltetradec-1-en-l3-yne E-171c (n = 10) Zirconocene dichloride (0.6 g, 2.05 mmol) was reacted with trimethyl aluminum (0.15 g, 0.2 mL, 2.05 mmol) in methylene chloride (5 mL) and 188c (0.39 g, 2.05 mmol) in methylene chloride (3 mL) following the general procedure 111. 12 (0.64 g, 2.52 mmol) was dissolved in THF (3 mL) and used to quench the reaction. Compound E-l7lc was obtained as a colorless oil (0.29 g, 0.9 mmol, 42%) after purification and was a single diastereomer. Compound 189c (0.07 g, 28%) was obtained as the by-product. Compound E-l7lc: R, = 0.40 (hexanes); 1H NMR (CDCl3) 6 1.25-1.40 (m, 14H), 1.40-1.48 (m, 2H), 1.80 (s, 3H), 1.92 (t, 1H, J = 1.8 Hz), 2.10-2.19 (m, 4H), 5.82 (s, 1H); 13C NMR (CDCI3) 6 18.05, 23.46, 27.33, 28.12, 28.38, 28.67, 28.73, 29.00, 29.11, 39.23, 67.71, 73.99, 84.45, 147.98 (1 sp3 carbon not located); IR (neat) 3310, 2928, 2855, 2118 cm"; MS (El) m/z (% rel intensity) 332 M+ (0.04), 233 (0.02), 220 (0.07), 205 (0.45), 182 (11), 55 (100). Anal calcd for C,5H251: C 54.22, H 7.58. Found: C 54.31, H 7.74. Preparation of E-l-Iodo-Z-methylheptadec-1-en-l6-yne E-171d (n = 13) Zirconocene dichloride (1.0 g, 3.42 mmol) was reacted with trimethyl aluminum (2.0 M solution in hexanes) (1.7 mL, 3.40 mmol) in methylene chloride (10 mL) and 188d (0.79 g, 3.40 mmol) in methylene chloride (7 mL) following the general procedure 111. 12 (2.5 g, 9.84 mmol) was dissolved in THF (5 mL) and used to quench the reaction. After purification compound E-17 1d (0.55 g, 1.5 mmol, 43%) was obtained as a colorless 112 liquid and as a single diastereomer. Compound 189d was observed to form as the by- product. R, = 0.45 (hexanes); 1H NMR (CDC13) 6 1.20-1.42 (m, 18 H), 1.50 (m, 4H), 1.80 (s, 3H), 1.92 (t, 1H, J = 2.7 Hz), 2.17 (m, 4H), 5.83 (s, 1H); 13C NMR (CDCI3) 6 18.39, 23.81, 27.69, 28.49, 28.76, 29.03, 29.10, 29.19, 29.37, 29.49, 29.52, 29.58, 29.60, 39.58, 68.00, 74.29, 84.80, 148.33. Anal calcd for C,8H3,I: C 57.75, H 8.35. Found: C 57.46, H 8.25. Preparation of Fischer Carbene Complexes E-153a-d OMe (n: 1 z: n E-171a-d 5153“ General Procedure IV: To a flame-dried round bottom flask charged with argon and filled with a THF solution (0.03 M) of vinyl iodide E-l71a-d. PhLi (1.0 equiv) was added at ——78 °C and the mixture was stirred at —78 °C for 1.5 hours. Then t-BuLi (1.7 M in pentane) (2.0 equiv) was added. After 10 minutes, Cr(CO),, (1.0 eq) was added to the dianion as a powder and a yellow-brown solution was obtained. The solution was raised to room temperature and stirred for 2 hours before the solvent was removed on rotorary evaporator and the residue was taken up in a two-phase solvent system of CHzCl2 and H20 (1:1). Me30*BF,' (1.0-2.0 eq) was added to the above mixture as a solid at room temperature and the yellow suspension turned red after it was stirred for 30 minutes. The reaction was quenched with saturated NaHCO3, extracted with ether, and the ether layers were combined, washed with brine, and dried with MgSO4. Concentration followed by flash column chromatography on a silica gel column with 113 5% ethyl acetate in hexanes as the eluant yielded the carbene complexes E-153a-d as red oils. Preparation of Carbene Complex E- 153a (n = 6) Compound 171a (0.40 g, 1.77 mmol) was reacted with PhLi (2.0 M in di-n-butyl ether solution) (0.90 mL, 1.80 mmol), t-butyllithum (2.08 mL, 3.54 mmol), Cr(CO)6 (0.40 g, 1.82 mmol) and Me3OBF4 (0.58 g, 3.92 mmol) following the general procedure IV. After purification, complex E-153a was obtained as a red oil (0.26 g, 0.3 mmol, 38%). R, = 0.06 (hexanes); 1H NMR (CDCl;,) 6 1.30-1.35 (m, 2H), 1.38-1.43 (m, 2H), 1.46-1.53 (m, 4H), 1.82 (s, 3H), 1.93 (t, 1H, J = 2.5 Hz), 2.10 (t, 2H, J = 7.5 Hz), 2.16 (td, 2H, J = 7.5, 2.5 Hz), 4.70 (s, 3H), 7.22 (s, 1H); 13C NMR (CDCl3) 6 18.34, 20.54, 27.62, 28.29, 28.50, 28.72, 41.08, 66.19, 68.19, 84.56, 141.07, 143.11, 216.83, 223.96, 339.59; IR (neat) 3312, 2934, 2859, 2058, 1925 cm"; MS (EI) m/z (% rel intensity) 384 M” (1.6), 328 (6), 272 (8), 244 (32), 210 (38), 91 (30), 52 (96); HRMS (FAB) calcd for C,,,H2,,CrO6 m/z 384.0665 (M‘), measd 384.0663. Preparation of Carbene Complex E-153b (n = 8) Compound 171b (0.25 g, 0.96 mmol) was reacted with PhLi (0.97 M in diethyl ether solution after titration) (1.0 mL, 0.97 mmol), t-butyllithum (1.93 mmol), Cr(CO),S (0.21 g, 0.96 mmol) and Me30BF, (0.29 g, 1.93 mmol) following the general procedure IV. After purification complex E-153b (52.7 mg, 0.1 mmol, 13%) was obtained as a red oil. R, = 0.09 (hexanes); ‘H NMR (CDC13) 6 1.29 (m, 8H), 1.52 (m, 4H), 1.82 (s, 3H), 1.91 (t, 1H, J = 2.7 Hz), 2.08 (t, 2H, J = 7.8 Hz), 2.16 (td, 2H, J = 6.9, 2.4 Hz), 4.70 (s, 114 3H), 7.23 (s, 1H); 13C NMR (CDCl,) 6 18.36, 20.58, 27.76, 28.42, 28.66, 28.94, 29.19, 29.28, 41.19, 66.17, 68.06, 84.72, 141.04, 143.40, 216.83, 223.97, 339.50; IR (neat) 3312 (w), 2930, 2857, 2058 (s), 1923 (vs), 1583 cm"; MS (EI) m/z (% rel intensity) 412 M+ (0.83), 356 (0.46), 300 (2), 272 (14), 255 (22), 151 (30), 52 (100); HRMS (FAB) calcd for C2,,H24CrO6 m/z 412.0978 (M*), measd 412.0980. Preparation of Carbene Complex E-153c (n = 10) Compound l71c (0.78 g, 2.35 mmol) was reacted with PhLi (1.7 M in di-n-butyl ether solution) (1.40 mL, 2.38 mmol), t-butyllithum (2.80 mL, 4.76 mmol), Cr(CO),5 (0.52 g, 2.36 mmol) and Me3OBF4 (0.34 g, 2.30 mmol) following the general procedure IV. After purification complex E-153c was obtained as a red oil (0.50 g, 1.2 mmol, 49%). R, = 0.11 (hexanes); 1H NMR (CDCl3) 6 1.10-1.50 (m, 16H), 1.84 (s, 3H), 1.92 (t, 1H, J = 2.5 Hz), 2.10 (t, 2H, J = 7.7 Hz), 2.19 (td, 2H, J = 7.2, 2.7 Hz), 4.71 (s, 3H), 7.28 (s, 1H); 13C NMR (CDCI3) 6 18.63, 20.83, 28.04, 28.71, 28.97, 29.30, 29.49, 29.67, 41.54, 66.41, 68.26, 85.02, 141.28, 143.47, 217.09, 223.23, 339.69 (2 sp3 carbon not located); IR (neat) 3312 (w), 2930, 2857, 2058 (s), 1925 (vs), 1582, 1456, 1248, 982 cm"; MS (EI) m/z (% rel intensity) 440 M‘“ (0.29), 370 (0.20), 328 (1), 300(7), 276 (26), 220 (52), 108 (60), 80 (63); HRMS (FAB) calcd for c,,H,,Cro, m/z 440.1292 (M), measd 440.1290. Preparation of Carbene Complex E-153d (n = 13) Compound 171d (0.15 g, 0.46 mmol) was reacted with PhLi (1.5 M in di-n-butyl ether solution) (0.24 mL, 0.36 mmol), t-butyllithum (0.92 mmol), Cr(CO),5 (101.2 mg, 0.46 mmol) and Me3OBF4 (136 mg, 0.92 mmol) following the general procedure IV. 115 After purification, complex E-153d was obtained as a red oil (77.5 mg, 0.2 mmol, 39%). R, = 0.15 (hexanes); 1H NMR (CDCI3) 6 1.24—1.36 (m, 18H), 1.51 (m, 4H), 1.82 (s, 3H), 1.92 (t, 1H, J = 2.4 Hz), 2.08 (t, 2H, J = 6.3 Hz), 2.16 (td, 2H, J = 7.2, 2.7 Hz), 4.70 (s, 3H), 7.23 (s, 1H); 13C NMR (CDC13) 6 18.38, 20.59, 27.81, 28.48, 28.75, 29.09, 29.28, 29.44, 29.48, 29.49, 29.58, 29.69, 41.22, 66.16, 67.99, 84.81, 141.02, 143.53, 216.84, 223.99, 339.55 (one aliphatic carbon not located); IR (neat) 3314 (w), 2928, 2855, 2058 (s), 1933 (vs), 1583, 1456, 1250, 982 cm"; MS (EI) m/z (% rel intensity) 482 M+ (0.11), 398 (0.08), 370 (0.70), 342 (4), 318 (19), 304 (25), 220 (26), 151 (23), 108 (57), 52 (100); HRMS calcd for C25H34CrO6 m/z 482.1761 (M*), measd 482.1763. Preparation of 2-Dodecyn-1-ol 164”5 MBr EflOH 163 W—flOH 162 164 To a suspension of LiNH2 (5.02 g, 0.22 mol) in liquid NH3 (250 mL), was added dropwise 5.8 mL 2-propyn-1-ol 162 (5.6 g, 0.10 mol) at —78 °C. After stirring for 1 hour, a solution of 1-bromononane 163 (18.6 g, 0.09 mol) in diethyl ether (23 mL) was added at —33 °C through a dropping funnel. The mixture was stirred under reflux at — 33 °C for 2 hours. The reaction mixture was left to stand overnight at room temperature for the NH3 to evaporate. The residue was taken up in ice water (500 mL) and extracted with diethyl ether (3 x 250 mL). The combined ether solution was washed with brine (500 mL), dried over MgSO, and concentrated. Flash chromatography (eluant: 10% ethylacetate in hexanes) on silica gel column provided 164 as white solid (16.1 g, 0.9 mmol, 98.6%). R, = 0.41 (ethyl acetate: Hexanes = 1: 5); 1H NMR (CDCl;,) 6 0.86 (t, 3H, J = 6.3 Hz), 1.25 116 (s, 12H), 1.44-1.51 (m, 2H), 2.16-2.20 (m, 2H), 4.23 (t, 2H, J = 6.0 Hz) (OH proton not located); 13C NMR (CDC13) 6 14.09, 18.72, 22.65, 28.59, 28.86, 29.13, 29.27, 29.47, 31.87, 51.46, 78.22, 86.72; IR (neat) 3345 (broad), 2926, 2857, 2300, 2250 cm". These spectral data are identical with those reported for this compound.35 Preparation of ll-Dodecyn-l-ol 165“"5 *6 : \OH = : (CH2)10'OH 164 165 KH (mineral oil dispersion, 26.3 mL, 30 wt%) was transferred to a flask (flame- dried under argon). Dry ether (20 mL) was added to wash the KH, which was then allowed to settle before the ether was drawn off with a syringe. Residual ether was removed in vacuo. The system was then fluxed with argon. 1,3-diaminopropane (85 mL) was transferred to the flask and foaming was observed. After stirring for 1.5 hours at room temperature, a yellow-green solution resulted. Dec-2-yn-ol 164 (4.5 g, 24.3 mmol) in 1,3-diaminopropane (12 mL) was added dropwise via syringe to the reaction mixture at 0 °C. A precipitate was observed to form and the reaction mixture was left to stir at room temperature for 3 to 5 hours. The mixture was poured into iced-water and the aqueous layer was extracted with diethyl ether (20 mL x 3). The combined ether layer was washed with HCl (3N) until neutral and then sequentially with NaHCO3 (30 mL) and brine (30 mL). It was dried with MgSO4 and concentrated. Flash chromatography on silica gel column (5% ethyl acetate solution in hexanes as the eluant) provided compound 165 as a white solid (3.4 g, 18.7 mmol, 77%). R, = 0.20 (1: 9 ethyl acetate: hexanes); 1H NMR (CDCl3) 6 1.26-1.37 (m, 12H), 1.46-1.54 (m, 4H), 1.90 (t, 1H, J = 2.5 Hz), 2.14 (dt, 2H, J, = 7.5 Hz, J, = 2.5 Hz), 3.60 (s, 2H) (OH proton not located); 13C NMR (CDC13) 6 117 18.35, 25.69, 28.44, 28.70, 29.04, 29.36, 29.37, 29.49, 32.75, 62.99, 68.02, 84.75; IR (neat) 3312 (broad), 2930, 2857, 2118 (weak), 1466, 1057 cm". These spectral data are identical with those reported for this compound.57 Preparation of 1l-Trimethylsilylundec-l0-yn-l-ol 166 and Its Derivatives Toluene- p-sulphonate 167 and Iodide 1685‘ Z—(CH2)1o-OH TMS I (CH2)100H _. 165 166 TMS : (CH2)1o-OTs TMS : (CH2)1o-l 167 168 To a solution of 10-dodecyne-1-ol 165 (1.0 g, 5.5 mmol) in THF (20 mL) at —78 °C was added n-BuLi (2.5 M solution in hexane) (4.8 mL, 12.0 mmol) under inert atmosphere. The reaction mixture turned pasty. After 30 minute, the reaction was warmed to 0 °C for one hour and then treated with Me3SiCl (1.52 mL, 12.0 mmol). The reaction was further warmed to 25 °C and the pasty solution turned clear. After stirring for 2.5 hours, the reaction was quenched with H20 (30 mL) and extracted with ether (20 mL x 3). The combined ether layer was concentrated and treated with 2N HCI (20.0 mL) and stirred at room temperature for 5 minutes. Then the organic layer was separated and washed sequentially with saturated NaHCO, (50 mL) and brine (50 mL), dried over MgSO4 and concentrated. Crude 166 was obtained as a colorless oil and used directly in the next step. R, = 0.30 (1: 9 EtOAc: Hexanes); 1H NMR (CDCl3) 6 0.12 (s, 9H), 1.26 (br, s, 12H), 1.44-1.54 (m, 4H), 2.18 (t, 2H, J = 7.2 Hz), 3.62 (t, 2H, J = 6.5 Hz) (OH proton not located); 13C NMR (CDCl,) 6 0.166, 19.83, 25.72, 28.61, 28.76, 29.04, 29.39, 29.50, 32.80, 63.07, 84.23, 107.75 (1 sp3 carbon not located); IR (neat) 3324, 2930, 2857, 2176, 118 1466, 1250, 1055 cm“; MS (EI) m/z (% rel intensity) 239 M"-15 (0.04), 221 (0.02), 163 (4), 75 (100). Crude alcohol 166 obtained as described above was redissolved in THF (10 mL) and treated with n-BuLi (2.5 M solution in hexane) (2.2 mL, 5.5 mmol). After the mixture was stirred at —78 °C for 1 hour, a solution of p-toluene sulfonyl chloride (p- TsCl) (1.05 g, 5.5 mmol) in THF (2 mL) was added. The chunky mixture turned clear upon the addition and stirring. The stirring was continued at room temperature for 5 hours before the reaction was quenched with water (10 mL). Diethyl ether (10 mL x3) was added to extract the product from the water layer. The combined organic layer was washed sequentially with saturated NaHCO3 (20 mL) and brine (20 mL), and then dried over MgSO4. After concentration and flash chromatography on a silica gel column (eluant: 10% ethyl acetate in hexanes) compound 167 was obtained as a white solid (2.06 g, 5.2 mmol, 92% from compound 165). R, = 0.36 (l: 9 ethyl acetate: Hexanes); 1H NMR (CDCI3) 6 0.10 (s, 9H), 1.16-1.37 (m, 12H), 1.42-1.50 (m, 2H), 1.54—1.64 (m, 2H), 2.18 (t, 2H, J = 11.5 Hz), 2.42 (s, 3H), 3.98 (t, 2H, J = 11.0 Hz), 7.30 (d, 2H, J = 13.0 Hz), 7.75 (d, 2H, J = 12.5 Hz); IR (neat) 2930, 2857, 2174, 1365, 1170, 841 cm". The tosylate 167 (2.06 g, 5.0 mmol) was treated with Nal (1.5 g, 10.0 mmol) in acetone (10 mL) at refluxing temperature for 3 hours. The reaction mixture was poured into water (25 mL) and extracted with pentane (4x10 mL). The combined pentane layer was washed sequentially with saturated NaHCO3 (40 mL) and brine (40 mL) and then dried with MgSO4. Concentration followed by flash chromatography yielded 168 as a light yellow liquid (1.50 g, 4.1 mmol, 81%). R, = 0.4 (1: 9 CHZCIZ: Hexanes); 'H NMR (CDCl3) 6 0.12 (s, 9H), 1.26 (s, 10H), 1.32-1.40 (br, 2H) 1.44-1.50 (m, 2H), 1.71-1.82 119 (m, 2H), 2.16 (t, 2H, J = 7.2 Hz), 3.15 (t, 2H, J = 7.2 Hz); 13C NMR (CDC13) 6 0.14, 7.27, 19.79, 28.46, 28.55, 28.70, 28.96, 29.28, 29.32, 30.45, 33.50, 84.20, 107.68; IR (neat) 2928, 2855, 2176, 1464, 1248 cm". MS (EI) m/z (% rel intensity) 364 M+ (0.03), 345 (0.5), 349 (2.6), 290 (0.85), 221 (4), 185 (78), 73 (100). These spectral data are identical with those reported for this compound.59 Preparation of Model Z- Vinyl iodide Z- 176 CH3-(CH2)9-l ___. CHaiCH2)9Mgi CHa-(CH2)9-Cu MgBrl 172 173 174 —. . '/-_:<-’— -—__. IF:<_'_ + )9— _ Cu ( 9 l 9 l 9 175 Z-176 177 'Cu' = Cu. MgBrl A 25 mL round bottom flask was flame dried and charged with argon. Then 0.25 g (10.4 mmol) Mg turning and a crystal of iodine were transferred to the flask followed by the addition of diethyl ether (5 mL). Several drops of 1-iododecane 172 was added to the mixture and refluxed until the color of 12 faded. Then all the remaining iodide 172 (1.4 g, 5.2 mmol) was added to the flask and the reflux was continued for 3 hours. The resulting Grignard reagent was transferred to a well-stirred suspension of CuBr 'MeZS (1.025 g, 5.0 mmol) in 10 m1. diethyl ether at —30 °C under an argon atmosphere. A yellow-brown reaction mixture containing complex 174 was obtained. Propyne was liquidified in a trap cooled by a dry ice bath and then diluted with cold diethyl ether (0.2 ml. propyne in 5 mL 3,0). This solution was then transferred via cannula to the above yellow-brown solution of 174. The temperature was raised slowly to —20 °C and the reaction was stirred for 3 hours. The dark green alkenyl copper complex 175 was cooled to —50 °C and a solution of 12 (1.27 g, 5.0 mmol) in THF (4 mL) was added dropwise. 120 The temperature was slowly raised to —30 °C and the reaction was stirred for an additional 30 minutes before it was quenched with saturated NH4Cl (15 mL) and extracted with pentane (3x15 mL). The organic layer was sequentially washed with NaZSZO3 (30 mL), NH4OH (30 mL), NH4C1 (30 mL) and then dried with MgSO4. After concentration, the residue was purified by distillation under reduced pressure (b.p. 140 °C/0.5 Torr) to provide the title compound Z-176 as a colorless liquid (0.48 g, 1.5 mmol, 30%). 1H NMR (CDCl,) 6 0.86 (t, 3H, J = 7.5 Hz), 1.20—1.50 (m, 16H), 1.85 (d, 3H, J = 1.4 Hz), 2.15 (t, 2H, J = 7.5 Hz), 5.79 (q, 1H, J = 1.4 Hz); 13C NMR (CDC13) 6 14.09, 22.67, 23.25, 26.93, 28.53, 29.27, 29.48, 29.56, 29.64, 31.88, 38.62, 73.77, 147.77; MS (EI) m/z (% rel intensity) 309 (6), 308 M“ (38), 182 (61), 181 (23), 168 (14), 125 (13). 111 (50), 97 (82); GC analysis (SE-54, 30 m x 0.55 mm, 100-220 °C, 10 °C/min) retention time 18.96 min. Compound 177 (0.18 g, 0.5 mmol, 20%) was left as solid residue from the distillation. 1H NMR (CDC13) 6 0.85 (t, 6H), 1.20-1.40 (br, s, 32H), 1.75 (s, 6H), 2.10 (t, 4H, J = 7.4 Hz), 5.95 (s, 2H); 13C NMR (CDC13) 6 14.12, 22.69, 24.15, 28.20, 29.30, 29.36, 29.58, 29.66, 29.70, 31.92, 32.04, 121.05, 136.61; IR (neat) 2955, 2923, 2853, 1717, 1470 cm"; MS (EI) m/z (% rel intensity) 362 M” (100), 235 (10), 109 (30), 95 (89). 81 (48); GC (SE-54, 30 m x 0.55 mm, 100-220 °C, 10 °C/min) retention time 22.90 min. Preparation of E-176 121 To a suspension of 0,2GC2 (1.46 g, 5.0 mmol) in 1,2-dichloroethane (10 mL) was added AlMe3 (2.0 M in hexane) (5.0 mL, 10.0 mmol) at room temperature. A lemon- yellow solution was obtained. To this solution was added I-dodecyne (0.80 g, 4.8 mmol). After stirring for 12 hours at room temperature, the reaction mixture was cooled to 0 °C and a solution of I2 (1.27 g, 5.0 mmol) in THF (3 mL) was added..Then the reaction was warmed to room temperature, stirred for 1 hour and quenched by the dropwise addtion of ice water (10 mL). The water layer was extracted with ether (15 mL x 3). The ether layers were combined and washed with Na28203 (40 mL), brine (40 mL), dried over MgSO4 and concentrated. Chromatography with hexanes as solvent provided E-l76 as a yellow liquid (1.2 g, 3.8 mmol, 80 %). R, = 0.68 (hexanes); 1H NMR (CDC13) 6 0.86 (t, 3H, J = 7.4 Hz), 1.25 (m, 14H), 1.38 (m, 2H), 1.8 (t, 3H, J = 1.1 Hz), 2.15 (t, 2H, J = 7.4 Hz), 5.83 (m, 1H, J = 1.1 Hz); 13C NMR (CDCI3) 6 14.11, 22.67, 23.79, 27.69, 29.03, 29.31, 29.38, 29.54, 29.57, 31.88, 39.57, 74.30, 148.35; GC (SE-54, 30 m x 0.55 mm, 100-220 °C) retention time 15.98 min. Preparation of Z- Vinyl Trimethylsilyl Compound 1813‘ TMS : TMS é 0% ——.- — 0 TMS TMS 181 180c To a dark red suspension of ClzTiCp2 (1.31 g, 5.10 mmol) in 20 mL CHzCl2 was added AlMe3 (0.5 mL, 5.10 mmol) at 0 °C under an argon atmosphere. A dark orange solution was formed immediately. After stirring 10 minutes at room temperature, the solution was cooled again to 0 °C and a solution of compound 180c (1.70 g, 5.08 mmol) in CH2C12 (5 mL) was added dropwise. The solution was left to stir at room temperature 122 for 8 hours before it was poured onto an ice cold aqueous NaHCO3 solution (20 mL). The aqueous layer was separated and extracted with diethyl ether (15 mL x 3). The organic layers were combined and washed with brine (40 mL) and dried over MgSO,,. Flash chromatography on a silica gel column using hexanes as the eluant yielded compound 181 as a colorless oil (0.64 g, 1.8 mmol, 36.0%). The ratio of Z.'E could not be determined on this compound but after conversion to 171 was found to be 13:1. R, = 0.27 (hexanes); 1H NMR (CDC13) 6 0.06 (s, 9H), 0.12 (s, 9H), 1.20-1.52 (m, 16H), 1.79 (s, 3H), 2.19 (t, 4H, J = 7.4 Hz), 5.14 (s, 1H). Preparation of Z-1-Iodo-2-methyltetradec-l-en-13-yne Z-171c TMS\__—8B—E~TMS _’ \fws _. I\____{1‘——0: + = 1 5 + 15 9 Q OMe OMe 1553 CH2)9 (CH2)9 1568 1568' Alkenyl complex 1553 (60.0 mg, 0.086 mmol) was dissolved in THF (17 m1.) and put in a Schlenk flask that was equipped with a threaded Teflon hi gh-vacuum stopcock and deoxygenated by the freeze-pump-thaw method (3 circles) and backfilled with argon at room temperature. The stopcock was sealed and the flask heated to the proper temperature and stirred until the reaction was complete (indicated by the fading of the red color). The solvent was removed and the residue was taken up in EtzO/CHZCI2 (5 mL/ SmL) and the resulting solution was stirred in air overnight. After the air oxidation, the solvent was removed again and the residue was taken up in pure ether (10 mL). The insoluble material was removed by filtration through a pipette-sized silica gel column (2 x 10 cm) using ether as the eluant (10 mL). Concentration provided a crude mixture, which was further purified by flash column chromatography on silica gel (eluant: CH2C12: ether: hexanes = l: 1: 30). Compound 1563 and 1563’ were obtained as a white solid and as an inseparable mixture (R, = 0.038 in 1:1:10 EtzO: CHZCIZ: Hexanes). The diastereomeric ratio of 1563 and 1563’ was determined by 1H NMR on the crude mixture and based on the integral of the vinyl proton of C (15): 6 6.5 ppm (1563) and 5.6 ppm (1563’). Cyclization at 100 °C was stopped after 19 hours providing 24.0 mg (0.045 mmol, 52% combined yield) of a mixture 156a and 1563’. Diastereomeric ratio of 1563: 1563’ = 144 1.2: 1. Cyclization at 55 °C was stopped after 24 hours providing 30.0 mg (0.056 mmol, 55% combined yield) of the mixture 156a and 1563’. Diastereomeric ratio 1563: 1563’ = l: 1.1. The following data were obtained from a mixture of compounds 1563 and 1563’. 1H NMR (CDCl,) (inseparable peaks): 6 0.50-1.80 (m, 4H), 0.98 (s, 3H), 1.08 (s, 3H), 2.08-2.18 (m, 2H), 7.12-7.28 (m, 30H), 7.44-7.54 (m, 30H); (separated peaks): Compound 1563 6 3.49 (s, 3H), 3.98-4.04 (m, 1H), 4.69 (d, 1H, J = 5.4Hz), 6.50 (d, 1H, J = 3.3 Hz); Compound 1563’ 6 3.48 (s, 3H), 3.73 (dd, 1H, J =11.0, 3.0 Hz), 4.76 (d, 1H, J = 3.0Hz), 5.64 (d, 1H, J = 3.0 Hz); IR (neat) 2930, 2850, 1675, 1648, 1599, 1449 cm"; MS (EI) m/z (% rel intensity) 291 (1), 259 (2), 244 (15), 243 (CPh3) (100), 228 (4), 183 (6), 165 (55), 105 (38). Thermolysis of Fischer Carbene Complex 155b O OTips O OTips OMe (0%ch 15 + 15 OMe 9 § OMB 0112111 (CH2)9 155” 156b 156b' Alkenyl complex 155b was dissolved in THF to make a 0.005 M solution which was introduced to a Schlenk flask equipped with a threaded Teflon high-vaccum stopcock. The solution was deoxygenated by the freeze-pump-thaw method (3 circles) and backfilled with argon at room temperature. The stopcock was closed and the flask heated at the proper temperature for 16 hours. After the reaction was completed (indicated by the fading of the red color), the solvent was removed and the residue was 145 taken up in EtzO/CHZCI2 (1: 1) and the resulting solution was stirred in air for 12 hours. After the air oxidation, the solvent was removed again and the residue was taken up in pure ether. The insoluble material was removed by filtration through a pipette-sized silica gel column (2 x 10 cm) using ether as the eluant. Concentration provided the crude product mixture which was further purified by flash column chromatography on silica gel (eluant: CHzClz: ether: hexanes = 1: 1: 30). The diastereomeric ratio of 156b/156b’ was determined by 1H NMR of the crude mixture and based on the integral of vinyl proton on C (15): 6 6.97 ppm (156b) and 6.54 ppm (156b’). Careful chromatographic separation on silica gel gave a pure sample of 156b and an enriched sample of 156b’. Thermolysis of Fischer carbene complex 155b (79.5 mg, 0.13 mmol) at 100 °C for 16 hours yielded 156b + 156b’ (27.1 mg, 0.06 mmol, 47%) after isolation together from the column. Diastereomeric ratio 156b: 156b’ = 2.0: 1. Thermolysis of Fischer carbene complex 155b (66.0 mg, 0.11 mmol) at 55 °C for 16 hours yield 156b + 156b’ (21.8 mg, 0.048 mmol, 45%) after isolation together from the column. Diastereomeric ratio 156b: 156b’ = 3.0: 1. Compound 156b was obtained as a white solid: R, = 0.65 (1:1:10 EtzO: CHzClzz Hexanes); 1H NMR (CDC13) 6 0.79-0.86 (m, 1H), 1.00-1.03 (m, 21H), 1.03-1.23 (m, 12H), 1.14 (s, 3H), 1.33-1.55 (m, 1H), 1.55-1.68 (m, 4H), 3.62 (s, 3H), 4.85 (d, 1H, J = 3.3 Hz), 5.05-5.07 (m, 1H), 6.96-6.97 (m, 1H); 13C NMR (CDC13) 6 12.18, 18.05, 21.71, 21.94, 23.97, 25.80, 26.17, 26.42, 26.54, 29.71, 33.04, 43.83, 50.29, 54.72, 67.93, 110.74, 138.21, 140.35, 150.06, 205.40; IR (neat) 2936, 2865, 1645 cm"; MS (EI) m/z (% rel intensity) 448 M” (0.32), 405 (46), 363 (26), 321 (5), 279 (52), 239 (21), 209 (31), 195 (22), 75 (66), 43 (100). (X-ray crystallography data is available in the Appendics). 146 Compound 156b’ was obtained as a white solid. The spectral data were obtained on a sample of 156b’ contaminated by a small amount of 156b (ratio after purification is 3:1): R, = 0.5 (1:1:10 EtzO: CHZCIZ: Hexanes); 1H NMR (CDC13) 6 0.71—0.92 (m, 1H), 0.96-1.01 (m, 21H), 1.01-1.28 (m, 10H), 1.12 (s, 3H), 1.51-1.68 (m, 5H), 1.80-1.84 (m, 1H), 2.26-2.36 (m, 1H), 3.61 (s, 3H), 4.07-4.10 (m, 1H), 5.01 (d, 1H, J = 1.8 Hz), 6.54 (d, 1H, J = 1.8 Hz); 13C NMR (CDCl,) 6 12.52, 18.36, 22.46, 22.66, 23.03, 24.57, 26.13, 26.79, 27.05, 27.53, 34.48, 43.15, 51.31, 53.67, 68.16, 112.29, 138.46, 140.37, 149.26, 203.42; IR (neat) 2934, 2865, 1649 cm"; MS (EI) m/z (% rel intensity) 448 M" (0.18), 405 (95), 363 (80), 279 (100), 239 (29), 208 (59), 195 (39), 95 (38), 76 (66); HRMS (FAB) calcd for C27H49O3Si m/z 449.3451 (MH*), measd 449.3454._ Thermolysis of Fischer Carbene Complex 155c O OCH3 O QCHa OMe (OC)5Cr _ OCH3 ___, 15 + 13 (CH2)9 (CH2)9 155c 156c 1560' Alkenyl complex 155c (50.0 mg, 0.106 mmol) was dissolved in THF (20 mL) and placed in a Schlenk flask equipped with a threaded Teflon high vacuum stopcock. The reaction mixture was deoxygenated by freeze-pump-thaw method (3 circles). The stopcock was closed and the flask heated to the proper temperature and stirred for 16 hours. The solvent was removed and the residue was taken up in EtQO/CHZCI2 (5 mL/ 5 mL) and stirred in air for 12 hours. After the air oxidation, the solvent was removed again and the residue was taken up in pure ether (10 mL). The insoluble material was removed 147 by filtration through a pipette-sized silica gel column (2 x 10 cm). Concentration provided a mixture of the crude products. The diastereomeric ratio of 156c/156c’ was determined by 1H N MR of the crude mixture and based on the integral of the vinyl proton at C (15): 6 6.67 ppm (156c) and 5.06 ppm (156c’). Compound 156c and 156c’ were isolated by another flash column chromatography on silica gel (eluant: CHzClz: ether: hexanes = 1: 1: 30) and obtained as colorless oils. The stereochemical assignment was made based on the known X-ray structure of 156b. The isomer with higher R, value was assigned the same stereochemistry as 156b. Thermolysis at 100 °C yielded products 156c + 156c’ (22.1 mg, 0.072 mmol, 69%) with a diastereomeric ratio 156c: 156c’ = 1.6: 1; Thermolysis at 55 °C yield 156c + 156c’ (21.8 mg, 0.071 mmol, 66%) after isolation together from the column. Diastereomeric ratio 156c: 156c’ = 2.1: 1. Compound 156c: R, = 0.29 (1:1:10 Et,O: CHZCIZ: Hexanes); 1H NMR (CDCl;,) 6 0.61-0.90 (m, 1H), 0.98-1.34 (m, 12H), 1.18 (s, 3H), 1.36-1.48 (m, 1H), 1.58-1.74 (m, 4H), 3.27 (s, 3H), 3.62 (s, 3H), 4.45-4.47 (m, 1H), 5.00 (d, 1H, J = 3.3 Hz), 6.81 (dd, 1H, J = 3.3, 1.2 Hz); 13C NMR (CDC13) 6 18.44, 21.83, 21.97, 24.00, 25.60, 26.21, 26.32, 26.40, 30.40, 35.48, 43.77, 50.31, 56.78, 76.24, 111.07, 137.10, 137.87, 149.92, 205.90; IR (neat) 2930, 2840, 1645 cm"; MS (EI) m/z (% rel intensity) 306 M” (2), 274 (58), 259 (17), 247 (10), 217 (6), 175 (43), 151 (48), 91 (45), 41 (100); HRMS (FAB) calcd for C,,,H3,O3 m/z 307.2273, measd 307.2274. Compound 156c’: R, = 0.063 (1:1:10 EtzO: CHzClz: Hexanes); 1H NMR (CDCl,) 6 0.64-0.80 (m, 1H), 0.82-0.94 (m, 1H), 1.06-1.32 (m, 12H), 1.54 (s, 3H), 1.54-1.68 (m, 2H), 1.76-1.83 (m, 1H), 2.14—2.24 (m, 1H), 3.19 (s, 3H), 3.50 (dd, 1H, J = 11.3, 3.3 Hz), 3.62 (s, 3H), 5.06 (d, 1H, J = 3.0 Hz), 6.67 (d, 1H, J = 3.0 Hz); 13C NMR (CDCI3) 6 148 22.17, 22.31, 22.80, 24.24, 25.57, 26.47, 26.77, 27.09, 30.86, 43.21, 51.04, 54.77, 56.64, 85.77, 112.67, 134.66, 142.85, 148.87, 203.72; IR (neat) 2930, 2857, 1647 cm"; MS (EI) m/z (% rel intensity) 306 M’ (10), 274 (53), 259 (11), 247 (4), 217 (9), 175 (41), 151 (54), 91 (39), 41 (100); HRMS (FAB) calcd for C,,H,,0, m/z 307.2273, measd 307.2275. Thermolysis of Fischer Carbene Complex 155d 0 OMOM Q OMOM 00H3 ? (005ch __. 15 + 15 9 Q OMe OMe CH2)9 (CH2)9 155d 156d 1 56d' Thermolysis of Fischer carbene complex 155d (30.0 mg, 0.06 mmol) was performed in THF following the general procedure described for the thermolysis of 155b. The diastereomeric ratio of 156d/156d’ was determined by crude 1H N MR and based on the integral of the vinyl proton on C(15): 6 6.88 ppm (156d) and 6.68 ppm (156d’). Cyclization at 100 °C provided 156d/156d’ with a combined yield of 36% (7.3 mg, 0.02 mmol) after isolation together from the column. Diastereomeric ratio of 156d: 156d’ = 1: l; Cyclization at 55 °C provided 156d/156d’ with a combined yield of 44% (8.1 mg, 0.024 mmol). Diastereomeric ratio of 156d: 156d’ = 1: 1.1. Compound 156c and 156c’ were separated by another flash column chromatography on silica gel (eluant: CH2C12: ether: hexanes = 1: 1: 30) and obtained as colorless oils. The stereochemical assignment was made based on the known X-ray structure of 156b. The isomer with higher R, value was assigned the same stereochemistry as 156b. 149 Compound 156d was obtained as a colorless oil: R, = 0.15 (1:1:10 EtzO: CHZCIZ: Hexanes); 1H NMR (CDC13) 6 0.78-0.85 (m, 1H), 1.05-1.26 (m, 12H), 1.17 (s, 3H), 1.54- 1.72 (m, 4H), 2.09-2.15 (m, 1H), 3.33 (s, 3H), 3.62 (s, 3H), 4.53 (d, 1H, J = 6.5 Hz) 4.63 (d, 1H, J = 6.5 Hz), 4.87-4.89 (m, 1H), 5.00 (d, 1H, J = 3.3 Hz), 6.88 (dd, 1H, J = 3.5, 1.5 Hz); 13C NMR (CDC13) 6 18.69, 21.86, 21.94, 24.03, 25.62, 26.21, 26.33, 26.49, 30.66, 43.80, 50.26, 54.74, 55.48, 71.47, 94.73, 111.01, 137.59, 137.94, 149.83, 205.35; IR (neat) 2932, 2859, 1645 cm"; MS (EI) m/z (% rel intensity) 336 M+ (2), 291 (2), 274 (28), 247 (3), 175 (11), 151 (22), 91 (14), 45 (100); HRMS (FAB) calcd for C2,,H33O4 m/z 337.2379, measd 337.2380. Compound 156d’ was obtained as a colorless oil: R, = 0.025 (1:1:10 Et,O: CHzClz: Hexanes); 1H NMR (CDC13) 6 0.72-0.80 (m, 1H), 0.82-0.96 (m, 1H), 1.04—1.34 (m, 12H), 1.15 (s, 3H), 1.54—1.64 (m, 2H), 1.78-1.81 (m, 1H), 2.22-2.32 (m, 1H), 3.28 (s, 3H), 3.60 (s, 3H), 3.90 (dd, 1H, J = 11.0, 3.6 Hz), 4.57(s, 2H), 5.05 (d, 1H, J = 2.7 Hz), 6.68 (d, 1H, J = 2.5 Hz); 13C NMR (CDC13) 6 22.21, 22.33, 22.72, 24.29, 25.59, 26.51, 26.75, 27.08, 30.97, 43.12, 51.00, 54.74, 55.37, 80.30, 94.38, 112.58, 134.80, 142.46, 148.98, 203.94; IR (neat) 2930, 2863, 1647, 1047 cm"; MS (EI) m/z (% rel intensity) 336 M+ (1), 291 (4), 274 (35), 259(6), 247 (10), 175 (15), 151 (24), 91 (19), 45 (100); HRMS (FAB) calcd for (12,,H33O4 m/z 337.2379, measd 337.2380. 150 Preparation of E-l4-iodo-2,2,13-trimethyltetradec-l3-en-3-ol 1983 l I OH %cno Wt-Bu 9 9 195 1083 Aldehyde 195 (0.57g, 1.4 mmol) was dissolved in THF (5 mL) under an argon atmosphere and the resulting solution added to a solution of t-butyl magnesium bromide (1.0 M in THF) (5.4 mL) at —30 °C. The mixture was stirred at —30 °C for 30 minutes and then slowly quenched with saturated aqueous NH,C1 (5 mL). The reaction mixture was extracted with ether (5 mL x 2). The combined organic layers were washed with brine (15 mL), dried over MgSO, and concentrated by rotorary evaporator. Pure compound 1983 was obtained after flash chromatography on a silica gel column (5% - 10% ethyl acetate in hexanes as the eluant) as a colorless liquid (0.20 g, 0.53 mmol, 38%). R, = 0.43 (10% ethyl acetate in hexanes); 1H NMR (CDCl,) 6 0.87 (s, 9H), 1.25-1.50 (m, 16H), 1.79 (d, 3H, J = 0.9 Hz), 2.16 (t, 2H, J = 7.8 Hz), 3.16 (d, 1H, J = 10.2 Hz), 5.82 (d, 1H, J = 0.9 Hz) (OH proton not located); 13‘C NMR (CDCl,) 6 23.79, 25.67, 27.07, 27.66, 29.00, 29.32, 29.48, 29.60, 29.68, 31.48, 34.89, 39.56, 74.28, 79.96, 148.28; MS (EI) m/z (% rel intensity) 379 M’-1 (0.02), 362 (0.51), 305 (0.94), 235 (9), 195 (17), 177(17), 109 (74), 95 (100); HRMS (FAB) calcd for C,7H321 m/z 363.1549 (M* - OH), measd 363.1548. 151 Preparation of E-13-iodo-12-methyltridec-12-en-2-ol 198b L6 L191“ 9CHO 9 CH3 105 198b Aldehyde 195 (0.10 g, 0.30 mmol) was dissolved in THF (1 mL) under an argon atmosphere and added to a solution of methyl magnesium bromide (0.5 mL, 3.0 M in diethyl ether) at —-30 °C. The mixture was stirred at ~30 °C for 30 minutes and then quenched by slowly adding saturated aqueous NH4Cl (1 mL) at low temperature. The reaction mixture was extracted with ether (2 mL x 2). The combined organic layers were washed with brine (5 mL), dried over MgSO4 and concentrated by rotorary evaporator. Pure compound 198b was obtained after flash chromatography on silica gel (5%-10% ethyl acetate in hexanes as the eluant) as a colorless liquid (70.0 mg, 0.21 mmol, 69%). R, = 0.35 (25% ethyl acetate in hexanes); ‘H NMR (CDC13) 6 1.15 (d, 3H, J = 7.0 Hz), 1.24— 1.40 (bs, 16H), 1.79 (s, 3H), 2.15 (t, 2H, J = 7.2 Hz), 3.78 (m, 1H), 5.82 (s, 1H) (OH proton not located); 13C NMR (CDCI3) 6 23.47, 23.78, 25.72, 27.65, 28.98, 29.31, 29.43, 29.53, 29.58, 39.32, 39.54, 68.12, 74.29, 148.27; IR (neat) 3354 (broad), 2965, 2926, 2855, 1464, 1375, 1269, 1142 cm"; HRMS (FAB) calcd for C,4H2,,IO m/z 339.1185 (MH’), measd 339.1187. Preparation of E-12-iodo-ll-methyl-l-phenyldodec-ll-en-l-ol 198c I I OH \‘é-yCHO ___' Wm 9 9 195 193:: Aldehyde 195 (1.13 g, 3.5 mmol) was dissolved in diethyl ether (5 mL) under an argon atmosphere and added to a solution of phenyl magnesium bromide (2.5 mL, 3 M in 152 diethyl ether) at —30 °C. The mixture was stirred at -—30 °C for one hour and then quenched with saturated NH4C1 solution (5 mL). The ether layer was separated and the water layer was extracted with diethyl ether (10 m1. x 2). The combined organic layers were washed with brine, dried over MgSO4 and concentrated by rotorary evaporator. Pure compound 198c was obtained after flash chromatography on silica gel (5% - 10% ethyl acetate in hexanes as the eluant) as a colorless liquid (0.94 g, 2.35 mmol, 67 %). R, = 0.45 (25% ethyl acetate in hexanes); 1H NMR (CDC13) 6 1.10-1.45 (m, 12H), 1.60-1.80 (m, 4H), 1.82 (s, 3H), 1.90 (s, 1H), 2.20 (t, 2H, J = 7.2 Hz), 4.65 (m, 1H), 5.82 (s, 1H), 7.20- 7.40 (m, 5H); 13C NMR (CDCl,) 6 23.79, 25.79, 27.65, 28.97 , 29.30, 29.41, 29.46, 39.06, 39.55, 74.31, 74.71, 125.87, 127.49, 128.42, 144.86, 148.31 (one carbon not located); IR (neat) 3339 (broad), 2928, 2855 cm"; MS (EI) m/z (% rel intensity) 382 M+ - 18 (0.17), 332 (0.11), 273 (0.75), 255 (5), 107 (100), 79 (35); HRMS (FAB) calcd for C,9Hz,,1 m/z 383.1236 (M+ — OH), measd 383.1233. Preparation of Ketones 1993-c I OH I 0 $12 Wu 9 9 198312 =1 Bu, 1993-c 198bF1 = CH3 198cF1 = Phenyl General Procedure VI (J ones’ oxidation) The chromic acid solution was prepared by dissolving 5.0 g of NaCrzO7 (sodium dichromate dihydrate) in H20 (15 mL). To this solution was added H2804 (97 % aqueous 153 solution, 6.8 g) dropwise. The resulting solution was then diluted to a total volume of 25 mL . Diethyl ether and secondary alcohol 1983-c were placed in a round-bottomed flask and chilled to 0 °C (0.5 M solution). Chromic acid solution (1.0 mL/1.0 mmol of alcohol) was also chilled to 0 °C and added slowly to the above solution. After 1 hour, the reaction was extracted with ether. The combined ether layers were washed sequentially with aqueous NazCO3 and brine then dried over MgSO4. The crude ketone was obtained by concentrating the ether layer in vacuo. This gave nearly pure compounds which were used without further purification. Preparation of Ketone 1993 (R = t-Bu) Chromic acid solution (0.25 mL) was added to a solution of the secondary alcohol 1983 (86.0 mg, 0.23 mmol) in diethyl ether (0.5 mL) following the general procedure VI to provide crude ketone 1993 (73.0 mg, 0.19 mmol, 85%) as a colorless oil. R, = 0.75 (25% ethyl acetate in hexanes); 1H NMR (CDCI3) 6 1.10 (s, 9H), 1.23 (broad, s, 10H), 1.32-1.42 (m, 2H), 1.46-1.56 (m, 2H), 1.79 (s, 3H), 2.15 (t, 2H, J = 7.2 Hz), 2.43 (t, 2H, J = 7.2 Hz), 5.82 (s, 1H); 13C NMR (CDCl,) 6 23.77, 23.88, 26.37, 27.64, 28.96, 29.27, 29.33, 29.43, 36.38, 39.53, 44.04, 74.27, 148.25, 216.06 (1 sp3 C not located); IR (neat) 2928, 2855, 1707, 1462 cm"; MS (E1) m/z (% rel intensity) 379 M’ + 1 (0.22), 335 (0.04), 321 (0.52), 251 (12), 194 (30), 95 (48), 57 (100); HRMS (FAB) calcd for (3,711,210 m/z 379.1498 (Mir), measd 379.1496. 154 Preparation of Ketone 199b (R = CH,) Chromic acid solution (0.22 mL) was added to a solution of the secondary alcohol 198b (70.0 mg, 0.21 mmol) in diethyl ether (0.5 ml.) following the general procedure VI to provide crude ketone 199b (56.0 mg, 0.17 mmol, 80%). R, = 0.55 (25% ethyl acetate in hexanes); 1H NMR (CDCI3) 6 1.24 (broad, s, 10H), 1.30-1.45 (m, 2H), 1.45—1.60 (m, 2H), 1.79 (s, 3H), 2.11 (s, 3H), 2.18 (t, 2H, J = 7.2 Hz), 2.39 (t, 2H, J = 7.2 Hz), 5.82 (s, 1H); 13C NMR (CDC13) 6 23.78, 23.80, 27.64, 28.95, 29.11, 29.26, 29.30, 29.31, 29.83, 39.53, 43.76, 74.30, 148.25, 209.27; IR (neat) 2926, 2855, 1717 cm“; MS (EI) m/z (% rel intensity) 336 M+ (0.02), 209(5), 191 (11), 109 (42), 95 (63). Preparation of Ketone l99c (R = Ph) Chromic acid solution (1.0 mL) was reacted with secondary alcohol 198c (0.41 g, 1.02 mmol) in diethyl ether (1.0 mL) following the general procedure VI to provide crude ketone 199c which was purified by flash chromatography (eluant: 10% ethyl acetate) on silica gel column as a colorless oil (0.36 g, 0.9 mmol, 89%). R, = 0.73 (25% ethyl acetate in hexanes); 1H NMR (CDCI3) 6 1.25-1.50 (broad, s, 12H), l.60-l.70 (m, 2H), 1.80 (s, 3H), 2.16 (t, 2H, J = 7.2 Hz), 2.94 (t, 2H, J = 7.5 Hz), 5.83 (s, 1H), 7.44 (t, 2H, J = 6.3 Hz), 7.54 (t, 1H, J = 6.9 Hz), 7.93 (d, 2H, J = 6.9 Hz); 13C NMR (CDCl,) 6 23.79, 24.34, . 27.67, 28.99, 29.14, 29.29, 29.32, 29.41, 38.59, 39.55, 74.30, 128.04, 128.53, 132.82, 137.12, 148.28, 200.53; IR (neat) 3061, 2928, 2853, 1688, 1448 cm"; MS (EI) m/z (% rel intensity) 399 (0.32), 398 M+ (0.02), 349 (0.44), 348 (1.37), 271 (5.49), 197 (4.83), 145 (34), 119 (54), 104 (100); HRMS (FAB) calcd for C,9H2,,IO m/z 339.1185 (MH‘), measd 339.1187. 155 Preparation of Tertiary Alcohols 2003-c 1% 'Lfl 9 R 9 R Q 1903-9 2003-1: General Procedure VII The appropriate ketone 1993-c obtained from oxidation of the corresponding secondary alcohol 198a-c was dried in a round-bottomed flask under hi gh-vacuum for 20 min and then dissolved in THF (0.1 — 0.2 M solution) under an argon atmosphere. This solution was cooled to 0 °C and then ethynyl magnesium bromide (0.5 M in THF) (3.0 - 4.0 equiv.) was added dropwise. The mixture was warmed to room temperature and stirred for one to five hours and the reaction monitored by TLC analysis until the reaction was complete. Then the reaction was slowly quenched with saturated aqueous NH4CI. The aqueous layer was extracted with ether, and the combined organic layer washed with brine and dried over MgSO,,. The pure tertiary alcohol 2003-c was obtained by flash chromatography on a silica gel column (eluant: hexanes: ethyl acetate = 9:1) as a colorless liquid. Preparation of Tertiary Alcohol 2003 (R = t-Bu) Following the general procedure VII, crude ketone 1993 (73.0 mg, 0.19 mmol) was dissolved in THF (1.0 mL) and reacted with 1.1 mL (0.55 mmol) of ethynyl magnesium bromide solution for 1.5 hours. Tertiary alcohol 2003 (79.5 mg, 0.20 mmol, 87% over two steps from 1983) was obtained as a colorless oil after purification. R, = 156 0.68 (25% ethyl acetate in hexanes); 1H NMR (CDC13) 6 1.02 (s, 9H), 1.25-1.45 (m, 14H), 1.56 (d, 2H, J = 4.8 Hz), 1.80 (s, 3H), 1.83 (s, 1H), 2.17 (t, 2H, J = 7.2 Hz), 2.40 (s, 1H), 5.83 (s, 1H); 13C NMR (CDCl,) 6 23.80, 24.73, 25.07, 27,68, 29.00, 29.32, 29.48, 29.62, 29.93, 35.29, 38.37, 39.56, 73.34, 74.30, 85.87, 148.28 (1 sp3 C not located); IR (neat) 3550 (broad), 3304, 2900, 2928, 2853 1464 cm“; MS (EI) m/z (% rel intensity) 347 (0.35), 277 (1), 259 (3), 181 (4), 126 (18), 111 (67), 95 (40), 57 (100); HRMS (FAB) calcd for C,9H321 m/z 387.1549 (M+ — OH), measd 387.1546. Preparation of Tertiary Alcohol 200b (R= CH3) Following the general procedure VII, crude ketone 199b (56.0 mg, 0.17 mmol) was dissolved in THF (1.0 mL) and reacted with 1.2 mL (0.60 mmol) of ethynyl magnesium bromide solution for 1.5 hours. Tertiary alcohol 200b (42.0 mg, 0.12 mmol, 56% over two steps from 198b) was obtained as a colorless oil after purification. R, = 0.50 (25% ethyl acetate in hexanes); 1H NMR (CDCI3) 6 1.25-1.45 (m, broad, 14H), 1.47 (s, 3H), l.60-1.70 (m, 2H), 1.79 (s, 3H), 1.95 (s, 1H), 2.16 (t, 2H, J = 7.2 Hz), 2.41 (s, 1H), 5.82 (s, 1H); 13C NMR (CDCI3) 6 23.80, 24.51, 27.66, 28.99, 29.32, 29.46, 29.61, 29.69, 29.73, 39.55, 43.45, 68.08, 71.11, 74.27, 87.75, 148.29; IR (neat) 3400 (broad), 3304, 2978, 2928, 2855, 1460 cm"; MS (EI) m/z (% rel intensity) 238 (30), 235 (20), 217 (19), 182 (49), 181 (100); HRMS (FAB) calcd for C,6H2,,I m/z 345.1079 (M+ — OH), measd 345.1077. 157 Preparation of Tertiary Alcohol 200c (R= Ph) Following the general procedure VII, purified ketone l99c (0.36 g, 0.90 mmol) was dissolved in THF (5.0 mL) and reacted with 5.4 mL (2.7 mmol, 0.91 mmol) of ethynyl magnesium bromide (0.5 M in THF) for 4 hours. Tertiary alcohol 200c (0.37 g, 0.88 mmol, 97%) was obtained as a colorless oil after purification. R, = 0.58 (25% ethyl acetate in hexanes); 1H NMR (CDC13) 6 1.22-1.50 (broad, m, 12H), 1.80 (s, 3H), 1.83- 1.96 (m, 4H), 2.16 (t, 2H, J = 7.2 Hz), 2.35 (s, 1H), 2.67 (s, 1H), 5.83 (s, 1H), 7.26 (t, 1H, J = 4.5 Hz), 7.34 (t, 2H, J = 4.5 Hz), 7.61 (d, 2H, J = 4.5 Hz); 13C NMR (CDC13) 6 23.80, 24.49, 27.66, 28.96, 29.28, 29.35, 29.42, 39.55, 45.20, 73.25, 74.03, 74.30, 86.38, 125.33, 127.73, 128.17, 144.24, 148.28 (1 sp3 C not located); IR (neat) 3550, 3300, 2926, 2853, 1449 cm“; MS (EI) m/z (% rel intensity) 298 (0.07), 297 M” - 127 (0.29), 279 (0.49), 180 (1), 146 (7), 131 (100), 53 (27); HRMS (FAB) calcd for Q,H2910 m/z 424.1263 (M’), measd 424.1256. Preparation of E-l-iodo-l-en-l3-yne 2013-6“ 913% —-—> 9 \\ 2003 R=tBu 2009 9:011, 2018-9 200: n = Phenyl General Procedure VIII The appropriate tertiary alcohol 2003-c (1.0 equiv.) was dissolved in CHZCl2 under an argon atmosphere to make a 0.2 M solution. Co,(CO)8 (1.1 equiv.) was added as , a solid while the solution was stirred. After addition, the solution was stirred at room 158 temperature for 4.5 h and then cooled to 0 °C. The reaction mixture was diluted with CH2C12 to half the concentration. Borane-dimethyl sulfide complex (10.0-10.2 M in excess dimethyl sulfide) (2.1 equiv.) was added followed by the addition of trifluoroacetic acid (10-15 equiv). After the mixture was stirred at 0 °C for 30 min, it was poured into ice water and stirred for 5 min. The organic layer was separated, concentrated in vacuo and redissolved in a 1:1 mixture of acetone and water. Cerium ammonium nitrate (CAN) (3.3 equiv.) was added as a powder and the mixture was stirred at room temperature for 30 min. After the reaction was complete, acetone was removed by the rotorary evaporator. More water was added and extracted with ether. The ether layer was washed with brine and dried over MgSO,. Pure compounds 2013-c were obtained after flash chromatography on silica gel (hexanes: ethyl acetate = 9:1 as the eluant) as colorless liquids. Preparation of E-12-tert-butyl-l-iod0-2-methyltetradec-l-en-l3-yne 2013 (R = t- Butyl) Following the general procedure VIII, the tertiary alcohol 2003 (78.0 mg, 0.19 mmol) was dissolved in CHzCl2 (1.0 mL) and reacted with C02(CO)8 (74.5 mg, 0.22 mmol). After dilution with CHzCl2 (1.0 mL), borane dimethylsulfide complex (40.0 11L, 0.4 mmol) and TFA (0.2 mL) were added. Finally CAN (0.36 g, 0.66 mmol) was used for demetallation. Compound 2013 (51.6 mg, 0.13 mmol, 70%) was obtained as a colorless oil after purification. R, = 0.73 (25% ethyl acetate in hexanes); 1H NMR (CDC13) 6 0.95 (s, 9H), 1.25-1.65 (m, broad, 16H), 1.79 (s, 3H), 2.00 (s, 1H), 2.03 (s, 1H), 2.17 (t, 2H, J = 7.2 Hz), 5.83 (s, 1H); 13C NMR (CDC13) 6 23.81, 27.44, 27.69, 28.50, 29.02, 29.35, 159 29.38, 29.50, 29.55, 33.13, 39.58, 43.58, 70.30, 74.29, 86.79, 148.31 (1 sp3 C not located); IR (neat) 3308, 2926, 2855 cm-1; MS (EI) m/z (% rel intensity) 261 M+ - 127 (33), 205 (4), 181 (7), 95 (100), 57 (91); HRMS (FAB) calcd for C,9H33 m/z 261.2582 (M+ - I), measd 261.2583. Preparation of E-l-iodo-2, lZ-dimethyltetradec-l-en- l3-yne 201b (R = CH,) Following the general procedure VIII, the tertiary alcohol 200b (42.0 mg, 0.116 mmol) was dissolved in CHzCl2 (0.6 mL) and reacted with C02(CO)8 (43.6 mg, 0.13 mmol). After dilution with CHzCl2 (0.6 mL), borane dimethylsulfide complex (24.0 11L, 0.4 mmol) and TFA (0.12 mL) were added. Finally CAN (0.22 g, 0.40 mmol) was used for demetallation. Compound 201b (36.0 mg, 0.11 mmol, 90%) was obtained as a colorless oil after purification. R, = 0.85 (25% ethyl acetate in hexanes); ‘H NMR (CDCI3) 6 1.15 (d, 3H, J = 7.2 Hz), 1.25-1.45 (m, broad, 16H), 1.80 (s, 3H), 2.01 (d, 1H, J = 2.4 Hz), 2.17 (t, 2H, J = 7.5 Hz), 2.39 (m, 1H), 5.83 (s, 1H); 13C NMR (CDC13) 6 20.98, 23.82, 25,67, 27.22, 27.69, 29.02, 29.35, 29.40, 29.48, 29.50, 36.74, 39.58, 67.99, 74.30, 89.32, 148.30; IR (neat) 3310, 2928, 2855, 2120 (weak), 1464 cm"; MS (EI) m/z (% rel intensity) 346 M“(0.02), 219 (6), 194 (3), 181 (10), 123 (17), 109 (37), 95 (100); HRMS (FAB) calcd for C,,,H27 m/z 219.2113 (M+ - I), measd 219.2112. Preparation of E-1-(14-iodo-l3-methyltetradec-l3-en-1-yn-3-yl)benzene 201c (R = Ph) Following the general procedure VIII, the tertiary alcohol 200c (45.6 mg, 0.11 mmol) was dissolved in CH2C12 (0.6 mL) and reacted with C02(CO)8 (40.6 mg, 0.12 160 mmol). After dilution with CHzCl2 (0.6 mL), borane dimethylsulfide complex (23.0 11L, 0.23 mmol) and TFA (0.11 mL) were added. Finally CAN (0.23 g, 0.42 mmol) was used for demetallation. Compound 201c (30.0 mg, 0.07 mmol, 68%) was obtained as a colorless oil after purification. R, = 0.74 (25% ethyl acetate in hexanes); 1H NMR (CDCl,) 6 1.23-1.50 (m, 14H), 1.62-1.80 (m, 2H), 1.80 (s, 3H), 2.16 (t, 2H, J = 7.5 Hz), 2.24 (d, 1H, J = 0.9 Hz), 3.59 (t, 1H, J = 6.0 Hz), 5.83 (s, 1H), 7.20 - 7.33 (m, 5H); ”C NMR (CDC13) 6 23.80, 27.23, 27.67, 29.00, 29.24, 29.32, 29.41, 29.45, 37.58, 38.31, 39.57, 70.77, 74.32, 86.16, 126.71, 127.33, 128.47, 141.71, 148.33; IR (neat) 3302, 2926, 2855 cm"; MS (EI) m/z (% rel intensity) 355 (1), 281 (49), 207 (4), 157 (33), 115 (100), 67 (23); HRMS (FAB) calcd for 9,11,, m/z 281.2269 (M“ — I), measd 281.2268. Preparation of Fischer Carbene Complexes 1923-c I R OMe w (OC),,Cr R 9 § — \ 201. R :1 Bu, 9 \ 2019 n = CH3 1923-c 201c R = Phenyl General Procedure IX A solution of PhLi (freshly-prepared, 0.28 M in ether) (1.1 equiv.) was added to the vinyl iodide 2013-c (1.0 eq.) under argon at —15 °C. The solution was stirred for 1 hour before t-BuLi (1.7 M in pentane) (2.2 equiv.) was added. After 30 min, Cr(CO),5 (1.1 eq.) was added as a solid followed by slow addition of THF which helped to dissolve the Cr(CO)6. The mixture was warmed to room temperature and stirred for 1-2 hours. The solvent was removed and the residue was taken up in deoxygenated mixture of CH2C12/ 161 H20 (1:1) which was added under argon. Me3OBF, (2.2 equiv.) was added as a solid and the brown suspension turned orange. The reaction mixture was stirred for 20 min at room temperature before it was quenched with saturated aqueous NazCO3. Diethyl ether was used to extract the product from the aqueous layer three times. The ether layer was combined, washed with brine and dried over MgSO4. Concentration followed by flash chromatography on silica gel (hexanes: ethyl acetate = 98: 2) provided the desired carbene complexes 1923-c as red oils. Preparation of Fischer Carbene Complex 1923 (R = t-Bu) Following the general procedure IX, vinyl iodide 2013 (0.10 g, 0.26 mmol) was reacted with 1.0 mL of PhLi (0.28 mmol) and 0.33 mL of t-BuLi (0.56 mmol) and diluted with THF (2.0 mL). Cr(CO),, (85.0 mg, 0.39 mmol) was added and this was followed by methylation with Me3,OBF4 (83.9 mg, 0.57 mmol). Carbene 1923 (40.0 mg, 0.08 mmol, 31%) was obtained as a red oil after purification. R, = 0.73 (25% ethyl acetate in hexanes); 1H NMR (CDCI3) 6 0.96 (s, 9H), 1.28 (bs, 12H), 1.40-1.45 (m, 3H), 1.58-1.62 (m, 1H), 1.82 (s, 3H), 2.00 (s, 1H), 2.03 (s, 1H), 2.09 (t, 2H, J = 7.2 Hz), 4.70 (s, 3H), 7.22 (s, 1H); 13C NMR (CDC13) 6 20.62, 27.43, 27.82, 28.51, 29.28, 29.37, 29.44, 29.50, 29.56, 33.13, 41.25, 43.58, 66.20, 70.29, 86.82, 141.03, 143.62, 216.84, 224.00, 339.39 (1 sp3 C not located); IR (neat) 3309 (weak), 2924, 2851, 2058, 1941, 1723, 1460, 1150 cm"; MS (EI) m/z (% rel intensity) 496 M+ (0.1), 440 (0.04), 384 (0.14), 356(2), 292 (1), 289 (3), 276 (4), 263 (5), 204 (7), 149 (29), 95 (71), 57 (100); HRMS (FAB) calcd for C2,,H36CrO,5 m/z 496.1917 (M’), measd 496.1915. 162 Preparation of Fischer Carbene Complex 192b (R = CH3) Following the general procedure IX, vinyl iodide 201b (0.15 g, 0.43 mmol) was reacted with 1.7 mL of PhLi (0.48 mmol) and 0.56 mL of t-BuLi (0.95 mmol) and diluted with THF (2.0 mL). Cr(CO),5 (104.0 g, 0.47 mmol) was added and this was followed by methylation with Me3OBF4 (140.0 mg, 0.95 mmol). Carbene 192b (53.0 mg, 0.12 mmol, 27%) was obtained as a red oil after purification. R, = 0.68 (25% ethyl acetate in hexanes); 1H NMR (CDCI3) 6 1.15 (d, 3H, J = 6.9 Hz), 1.25-1.50 (m, 16H), 1.83 (s, 3H), 2.01 (d, 1H, J = 2.4 Hz), 2.09 (t, 2H, J = 7.2 Hz), 2.34-2.46 (m, 1H), 4.7 (s, 3H), 7.23 (s, 1H); 13C NMR (CDC13) 6 20.61, 20.96, 25.64, 27.21, 27.79, 29.25, 29.37, 29.41, 29.44, 29.48, 36.71, 41.23, 66.16, 67.97, 89.32, 141.02, 143.60, 216.82, 223.98, 339.30; IR (neat) 3312, 2930, 2857, 2058, 1925 cm"; MS (EI) m/z (% rel intensity) 454 M’ (0.18), 398 (0.18), 370 (0.1), 342(1), 290 (38), 262(8), 165 (72), 123 (100), 97 (55), 55 (73), 41 (87); HRMS (FAB) calcd for C‘qumCrO6 m/z 454.1447 (M’), measd 454.1445. Preparation of Fischer Carbene Complex l92c (R = Ph) Following the general procedure IX, vinyl iodide 201c (56.0 mg, 0.14 mmol) was reacted with 0.65 mL of PhLi (0.15 mmol) and 0.18 mL of t-BuLi (0.30 mmol) and diluted with THF (0.4 mL). Cr(CO),, (33.0 mg, 0.15 mmol) was added and this was followed by methylation with Me,OBF,, (44.4 mg, 0.30 mmol). Carbene 192c (9.1 mg, 0.02 mmol, 13%) was obtained as a red oil after purification. R, = 0.65 (25% ethyl acetate in hexanes); 1H NMR (CDC13) 6 1.24-1.30 (bs, 10H), 1.40-1.50 (s, 4H), 1.60-1.80 (m, 2H), 1.82 (s, 3H), 2.08 (t, 2H, J = 7.5 Hz), 2.23 (d, 1H, J = 2.1 Hz), 3.59 (td, 1H, J = 7.5, 2.1 Hz), 4.70 (s, 3H), 7.22 (s, 1H), 7.27-7.35 (m, 5H); 13C NMR (CDC13) 6 20.62, 27.23, 163 27.79, 27.97, 29.23, 29.40, 29.48, 37.57, 38.31, 41.23, 66.17, 70.75, 86.16, 126.70, 127.33, 128.45, 141.03, 141.70, 143.60, 216.84, 224.00, 339.90 (1 sp3 C not located); IR (neat) 3314, 2928, 2855, 2058, 1931, 1584, 1453, 1252 cm"; MS (EI) m/z (% rel intensity) 516 M+ (0.32) 460 (0.25), 432 (0.31), 404 (4), 376 (12), 352 (9), 220 (7), 157 (9), 143 (14), 130 (28), 115 (62), 84 (100); HRMS (FAB) calcd for CmHnCrO, m/z 516.1604 (M*), measd 516.1606. Thermolysis 01' Fischer Carbene Complex 1923 O OMe ,5 OC Cf ————> + ( )5 W 01.19 9 § (01139 1923 1933 1933' Carbene complex 1923 (40.0 mg, 0.081 mmol) was dissolved in THF (16 mL) and deoxygenated by the freeze-pump-thaw method (3 cycles) in a Schlenk flask equipped with a threaded Teflon high-vacuum stopcock. The flask was back-filled with argon at room temperature, the stopcock closed and the flask heated to 100 °C for 15 hours. Then the reaction mixture was cooled and the solvent was removed in vacuo. The residue was taken up by CHzClzl 3,0 (5 mL/ 5mL) and stirred in air for 24 hours. After the air oxidation, the solvent was removed again and the residue was taken up in diethyl ether (10 mL). The insoluble material was removed by filtration on a pipette-sized silica gel column (2 x 10 cm) using ether as the eluant. Concentration provided the crude mixture of 1933 and 1933’ in a 1:1 ratio. The isomeric ratio was determined by GC analysis as well as GC—mass analysis on the crude reaction mixture. GC analysis (SE—54, 164 30 m x 0.55 mm, 150-250 °C, 10 °C/min) indicates equal amount of compounds at retention time of 16.99 min and 17.34 min respectively. GC-mass analysis indicates the molecular weights of both compounds at retention time 4.14 min and 4.33 min to be m/z 332 (M”). The combined yield after flash column chromatography on silica gel using 1:1:10 diethyl ether: dichloromethane: hexanes as the eluant was 17.7 mg (0.05 mmol, 66%). Pure compound 1933 and 1933’ can be obtained by flash column chromatography (eluant: CHZCIZ: ether: hexanes = 1:1:30) as colorless oils after careful separation. The stereochemical assignment was made based on the known X-ray structure of 156b. The isomer with higher R,value was assigned the same stereochemistry as 156b. Isomer 1933: R, = 0.5 (1:1:10 diethyl ether: dichloromethane: hexanes); 1H NMR 6 0.64-0.74 (m, 1H), 0.88 (s, 9H), 0.90-1.01 (m, 1H), 1.01-1.31 (m, 14H), 1.11 (s, 3H), 1.38-1.48 (m, 1H), 1.78-1.82 (m, 1H), 2.02-2.12 (m, 1H), 3.60 (s, 3H), 4.98 (d, 1H, J = 2.7 Hz), 6.58 (d, 1H, J = 2.7 Hz); 13C NMR (CDC13) 6 22.50, 23.59, 24.51, 25.01, 25.88, 26.44, 26.84, 27.15, 27.81, 29.56, 33.95, 42.53, 51.19, 54.64, 58.61, 111.11, 139.34, 143.79, 149.24, 205.58; IR (neat) 2932, 2863, 1645 cm"; MS (EI) m/z (% rel intensity) 332 M+ (15), 276 (68), 247 (8), 177 (16), 151 (100), 91 (22); HRMS (FAB) calcd for C22H37O2 m/z 333.2794 (MH’), measd 333.2793. Isomer 1933’: R, = 0.4 (1:1:10 diethyl ether: dichloromethane: hexanes); 1H NMR 6 0.80 (s, 9H), 0.95 (s, 3H), 0.76-1.31 (m, 13H), 1.40-1.50 (m, 1H), 1.57-1.65 (m, 2H), 1.90-2.04 (m, 1H), 2.11-2.15 (m, 1H), 3.04 (dd, 1H, J, = 7.5 Hz, 3.4 Hz), 3.62 (s, 3H), 4.98 (d, 1H, J = 3.0 Hz), 6.58 (d, 1H, J = 3.1 Hz); 13C NMR (CDCl,) 6 22.50, 23.59, 24.51, 25.01, 25.88, 26.44, 26.84, 27.16, 27.81, 29.57, 33.95, 42.53, 51.19, 54.64, 58.61, 111.10, 139.34, 143.79, 149.24, 205.17; IR (neat) 2930, 2859, 1645 cm'l; MS (EI) m/z (% 165 rel intensity) 332 M" (10), 276 (48), 247 (5), 191 (9), 177 (13), 151 (60), 57 (80), 41 (100); HRMS (FAB) calcd for C22H37O2 m/z 333.2794 (MH*), measd 333.2792. Thermolysis of Fischer Carbene Complex l92b O OMe (OC)5Cr ————* + - OMe 9 § CH2)9 192b 1931) Carbene complex 192b (25.0 mg, 0.06 mmol) was dissolved in THF (15 mL) and deoxygenated by the freeze-pump-thaw method in a Schlenk flask equipped with a threaded Teflon high-vacuum stopcock. The flask was then back filled with argon at room temperature, the stopcock was closed and the flask heated to 100 °C for 10 hours. Then the solvent was removed. The residue was taken up in CHZCIZIEQO (5 mL: 5 mL) and stirred in open air for 24 hours. After the air oxidation, the solvent was removed again and the residue was taken up in diethyl ether (10 mL). The insoluble material was removed by filtration on a pipette-sized silica gel column (2 x 10 cm). Concentration provided the crude mixture of 193b and 193b’ in a 1: 1 ratio. The isomeric ratio was determined by GC analysis as well as GC-mass analysis on the crude reaction mixture. GC analysis (SE-54, 30 m x 0.55 mm, 150-250 °C, 10 °C/min) indicates equal amount of compounds at retention time of 14.83 min and 15.84 min respectively. GC-mass analysis indicates two peaks of equal height at retention times 3.35 min (m/z 290 M*) and 3.17 min (m/z 290 M’). The combined yield after flash column chromatography on silica gel using 1:1:10 diethyl ether: dichloromethane: hexanes as the eluant was 15.4 mg (0.053 mmol, 94%). Pure compounds 193a and 1933’ can be obtained by flash column 166 chromatography (eluant: CHzClz: ether: hexanes = 1: 1: 30) as colorless oils after careful separation. Stereochemical assignment was made based on the known X-ray structure of 156b. The isomer with higher R,value was assigned the same stereochemistry as 156b. Compound l93b: 1H NMR 6 0.78-0.90 (m, 1H), 0.95-1.38 (m, 15H), 1.02 (d, 3H, J = 7.5 Hz), 1.17 (s, 3H), l.57-1.74 (m, 2H), 3.12-3.17 (m, 1H), 3.61 (s, 3H), 4.94 (d, 1H, J = 3.0 Hz), 6.54 (dd, 1H, J = 3.5, 1.0 Hz); 13C NMR (CDC13) 6 16.13, 20.80, 22.14, 23.33, 24.20, 25.58, 26.30, 26.57, 26.76, 28.92, 32.68, 43.78, 49.70, 54.64, 109.89, 136.69, 142.27, 149.81, 205.61; IR (neat) 2930, 2859, 1647 cm"; MS (EI) m/z (% rel intensity) 290 M“ (41), 275 (5), 191 (9), 165 (100), 151 (25), 91 (36), 41 (48); HRMS (FAB) calcd for C,,,H,,,O2 m/z 291.2324 (MH’), measd 291.2323. Compound 193b’: 1H NMR 6 0.76-0.86 (m, 1H), 1.01 (d, 3H, J = 7.2 Hz), 0.94— 1.36 (m, 15H), 1.17 (s, 3H), 1.56-1.76 (m, 2H), 3.14—3.19 (m, 1H), 3.61 (s, 3H), 4.94 (d, 1H, J = 3.0 Hz), 6.54 (dd, 1H, J = 3.2, 1.1 Hz); 13C NMR (CDC13) 6 18.32, 20.97, 22.35, 23.50, 24.43, 25.80, 26.54, 26.79, 27.01, 29.18, 32.86, 44.06, 49.95, 54.91, 110.14, 136.98, 142.50, 150.05, 205.90; IR (neat) 2928, 2853, 1647 cm“; MS (EI) m/z, (% rel intensity) 290 M+ (66), 275 (7), 247(2), 191 (9), 165 (100), 151 (28), 91 (34), 55 (68), 41 (84); HRMS (FAB) calcd for C,9I-I3,02 m/z 291.2324 (MH’), measd 291.2323. Thermolysis of Fischer Carbene Complex l92c OMe O ,5 (OC)5Cr _ —'—" + 192c 1936 167 Carbene complex 192c (15.0 mg, 0.03 mmol) was dissolved in THF (5.6 mL) and deoxygenated by the freeze-pump-thaw method in a Schlenk flask which was equipped with a threaded Teflon high vacuum stopcock. The flask was then back filled with argon at room temperature, the stopcock was closed and the flask heated to 100°C for 10 hours. Then the solvent was removed. The residue was taken up in CHzClz/EtzO (5 mL: 5 mL) and stirred in open air for 24 hours. After the air oxidation, the solvent was removed again and the residue was taken up in diethyl ether (10 mL). The insoluble material was removed by filtration on a pipette-sized silica gel column (2 x 10 cm). Concentration provided the crude mixture of 193c and l93c’ in a 1: 1 ratio. The isomeric ratio was detemiined by lH NMR analysis based on the integral of vinyl protons at 6 7.22 ppm and 6.82 ppm. The combined yield after flash column chromatography on silica gel using 1:1:10 diethyl ether: dichloromethane: hexanes as the eluant was 54% (5.5 mg, 0.015 mmol). This 1:1 mixture was obtained as a white solid. R, = 0.34 (1:1:10 : CHZCIZ: ether: hexanes ). The following spectral data was collected on a 1:1 mixture of 193c and 193c’. 1H NMR 6 0.84-0.94 (m, 2H), 0.98 (s, 3H), 1.14 (s, 3H), 1.04-1.40 (m, 21H), 1.50-1.98 (m, 10H), 2.10-2.24 (m, 2H), 2.42-2.47 (m, 1H), 3.29 (d, 1H, J = 12.0 Hz), 3.58 (s, 3H), 3.61 (s, 3H), 4.40 (dd, 1H, J, = 12.0 Hz, 4.5 Hz), 4.96 (d, 1H, J = 3.0 Hz), 4.98 (d, 1H, J = 2.5 Hz), 6.65 (d, 1H, J = 3.0 Hz), 6.82 (d, 1H, J = 3.5 Hz), 7.10-7.34 (m, 10H); 13C NMR (CDC13) 6 22.21, 22.79, 23.07, 24.49, 25.04, 25.16, 25.54, 25.60, 25.69, 26.60, 26.95, 27.00, 27.07, 27.67, 29.45, 34.49, 38.53, 42.85, 43.03, 49.87, 50.71, 51.32, 54.67, 54.72, 110.72, 111.44, 125.77, 126.01, 127.34, 127.54, 127.77, 128.38, 128.46, 138.21, 139.28, 141.02, 143.56, 144.95, 149.42, 149.71, 204.62, 204.90 (2 aliphatic carbons not located); MS (EI) m/z (% rel intensity) 352 M+ (57), 337 (2), 253 (6), 239 (17), 227 (100), 165 168 (16), 151 (23), 115 (55), 91 (67), 41 (70); HRMS (FAB) calcd for C24H3302 m/z 353.2481 (MH+), measd 353.2482. Preparation of Geraniol Benzoate 21342 Geraniol 212 ( 2.0 g, 13.0 mmol) was dissolved in pyridine (11 mL) and cooled to 0 °C. Benzoyl chloride (2.3 mL, 19.5 mmol) was added dropwise to the above solution and a white paste was observed to form. The mixture was diluted with CH2C12(4.0 mL) and stirred at 0 °C overnight. Water (10 ml.) was added to quench the reaction and ether (10 mL x 3) was used to extract the aqueous layer. The combined organic layer was washed repeatedly with water (10 mL x 4) and finally with brine (20 mL) and dried over MgSO4. Flash chromatography on a silica gel column (eluant: 10% ethyl acetate in hexanes) yielded the known geraniol benzoate 213 as a colorless liquid (3.3 g, 12.77 mmol, 99%). R, = 0.66 (25% ethyl acetate in hexanes); 1H NMR (CDCI3) 6 1.59 (s, 3H), 1.66 (s, 3H), 1.75 (s, 3H), 2.02-2.14 (m, 4H), 4.82-4.84 (d, 2H, J = 7.2 Hz), 5.08 (t, 1H, J = 6.6 Hz), 5.46 (t, 1H, J = 6.9 Hz), 7.43 (t, 2H, J = 7.5 Hz), 7.52 (t, 1H, J = 6.9 Hz), 8.03 (d, 2H, J = 7.2 Hz); l3C NMR(CDC13) 6 16.53, 17.67, 25.64, 26.29, 39.53, 61.85, 118.40, 123.73, 128.26, 129.57, 130.53, 131.80, 132.74, 142.32, 166.62; IR (neat) 2967, 2924, 2857, 1729, 1271, 1107, 712 cm'l. 169 Preparation of E, E-Hydroxy-3,7-dimethy1-2,6-oct3dienyl benzoate 215 ‘2 NaBH,, 0 °C, 5 min W082 OHWOBZ WWW _ _—. __ — + _ — 213 214 215 A suspension of SeO2 (0.71 g, 6.4 mmol) and t-BuOOH (70% aqueous solution) (3.5 mL, 25.6 mmol) in CHzCl2 (25 mL) was stirred for 30 minutes at room temperature in the dark. To the resulting solution was added diene 213 (3.3 g, 12.8 mmol) at 10 °C and the mixture was stirred for 5 hours before it was quenched with aqueous NaHCO3 (25 mL). The aqueous layer was extracted with 3 portions of ether (30 mL x 3). The combined ether layer was washed with brine (40 mL), dried over MgSO4 and concentrated. The resultant crude product 214 was redissolved in absolute ethanol and briefly treated with NaBH4 (1.45 g, 38.0 mmol) for several minutes at 0 °C. After the reduction was complete, acetone was added and the reaction mixture was stirred for 10 minutes to get rid of the excess boron reagent. Then the solvents were removed by rotorary evaporator and the residue was taken up in water (30 mL) and extracted with diethyl ether (20 mL x 3). The combined ether layer was washed with brine (30 mL) and then dried over MgSO4. Removal of the solvent under reduced pressure followed by flash chromatography provided the allylic alcohol 215 (2.0 g, 7.3 mmol, 57%) as a colorless oil. R, = 0.23 (25% ethyl acetate in hexanes); 1H NMR (CDCI3) 6 1.44 (bs, 1H, OH proton), 1.64 (s, 3H), 1.75 (s, 3H), 2.08-2.15 (m, 2H), 2.15-2.20 (m, 2H), 3.95 (d, 2H, J = 4.5 Hz), 4.82 (d, 2H, J = 7.0 Hz), 5.37 (t, 1H, J = 7.0 Hz), 5.45 (t, 1H, J = 7.0 Hz), 7.41 (t, 2H, J = 10.5 Hz), 7.53 (t, 1H, J = 10.5 Hz), 8.02 (d, 2H, J = 10.5 Hz); 13C NMR (CDC13) 6 13.68, 16.52, 25.67, 39.06, 61.88, 68.88, 118.86, 125.24, 128.32, 129.57, 170 130.45, 132.83, 135.27, 141.77, 166.69; IR (neat) 3416, 2923, 2867, 1719, 1451, 1271 cm". Preparation of E, E-Bromo-3,7-dimethyl-2,6-oct3dienyl benzoate 216 ‘2 HUM/“032 BrWOBz 215 213 A 10 mL round bottomed flask was flame dried and charged with argon. To this flask was added allylic alcohol 215 (0.33 g, 1.15 mmol) and dry diethyl ether (2.5 mL). After the reaction mixture was cooled to 0 °C, a catalytic amount of pyridine (4.6 11L, 0.057 mmol) was added followed by the slow addition of PBr3 (44.5 11L, 0.47 mmol). After stirring at 0 °C for 3.5 hours, the reaction was carefully quenched by H20 (3 mL). The water layer was extracted with diethyl ether (2 mL x 3). The ether layers were combined and washed with aqueous NaHCO3 (5 mL) and brine (5 mL) and then dried with MgSO, and concentrated. Flash chromatography on silica gel (eluant: 10% ethyl acetate in hexanes) yielded the desired allylic bromide 216 (0.33 g, 0.98 mmol, 85.5%) as a colorless oil. Bromide 216 is not very stable and turned black while standing in the light at room temperature. R, = 0.63 (25% ethyl acetate in Hexanes); 1H NMR (CDCl,) 6 1.73 (s, 3H), 1.75 (s, 3H), 2.09-2.15 (m, 2H), 2.15—2.20 (m, 2H), 3.93 (s, 2H), 4.82 (d, 2H, J = 6.9 Hz), 5.45 (td, 1H, J = 7.2, 1.2 Hz), 5.55 (t, 1H, J = 6.3 Hz), 7.40—7.43 (m, 2H), 7.50—7.56 (m, 1H), 8.02-8.04 (d, 2H, J = 6.9 Hz); 13C NMR (CDC13) 6 14.64, 16.49, 26.35, 38.53, 41.56, 61.70, 118.96, 128.27, 129.54, 130.42, 132.41, 132.79, 141.41, 156.98, 166.59; MS (EI) m/z (% rel intensity) 257 M*-Br (3), 217 (21), 215 (21), 135 (100), 105 (76). 171 2E, 6E-3,7-dimethy1-ll-(trimethylsilyl)undeca-2,6-dien-10-yn-1-ol 218 TMS 3.0 -5.0 eq 11' TMs—:—/ \\ Br 082 217 _ OH W ~20 °co °C. 6 h — ‘— 219 219 A solution of TMS propyne (0.74 mL, 4.8 mmol) in THF (10 mL) was added to a 100 mL round bottom flask under an argon atmosphere. The solution was cooled to —20 °C and n-BuLi (1.6 M in hexanes, 3.0 mL) was added dropwise. After 30 minutes, the bromide 216 (0.33 g, 0.98 mmol) dissolved in THF (10 mL) was transferred to this solution and the temperature was raised to 0 °C. The resulting brown reaction mixture was stirred at 0 °C overnight and then quenched with H20 (10 mL). Diethyl ether (40 mL) was added to extract the product from the aqueous layer. The combined ether layer was washed with 2 N aqueous HCI (10 mL x 3), aqueous NaHCO3 (10 mL) and brine (10 mL x 1) and it was then dried over MgSO, Removal of the solvent under reduced pressure followed by flash chromatography on silica gel (eluant: 10% ethyl acetate in hexanes) provided the title compound 218 (0.27 g, 1.02 mmol, 100%) as a colorless oil which is usually obtained together with a small amount of a yellow impurity. The impurity has a close R, value as 218 but can not be detected in 1H NMR. Compound 218: R, = 0.35 (25% EtOAc in hexanes); 1H NMR (CDC13) 6 0.07 (s, 9H), 1.13-1.23 (b, 1H, OH proton), 1.58 (s, 3H), 1.66 (s, 3H), 2.02-2.28 (m, 8H), 4.13 (d, 2H, J = 6.6 Hz), 5.14 (t, 1H, J = 6.6 Hz), 5.39 (t, 1H, J = 6.6 Hz); 13C NMR (CDC13) 6 0.09, 15.80, 16.22, 19.17, 26.18, 38.52, 39.37, 59.36, 84.55, 107.28, 123.33, 125.04, 133.75, 139.61. 172 Preparation of 2E, 6E-3,7-dimethylundeca-2,6-dien-10-yn-l-ol 209 TMS OH __. _ _ 0H —— 219 209 The TMS protected acetylene 218 (0.23 g, 0.87 mmol) was dissolved in THF (3 mL) and TBAF (1.0 M solution in THF) (3.0 mL) was added at room temperature. The reaction was stirred for 12 hours and quenched with brine (6 mL). The organic layer was separated and combined with the diethyl ether (20 mL) which was added to extract the aqueous layer. The organic layer was washed sequentially with 2 N aqueous HCI (15 mL), aqueous NaHCO3 (15 mL) and brine (15 mL) and then dried with MgSO,. Removal of the solvent under reduced pressure followed by flash chromatography on silica gel (eluant: 25% ethyl acetate in hexanes) provided desired product 209 as colorless 011 (0.131 g, 0.68 mmol, 78%); R, = 0.29 (25% ethyl acetate in hexanes); 1H NMR (CDC13) 6 1.15 (t, 1H, OH, J = 5.0 Hz), 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); 13C NMR (CDC13) 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) 3350 (broad), 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), 161(3), 159(6), 105 (43), 91 (100), 79 (76). 173 Preparation of 2E,6E-8-hydroxy-3,7-dimethylocta-2,6-dienyl acetate 221‘“ NaBH,, 0 °C, 5 min WOAC OHC)—\—>——/—OAC HOWOAC 21 ‘l 232 221 Geranyl acetate 211 (2.0 mL, 9.3 mmol) and selenium dioxide (1.14 g, 10.3 mmol) were dissolved in ethanol (10 mL) (95% aqueous solution) and refluxed under N2 atmosphere for 1 hour. Then the solvent was removed by rotorary evaporator and the residue was taken up in water (10 mL) and diethyl ether (20 mL). The ether layer was separated and washed with NaHCO3 (20 mL), brine (20 mL) and then dried with MgSO4. Removal of solvent under reduced pressure gave the crude product mixture which was comprised mainly of aldehyde 232. R, = 0.50 (25% ethyl acetate in hexanes); 1H NMR (CDC13) 6 1.72-1.73 (m, 6H), 2.03 (s, 3H), 2.20 (t, 2H, J = 1.8 Hz), 2.44-2.51 (m, 2H), 4.57 (d, 2H, J = 7.0 Hz), 5.36 (t, 1H, J = 7.0 Hz), 6.42 (t, 1H, J = 7.0 Hz), 9.37 (s, 1H); 13C NMR (CDCl,) 6 9.24, 16.39, 21.00, 26.95, 27.75, 61.11, 119.62, 139.70, 140.36, 153.33, 171.02, 195.11. The crude product was redissolved in absolute ethanol (10 mL), cooled to 0 °C and briefly (5-10 minutes) treated with NaBH4 (0.39 g, 10.2 mmol). Acetone was added to the stirred reaction mixture after 10 minutes to destroy the excess boron reagent. Then the solvents were removed by rotorary evaporator and the residue was taken up in water (10 mL) and extracted with diethyl ether (10 mL x 3). The combined ether layer was washed with brine (30 mL) and dried over MgSO,,. Removal of the solvent under reduced pressure followed by flash chromatography on silica gel provided compound 221 (0.88 g, 4.72 mmol, 45% over 2 steps from geranyl acetate 211) as a colorless liquid. R, = 0.18 174 (25% ethyl acetate in hexanes); lH NMR (CDC13) 6 1.65 (s, 3H), 1.69 (s, 3H), 2.04 (s, 3H), 2.05-2.09 (m, 2H), 2.13-2.18 (m, 2H), 3.98 (s, 2H), 4.56 (d, 2H, J = 7.2 Hz), 5.32- 5.35 (m, 2H) (OH proton not located); 13C NMR (CDC13) 6 13.68, 16.40, 21.04, 25.64, 39.04, 61.41, 68.92, 118.70, 125.32, 135.27, 141.68, 165.58; IR (neat) 3424 (broad), 2926, 1740 (sharp), 1443, 1368, 1235, 1022 cm". Preparation of 2E, 6E-8-Bromo-3,7-dimethylocta-2,6-dienyl acetate 222‘“ Ho->_\'>=/—0Ac Br—>_\—>=/—0Ac 221 222 A 100 mL round bottom flask was flame dried and charged with argon. To this flask was added allylic alcohol 221 (1.96 g, 9.24 mmol) and dry diethyl ether (25 mL). After the reaction mixture was cooled to 0 °C, catalytic amount of pyridine (37.2 11L, 0.46 mmol) was added followed by slow addition of PBr3 (0.35 mL, 3.7 mmol). After stirring at 0 °C for 4.5 hours, the reaction was carefully quenched by H20 (20 mL). The water layer was extracted with diethyl ether (20 ml. x 3). The ether layer was combined and washed with aqueous NaHCO, solution (50 mL) and brine (50 mL), then dried with MgSO, and concentrated. Flash chromatography on silica gel (eluant: 10% ethyl acetate in hexanes) yielded the desired allylic bromide 222 (1.85 g, 6.75 mmol, 74%) as a colorless oil. R,= 0.53 (25% ethyl acetate in Hexanes); 1H NMR (CDC13) 6 1.68 (s, 3H), 1.73 (s, 3H), 2.03 (s, 3H), 2.03-2.16 (m, 4H), 3.94 (s, 2H), 4.56 (d, 2H, J = 7.2 Hz), 5.32 (t, 1H, J = 7.2 Hz), 5.54 (t, 1H, J = 6.6 Hz); 13C NMR (CDC13) 6 14.66, 16.40, 26.39, 38.54, 41.50, 61.26, 98.55, 118.90, 130.44, 132.45, 141.28, 171.04. These spectral data are comparable with those reported for this compound.63 175 Preparation of 2E, 6E, l0E-1l-iodo-3,7,10-trimethylundeca-2,6-10-trien-l-ol 208 \\ ' _ \WOH _ OH 209 209 A 25 mL round bottomed flask was flame-dried and charged with argon. To this flask was added zirconocene dichloride (0.24 g, 0.79 mmol) and methylene chloride (2 mL). Trimethylaluminum (2 M solution in pentane) (1.16 mL, 2.31 mmol) was added dropwise at 0 °C and a light yellow solution was obtained. After the solution was stirred for 5 minutes, a solution of the terminal alkyne 209 solution (148 mg, 0.77 mmol) in methylene chloride (2 mL) was added and the reaction mixture was stirred at 0 °C for 12 hours. The reaction mixture was cooled to -20 °C and slowly quenched with a solution of iodine (0.78 g, 3.08 mmol) in THF (3 mL). The resultant brown slurry was stirred at 0°C for 5 minutes before it was poured slowly into a mixture of aqueous NaHCO3 (10 mL) and ice chips. The water layer was extracted with pentane (5 mL x 3). The pentane layers were combined, washed with brine (15 mL) and dried with MgSO4. Removal of the solvent followed by flash chromatography on a silica gel column (eluant: 10% ethyl acetate in hexanes) provided the desired product 208 as a colorless oil (0.12 g, 0.36 mmol, 47%). R, = 0.30 (25% ethyl acetate in hexanes); lH NMR(CDC13) 6 1.10 (t, 1H, J = 5.0 Hz, OH proton), 1.57 (s, 3H), 1.66 (s, 3H), 1.80 (s, 3H), 1.97-2.10 (m, 6H), 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, 1H, J = 6.9 Hz), 5.83 (s, 1H); 13C NMR (CDC13) 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) 3312 (broad), 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). 176 Preparation of 2E, 6E, 10E-11-iodo-3,7,lO-trimethylundeca-2,6-lO-trienal 223 OH CHO 209 223 To a solution of allylic alcohol 208 (0.80 g, 2.4 mmol) in methylene chloride (10 mL) under an argon atmosphere was added freshly prepared Dess-Martin reagent45 (1.1 g, 2.6 mmol) as a powder. The reaction 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 diethyl ether (10 mL x 3) was added to extract the product from the reaction mixture. The combined ether layers were dried over MgSO4. Removal of the solvent under reduced pressure followed by flash chromatography on a silica gel column (eluant: 10% ethyl acetate in hexanes) provided the desired aldehyde 223 as a colorless oil (0.784 g, 2.36 mmol, 98%). R, = 0.6 (25% ethyl acetate in hexanes); lH NMR(CDC13) 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 NMR (CDC13) 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. Preparation of Propargyl Alcohol 224 _ _ \\ CHO OH 223 224 Ethynyl magnesium bromide (0.5 M solution in THF) (3.86 mL, 1.93 mmol) was diluted with dry THF (2 mL) and precooled to —30 °C under argon atmosphere. The 177 aldehyde 223 (0.16 g, 0.48 mmol) in THF (2 mL) was added dropwise to the above solution. The reaction mixture was stirred at —30 °C for 30 minutes and quenched with saturated ammonium chloride solution (8 mL). The aqueous layer was extracted with ether (5 m1. x 3). The ether layers were combined, washed with brine (5 mL) and dried with MgSO,. Flash chromatography on a silica gel column (eluant: 10% ethyl acetate in hexanes) provided the desired propargylic alcohol 224 as a colorless oil (0.16 g, 0.45 mmol, 93.1%). R, = 0.43 (25% ethyl acetate in hexanes); 1H NMR (CDC13) 6 1.57 (s, 3H), 1.70 (s, 3H), 1.80 (s, 3H), 2.01-2. 10 (m, 6H), 2.27 (t, 2H, J = 7.2 Hz), 2.47 (d, 1H, J = 2.1 Hz), 5.07 (m, 2H), 5.37 (d, 1H, J = 8.4 Hz), 5.83 (s, 1H) (OH proton not located); l3C NMR(CDC13) 6 15.87, 16.59, 23.86, 25.94, 37.82, 38.22, 39.13, 58.89, 72.49, 74.69, 84.44, 124.09, 124.36, 134.46, 140.77, 147.81; IR (neat) 3400 (broad), 3299, 2919, 2853, 2120 (weak), 1956, 1667 cm". Preparation of Tips Propargyl Ether 225 l _ \\ l _ \\ OH OTips _ -———> _ 224 225 To a solution of propargyl alcohol 224 (1.0 g, 2.8 mmol) in methylene chloride (10 mL) was added 4-dimethylaminopyridine (DMAP) (0.68 g, 5.6 mmol) followed by the addition of triisosilyl chloride (1.2 mL, 5.6 mmol). The reaction mixture was stirred at room temperature for 12 hours and quenched with water (10 mL). Diethyl ether (20 mL x 3) was added to extract the product from the aqueous layer. The organic layers were combined and washed with saturated NH4C1 solution (50 mL), brine (50 mL),and then dried over MgSO,,. Removal of the solvent Under reduced pressure followed by flash 178 chromatography on silica gel (eluant: 10% ethyl acetate in hexanes) provided the desired product 225 as a colorless oil (1.43 g, 2.8 mmol, 100%). R, = 0.8 (25% ethyl acetate in hexanes); 1H NMR (CDC13) 6 1.03-1.13 (m, 21H), 1.57 (s, 3H), 1.65 (s, 3H), 1.80 (s, 3H), 1.98-2.08 (m, 6H), 2.58 (t, 2H, J = 2.7 Hz), 2.41 (d, 1H, J = 2.1 Hz), 5.07-5.12 (m, 2H), 5.32-5.34 (d, 1H, J = 7.8 Hz), 5.84 (s, 1H); 13C NMR (CDCI3) 6 12.19, 15.89, 16.68, 17.90, 23.88, 25.98, 37.90, 38.29, 39.08, 59.94, 71.43, 74.61, 85.08, 124.54, 126.19, 134.25, 136.56, 147.91; IR (neat) 3308, 2942, 2889, 1462 cm"; MS (EI) m/z (% rel intensity) 471 M“- 43 (1.4), 131 (81), 103 (100), 75 (83). Preparation of Fischer Carbene Complex 226 OMe I _ \\ (00150 _ \\ OTips OTips 225 228 Phenyl lithium (1.6 M solution in di-n-butyl ether) (0.43 mL, 0.69 mmol) was added to a solution of vinyl iodide 225 (0.32 g, 0.62 mmol) in THF (20 mL) at -78 °C under an argon atmosphere. After 1.5 hours, tert-butyllithium (1.7 M solution in hexane) (0.83 mL, 1.4 mmol) was added dropwise. The reaction mixture was stirred at -78 °C for 5 minutes followed by addition of Cr(CO),5 (0.24 g, 1.10 mmol). The reaction mixture was stirred at room temperature for 2 hours. Then the solvent was removed by rotary evaporator and the residue was taken up with a deoxygenated 1:1 mixture of methylene chloride/water. Me3OBF4 (0.21 g, 1.42 mmol) was added as a solid and the reaction was stirred under an argon atmosphere for 40 minutes. The reaction was quenched with aqueous NaHCO, (20 mL) and the aqueous layer was extracted with ether ( 15 mL x 3). 179 The combined ether layers were washed with brine (50 mL) and dried over MgSO4. Removal of the solvent under reduced pressure followed by flash chromatography on silica gel (eluant: 10% ethyl acetate in hexanes) provided the desired carbene complex 226 as a red oil (0.2 g, 0.32 mmol, 54%). R,= 0.63 (25% ethyl acetate in hexanes); 1H NMR (CDCI3) 6 1.03-1.10 (m, 21H), 1.60 (s, 3H), 1.65 (s, 3H), 1.82 (s, 3H), 2.00-2.15 (m, 8H), 2.40 (d, 1H, J: 2.1 Hz), 4.69 (s, 3H), 5.01-5.12 (m, 2H), 5.32 (d, 1H, J = 7.8 Hz), 7.20 (s, 1H). General Procedure for Intramolecular Cyclohexadienone Annulation of Fischer Carbene Complex 226 OMe (OC)5CT \\ The carbene complex 226 was dissolved in the appropriate solvent and transferred to a Schlenk flask equipped with a threaded Teflon high vacuum stopcock. The reaction mixture was deoxygenated by freeze-pump-thaw procedure for 3 cycles. Then the flask was back filled with argon at room temperature, the stopcock sealed and the flask heated to the specific temperatures. After the reaction was complete (indicated by the fading of the red color of 226), the solvent was removed in vacuo . The residue was taken up in a 1:1 mixed solvent of ether and methylene chloride and stirred in air for 12 hours. Then the solvent was removed again and the residue was taken up in pure diethyl ether. The insoluable material was removed by filtration through silica gel in a pipette-sized column using ether as the eluant. Concentration of the filtrate provided the crude product mixture 180 which was further purified by flash column chromotography on silica gel (1:1:30 ether: methylene chloride: hexanes as the eluant). The yields obtained were of isolated material after the column chromatography. The ratio of the diastereomers 227 and 228 were determined on the crude reaction mixture by 1H NMR based on the integral of the following vinyl peaks: 6 6.99 for 227 and 6.42 for 228. Cyclization in THF at 60 °C at a concentration of 0.005 M: Fischer carbene complex 226 (31.8 mg, 0.05 mmol) was dissolved in THF (10 mL) to make a 0.005 M solution and thermolyzed for 40 hours to provide 227 (9.5 mg, 0.02 mmol, 40%) and a mixture of 227 and 228 (227:228 = 1:3) (4.6 mg, 0.01 mmol, 20%) after isolation by column chromatography. lH N MR determined ratio 227: 228 = 4: 1. Cyclization in THF at 100 °C at a concentration of 0.005M: Fischer carbene complex 226 (27.9 mg, 0.045 mmol) was dissolved in THF (9 mL) and thermolyzed for 2.5 hours to provide 227 (8.9 mg, 0.02 mmol, 43%), 228 (4.3 mg, 0.01 mmol, 20%) after isolation by column chromatography. The ratio 227: 228 was determined to be 2:1 by 1H NMR on the crude reaction mixture. Cyclization in THF at 80 °C at 3 concentration of 0.005 M: The reaction was performed several times and compound 227 and 228 were obtained with an average combined yield of 50%. The run of the largest scale: Fischer carbene complex 226 (0.66 g, 1.06 mmol) was dissolved in THF (200 mL) and thermolyzed for 22 hours to provide 227 (0.16 g, 0.35 mmol, 33%), 228 (68.0 mg, 0.15 mmol, 14%) after isolation by column chromatography. 1H N MR determined ratio 227: 228 = 3: 1. Cyclization in THF at 80 °C at a concentration of 0.001 M: Fischer carbene complex 226 (63.0 mg, 0.105 mmol) was dissolved in THF (124 mL) and thermolyzed 181 for 15 hours. Compound 227 and 228 (26.3 mg, 0.057 mmol, 55%) were isolated together from flash column chromatography on silica gel. Crude ratio 227:228 = 3: 1 (‘H NMR). Cyclization in THF at 80 °C at a concentration of 0.05 M: Fischer carbene complex 226 (63.0 mg, 0.105 mmol) was dissolved in THF (2.5 mL) and thermolyzed for 15 hours. Compound 227 and 228 (20.1 mg, 0.043 mmol, 41%) were isolated together from a flash column chromatography on silica gel. Crude ratio 227:228 = 3:1 (1H NMR). Cyclization in THF at 80 °C at a concentration of 0.14 M: Fischer carbene complex 226 (67.0 mg, 0.107 mmol) was dissolved in THF (0.76 mL) and thermolyzed for 10 hours. Compound 227 and 228 (15.0 mg, 0.033 mmol, 31%) were isolated together from flash column chromatography on silica gel. Crude ratio 227: 228 = 3:1 (‘H NMR). Cyclization in CH3CN at at 80 °C at 3 concentration of 0.005 M: Fischer carbene complex 242 (32.3 mg, 0.052 mmol) was dissolved in THF (12 mL) and thermolyzed for 14 hours. Compound 227 and 228 (10.0 mg, 0.022 mmol, 42%) were isolated together from flash column chromatography. Crude ratio 227:228 = 2:1 (‘H NMR). Cyclization in benzene at 80 °C at 3 concentration of 0.05 M: Fischer carbene complex 226 (31.2 mg, 0.05 mmol) was dissolved in THF (10 mL) and thermolyzed for 14 hours. Compound 227 and 228 (containing an unknown impurity, 6.4 mg, 0.014 mmol, 28%) were isolated together from flash column chromatography on silica gel. Ratio of 227: 228 can not be determined due to the presence of inseparable impurity. Major isomer 227 was obtained as a light green oil. R, = 0.65 (1:1:10 ether: methylene chloride: hexanes); 1H NMR (CDC13) 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, 182 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 (CDCl,) 6 12.13, 15.28, 15.67, 17.91, 17.96, 25.53, 29.85, 36.24, 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"; MS(EI) 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 CEH“03Si m/z 458.3216, measd 458.3218. Minor isomer 228 was obtained as a light green solid (mp 84—86 °C). R, = 0.60 (1:1:10 ether: methylene chloride: hexanes); 1H NMR (CDC13) 6 0.99-1.03 (m, 21H), 1.12 (s, 3H), 1.35-1.56 (m, 2H), 1.43 (s, 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) 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 C2,,H4603Si m/z 458.3216, measd 458.3216. X-ray crystallography data is available in the Appendics 2. 183 General Procedure of Olefin Cross Metathesis (CM) 1 __ OR Hz 235 R2 0R1 NaBH4 HO 0R1 >=\_>f + A ----r >=\_>=/ —-+ —>=\_>=r 238 239 236 237 2399 R’ = Ac 2373 a? = CHO 2399 R‘ = Ac, R2 = CHO 2399 R‘ = Ac 2369 R‘ = 32 2379 R2 = 0020113 2389 Fi‘ = 82. R2 = CHO 236c R‘ =Tips 239c R‘ = Bz, R2 = COZCH3 2339 R‘ =Tips, 92 = 002CH3 r j QM} CIT 01'7“— PC;\_—_< 235 To a Schlenk flask equipped with threaded Teflon high vacuum stopcock was added the proper geraniol derivative 236, the olefin 237 (0.38 to 3.0 equiv.), Grubb’s catalyst 235 (6.3 mol%) and CHZCIZ. The resultant clear brown solution was deoxygenated using the freeze-pump-thaw procedure (2 cycles). The flask was back filled with argon at room temperature, the stopcock sealed and the flask heated in an oil bath at 40 °C for the specific period of time. To isolate compound 238, the reaction mixture was concentrated and directly loaded onto a silica gel column and eluted with 9:1 mixture of hexane: ethyl acetate. To isolate alcohol 239 via direct reduction, the reaction solvent (CHZCIZ) was removed and the residue was taken up in absolute ethanol at 0 °C. NaBH4 (4.0 equiv) was then added. After 10 minutes, the solvent was removed. The residue was taken up in water, extracted with ether and dried with MgSO4. The product was purified by flash column chromatography on silica gel (eluant: 10% ethyl acetate in hexanes). Geranyl acetate 2363 (same as 211) (R1 = Ac) was commercially available; Geranyl benzoate 236b (same as 213) (R1 = B2) was made and its preparation was described earlier in this chapter. Compound 236c (R1 = Tips) was prepared using the 184 following procedure: To a stirred solution of geraniol (2.17 g, 13.8 mmol) in CHZCl2 (14 mL) was added dimethylaminopyridine (3.4 g, 27.6 mmol) and triisopropylsilyl chloride (6.1 mL, 27.6 mmol). The reaction mixture was stirred at room temperature for 16 hours and quenched with H20 (20 mL). Diethyl ether (20 mL x 2) was added to extract the product from the aqueous layer. The organic layers were combined and washed with 2N aqueous HCI (40 mL) and brine (40 mL) and then dried over MgSO4. Flash column chromatography on silica gel (eluant: 2% ethyl acetate in hexanes) provided 236c (3.8 g, 12.2 mmol, 95%) as a colorless oil. Rf = 0.8 (10% ethyl acetate in hexanes); 1H NMR (CDCI3) 6 l.04-1.08 (m, 21H), 1.58 (s, 3H), 1.59 (s, 3H), 1.66 (s, 3H), 1.96-2.10 (m, 4H), 4.24 (d, 2H, J = 6.1 Hz), 5.08 (t, 1H, J = 7.0 Hz), 5.31 (t, 1H, J = 7.0 Hz); 13C NMR (CDCl3) 6 12.05, 16.41, 17.67, 18.01, 25.68, 26.36, 39.48, 60.51, 124.13, 124.82, 131.49, 136.20; IR (neat) 2944, 2867, 1464, 1063, 883 cm"; MS (EI) m/z (% rel intensity) 295 M*—43 (l), 267 (56), 23909), 211 (7), 137 (100), 103 (31), 81 (59); HRMS (FAB) calcd for C19H390Si m/z 311.2011 (MH*), measd 311.2009. Preparation of 239a via CM Reaction between Geranyl Acetate 236a and Methacrolein 237a _ 0” CH0 235 OHC OAc NaBH, H0 _ OAc — +a ——» r—QJ ———- — 2361! 237a 238a 239: General procedure for the cross metathesis was followed for the reaction of 236a and 237a. The reaction was run four times with different reaction times and different ratios of 236a: 237a. The first run (236a: 237a = 2.6:1): 0.28 mL (1.3 mmol) of 2363 and 40.0 uL (0.48 mmol) of 237a in CH2C12(2.5 mL) with the catalyst 235 (20 mg, 0.023 185 mmol) were reacted for 2 hours followed by the addition of 76.0 mg (2.0 mmol) of NaBH4 in ethanol (2 mL). Compound 239a (R‘= Ac) (34.8 mg, 34%) was obtained as the only isomer. The second run (236a: 237a = 2.6:1): 0.28 mL (1.3 mmol) of 236a and 40.0 uL (0.48 mmol) of 237a in CH2C12(2.5 mL) with the catalyst 235 (20 mg, 0.023 mmol) were reacted for 18 hours followed by the addition of 76.0 mg (2.0 mmol) of NaBH4 in ethanol (2 mL). Compound 239a (R1: Ac) (22.0 mg, 0.10 mmol, 22%) was obtained as the only stereoisomer. The third run (236a: 237a = 2.6:1): 0.14 mL (0.65 mmol) of 236a and 20.0 uL (0.48 mmol) of 237a in CHZCI2 (2.5 mL) were reacted with the catalyst 235 (10 mg, 0.012 mmol) for 24 hours followed by the addition of 38.0 mg (1.0 mmol) of NaBH4 in ethanol (1 mL). Compound 239a (R'= Ac) (4.4 mg, 0.02 mmol, 8.6%) was obtained as the only stereoisomer. The fourth run (236a: 237a = 1:2) geranyl acetate 236a (0.24 mL, 1.10 mmol) and 237a (0.20 mL, 2.40 mmol) in CHZCI2 (10 mL) were reacted with the catalyst 235 (60.0 mg, 0.071 mmol) for 12 hours followed by treatment of NaBH,4 (0.20 g, 5.26 mmol) in ethanol (10 mL) and provided 239a (60.0 mg, 0.28 mmol, 26%) as the only stereoisomer after purification. Characterization of product 239a (221) was accomplished earlier in this chapter. Preparation of 238a via CM Reaction between Geranyl Acetate 236a and Methacrolein 237a >—_\_—>—_=/—0Ac fig) 235 OHWOAC 236a 237a 238‘ Reaction of equal amounts of 236a and 237a (236a: 237a = l: l) were used to prepare 238a following the general procedure for olefin metathesis. The reaction was run 186 two times with an average yield of 39%. The first run reacted 24.0 uL (0.11 mmol) of geranyl acetate 236a with 10.0 uL (0.12 mmol) of 237a in CH2Cl2 (1.0 mL) with the catalyst 235 (6.0 mg, 0.007 mmol) for 10 hours and provided 238a (8.0 mg, 0.038 mmol, 31.7%) as the only stereoisomer after purification. The second run reacted 24.0 uL (0.11 mmol) of geranyl acetate 236a with 10.0 uL (0.12 mmol) of 237a in CHzCl2 (1.0 mL) with the catalyst 235 (6.0 mg, 0.007 mmol) for 12 hours and provided 2383 (same as 232) (10.8 mg, 0.051 mmol, 47 %) as the only isomer after purification. Characterization of product 238a (232) was accomplished earlier in this chapter. Reaction with an excess amount of 237a (236a: 237a = 1: 2) in the preparation of 238a with the general cross metathesis procedure. The reaction was run two times with an average yield of 46%. The first run reacted geranyl acetate 236a (24.0 uL, 0.11 mmol) with 237a (20.0 uL 0.24 mmol) in CHZCI2 (1.0 mL) with the catalyst 235 (6.0 mg, 0.007 mmol) for 10 hours and provided 238a (10.2 mg, 0.048 mmol, 44%) as the only stereoisomer after purification. The second run reacted 0.24 ml. (1.10 mmol) of geranyl acetate 236a with 0.20 mL (2.40 mmol) of 237a in CHZCl2 (10 mL) with the catalyst 235 (60.0 mg, 0.071 mmol) for 12 hours and provided 238a (109.2 mg, 0.52 mmol, 47%) as the only stereoisomer after purification. Reaction of an excess amount of 237a (236a: 237a = l: 3) in the preparation of 238a following the general cross metathesis procedure. Geranyl acetate 236a (24.0 uL, 0.11 mmol) was reacted with 237a (30.0 uL, 0.36 mmol) in CHZCI2 (1.0 mL) with the catalyst 235 (6.0 mg, 0.007 mmol) for 12 hours and provided 238a (14.8 mg, 0.07 mmol, 64%) as the only stereoisomer after purification. 187 Preparation of 238b via CM Reaction between Geranyl Benzoate 236b and Methacrolein 237a _ OBz CHO 235 OHC _ 082 W + /K —~ W 235:: 237. 2381) Following the general cross metathesis procedure this reaction was run starting with a l: 3 mixture of 236b: 237a at two different concentrations. The first run reacted geranyl benzoate 236b (31.7 mg, 0.12 mmol) with 237a (30.0 uL 0.36 mmol) in CHZCl2 (1.0 mL) with the catalyst 235 (6.0 mg, 0.007 mmol) for 14 hours and provided 238b as a colorless oil (8.4 mg, 0.03 mmol, 70% based on reacted 236b) with a stereoisomer ratio of 20:1 (E:Z) after purification. The ratio was determined by 1H NMR based on the following peaks: 6 9.36 and 4.83 for the major isomer; 6 9.48 and 5.14 for the minor isomer. Starting material 236b (20.2 mg, 64%) was also recovered after the reaction. The second run reacted 56.8 mg (0.22 mmol) of geranyl benzoate 236b and 60.0 uL (0.72 mmol) of 237a in CHzCl2 (0.5 mL) with the catalyst 235 (12.0 mg, 0.014 mmol) for 19 hours and provided 238b (14.5 mg, 0.053 mmol, 48% based on reacted 236b) as a colorless oil with a stereoisomer ratio of 20:1 (E:Z) after purification. Starting material 236b (28.0 mg, 49%) and also recovered after the reaction. Compound 238b (214) (R'= Bz, R2 = CHO): R1 = 0.67 (25% ethyl acetate in hexanes); 1H NMR (CDC13) 5 1.73 (s, 3H), 1.79 (s, 3H), 2.45 (t, 2H, J = 7.6 Hz), 2.47-2.52 (m, 2H), 4.83 (d, 2H, J = 7.0 Hz), 5.50 (t, 1H, J = 2.5 Hz), 6.44 (t, 1H, J = 2.5 Hz), 7.40-7.44 (m, 2H), 7.54 (t, 1H, J = 7.0 Hz), 8.02 (d, 2H, J = 7.0 Hz), 9.36 (s, 1H); 13C NMR (CDC13) 6 9.25, 16.49, 26.95, 37.77, 61.57, 119.71, 128.34, 129.55, 130.29, 132.91, 139.67, 140.53, 153.39, 166.57, 195.15; IR (neat) 2928, 2850, 1717, 1686, 1271, 711 cm". 188 Preparation of 238c via CM Reaction between Geranyl Benzoate 236b and Methyl Acrylate 237b W08: £2013 £33» H3C02C>=\—>=/-OBZ 236b 237b 2336 Geranyl benzoate 236b (28.3 mg, 0.11 mmol) was reacted with 237b (30.0 uL 0.36 mmol) in CHzCl2 (1.0 mL) in the presence of catalyst 235 (6.0 mg, 0.007 mmol) according to the geraniol cross metathesis procedure for 14 hours and provided 238c (4.3 mg, 0.016 mmol, 33% based on reacted 237b) as a colorless oil with a stereoisomer ratio of 4:1 (E:Z) after purification. The ratio was determined by 1H NMR based on the following peaks: 6 6.7land 4.82 for the major isomer; 6 6.87 and 4.98 for the minor isomer. Starting material 236b (17.1 mg, 66%) was also recovered after the reaction. Compound 238c (major isomer) (R1: Bz, R2 = COZCH3): Rf = 0.30 (10% ethyl acetate in hexanes); 1H NMR (CDC13) 6 1.77 (s, 3H), 1.82 (s, 3H), 2.15-2.20 (m, 2H), 2.28-2.35 (m, 2H), 3.69 (s, 3H), 4.82 (d, 2H, J = 6.9 Hz), 5.48 (t, 1H, J = 7.2 Hz), 6.71 (t, 1H, J = 7.2 Hz), 7.39-7.45 (m, 2H), 7.50-7.53 (m, 1H), 8.03 (d, 2H, J = 2.0 Hz); 13C NMR (CDCI3) 6 12.43, 16.54, 26.83, 38.04, 51.69, 61.67, 119.24, 127.95, 128.30, 129.59, 130.42, 132.83, 141.10, 141.39, 166.60, 168.55; IR (neat) 2924, 1719, 1271 cm". Preparation of 238d via CM Reaction between Tips Geraniol 236c and Methyl Acrylate 237b _ OTips C02CH3 235 H3C02C _ OTips W + /§ W 236c 237b 23"" 189 The triisopropylsilyl ether of geraniol 236c (0.19 g, 0.65 mmol) was reacted with 237b (25.6 uL 0.24 mmol) in CHZCl2 (1.0 mL) in the presence of the catalyst 235 (10.0 mg, 0.012 mmol) for 12 hours according to the geraniol cross metathesis procedure and provided 238d (27.9 mg, 0.079 mmol, 33%) as a colorless oil with a stereoisomer ratio of 4:1 (E:Z) after purification. The ratio was determined by 1H NMR based on the following peaks: 6 4.22 for the major isomer, and 6 4.41 for the minor isomer. Compound 238d (major isomer) (R1: Tips, R2 = COZCH3): Rf = 0.50 (10% ethyl acetate in hexanes); 1H NMR (CDCl;,) 6 1.04—1.08 (m, 21H), 1.61 (s, 3H), 1.81 (s, 3H), 2.07-2.15 (m, 2H), 2.24—2.32 (m, 2H), 3.07 (s, 3H), 4.22 (d, 2H, J = 6.1 Hz), 5.31-5.35 (m, 1H), 6.69-6.74 (m, 1H); 13C NMR (CDCI3) 6 11.90, 12.02, 16.41, 17.98, 26.97, 37.94, 51.64, 60.40, 125.59, 127.64, 135.05, 141.91, 168.59; IR (neat) 2944, 2867, 1719 cm"; Hydrolysis of Major Key Intermediate 227 to Diketone 240a O OTips O OTips Compound 227 (54.4 mg, 0.12 mmol) was dissolved in THF (8.4 mL) and treated with 10% HCI aqueous solution (7.0 mL) at room temperature. After 2.5 hours, the reaction was diluted with H20 (5 mL) and extracted with diethyl ether (10 mL x 2). The organic layers were combined and washed sequentially with Na2C03 (20 mL) and brine (20 mL) then dried over MgSO4. Flash chromatography on silica gel (eluant: 10% ethyl acetate in hexanes) yielded the purified product 240a (31.0 mg, 0.07 mmol, 60%) as a 190 white solid (mp 85-86 °C). Rf = 0.70 (25% ethyl acetate in hexanes); 1H NMR (CDCl3) 6 1.00 (m, 21H), 1.16 (s, 3H), 1.41-1.50 (m, 1H), 1.57 (s, 3H), 1.66 (s, 3H), 1.93-2.00 (m, 3H), 2.07-2.15 (m, 3H), 2.26-2.31 (m, 1H), 2.45 (d, 1H, J = 15.5 Hz), 2.92 (d, 1H, J = 15.5 Hz), 4.62 (d, 1H, J = 10.0 Hz), 4.67 (d, 1H, J = 10.0 Hz), 5.44 (d, 1H, J = 9.3 Hz), 6.82 (s, 1H); 13C NMR (CDC13) 6 12.12, 16.25, 16.27, 17.89, 17.99, 25.41, 35.09, 36.38, 39.07, 47.94, 50.59, 65.71, 125.04, 126.04, 131.77, 134.91, 138.46, 154.56, 199.65, 201.19; IR (neat) 2946, 2867, 1682 cm"; MS (EI) m/z (% rel intensity) 444 M+ (0.78), 401 (90), 359(9), 291 (5), 237 (8), 131 (12), 103 (28), 75 (100); HRMS (FAB) calcd for C27H4503Si m/z 445.3138 (MHi), measd 445.3136. Anal calcd for C27H4503Si: C, 72.92, H, 9.97. Found: C, 72.65, H, 10.14. Desilylated compound 245 (5.2 mg, 0.018 mmol, 15%) was also produced from this reaction and was isolated as a white solid (mp 162-164 °C). Rf = 0.27 (25% ethyl acetate in hexanes); 1H NMR (CDC13) 6 1.17 (s, 3H), 1.55 (s, 3H), 1.67 (d, 1H, CH, J = 4.5 Hz), 1.72 (d, 3H, J = 1.5 Hz), 1.94-2.30 (m, 8H), 2.51 (d, 1H, J = 15.3 Hz), 2.87 (d, 1H, J = 15.6 Hz), 4.61-4.65 (m, 1H), 4.68-4.69 (m, 1H), 5.46 (d, 1H, J = 9.6 Hz), 6.80 (s, 1H); 13C NMR (CDC13) 6 16.34, 16.40, 25.27, 25.83, 34.80, 36.78, 39.01, 48.20, 51.12, 65.05, 124.58, 125.07, 131.44, 135.08, 141.29, 153.44, 198.98, 201.04; IR (neat) 3476 (broad), 2919, 2861, 1678 cm"; MS (EI) m/z (% rel intensity) 288 M+ (2), 270 (9), 255 (11), 227 (6), 161 (24), 135 (20), 107 (32), 91 (46), 81 (100), 69 (56); HRMS (FAB) calcd for C18H2503 m/z 289.1804 (MH*), measd 289.1803. 191 Formation of Ketal 256 from Major Key Intermediate 227 O OTips O OTips To a round bottomed flask equipped with a condenser was added compound 227 (70.0 mg, 0.15 mmol), benzene (0.5 mL), ethylene glycol (51.0 uL, 0.92 mmol) and TsOH'HZO (10.0 mg, 0.05 mmol). The flask was heated to 90 °C for 21 hours (additional benzene was added during the process to avoid drying out) before it was cooled to room temperature. Then the reaction mixture was diluted with diethyl ether (5 mL) and water (5 mL). The ether layer was separated and washed sequentially with aqueous NaHCO3 (5 mL) and brine (5 mL) and then dried over MgSO4. The product was purified by flash chromatography on silica gel (ether: CH2C12: hexanes = 1:1:20 as the eluant) to provide pure compound 256 (21.9 mg, 0.045 mmol, 30%), mixture of 256 + 240a (27.5 mg, 256: 240a = 1.34: 1) and 240a (5.7 mg, 0.013 mmol, 8.6%). Calculated yield for Compound 256 was obtained as a white solid (mp: 85-86 °C): Rf = 0.50 (1: 1: 10 ethyl acetate: CHZCIZ: hexanes); 1H NMR (CDCI3) 6 0.96-1.01 (m, 21H), 1.17 (s, 3H), 1.37-1.42 (m, 1H), 1.57 (s, 3H), 1.64 (d, 3H, J = 1.2 Hz), 1.69-1.76 (m, 1H), 1.84—2.34 (m, 7H), 2.39 (d, 1H, J = 14.0 Hz), 3.98-4.02 (m, 4H), 4.60-4.63 (m, 2H), 5.33 (dd, 1H, J = 9.5, 1.5 Hz), 6.70 (t, 1H, J = 1.5 Hz); 13C NMR (CDCI3) 6 15.78, 15.91, 17.88, 17.96, 25.51, 27.62, 35.04, 36.50, 39.07, 42.88, 44.50, 64.13, 64.76, 65.49, 104.72, 124.59, 128.08, 135.02, 135.39, 135.80, 143.05, 201.24; IR (neat) 2946, 2689, 1674 cm"; MS (EI) m/z (% rel intensity) 488 M: (3), 445 (25), 401 (15), 359 (12), 314 (31), 286 (22), 233 (19), 175 192 (24), 159 (28), 131 (65), 75 (100); HRMS (FAB) calcd for 9,11,90,81 m/z 489.3400 (MH‘), measd 489.3397. Preparation of 4-Methoxy-2,6,6-trimethylcyclohexa-2,4-dienone 26252 o o 248 262 To a solution of KHMDS (0.5 M solution in toluene) (2.2 mL, 11.0 mmol) in dry THF (12 mL) was added endione 248 (1.55 g, 10.0 mmol) under a N2 atmosphere at —78 °C. After 40 minutes, DMPU (12.0 mL, 10.0 mmol) was added to the above dark red solution and the mixture was stirred for 15 minutes. Upon addition of MeOTf (1.4 mL, 12.0 mmol), the solution turned light yellow. The reaction mixture was stirred at —78 °C for one hour and at 0 °C for 1.5 hours. Then water (30 mL) was slowly added. The aqueous layer was extracted with diethyl ether (20 mL x 3), and the combined ether layer was washed sequentially with H20 (50 mL) and brine (50 mL) and then dried over Na2SO4 and concentrated. Flash column chromatography on Et3N treated silica gel using ethyl acetate/hexanes (1:9) as eluant afforded the desired enol ether 262 (1.30 g, 7.70 mmol, 78%) as a yellow oil. R, = 0.5 (ether/hexanes 1:4); 1H NMR (CDCI3) 6 1.19 (s, 6H), 1.86 (d, 3H, J = 0.6 Hz), 3.56 (s, 3H), 4.99 (d, 1H, J = 3.0 Hz), 6.65-6.66 (m, 1H); 13C NMR (CDCl3) 6 15.30, 27.57, 44.91, 54.57, 111.09, 133.60, 137.98, 148.66, 165.56, 205.80; IR (neat) 2969, 1651, 1607, 1372, 1146 cm". The spectral data are identical with those reported for this compound.64 193 Formation of 263 and 266 from Cyclopropanation and Hydrolysis of 262 O HO HOE g OMe OMe O 262 263 266 To a solution of compound 262 (69.0 mg, 0.42 mmol) in toluene (1 mL) was added diethyl zinc (15% solution in toluene) (0.76 mL, 0.84 mmol) at 0 °C under an argon atmosphere. CH212 (68 uL, 0.84 mmol) was added to the resulting solution followed by the removal of the ice bath. The formation of a white suspension was observed as the reaction progressed. The mixture was stirred at room temperature for 15 minutes and quenched with aqueous NH4Cl (2 mL). The aqueous layer was extracted with ether (2 mL x 2) and the combined organic layer was washed with brine (5 mL), dried over N31804 and concentrated. After flash chromatography on silica gel using a 1:4 mixture of ether/hexanes as the eluant, compound 263 (32 mg, 0.15 mmol, 36%) (R{ = 0.16 in 1:9 ethyl acetate/hexanes) was separated from the unreacted 262 as a single diastereomer and as a colorless oil. Spectrum data for 263: 1H NMR (CDCI3) 6 0.31 (d, 1H, J = 4.8 Hz), 0.78 (d, 1H, J = 5.1 Hz), 0.907 (t, 3H, J = 7.8 Hz), 1.16 (s, 3H), 1.21 (s, 3H), 1.28 (s, 3H), 1.38-1.48 (m, 1H), 1.69 (s, 1H), 1.74—1.83 (m, 1H), 2.25 (t, 1H, J = 2.1 Hz), 3.43 (s, 3H), 4.23 (s, 1H); 13C NMR (CDCI3) 6 12.29, 17.34, 21.83, 25.40, 26.58, 27.25, 27.78, 36.63, 45.87, 53.75, 66.50, 103.07, 155.21; IR (neat) 3418 (broad), 2985, 2938, 2872, 1667, 1167 cm“; MS (EI) m/z (% rel intensity) 210 M+ (65), 193 (65), 181 (100), 163 (43), 149 (42), 139 (51), 123 (44), 107 (28). Ketone 266 was obtained by hydrolyzing compound 263 (32.0 mg, 0.15 mmol) with 10% aqueous HCI (1.0 mL) in methanol (1.0 mL) at room temperature overnight. 194 Yield of 266 was not determined. Compound 266: R, = 0.05 (1:9 ethyl acetate/hexanes); 1H NMR (CDC13) 6 0.52 (d, 1H, J = 6.0 Hz), 0.65 (d, 1H, J = 6.0 Hz), 0.92 (t, 3H, J = 7.5 Hz), 1.13 (s, 3H), 1.23 (s, 3H), 1.28 (s, 3H), 1.54-1.59 (m, 1H), 1.77 (s, 1H), 1.89- 1.94 (m, 1H), 2.03 (d, 1H, J = 18.5 Hz), 2.25 (d, 1H, J = 18.0 Hz), 2.33-2.36 (m, 1H); 13C NMR (CDC13)6 12.98, 17.58, 23.01, 23.58, 26.35, 26.74, 27.94, 36.00, 51.23, 56.22, 65.80, 212.61; IR (neat) 3451, 2960, 2928, 2850, 1691, 1460, 1154 cm"; MS (EI) m/z (% rel intensity) 196 M” (20), 179 (23), 167 (54), 154 (56), 139 (18), 125 (31), 112 (68), 97 (61), 83 (67), 70 (100), 55 (58). Preparation of 4-Methoxy-2,2,6-trimethylcyclohex-3-enone o o OMe OMe 282 267 To a solution of compound 262 (58.0 mg, 0.35 mmol) in THF (1 mL) at —78 °C was added L—selectn'de (1.0 M solution in THF) (0.4 mL, 0.4 mmol). After 40 minutes, 10% aqueous NaOH (0.7 mL) was added at 0 °C followed by addition of H202 (30%, 0.5 mL). The mixture was stirred at 0 °C for 30 minutes and warmed to room temperature for 1 hour. Then the aqueous layer was extracted with diethyl ether (3 mL x 3). The combined organic layer was washed with brine (6 mL) and dried over NaZSO4. Concentration followed by flash chromatography on Et3N treated silica gel provided the desired compound 267 as a colorless oil (54.8 mg, 0.32 mmol, 93%). R, = 0.6 (1:3 ethyl acetate/hexanes); 1H NMR (C6D6) 6 0.91 (d, 3H, J = 6.6 Hz), 1.01 (s, 3H), 1.16 (s, 3H), 2.19-2.27 (m, 1H), 2.40-2.53 (m, 1H), 2.85-3.00 (m, 1H), 3.06 (s, 3H), 4.16 (d, 1H, J = 195 1.7 Hz); 13C NMR (C6D6) 6 14.27, 26.67, 30.10, 36.71, 38.61, 43.21, 54.09, 102.85, 153.24, 213.77; IR (neat) 2969, 1715, 1669 cm"; MS (EI) m/z (% rel intensity) 169 M+ + 1 (45), 168(14), 151 (22), 140 (15), 125 (100), 93 (14). Preparation of 4-Methoxy-2,2,6-trimethylcyclohex-3-enol 269 O OH OMe OMe 267 269 LAH (9.6 mg, 0.25 mmol) was suspended in dry ether (4 mL) and cooled to 0 °C under an argon atmosphere. Then compound 267 (80.6 mg, 0.48 mmol) was dissolved in ether (1 mL) and added to this suspension. The reaction mixture was stirred at 0 °C for 3 hours, warmed to room temperature for another 3 hours and quenched slowly with H20 (4 mL). The insoluble material was removed by filtration through Celite and to the filtrate was added ether (10 mL). The ether layer was separated, washed with brine (10 mL) and dried over Na2804. After flash chromatography on Et3N treated silica gel (eluant: 10% ethyl acetate in hexanes), compound 269 (47.0 mg, 0.28 mmol, 58%) was obtained as a mixture of diastereomers (3:1). The diastereomeric ratio was determined by 1H NMR from the integral of the vinyl proton: 6 4.25 (major) and 6 4.10 ppm (minor). The following data for the major isomer were extracted from the 3:1 mixture of diastereomers. R, = 0.2 (1:3 ethyl acetate/hexanes); 1H NMR (C6D6) 6 0.85 (d, 3H, J = 6.0 Hz), 0.96 (s, 3H), 1.11 (s, 3H), 1.17 (d, 1H, J = 5.8 Hz, OH proton), 1.72-2.00 (m, 2H), 2.02-2.22 (m, 1H), 2.89-2.94 (m, 1H), 3.18 (s, 3H), 4.25 (s, 1H); 13C NMR (C6D6) 6 18.12, 23.92, 29.68, 31.54, 36.49, 36.76, 53.75, 80.86, 103.92, 152.86; IR (neat) 3410, 196 2955, 1670 cm“; MS (EI) m/z (% rel intensity) 170 M+ (16), 155 (21), 137 (28), 122 (8), 112 (47), 97 (100), 79 (16), 67 (25). Formation of 270 and 271 from Cyclopropanation and Hydrolysis of 269 OH OH OH 269 270 271 To a solution of compound 269 (3: 1) (45.0 mg, 0.26 mmol) in benzene (3 mL) at 0 °C was added diethyl zinc (1.0 M solution in hexanes) (0.52 mL, 0.52 mmol) under an argon atmosphere. The reaction was stirred for 5 minutes and then CH212 (42 uL, 0.52 mmol) was added dropwise. After one hour, the white reaction mixture was quenched with H20 (3 mL) and extracted with ether (3 mL x 2). The ether layer was combined, dried over Na2SO4 and concentrated. After flash chromatography on silica gel with 10% ethyl acetate in hexanes as eluant, two diastereomers of compound 270 were obtained and separated: minor isomer (8.5 mg, 0.043 mmol, 17.8%), R, = 0.2 (1:9 ethyl acetate: hexanes); major isomer (37.6 mg, 0.19 mmol, 78.6%), R, = 0.1 (1:9 ethyl acetate: hexanes). Minor isomer of 270 was obtained as a white solid: 1H NMR (CDC13) 6 0.63-0.65 (m, 1H), 0.72-0.74 (m, 1H), 0.81-0.84 (m, 1H), 0.94 (d, 3H, J = 6.5 Hz), 1.06 (s, 3H), 1.07 (s, 3H), 1.16 (d, 1H, J = 3.2 Hz), 1.56 (s, 1H), 1.68-1.74 (m, 1H), 1.90-1.95 (m, 1H), 3.10 (s, 1H), 3.21 (s, 3H); 13C NMR (CDCI3) 6 18.32, 18.49, 25.07, 29.41, 29.87, 30.28, 31.06, 33.63, 53.63, 62.14, 79.40; IR (neat) 3476 (broad), 2932, 2870, 1464, 1067 cm"; 197 MS (EI) m/z (% rel intensity) 184 M“ (4), 169 (13), 151 (44), 137 (100), 123 (25), 111 (87), 109 (75), 97 (53), 85 (50), 67 (54), 55 (69). Major isomer of 270 was obtained as a solid: 1H NMR (CDC!_,) 6 0.38 (t, 1H, J = 5.5 Hz), 0.69-0.72 (m, 1H), 0.78 (s, 3H), 0.94 (d, 3H, J = 6.0 Hz), 1.20 (s, 3H), 0.9-1.22 (m, 2H), 1.35 (s, 1H, OH proton), 1.64 (t, 1H, J = 12.0 Hz), 2.19-2.22 (dd, 1H, J = 12.5, 4.0 Hz), 2.90-2.92 (m, 1H), 3.21 (s, 3H); 13C NMR (CDC13) 6 14.65, 18.22, 20.26, 29.91, 31.30, 31.95, 33.92, 35.58, 53.59, 61.96, 82.27; IR (neat) 3476 (broad), 2951, 2930, 1464, 1371, 1084, 1039 cm"; MS (EI) m/z (% rel intensity) 184 M” (3), 169 (11), 151 (28), 137 (55), 123 (16), 111(100), 97 (50), 85 (57), 67 (36), 55 (39). The major isomer of compound 270 (37 mg, 0.2 mmol) was dissolved in methanol (1.5 mL) and treated with 10% aqueous HCI (1 mL) at room temperature. The reaction was monitored by TLC analysis. After stirring for 13 hours, only clean starting material was observed by TLC. Then the reaction was warmed to 80 °C for 12 hour and the reaction was still not complete. The reaction was further warmed to 100 °C and refluxed for 12 hours. Then reaction mixture was cooled down, concentrated and extracted with diethyl ether (2 mL x 2). The combined ether layer was washed with aqueous NaHCO3 (4 mL), brine (4 mL) and dried over MgSO4. Concentration followed by flash chromatography on silica gel using ethyl acetate/hexanes (1: 9) as the eluant afforded recovered starting material (5.4 mg, 14%) and compound 271 (22.3 mg, 0.17 mmol, 85%) as a white solid. R, = 0.08 (1:9 ethyl acetate/hexanes); 1H NMR (CDC13) 6 0.66 (s, 3H), 0.95 (d, 3H, J = 6.9 Hz), 1.09 (s, 3H), 1.10 (d, 3H, J = 6.0 Hz), 1.72 (broad, 1H), 1.91 (m, 1H), 2.08 (m, 1H), 2.24—2.38 (m, 2H), 3.32 (d, 1H, J = 10.2 Hz); l3C NMR (CDCl3) 6 7.75, 14.20, 19.40, 25.61, 29.66, 35.44, 47.54, 52.37, 81.93, 210.95. 198 Preparation of 4-Methoxy-l,2,2,6-tetramethylcyclohex-3-enol 272 0 H0 267 272 A solution of MeMgBr (3 M in ether) (0.32 mL) was diluted with dry ether (4 mL) and cooled to 0 °C under an argon atmosphere. Compound 267 (80 mg, 0.48 mmol) was dissolved in ether (1 mL) and added to this solution. The reaction was stirred at 0 °C for 3 hours. The reaction was quenched with H20 (4 mL) and extracted with ether (4 mL x 2). The combined ether layer was washed with brine (8 mL) and dried over Na2S04. After concentration and flash chromatography on Et3N treated silica gel using 1: 19 mixture of ethyl acetate/hexanes as the eluant, compound 272 (67 mg, 0.36 mmol, 76%) was obtained as a single diastereomer and a colorless oil. R, = 0.3 (1: 9 ethyl acetate/hexanes); 1H NMR (CDCI3) 6 0.97 (d, 3H, J = 6.7 Hz), 1.00 (s, 3H), 1.01 (s, 3H), 1.04 (s, 3H), 1.08 (s, 1H), 1.76-1.83 (m, 1H), 2.07-2.11 (m, 1H), 2.15-2.26 (m, 1H), 3.44 (s, 3H), 4.27 (d, 1H, J = 1.5 Hz); 13C NMR (CDC13) 6 14.60, 16.51, 24.94, 26.39, 33.78, 35.63, 39.27, 54.08, 75.47, 104.58, 152.11; IR (neat) 2961, 1667, 1466, 1375, 1227, 1159 cm"; MS (EI) m/z (% rel intensity) 184 M+ (71), 167 (100), 151 (11), 141 (7), 113(51), 97 (55). 199 Preparation of 6-Methoxy-2,2,3,4-tetramethylbicyclo[4.l.10]heptan-3-ol 273 HO HO OMe OMe 272 273 To a solution of compound 272 (60.0 mg, 0.26 mmol) in benzene (3.0 mL) at 0 °C was added diethyl zinc (1.0 M solution in hexanes) (0.64 mL, 0.64 mmol) under an argon atmosphere. The reaction was stirred for 5 minutes and then CH212 (51.5 uL, 0.64 mmol) was added dropwise. After one hour, the white reaction mixture was quenched with H20 (5 mL) and extracted with ether (5 mL x 2). The ether layers were combined, dried over NazSO4 and concentrated. Flash chromatography on silica gel (eluant: 10% ethyl acetate in hexanes) provided two isomers of 273. The major isomer of 273 (37.0 mg, 0.15 mmol, 59%) was obtained as a white solid (mp 72-74 °C). R, = 0.15 (1:9 ethyl acetate/hexanes); 1H NMR (CDC13) 6 0.32-0.34 (m, 1H), 0.68-0.72 (m, 1H), 0.85 (s, 3H), 0.89-0.91 (m, 5H), 1.09 (s, 3H), 1.11 (s, 3H), 1.41-1.46 (m, 1H), 1.64—1.70 (m, 1H), 2.14- 2.18 (m, 1H), 3.21 (s, 3H); 13C NMR (CDC13) 6 14.25, 14.83, 17.22, 23.00, 27.18, 31.80, 32.09, 34.58, 36.27, 53.34, 60.77, 75.52; IR (neat) 3476, 2969, 2919, 1460, 1204 cm"; MS (EI) m/z (% rel intensity) 180 M*-18 (10), 165 (34), 148 (26), 133 (30), 127 (28), 123 (35), 111 (100), 95 (61), 79 (37), 55 (33). The minor major isomer (6.0 mg, 0.024mmol, 9%) was isolated as a white solid. R, = 0.24 (1:9 ethyl acetate/hexanes); 1H NMR (CDCI3) 6 0.67-0.69 (m, 1H), 0.75-0.76 (m, 3H), 0.85 (d, 3H, J = 8.5 Hz), 1.05 (s, 6H), 1.09 (s, 3H), 1.48 (s, 1H), 1.80-1.98 (m, 2H), 3.21 (s, 3H). 200 Formation of Compound 277 from L-Selectride Reduction of Key Intermediates 227 O OTips L-selectride (1.0 M in THF) (0.35 mL, 0.35 mmol) was added to the solution of intermediate 227 (80.0 mg, 0.17 mmol) in THF (0.5 mL) at room temperature under an argon atmosphere. After 23 hours, the reaction was quenched with water (1.0 mL), extracted with diethyl ether (2.0 mL) and the ether layer was dried over Na2S04. Concentration followed by flash column chromatography (eluant: 1: 1:30 CHZCIZ: ether: hexanes) on silica gel provided Compound 277 (22.3 mg, 0.08 mmol, 79% based on reacted SM) was obtained together with recovered 227 (35.5 mg, 45%) and a small amount of by-product (4.6 mg, 9%) which could be the ketone after the hydrolysis of enol ether 277 (no clean spectral data of the by-product available). Compound 277 (R, = 0.18 in 1:1:30 ether/methylene chloride/hexanes) was obtained as a colorless oil. Spectrum data of 277: 1H NMR (C6D6) 6 1.00 (m, 1H), 1.09 (s, 3H), 1.10-1.20 (m, 1H), 1.57 (s, 3H), 1.66 (m, 1H), 1.71 (s, 3H), 1.78 (m, 1H), 1.88 (d, 1H, J = 14 Hz), 1.98-2.19 (m, 4H), 2.30-2.46 (m, 2H), 2.54-2.68 (m, 2H), 3.23 (s, 3H), 4.02 (s, 1H), 4.6 (d, 1H, J = 10 Hz), 5.11 (t, 1H, J = 8 Hz); 13C NMR (C6D6) 6 15.44, 17.27, 25.37, 25.91, 30.66, 32.38, 36.84, 37.46, 37.91, 45.45, 47.18, 54.11, 99.45, 122.10, 126.30, 134.96, 135.31, 154.91, 211.68; IR (neat) 2919, 2849, 1705, 1678, 1653 cm"; MS (EI) m/z (% rel intensity) 288 M+ (11), 241 (3), 205 (10), 151 (25), 139 (100), 123 (42), 109 (30). 201 Formation of Compound 277 from L-Selectride Reduction of Key Intermediates 228 O QTips 228 L-selectride (0.2 mL, 0.2 mmol) was added to neat 228 (30.0 mg, 0.065 mmol) at room temperature and stirred for 1 hour. Then the reaction was quenched with water (1.0 mL), extracted with diethyl ether (2.0 mL) and the ether layer was dried over NaQSO4. Concentration followed by flash column chromatography (eluant: 1: 1:30 CHZCIZ: ether: hexanes) on silica gel provided compound 277 (20.0 mg, 0.065 mmol, quantitative) as the only product after flash column chromatography on silica gel. Preparation of 4-Hydroxy-3,5,5-trimethylcyclohex-Z-enone 285 0 OH 8? <9“ 248 285 To a solution of 248 (0.125 g, 0.80 mmol) in MeOH (1 mL) was added NaBH4 (8.0 mg, 0.2 mmol) at 0 °C. After 30 minutes, acetone (1 mL) was added at room temperature and the mixture was stirred at room temperature for 10 minutes. Then the reaction mixture was concentrated, diluted with ether (3 mL) and washed with H20 (3 mL). The organic layer was separated and dried with MgSO4. Concentration followed by flash column chromatography on silica gel using 1:9 ethyl acetate/hexanes as the eluant provided the known enone compound 28557 (90.0 mg, 0.58 mmol, 72%) as a colorless oil. R, = 0.25 (1:3 ethyl acetate/hexanes); 1H NMR (CDC13) 6 0.98 (s, 3H), 1.04 (s, 3H), 2.01 202 (s, 3H), 2.55 (broad, 1H), 2.14-2.39 (dd, 2H, J = 58.5, 16.5 Hz), 4.0 (s, 1H), 5.82 (s, 1H); l3C NMR (CDCI3) 6 21.29, 21.50, 26.86, 38.47, 48.91, 76.61, 125.99, 161.81, 199.36. LAH Reduction of Ketone 227 to Alcohol 290 followed by its Hydrolysis to 281 OH OTips Compound 227 (37.4 mg, 0.08 mmol) was dissolved in dry THF (0.8 mL) under an argon atmosphere and lithium aluminum hydride (12.0 mg, 0.32 mmol) was added quickly as a powder to this solution at room temperature. The reaction was stirred for 17 h and quenched with H20 (2 mL). The aqueous layer was extracted with diethyl ether (2 mL x 2). The ether layers were combined and dried with Na,SO4. Filtration followed by concentration provided the crude product 290 which contained a small amount of 227 (290: 227 > 10: 1). The ratio was determined by 1H NMR based on the integral of the following peaks: 6 6.99 (vinyl) and 3.63 (methoxy) for 227; 6 5.95 and 3.48 for 290. R, = 0.3 (1:1:30 ether/methylene chloride/hexanes); The 1H NMR was obtained on the 1: 6 mixture of 290 and 227. 1H NMR (CDC13) 6 0.98-1.04 (m, 21H), 1.19 (s, 3H), 1.15-1.28 (m, 2H), 1.58 (s, 6H), 1.63 (s, 1H), 1.78-1.98 (m, 2H), 2.00-2.35 (m, 4H), 3.48 (s, 3H), 4.23 (d, 1H, J = 6.6 Hz), 4.29 (d, 1H, J = 1.5 Hz), 4.89-4.99 (m, 2H), 5.11-5.13 (m, 1H), 5.95 (s, 1H); MS (EI) m/z (% rel intensity) 460 M* (3), 417 (1), 324 (4), 279 (10), 241 (14), 189 (67), 131 (47), 81 (74), 75 (100). The crude compound 290 obtained above was treated with HCI ( 1% aqueous solution) (50.0 ptL) in MeOH (0.2 mL) at room temperature for 3 minutes. A white 203 suspension was observed immediately. Then ether (2 mL) and water (2 mL) was added. The organic layer was separated, washed with aqueous NaHCO,, (2 mL) and brine (2 mL) and then dried over MgSO4. Filtration and concentration followed by flash chromatography using 1:1:30 ether/methylene chloride/hexanes provided compound 281 (11.7 mg, 0.026 mmol, 32% two steps) as a white, crystalline solid (mp 140-142 °C). R, = 0.2 (1:1:10 ether/methylene chloride/hexanes); 1H NMR (CDC13) 6 0.84-0.87 (m, 1H), 1.01 (d, 21H), 1.19 (s, 3H), 1.22-1.40 (m, 2H), 1.61 (s, 6H), 1.94-2.44 (m, 8H), 4.30 (dd, 1H, J: 13.2, 2.7 Hz), 4.84 (d, 1H, J = 9.3 Hz), 4.95 (d, 1H, J = 8.7 Hz), 5.18 (d, 1H, J = 9.3 Hz), 6.33 (t, 1H, J = 1.2 Hz); 13C NMR (CDC13) 6 12.16, 16.36, 17.90, 18.01, 18.74, 24.33, 31.70, 31.94, 38.89, 44.36, 55.08, 67.85, 78.33, 123.18, 125.45, 129.13, 136.55, 138.27, 167.43, 198.33; IR (neat) 3468, 2910, 2865, 1671 cm“; MS (EI) m/z (% rel intensity) 446 M+ (0.12), 403 (13), 385 (4), 335 (3), 211 (7), 131 (21), 103 (37), 81 (60), 75 (100). LAH Reduction of 228 to Unexpected Compounds 291 and 292 Compound 228 (10.9 mg, 0.024 mmol) was dissolved in dry THF (0.3 mL) under an argon atmosphere and lithium aluminum hydride (3.6 mg, 0.096 mmol) was added quickly as a powder to this solution at room temperature. The reaction was stirred for 30 min and quenched with H20 (2 mL). The aqueous layer was extracted with diethyl ether (2 mL x 2). The ether layers were combined and dried with NaZSO4. Filtration followed 204 by concentration provided crude product 291 as a white solid (mp 99-101 °C). R,= 0.13 (1: 1: 30 ether/methylene chloride/hexanes). 1H NMR (CDCI3) 6 0.86-1.40 (m, 2H), 1.19 (s, 3H), 1.47 (s, 3H), 1.55 (s, 3H), 1.90-2.40 (m, 6H), 2.58 (d, 1H, J = 18.0 Hz), 2.02 (d, 2H, J = 18.0 Hz), 3.44 (s, 3H), 4.23 (d, 1H, J = 1.8 Hz), 4.29 (d, 1H, J = 9.0 Hz), 4.86 (d, 1H, J = 12.0 Hz), 6.09 (d, 1H, J = 9.0 Hz), 6.44 (d, 1H, J = 9.0 Hz); 13’C NMR (CDC13) 6 15.67, 23.35, 25.41, 34.17, 36.97, 39.27, 39.96, 41.30, 54.38, 83.88, 105.53, 121.80, 123.55, 124.06, 128.32, 133.55, 136.99, 138.76, 152.18; IR (neat) 3517, 2919, 2851, 1663, 1616 (weak), 1449, 1215 cm"; MS (131) m/z (% rel intensity) 288 M+ (19), 217 (16), 152 (54), 137 (100), 95 (46), 43 (37). The crude compound 291 obtained above was treated with HCl (1% aqueous solution) (20.0 11.1.) in MeOH (0.1 mL) at room temperature for 3 minutes. A white suspension was observed immediately. Then ether (2 mL) and water (2 mL) was added. The organic layer was separated, washed with NaHCO3 (2 mL) and brine (2 mL) and then dried over MgSO4. Filtration and concentration followed by flash chromatography using ether/methylene chloride/hexanes (1: 1 :30) provided compound 292 (2.0 mg, 0.007 mmol, 32% in two steps) as a white solid. R, = 0.05 (l: 1: 10 ether/methylene chloride/hexanes). 1H NMR (CDCI3) 6 0.80-0.85 (m, 1H), 1.00-1.80 (m, 4H), 1.23 (s, 3H), 1.54 (s, 3H), 1.58 (s, 3H), 1.85-2.43 (m, 6H), 2.87 (dd, 1H, J = 3.0, 1.5 Hz), 3.14 (d, 1H, J = 13.8 Hz), 4.57 (d, 1H, J = 7.5 Hz), 4.88 (d, 1H, J = 11.0 Hz), 6.07 (d, 1H, J = 10.8 Hz), 6.52 (d, 1H, J = 10.2 Hz); 13‘C NMR (CDC13) 6 15.61, 23.25, 26.09, 29.69, 32.71, 34.12, 39.78, 42.53, 53.50, 56.62, 84.23, 123.57, 124.40, 124.94, 130.53, 137.27, 138.28, 206.78; IR (neat) 3500 (broad), 2923, 2851, 1711, 1603, 1452 cm"; MS (EI) m/z 205 (% rel intensity) 272 M+ (21), 254(5), 239 (5), 211 (8), 201 (65), 199 (61), 173 (32), 159 (35), 129 (31), 105 (38), 91 (67), 77 (61), 43 (100). Convertion of 228 to 306 via Peterson Olefination 0 Q‘fips TMSHzC OH QTIDS A solution of trimethylsilylmethyl lithium (1.0 M in pentane) (85.0 uL, 0.085 mmol) was added to a stirred solution of 228 (13.0 mg, 0.028 mmol) in dry THF (0.3 mL) at room temperature under an argon atmosphere. The reaction mixture was stirred for 10 minutes and then it was quenched with H20 (2 mL). Diethyl ether (2 mL x 3) was added to extract the product from the reaction mixture. The ether layers were combined and dried with NaZSO4. Concentration in vacuo provided crude 304 (10.0 mg, 0.019 mmol, 68%) as a white solid. R, = 0.50 (5% ethyl acetate in hexanes); 1H NMR (CDC13) 6 0.00 (s, 9H), 0.65-0.90 (m, 1H), 1.03-1.04 (m, 21H), 1.20-1.25 (m, 3H), 1.40-1.65 (m, 2H), 1.45 (s, 3H), 1.52 (s, 3H), 1.50-1.60 (m, 4H), 1.80-1.90 (m, 1H), 1.95-2.25 (m, 3H), 3.49 (s, 3H), 4.33 (d, 1H, J = 2.4 Hz), 4.75-4.82 (m, 1H), 5.04 (d, 1H, J = 7.5 Hz), 5.41 (d, 1H, J = 2.4 Hz), 5.51 (d, 1H, J = 7.5 Hz); To the solution of crude intermediate 304 in THF (0.4 mL) was added KO‘Bu (7.0 mg, 0.06 mmol). The orange mixture was stirred at room temperature for 2 hours and carefully quenched by water (2 mL). The mixture was extracted with diethyl ether (2 mL x 2). The combined ether layer was dried with NaZSO4 and concentrated in vacuo to leave crude compound 305 (7.0 mg, 0.015mm01, 54%) as a white solid after purification by 206 flash column chromatography on Et3N treated silica gel (eluant: 2% ethyl acetate in hexanes). R,= 0.55 (5% ethyl acetate in hexanes); 1H NMR (CDC13) 6 0.80-0.90 (m, 2H), 1.00—1.01 (m, 21H), 1.11 (s, 3H), 1.36 (s, 3H), 1.42 (s, 3H), 1.50-2.40 (m, 6H), 3.50 (s, 3H), 4.50 (s, 1H), 4.64-4.70 (m, 1H), 4.94 (d, 1H, J = 7.2 Hz), 5.17 (s, 1H), 5.47 (d, 1H, J = 7.2 Hz), 5.58 (s, 1H), 5.95 (s, 1H); MS (EI) m/z (% rel intensity) 456 M+ (3.3), 413 (45), 345 (3), 305 (4), 265 (10), 171 (23), 131 (83), 103 (50), 81 (68), 75 (100); Intermediate 305 (7.0 mg, 0.015 mmol) was dissolved in methanol (0.3 mL) and treated with 1% aqueous HCl (0.2 mL). After stirring at room temperature for 10 minutes, diethyl ether (2 mL) was added to the reaction mixture. The ether layer was separated, dried over MgSO4 and concentrated in vacuo to provide crude 306. The product was purified by flash column chromatography on silica gel (2% ethyl acetate in hexanes as the eluant) and obtained as a white solid (5.0 mg, 0.11 mmol, 40% over 3 steps). R, = 0.34 (5% ethyl acetate in hexanes); 1H NMR (CDC13) 6 0.75-0.90 (m, 1H), 1.00-1.03 (m, 21H), 1.10 (s, 3H), 1.20-1.70 (m, 3H), 1.34 (s, 3H), 1.38 (s, 3H), 1.90-2.20 (m, 5H), 2.40-2.46 (d, 1H, J = 15.0 Hz), 4.61-4.64 (m, 1H), 4.98 (d, 1H, J = 7.8 Hz), 5.42 (d, 1H, J = 7.5 Hz), 5.46 (s, 1H), 5.78 (s, 1H), 6.44 (s, 1H); 13C NMR (CDC13) 6 12.07, 14.89, 17.92, 24.12, 24.63, 29.50, 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, 186.09, 200.74; MS (EI) m/z (% rel intensity) 442 M+ (3), 399 (41), 225 (3), 131 (31), 103 (55), 75 (100). 207 Methylation of 306 to Form 307 307 To a solution of ketone 306 (9.0 mg, 0.02 mmol) in dry THF (0.2 mL) under an argon atmosphere was added lithium hexamethyldisilazide (LHMDS) (1.0 M solution in hexanes) (30 uL, 0.03 mmol) at —78 °C. The mixture was stirred at —78 °C for 1 hour and Mel (5.7 mg, 2.5 uL, 0.04 mmol) was added to this mixture. The reaction mixture was warmed to room temperature and stirred for 18 hours before it was quenched with water (2 mL). Diethyl ether (2 mL x 2) was added. The combined ether layer was dried with MgSO4, concentrated in vacuo to yield the crude product 307 (8.5 mg, 0.019mmol, 95%) as a white solid. The product can be purified by flash chromatography (R, = 0.225 in 5% hexane solution of ethyl acetate) or recrystallized from hexanes. 1H NMR (CDCl,) 6 0.80-0.90 (m, 1H), 0.98-1.01 (m, 27H), 1.20-1.30 (m, 1H), 1.34 (s, 3H), 1.37 (s, 3H), 1.65-1.70 (m, 1H), 1.94—2.15 (m, 6H), 4.62 (d, 1H, J = 10.0 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 (CDCl,) 6 12.03, 13.66, 15.11, 17.91, 21.19, 24.15, 29.67, 34.63, 36.43, 39.30, 45.82, 55.00, 76.25, 122.85, 123.72, 124.96, 129.76, 134.74, 134.80, 142.10, 155.02, 205.67; IR (neat) 2942, 2867, 1678 cm"; MS (EI) m/z (% rel intensity) 456 M" (2), 413 (33), 357 (2), 305 (3), 265 (10), 185 (9), 131 (49), 103 (79), 75 (100), 61 (80). X-ray crystallography data is available in the Appendics. 208 Preparation of 319 from Addition of CH,” to Intermediate 228 O OTips H O grips 228 318 319 CH3Li (1.6 M solution in diethyl ether) (13.0 0.1., 0.02 mmol) was added to a solution of intermediate 228 (10.0 mg, 0.02 mmol) in THF (0.3 mL) at room temperature under argon atmosphere. After stirring overnight, the reaction was quenched with water (2 mL) and extracted with diethyl ether (2 ml. x 2). The ether layers were combined and dried with Na2S04. Filtration followed by concentration provided crude 318 (8.0 mg, 0.017 mmol, 85%). The crude compound 318 (8.0 mg, 0.017 mmol) was dissolved in methanol (0.3 mL) and treated with 1% aqueous HCI (50 01.). Ether (2 mL) was added after 10 minutes. The ether layer was separated, dried with NaZSO4 and filtered. Concentration followed by flash column chromatography using 1:1:10 ether/methylene chloride/hexanes as the eluant provided compound 319 (3.0 mg, 0.007 mmol, 33%) as a white solid. R, = 0.33 (1:1:10 ether/methylene chloride/hexanes); 1H NMR (CDCl,,) 6 0.80-0.90 (m, 1H), 1.03 (bs, 21H), 1.11 (s, 1H), 1.46 (s, 3H), 1.52 (s, 3H), 1.60 (s, 3H), 1.60-2.50 (m, 11H), 2.77 (s, 1H), 4.80-4.86 (m, 1H), 5.07 (d, 1H, J = 6.9 Hz), 5.40 (d, 1H, J = 7.2 Hz), 5.68 (s, 1H); 13C NMR (CDCl,) 6 12.07, 16.01, 16.91, 17.89, 18.04, 19.77, 24.08, 26.64, 32.69, 37.70, 39.15, 44.25, 52.57, 79.61, 122.51, 124.10, 130.42, 134.94, 137.95, 167.53, 199.60; IR (neat) 3500, 2940, 2886, 1671 cm"; MS (EI) m/z (% rel intensity) 291 (3), 243 (100), 183(9), 165 (44), 151 (7), 105 (23), 77 (13). 209 APPENDICES 210 Figure A-l. ORTEP Drawing of the Structure of Compound 190a IWeC) 1908 o °‘Ctt41 '... q .' ..“ . W'mmm C(14A ‘ o 211 Table 1. Crystal data and structure refinement for 190a 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 Index ranges Reflections collected / unique Completeness to theta = 28.30 Refinement method Data / restraints / parameters Goodness-of-fit on F2 Final R indices [l>2$igma(l)] F1 indices (all data) Largest diff. peak and hole 212 p21n Cze H40 04 440.60 173(2) K 0.71073 A Monoclinic P2(1)/n a = 12.336(3) A b: 11.201(2) A c = 18.593(4) A alpha = 90 °C beta = 9952(3) °C gamma = 90 °C 2533.6(9) A3 4 1.155 Mg/m3 0.075 mm'1 960 0.2 x 0.2 x 0.15 mm 1.85 to 28.30 °C -16<=h<=16, -14<=k<=14, ~24<=|<=24 29827 /6142 [R,m = 0.0780] 97.6% Full-matrix least-squares on F2 6142 / 0 I321 ,. 0.894 R, = 0.0557, sz = 0.1297 R, = 0.1260, wR2 = 0.1640 0.216 and -O.216 e.A'3 Table 2. Atomic coordinates (x 10‘), equivalent isotropic displacement parameters (A 2 x 103), and oocupancies for 190a x y z U(eq) Occ. C(1) -2406(2) 2454(2) 778(1) 28(1) 1 C(2) —3057(2) 1594(2) 1161(1) 28(1) 1 C(3) -3565(2) 1940(2) 1702(1) 28(1) 1 C(4) -3567(2) 3183(2) 1923(1) 31(1) 1 C(5) -3112(2) 4070(2) 1590(1) 27(1) 1 C(6) -2543(2) 3763(2) 977(1) 28(1) 1 0(7) -2160(1) 4550(1) 635(1) 43(1) 1 C(8) -1177(2) 2166(2) 1007(1) 38(1) 1 0(9) -4156(1) 1251(1) 2107(1) 38(1) 1 C(10) —4291(2) 33(2) 1896(1) 44(1) 1 C(11) -3283(2) 5361(2) 1761(1) 30(1) 1 C(12) —2712(2) 2316(2) -59(1) 30(1) 1 C(13) -3902(2) 2596(2) -357(1) 33(1) 1 C(14) -4150(2) 2594(2) -1184(1) 30(1) 1 C(15) -5337(2) 2922(2) -1497(1) 32(1) 1 C(16) -5618(2) 4208(2) -1342(1) 31(1) 1 C(17) 2494(2) 2567(2) 568(1) 33(1) 1 C(18) 1800(2) 3553(2) 794(1) 32(1) 1 C(19) 1368(2) 3481(2) 1403(1) 28(1) 1 C(20) 1509(2) 2420(2) 1855(1) 29(1) 1 C(21) 2035(2) 1427(2) 1695(1) 30(1) 1 C(22) 2531(2) 1428(2) 1025(1) 33(1) 1 0(23) 2996(1) 539(1) 844(1) 49(1) 1 C(24) 3696(2) 3016(2) 660(1) 49(1) 1 0(25) 735(1) 4316(1) 1674(1) 35(1) 1 C(26) 488(2) 5373(2) 1252(1) 48(1) 1 C(27) 2086(2) 308(2) 2154(1) 37(1) 1 C(28) 2096(2) 2240(2) -244(1) 37(1) 1 C(29) 935(2) 1744(2) -392(1) 37(1) 1 C(30) 541(2) 1379(2) -1178(1) 33(1) 1 C(31) -600(2) 821(2) -1296(1) 36(1) 1 C(32) -990(2) 359(2) -2063(1) 35(1) 1 U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. 213 Table 3. Bond lengths [A] and angles [°c] for 190a C(1)-C(2) C(1)-C(6) C(1)-C(8) C(1)-C(12) C(2)—C(3) C(3)-0(9) C(3)-C(4) C(4)-C(5) C(5)-C(6) C(5)-C(11) C(6)-0(7) C(9)-C(10) C(11)-C(16)#1 C(12)-C(13) C(13)-C(14) C(14)-C(15) C(15)-C(16) C(16)—C(11)#1 C(17)-C(18) C(17)-C(22) C(17)-C(24) C(17)-C(28) C(18)-C(19) C(19)~O(25) C(19)-C(20) C(20)-C(21) C(21)-C(22) C(21)-C(27) C(22)-C(23) 0(25)—C(26) C(27)—C(32)#2 C(28)—C(29) C(29)-C(30) C(30)-C(31) C(31)-C(32) C(32)-C(27)#2 C(2)—C(1)-C(6) HHHi—IHHHHHHHHHi—IHi—nHHHHHHHHHHHHi—IHHHHHHH 114. .506(3) .529(3) .540(3) .546(3) .328(3) .370(2) .45113) .342(3) .474(3) .50313) .227(2) .422(3) .527(3) .515(3) .518(3) .528(3) .520(3) .527(3) .500(3) .529(3) .548(3) .553(3) .331(3) .367(2) .450(3) .34513) .47513) .513(3) .223(2) .426(3) .529(3) .518(3) .517(3) .52213) .51913) .529(3) 17(16) C(2)-C(1)-C(8) 108. C(6)-C(1)-C(8) 106. C(2)-C(1)-C(12) 110. C(6)-C(1)-C(12) 108. C(8)-C(1)-C(12) 108. 24(16) 04(16) 63(16) 76(16) 79(16) C(3)-C(2)-C(1) C(2)-C(3)-O(9) C(2)-C(3)—C(4) O(9)-C(3)-C(4) C(5)-C(4)-C(3) C(4)-C(5)—C(6) C(4)-C(5)-C(11) C(6)-C(5)-C(11) O(7)-C(6)-C(5) O(7)-C(6)-C(1) C(5)-C(6)-C(1) C(3)-O(9)-C(10) C(5)-C(11)-C(l6)#l C(13)-C(12)—C(1) C(12)-C(13)-C(14) C(13)-C(14)-C(15) C(16)-C(15)-C(14) C(15)—C(16)-C(11)#1 C(18)—C(17)—C(22) C(18)-C(17)-C(24) C(22)-C(17)-C(24) C(18)-C(17)-C(28) C(22)-C(17)-C(28) C(24)—C(17)-C(28) C(19)-C(18)-C(17) C(18)-C(19)-O(25) C(18)-C(19)-C(20) O(25)-C(19)-C(20) C(21)—C(20)-C(19) C(20)—C(21)—C(22) C(20)-C(21)-C(27) C(22)-C(21)—C(27) 0(23)-C(22)-C(21) O(23)-C(22)-C(17) C(21)—C(22)-C(17) C(19)-O(25)-C(26) C(21)-C(27)-C(32)#2 C(29)-C(28)-C(17) C(28)-C(29)-C(30) C(29)-C(30)-C(31) C(32)-C(31)—C(30) C(31)-C(32)-C(27)#2 121. 127 121. 111. 123. 118. 122. 119. 120. 119. 119. 115. 109. 114. 112. 113. 112. 114. 115. 108. 105. 109. 108. 109. 121. 127. 121. 111. 124. 117. 122. 119. 120. 119. 119. 116. 112. 113. 114. 113. 114. 114. 85(18) .83(18) 14(18) 02(16) 97(18) 25(18) 03(18) 29(17) 45(18) 76(17) 77(16) 91(16) 92(16) 03(15) 98(16) 88(16) 93(17) 50(17) 14(16) 09(17) 66(18) 98(17) 64(17) 13(16) 38(19) 29(19) 09(18) 59(16) 42(18) 99(18) 43(18) 52(18) 70(19) 88(18) 39(17) 61(16) 90(18) 56(16) 57(16) 07(16) 68(17) 04(18) Symmetry transformations used to generate equivalent atoms: #1 -x-1,-y+1,-z #2 -x,-y,-z 214 Table 4. Anisotropic displacement parameters (A 2 x 103) for 190a 011 022 033 023 013 012 0(1) 28(1) 30(1) 29(1) 0(1) 7(1) 3(1) C(2) 32(1) 23(1) 30(1) 1(1) 4(1) 2(1) C(3) 30(1) 26(1) 29(1) 5(1) 4(1) -3(1) C(4) 34(1) 34(1) 27(1) -2(1) 8(1) 1(1) C(S) 28(1) 28(1) 24(1) -2(1) 0(1) 3(1) C(6) 26(1) 27(1) 30(1) 4(1) 1(1) -1(1) 0(7) 54(1) 32(1) 46(1) 4(1) 21(1) -4(1) C(8) 27(1) 42(1) 45(1) 2(1) 5(1) 4(1) 0(9) 48(1) 32(1) 38(1) 4(1) 17(1) -7(1) C(10) 53(2) 34(1) 48(1) 1(1) 15(1) -15(1) C(11) 34(1) 27(1) 29(1) -5(1) 3(1) -2(1) C(12) 30(1) 34(1) 28(1) -2(1) 10(1) 3(1) C(13) 33(1) 40(1) 29(1) -1(1) 10(1) 5(1) C(14) 35(1) 31(1) 26(1) -4(1) 8(1) 2(1) C(15) 39(1) 30(1) 28(1) -5(1) 5(1) 1(1) C(16) 36(1) 27(1) 28(1) -3(1) 2(1) 1(1) C(17) 32(1) 36(1) 35(1) —2(1) 14(1) —5(1) C(18) 31(1) 29(1) 34(1) —1(1) 4(1) —5(1) C(19) 25(1) 28(1) 29(1) —6(1) 4(1) -2(1) C(20) 28(1) 36(1) 24(1) -3(1) 5(1) -4(1) C(21) 25(1) 34(1) 28(1) -2(1) 0(1) -1(1) C(22) 27(1) 37(1) 35(1) -6(1) 6(1) -2(1) 0(23) 53(1) 41(1) 55(1) -5(1) 20(1) 12(1) C(24) 37(1) 57(2) 57(2) -8(1) 19(1) -12(1) 0(25) 39(1) 32(1) 37(1) -6(1) 9(1) 5(1) C(26) 52(2) 32(1) 58(2) 1(1) 9(1) 9(1) C(27) 39(1) 38(1) 31(1) 2(1) 0(1) 4(1) C(28) 41(1) 40(1) 33(1) -1(1) 17(1) -4(1) C(29) 47(1) 41(1) 27(1) -2(1) 13(1) -8(1) C(30) 43(1) 28(1) 29(1) 2(1) 12(1) 0(1) C(31) 42(1) 36(1) 31(1) 1(1) 12(1) 2(1) C(32) 48(1) 31(1) 27(1) 5(1) 7(1) 4(1) The anisotropic displacement factor exponent takes the form: -2 pi2 [h2 a"2 U11 + + 2 h k a" b" U12] 215 Table 5. Hydrogen coordinates (x 10‘), isotropic displacement parameters (A2 x 103), and occupancies for 190a x y z U(eq) Occ. H(2A) -3105 799 1015 34 1 H(4A) —3903 3376 2320 38 1 H(8A) —981 2240 1526 57 1 H(BB) -747 2714 774 57 1 H(8C) -1036 1365 863 57 1 H(10A) -4708 -373 2214 67 1 H(IOB) -3583 -337 1927 67 1 H(10C) -4674 -14 1403 67 1 H(11A) -3272(18) 5463(19) 2279(13) 43(6) 1 H(llB) -2682(18) 5844(19) 1649(11) 40(6) 1 H(12A) —2246 2841 -290 36 1 H(123) -2557 1502 -190 36 1 H(13A) -4083 3374 -180 40 1 H(13B) -4368 2011 -173 40 l H(14A) -3994 1806 -1359 36 1 3(143) -3662 3155 -1367 36 1 H(15A) -5457 2796 -2021 39 1 H(153) -5828 2394 -1292 39 1 H(16A) -5629(16) 4336(17) -831(12) 32(6) 1 H(16B) -5007(18) 4738(19) -1455(11) 34(6) 1 H(18A) 1668 4229 502 38 1 H(20A) 1216 2426 2284 35 1 H(24A) 3947 3217 1162 73 1 H(24B) 3732 3710 362 73 1 H(24C) 4155 2399 514 73 1 H(26A) 50 5897 1495 72 1 H(26B) 89 5167 780 72 1 H(26C) 1160 5768 1195 72 1 H(27A) 2294(17) 541(18) 2681(12) 40(6) 1 8(278) 2680(19) -230(20) 2040(12) 47(7) 1 8(28A) 2129 2948 -540 44 1 H(288) 2593 1654 -393 44 1 H(29A) 437 2343 -257 45 1 H(29B) 898 1055 -81 45 1 H(30A) 1057 811 -1323 39 1 H(308) 532 2076 -1488 39 1 H(3lA) -602 165 -956 43 1 3(313) -1121 1412 -1182 43 1 H(32A) -405(16) -179(17) -2179(10) 23(5) 1 3(323) -1015(16) 1040(20) -2397(11) 39(6) 1 216 Figure A-2. ORTEP Drawing of the Structure of Compound 156b Y. *1 OMe CH2 156b O I ’g. C ‘ T’4) c1161 . “01241 f W. 06’ ' ,2, ° :9 0115) ' 3 . "I . 1:1: 3.- ”§' 0 . .69 01291" ' 7‘ ‘v 0 0 ii 0 (“28’ t (‘1 C(26) . ,7/4 \J.127i O 217 Table 1. Crystal data and structure refinement for 156b 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 Indexranges Reflections collected I unique Completeness to theta = 28.14 Refinement method Data / restraints / parameters Goodness-of-fit on F2 Final R indices [l>2$igma(l)] R indices (all data) Largest diff. peak and hole 218 wulff06 0,,H,,o,Si 448.74 173(2) K 0.71073 A triclinic P-1 a = 11.714(2) A b = 12.064(2) A c = 12.691 (3) A alpha = 117.10(3) °C beta = 112.07(3) °C gamma = 9588(3) °C 1395.9(5) A3 2 1.068 Mg/m3 0.107 mrn‘1 496 04x05x05mm 1.96 to 28.14 °C -15<=h<=8, -15<=k<=15, -14<=l<=16 8784/6147 (R,,,, = 0.0141) 90.1% Full-matrix least-squares on F2 6147 / 0 / 284 0.921 R, = 0.0436, WR2 = 0.1271 R, = 0.0610, WR2 = 0.1364 0.496 and -0.255 e. A-3 Table 2. Atomic coordinates (x 10‘), equivalent isotropic displacement parameters (A 2 x 103), and occupancies for 156b x y z U(eq) Occ. C(l) 8784(2) 3435(1) 5352(1) 36(1) 1 C(2) 10210(2) 3826(1) 6382(2) 38(1) 1 C(3) 10380(2) 3627(1) 7539(2) 39(1) 1 C(4) 11806(2) 4219(2) 8655(2) 50(1) 1 C(5) 12297(2) 5735(2) 9567(2) 50(1) 1 C(6) 11778(2) 6223(2) 10584(2) 50(1) 1 C(7) 11939(2) 7696(2) 11304(2) 56(1) 1 C(8) 11276(2) 8176(2) 10371(2) 51(1) 1 C(9) 9849(2) 7320(2) 9322(2) 42(1) 1 C(10) 9186(2) 7816(1) 8412(2) 44(1) 1 C(11) 7981(2) 6741(2) 7049(2) 42(1) 1 C(12) 7392(2) 7370(2) 6228(2) 63(1) 1 C(13) 6958(2) 6181(2) 7292(2) 45(1) 1 C(14) 6587(2) 4908(2) 6901(2) 39(1) 1 0(15) 5658(1) 4296(1) 7062(1) 50(1) 1 C(16) 5036(2) 5122(2) 7713(3) 74(1) 1 C(17) 7180(1) 3990(1) 6247(1) 35(1) 1 C(18) 8102(1) 4350(1) 5965(1) 34(1) 1 C(19) 8505(2) 5716(1) 6278(2) 39(1) 1 0(20) 9277(1) 6052(1) 5950(1) 56(1) 1 0(21) 8086(1) 2100(1) 4858(1) 39(1) 1 Si(22) 7413(1) 802(1) 3295(1) 32(1) 1 C(23) 6053(2) 1016(2) 2080(2) 50(1) 1 C(24) 4938(2) 1223(2) 2438(2) 72(1) 1 C(25) 6540(2) 2113(2) 1883(2) 70(1) 1 C(26) 8692(2) 558(2) 2725(2) 46(1) 1 C(27) 9784(2) 233(2) 3548(3) 73(1) 1 C(28) 8137(3) -459(2) 1208(2) 76(1) 1 C(29) 6823(2) -613(2) 3441(2) 47(1) 1 C(30) 6351(3) -270(2) 4479(2) 75(1) 1 C(31) 5820(2) -1858(2) 2068(2) 55(1) 1 U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. 219 Table 3. Bond lengths [A] and angles [°C] for 156b 0(1)-0(21) C(1)-C(18) C(1)-C(2) C(2)—C(3) C(3)-C(4) C(4)-C(5) C(5)-C(6) C(6)-C(7) C(7)-C(8) C(8)-C(9) C(9)-C(10) C(10)-C(11) C(11)-C(13) C(11)-C(19) C(11)-C(12) C(13)-C(14) C(14)-0(15) C(14)-C(17) C(15)-C(16) C(17)-C(18) C(18)-C(19) C(19)-C(20) 0(21)-si(22) Si(22)-C(29) Si(22)-C(26) Si(22)-C(23) C(23)-C(24) C(23)-C(25) C(26)-C(27) C(26)-C(28) C(29)-C(30) C(29)-C(31) O(21)-C(1)-C(18) 0(21)-C(1)-C(2) C(18)-C(1)-C(2) C(1)-C(2)-C(3) C(4)-C(3)-C(2) C(3)—C(4)-C(5) C(6)-C(5)-C(4) .4427(18) .526(2) .535(2) .537(2) .537(2) .540(3) .534(3) .534(3) .538(3) .535(2) .531(2) .554(3) .513(2) .539(2) .557(2) .341(2) .3821(19) .467(2) .434(2) .348(2) .484(2) .230(2) .6581(14) 1.8887(17) 1.8889(18) 1.8926(18) 1.545(3) 1.547(3) 1.533(3) 1.542(3) 1.520(3) 1.546(2) 108.94(12) 109.57(13) 111.73(12) 114.51(13) 112.85(14) 113.99(14) 112.38(15) HHHHHHHHHHHHHHi—IHHHHHH l-‘H C(7)-C(6)-C(5) C(6)-C(7)-C(8) C(9)-C(8)-C(7) C(10)—C(9)-C(8) C(9)-C(10)-C(11) C(13)-C(11)-C(19) C(13)-C(11)-C(10) C(19)-C(11)-C(10) C(13)-C(11)-C(12) C(19)-C(11)-C(12) C(10)-C(11)-C(12) C(14)-C(13)-C(11) C(13)-C(14)-O(15) C(13)-C(14)-C(17) D(15)-C(14)-C(17) C(14)-O(15)-C(16) C(18)-C(17)-C(14) C(17)-C(18)-C(19) C(17)—C(18)-C(1) C(19)-C(18)-C(1) O(20)-C(19)-C(18) 0(20)-C(19)-C(11) C(18)-C(19)-C(11) C(1)-O(21)-Si(22) O(21)-Si(22)-C(29) 0(21)-Si(22)-C(26) C(29)—Si(22)-C(26) O(21)-Si(22)-C(23) C(29)-Si(22)-C(23) C(26)-Si(22)-C(23) C(24)-C(23)-C(25) C(24)—C(23)-Si(22) C(25)-C(23)-Si(22) C(27)-C(26)-C(28) C(27)-C(26)-Si(22) C(28)-C(26)-Si(22) C(30)-C(29)-C(31) C(30)-C(29)-Si(22) C(31)—C(29)-Si(22) 116. .05(14) .89(14) .68(14) 115 113 113 114. .12(13) 114 110. .01(14) .31(15) .92(14) 109. .05(15) .69(15) .66(15) .64(13) .70(14) .83(14) 106 109 107 122 126 121 111 115 122 119. .86(13) .00(13) .83(14) .27(14) .89(14) .38(9) .52(7) .62(8) .58(8) .80(8) .99(9) .27(9) .38(16) .30(13) .31(13) .98(17) .30(14) .17(14) .29(16) 123 117 120 119 119 127 103 109 110 111 112 108 110 113 113 109 113 114 111 115. .01(13) 113 19(16) 14(13) 22(14) 11(14) 13(14) 18(13) Symmetry transformations used to generate equivalent atoms: 220 Table 4. Anisotropic displacement parameters (A 2 x 103) for 1561) 011 022 033 023 013 012 0(1) 48(1) 25(1) 26(1) 7(1) 20(1) 4(1) 0(2) 42(1) 29(1) 37(1) 10(1) 24(1) 8(1) 0(3) 40(1) 30(1) 42(1) 16(1) 20(1) 10(1) 0(4) 40(1) 54(1) 54(1) 29(1) 19(1) 18(1) 0(5) 31(1) 53(1) 45(1) 19(1) 11(1) 3(1) 0(6) 44(1) 56(1) 35(1) 23(1) 11(1) 4(1) 0(7) 48(1) 56(1) 32(1) 8(1) 13(1) -6(1) 0(8) 57(1) 34(1) 44(1) 7(1) 28(1) —1(1) 0(9) 50(1) 30(1) 39(1) 12(1) 25(1) 6(1) 0(10) 65(1) 27(1) 48(1) 16(1) 38(1) 16(1) 0(11) 53(1) 36(1) 48(1) 26(1) 30(1) 20(1) 0(12) 74(1) 67(1) 82(1) 56(1) 43(1) 35(1) 0(13) 49(1) 45(1) 54(1) 30(1) 32(1) 25(1) 0(14) 36(1) 43(1) 42(1) 25(1) 19(1) 15(1) 0(15) 45(1) 52(1) 73(1) 40(1) 37(1) 23(1) C(16) 75(1) 73(1) 125(2) 63(2) 77(2) 43(1) 0(17) 36(1) 32(1) 30(1) 15(1) 12(1) 7(1) C(18) 41(1) 29(1) 23(1) 10(1) 12(1) 7(1) 0(19) 50(1) 33(1) 32(1) 15(1) 22(1) 11(1) 0(20) 84(1) 36(1) 62(1) 23(1) 54(1) 17(1) 0(21) 50(1) 25(1) 28(1) 6(1) 20(1) 2(1) 91(22) 41(1) 22(1) 25(1) 8(1) 15(1) 6(1) 0(23) 57(1) 36(1) 36(1) 14(1) 11(1) 14(1) 0(24) 47(1) 65(1) 74(1) 29(1) 12(1) 24(1) 0(25) 95(2) 52(1) 53(1) 34(1) 19(1) 26(1) C(26) 62(1) 28(1) 49(1) 14(1) 36(1) 13(1) 0(27) 67(1) 59(1) 107(2) 43(1) 52(1) 35(1) 0(28) 112(2) 43(1) 63(1) 6(1) 64(1) 11(1) 0(29) 51(1) 34(1) 45(1) 20(1) 18(1) 4(1) 0(30) 97(2) 61(1) 65(1) 31(1) 46(1) 2(1) 0(31) 55(1) 30(1) 57(1) 15(1) 20(1) 1(1) The anisotropic displacement factor exponent takes the form: -2 piz[h2a*2U11 +...+2hka*b* U12] 221 Table 5. Hydrogen coordinates (x 10“), isotropic displacement parameters (A 2 x 103), and occupancies for 156b x y z U(eq) Occ. H(l) 8773(15) 3494(15) 4614(16) 37(4) 1 H(2A) 10647 4748 6762 46 1 H(ZB) 10639 3312 5916 46 1 H(3A) 9849 4033 7926 47 1 H(BB) 10068 2690 7180 47 1 H(4A) 12359 3957 8241 60 1 H(4B) 11893 3851 9208 60 1 H(SA) 13244 6052 10050 59 1 H(SB) 12025 6103 9011 59 1 H(6A) 10857 5722 10118 60 1 H(6B) 12219 6025 11261 60 1 H(7A) 12864 8200 11835 68 1 H(7B) 11585 7885 11923 68 1 H(BA) 11310 9073 10917 61 1 H(BB) 11766 8191 9906 61 1 H(9A) 9816 6426 8765 51 1 H(9B) 9361 7292 9786 51 l H(IOA) 9821 8171 8232 53 1 H(IOB) 8914 8532 8892 53 1 H(12A) 8038 7722 6068 95 1 H(IZB) 7127 8066 6727 95 1 H(12C) 6649 6708 5382 95 1 H(13) 6575 6736 7726 54 1 H(16A) 4409 4610 7774 111 1 H(16B) 4602 5480 7199 111 l H(16C) 5681 5830 8601 111 1 H(17) 6909 3123 6017 42 1 H(23) 5670 186 1202 59 1 H(24A) 4641 532 2550 107 1 H(24B) 4228 1204 1726 107 1 H(24C) 5252 2061 3261 107 1 H(ZSA) 7231 1971 1660 105 1 H(ZSB) 6859 2957 2700 105 1 H(25C) 5833 2090 1167 105 1 H(26) 9107 1407 2886 55 l H(27A) 10121 867 4491 109 1 H(27B) 10472 265 3315 109 1 H(Z7C) 9442 -634 3353 109 1 H(28A) 7453 -250 700 115 1 H(288) 7792 -1326 1013 115 1 H(28C) 8819 -433 967 115 1 H(29) 7592 -864 3762 57 1 H(30A) 6997 498 5323 113 1 H(BOB) 6210 ~998 4592 113 1 H(3OC) 5547 —94 4176 113 1 H(31A) 6147 -2055 1436 82 1 H(3lB) 5010 -1701 1739 82 1 H(31C) 5681 -2590 2175 82 1 222 Figure A-3. ORTEP Drawing of the Structure of Compound 228 (shown as the enantiomer) .uc13 :L. 013‘ , 129101231 012 “Ml.- ""36 O Q «(9) .. 01281.6 “26’ 5' c1241 . '"- 01221 223 Table 1. Crystal data and structure refinement for 228 Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(OOO) Crystal size Theta range for data collection Indexranges Reflections collected / unique Completeness to theta = 28.24 Refinement method Data / restraints / parameters Goodness-of-fit on F2 Final R indices [l>2sigma(l)] R indices (all data) Largest diff. peak and hole 224 wulff07 CzeHwOSSi 458.74 173(2) K 0.71073 Monoclinic P2(1)/c a = 12.384(3) A b = 12.584(3) A c = 18.686(4) A alpha = 90 °C beta = 107.07(3) °C gamma = 90 °C 2783.9(10) A3 4 1.095 Mg/m3 0.109 mrn‘1 1008 08x03x01mm 1.72 to 28.24 °C -1 6<=h<=16, -1 6<=k<=16, -24<=|<=24 27573 / 6693 R,,,, = 0.0463 97.1% Full-matrix least-squares on F2 6693 / 0 / 317 1.01 1 R1 = 0.0495, W92 = 0.1429 R, = 0.0857, wR2 = 0.1602 0.345 and -0.351 e. A-3 Table 2. Atomic coordinates (x 10‘), equivalent isotropic displacement parameters (A2 x 103). and occupancies for 228 x y z U(eq) 000. Si 1981(1) 9034(1) 1936(1) 28(1) 1 0(1) 4273(1) 9484(2) 2520(1) 27(1) 1 0(2) 4837(1) 9026(2) 3284(1) 29(1) 1 0(3) 5507(2) 9549(2) 3864(1) 32(1) 1 0(4) 5789(2) 10709(2) 3843(1) 51(1) 1 0(5) 6125(2) 8964(2) 4574(1) 39(1) 1 0(6) 7405(2) 8874(2) 4661(1) 41(1) 1 0(7) 7595(2) 8443(2) 3953(1) 36(1) 1 0(8) 8322(2) 8777(2) 3605(1) 34(1) 1 0(9) 9217(2) 9617(2) 3909(1) 51(1) 1 0(10) 8271(2) 8358(2) 2835(1) 36(1) 1 0(11) 7820(2) 9206(2) 2225(1) 34(1) 1 0(12) 6722(2) 8916(2) 1585(1) 30(1) 1 0(13) 6927(2) 7924(2) 1158(1) 43(1) 1 0(14) 5792(1) 8694(1) 1956(1) 28(1) 1 0(15) 5678(1) 7814(1) 2196(1) 38(1) 1 C(16) 5067(1) 9603(1) 2038(1) 26(1) 1 0(17) 5074(2) 10496(2) 1645(1) 29(1) 1 C(18) 5738(2) 10602(2) 1119(1) 31(1) 1 0(19) 5482(1) 11522(1) 706(1) 42(1) 1 0(20) 6079(2) 11684(2) 164(1) 46(1) 1 0(21) 6476(2) 9859(2) 1069(1) 33(1) 1 0(22) 3350(1) 8811(1) 2122(1) 31(1) 1 0(23) 1526(2) 9052(2) 2816(1) 40(1) 1 0(24) 2007(2) 10015(2) 3324(1) 61(1) 1 0(25) 1805(2) 8012(2) 3252(1) 63(1) 1 C(26) 1633(2) 10364(2) 1451(1) 40(1) 1 0(27) 416(2) 10749(2) 1361(2) 63(1) 1 C(28) 1913(2) 10440(2) 703(1) 54(1) 1 0(29) 1358(2) 7828(2) 1365(1) 34(1) 1 0(30) 65(2) 7742(2) 1183(2) 55(1) 1 0(31) 1736(2) 7668(2) 658(1) 51(1) 1 U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. 225 Table 3. Bond lengths [A] and angles [°C] for 228 si-O(22) si-C(29) Si-C(23) Si-C(26) 0(1)—0(22) 0(1)-0(2) 0(1)—0(1) 0(2)-0(3) 0(3)-0(4) 0(3)-0(5) C(5)-C(6 C(6)-C(7) C(7)—C(8) C(8)-C(9 C(8)-C(10) C(10)-C(11) C(11)—C(12) C(12)-C(21) C(12)-C(14) C(12)-C(13) C(14)-0(15) C(14)-C(16) C(16)-C(17) C(17)—C(18) C(18)-C(21) C(18)-0(19) 0(19)—0(20) C(23)-C(25) C(23)—C(24) C(26)-C(28) C(26)-C(27) C(29)-C(31) C(29)-C(30) 0(22)-si-0(29) O(22)-Si-C(23) C(29)-Si—C(23) O(22)-Si-C(26) C(29)-Si-C(26) C(23)-Si-C(26) 0(22)- -0(1)-0(2) 0(22)-0 1) C(16) C(2)-C(IS-C-)(16) HHHHHHHHHHHHHi—IHHHHHHHHHHHHHHHHHH 1.4 .6528(13) .885(2) .888(2) .892(2) .442(2) .507(2) .523(2) .329(3) .504(3) .514(2) .549(3) .511(3) .325(3) .516(3) .517(3) .540(3) .569(2) .502(3) .535(2) .541(3) .219(2) .490(3) .344(3) .461(2) .330(3) .375(2) .433(2) .526(3) .546(3) .538(3) .546(3) .538(3) .540(3) 101 111 109 109 116. .85(10) 108 109. 107. .90(8) .66(8) .03(9) .01(8) 28(9) 96(14) 66( 113. 46(114)) 0(3)-0(2)-0(1) 0(2)-0(3)-0(4) 0(2)-0(3)—0(5) 0(4)-0(3)-0(5) C(3)-C(S)-C(6) 0(7)-0(6)-0(5) C(8)—C(7)-C(6) 0(7)-0(8)—0(9) C(7)-C(8)-C(10) 0(9)-0(8)-0(10) C(8)-C(10)-C(11) 0(10)-0(11)-0(12) 0(21)-0(12)-0(14) 0(21)-0(12)-0(13) 0(14)-0(12)-0(13) 0(21)-0(12)-0(11) 0(14)-0(12)-0(11) 0(13)-0(12)-0(11) 0(15)-C(14)-C(16) 0(15)-0(14)-0(12) C(16)-C(14)—C(12) C(17)-C(16)-C(14) C(17)-C(16)-C(1) C(14)-C(16)-C(1) C(16)-C(17)-C(18) C(21)-C(18)-O(19) C(21)-C(18)-C(17) 0(19)-0(18)-0(17) 0(18)-0(19)-0(20) C(18)-C(21)-C(12) 0(1)—0(22)-si 0(25)-0(23)-0(24) C(25)-C(23)-Si 0(24)-0(23)-si 0(28)-0(26)-0(27) C(28)-C(26)-Si C(27)-C(26)-Si 0(31)-0(29)-0(30) C(31)-C(29)—Si 0(30)-0(29)-si 125 123 120 115 111 110 128 124 120 114 111 116 113 109 110 105 110 121 120 117 119 120 119 122 127 121 111 121 112 112 114 114 111 114 114 .94(18) .62(18) .47(18) .67(17) .51(15) .56(16) .2(2) .41(19) .68(18) .86(17) .44(16) .62(16) .29(15) .96(16) .27(16) .83(15) 107. .24(15) .48(16) .96(16) .52(15) .01(16) .98(16) .87(15) .65(17) .05(17) .13(17) .82(16) 115. .69(17) 128. 111. .o7(16) .58(15) 110. .26(15) .01(16) .08(18) .54(14) .04(15) 11(14) 73(16) 19(12) 1(2) 78(19) Symmetry transformations used to generate equivalent atoms: 226 Table 4. Anisotropic displacement parameters (A 2 x 103) for 228 011 022 033 023 013 012 Si 20(1) 36(1) 25(1) -1(1) 4(1) —2(1) 0(1) 20(1) 31(1) 28(1) -1(1) 6(1) -2(1) 0(2) 26(1) 34(1) 28(1) 5(1) 10(1) -1(1) 0(3) 29(1) 41(1) 27(1) 2(1) 10(1) 3(1) 0(4) 60(1) 38(1) 43(1) -7(1) -2(1) 0(1) 0(5) 36(1) 56(1) 26(1) 6(1) 9(1) 2(1) 0(6) 35(1) 58(1) 26(1) 10(1) 4(1) 2(1) 0(7) 31(1) 39(1) 32(1) 5(1) 3(1) 4(1) 0(8) 25(1) 41(1) 32(1) 2(1) 4(1) 5(1) 0(9) 40(1) 71(2) 42(1) -12(1) 10(1) —14(1) 0(10) 28(1) 40(1) 39(1) -3(1) 8(1) 5(1) 0(11) 27(1) 42(1) 33(1) -4(1) 9(1) -4(1) 0(12) 27(1) 35(1) 28(1) -7(1) 9(1) 1(1) 0(13) 40(1) 47(1) 42(1) -15(1) 12(1) 6(1) 0(14) 25(1) 28(1) 27(1) -6(1) 5(1) -4(1) 0(15) 38(1) 27(1) 50(1) -2(1) 14(1) -2(1) C(16) 21(1) 31(1) 24(1) -2(1) 4(1) -2(1) 0117) 28(1) 32(1) 28(1) 1(1) 9(1) 1(1) C(18) 30(1) 38(1) 26(1) 3(1) 8(1) —4(1) 0(19) 45(1) 44(1) 40(1) 15(1) 20(1) 4(1) 0(20) 49(1) 55(1) 38(1) 13(1) 20(1) -3(1) 0(21) 31(1) 44(1) 27(1) —2(1) 13(1) -2(1) 0(22) 21(1) 36(1) 34(1) -1(1) 6(1) -5(1) 0(23) 26(1) 61(1) 35(1) -5(1) 11(1) -3(1) 0(24) 45(1) 98(2) 43(1) -28(1) 19(1) -16(1) 0(25) 55(1) 99(2) 44(1) 22(1) 26(1) 6(1) 0(26) 36(1) 35(1) 40(1) -2(1) -2(1) 0(1) 0(27) 47(1) 49(2) 77(2) 1(1) -5(1) 14(1) 0(28) 71(2) 44(1) 39(1) 10(1) 1(1) -4(1) 0(29) 26(1) 39(1) 35(1) -4(1) 6(1) -3(1) 0(30) 29(1) 56(2) 72(2) —19(1) 4(1) -9(1) 0(31) 64(2) 47(1) 46(1) -10(1) 20(1) -4(1) The anisotropic displacement factor exponent takes the form: -2pi2[h2a*2U11+...+2hka*b*U12] 227 occupancies for 228 Table 5. Hydrogen coordinates (x 10‘), isotropic displacement parameters (A 2 x 103), and x y z U(eq) Occ. H(l) 3971 10186 2583 32 1 H(Z) 4694(17) 8256(19) 3306(11) 43(6) 1 H(4A) 6276 10922 4323 76 1 H(4B) 5106 11120 3725 76 1 H(4C) 6164 10826 3468 76 1 H(SA) 5808 8257 4563 47 1 H(SB) 6019 9337 5002 47 1 H(GA) 7754 9569 4770 49 1 H(6B) 7758 8406 5077 49 1 8(7) 7045(18) 7888(18) 3693(12) 43(6) 1 H(9A) 9640 9730 3560 77 1 H(9B) 9717 9383 4379 77 1 H(9C) 8861 10269 3980 77 1 8(10A) 7784 7739 2724 43 1 H(IOB) 9021 8140 2831 43 1 H(llA) 8412 9367 1998 41 1 H(llB) 7674 9850 2467 41 1 H(13A) 7079 7324 1489 65 1 H(13B) 7562 8047 972 65 1 H(13C) 6268 7785 745 65 1 9(17) 4594(18) 11098(16) 1651(11) 40(6) 1 H(ZOA) 5847 12344 -91 69 1 H(ZOB) 5914 11111 -191 69 1 H(ZOC) 6876 11704 412 69 1 H(21) 6943(17) 9916(17) 768(11) 38(5) 1 H(23) 721(17) 9097(15) 2662(11) 34(5) 1 H(24A) 1817 10659 3038 91 1 H(24B) 2813 9953 3513 91 1 H(24C) 1689 10033 3734 91 1 H(ZSA) 1492 7428 2927 95 1 H(ZSB) 1487 8022 3663 95 1 H(ZSC) 2609 7932 3440 95 1 H(26) 2214(19) 10865(17) 1758(13) 48(6) 1 H(27A) 258 10695 1833 94 1 H(27B) -108 10316 997 94 1 H(27C) 341 11476 1198 94 1 H(28A) 2671 10198 770 82 1 H(ZBB) 1844 11165 536 82 1 H(28C) 1397 10005 336 82 1 H(29) 1717(18) 7205(18) 1709(12) 45(6) 1 H(BOA) -148 7843 1632 82 1 H(BOB) -176 7052 979 82 1 H(30C) -286 8278 824 82 1 H(31A) 2544 7718 787 77 1 H(3lB) 1401 8205 297 77 1 H(31C) 1499 6979 450 77 1 228 Figure A-4. ORTEP Drawing of the Structure of Compound 307 . M01311) \1‘.‘ "251 0 01311 c, "\o ‘5. 0130) IL I. 5.123. a 7 v.- ”26’ .‘g 0‘24. 01221 229 Table 1. Crystal data and structure refinement for 307 Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume 2 Density (calculated) Absorption coefficient F(OOO) Crystal size Theta range for data collection Indexranges Reflections collected / unique Completeness to theta = 28.23 Refinement method Data / restraints / parameters Goodness-of-fit on F2 Final R indices [I>2sigma(l)] R indices (all data) Absolute structure parameter Largest diff. peak and hole p21 05,119,331, 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 °C beta = 108.01 (3) °C gamma = 90 °C 2919.9(10) A3 2 1.036 Mg/m3 0.101 mm" 1002 06x04x02mm 1.69 to 28.23 °C -14<=|'I<=14, -29<=k<=30, ~16<=|<=16 35046 / 13757 (1:1,, = 0.0940) 97.8% Full-matrix least-squares on F2 13757 / 1 I 593 0.245 R, = 0.0449, sz = 0.1101 R, = 0.1004, sz = 0.1236 0.5(3) 0.259 and -0.217 e. A3 230 Table 2. Atomic coordinates (x 10‘), equivalent isotropic displacement parameters (A 2 x 103), and occupancies for 307 x y z U(eq) Occ. C(l) -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 C(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 C(7) 1934(8) 5135(3) 2665(6) 37(2) 1 C(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(11) 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 0(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) 1187(4) 4265(6) 109(4) 1 C(27) 1945(7) 1916(3) 2189(6) 37(2) 1 C(28) 3348(7) 2115(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) -1142(8) 1335(3) 1312(7) 58(2) 1 C(32) -2307(7) 2120(4) 2085(7) 61(3) 1 C(33) 5710(6) 3297(3) 7578(6) 26(2) 1 C(34) 5569(6) 2998(3) 6553(6) 27(2) 1 C(35) 6615(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 C(42) 3003(7) 3018(3) 8376(5) 32(2) 1 C(43) 3309(7) 3330(3) 7607(6) 36(2) 1 C(44) 4537(6) 3678(3) 7746(6) 28(2) 1 C(45) 6787(7) 3288(3) 8430(6) 36(2) 1 C(46) 7954(7) 2958(3) 8405(6) 33(2) 1 0(47) 8934(5) 2884(2) 9263(5) 48(2) 1 C(48) 7989(6) 2763(3) 7294(6) 30(2) 1 C(49) 8438(7) 3306(3) 6732(6) 44(2) 1 C(50) 6664(7) 2328(3) 5492(6) 47(2) 1 231 Table 2 (cont’d) 0(51) C(52) 0(53) 0(54) 31(55) C(56) 0(57) 0(58) 0(59) C(60) C(61) C(62) 0(63) 0(64) 4608(7) 4849(8) 3925(6) 4295(4) 4412(2) 6051(7) 6167(8) 7277(8) 3056(7) 3235(7) 1720(7) 4103(7) 3700(8) 5097(8) 3111(3) 1258(3) 3003(3) 4152(2) 4864(1) 5040(3) 5651(4) 4866(4) 5098(3) 4873(3) 4925(3) 5172(3) 5826(3) 4943(4) 5596(6) 8608(6) 9579(5) 6957(4) 7233(2) 8306(6) 8720(8) 7956(8) 7808(5) 9009(5) 7092(6) 5764(4) 5645(6) 5209(6) 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) HHHHI—‘l—‘I—‘Hl—‘l—‘l—‘I—‘HH U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. 232 Table 3. Bond lengths [A] and angles [°C] for 307 C(1)-Q(13) 1.370(9) C(46)-C(48) 1.487(9) 0(1)-0(12) 1.477(8) C(48)-C(49) 1.577(10) 0(1)-0(2) 1.528(8) 0(54)-91(55) 1.662(5) 0(2)-0(19) 1.321(9) 31(55)-0(59) 1.878(7) 0(2)—0(3) 1.492(9) Si(55)-C(56) 1.889(7) C(3)-C(16) 1.548(9) Si(55)-C(62) 1.920(6) 0(3)-0(18) 1.586(8) C(56)-C(57) 1.485(10) 0(3)-0(4) 1.610(9) C(56)—C(58) 1.549(10) 0(4)-0(5) 1.480(9) C(59)-C(61) 1.480(10) C(5)-C(6) 1.557(9) C(59)-C(60) 1.560(9) C(6)-C(7) 1.302(10) C(62)-C(64) 1.529(9) C(6)-C(20) 1.502(10) C(62)-C(63) 1.551(9) C(7)-C(8) 1.478(10) Q(13)-C(1)-C(12) 118.6(6) C(8)-C(9) 1.485(10) Q(13)-C(1)-C(2) 118.2(6) 0(9)-0(10) 1.564(9) 0(12)-0(1)-0(2) 123.2(6) C(10)-C(11) 1.342(9) 0(19)-0(2)—0(3) 125.3(6) C(10)-C(21) 1.482(10) 0(19)-0(2)—0(1) 118.3(6) C(11)—C(12) 1.524(8) 0(3)-0(2)-0(1) 116.4(5) C(12)-0(22) 1.445(8) C(2)-C(3)-C(16) 111.1(5) Q(13)-C(14) 1.486(9) C(2)-C(3)-C(18) 112.6(5) C(14)-0(15) 1.191(8) C(16)-C(3)-C(18) 108.6(5) C(14)-C(16) 1.541(10) 0(2)-0(3)-0(4) 111.2(5) C(16)-C(17) 1.558(10) C(16)-C(3)-C(4) 106.1(5) 0(22)-Si(23) 1.649(5) C(18)-C(3)—C(4) 107.1(5) Si(23)-C(24) 1.829(7) 0(5)-0(4)—0(3) 114.9(6) Si(23)—C(30) 1.869(7) 0(4)-0(5)-0(6) 114.5(6) Si(23)-C(27) 1.890(7) C(7)-C(6)-C(20) 122.3(7) C(24)-C(26) 1.551(10) C(7)-C(6)-C(5) 122.7(7) C(24)-C(25) 1.562(10) 0(20)-0(6)-0(5) 114.8(7) C(27)-C(29) 1.502(9) 0(6)-0(7)-0(8) 130.5(8) C(27)-C(28) 1.579(10) C(7)-C(8)-C(9) 116.0(6) C(30)-C(32) 1.546(9) C(8)-C(9)-C(10) 111.7(6) C(30)-C(31) 1.597(9) C(11)-C(10)—C(21) 126.1(6) C(33)-C(45) 1.307(9) 0(11)-0(10)-0(9) 119.9(7) C(33)-C(34) 1.432(9) 0(21)-0(10)-0(9) 113.2(6) C(33)-C(44) 1.586(8) 0(10)-0(11)-0(12) 124.7(6) C(34)-C(51) 1.345(9) 0(22)-C(12)-C(l) 110.4(5) C(34)-C(35) 1.574(8) 0(22)—C(12)-C(11) 109.3(5) C(35)-C(50) 1.484(9) 0(1)-0(12)-0(11) 112.5(5) C(35)-C(36) 1.503(9) 0(1)-Q(13)-0(14) 124.8(6) C(35)-C(48) 1.565(9) O(15)-C(14)-Q(13) 121.3(7) C(36)-C(37) 1.594(8) 0(15)-C(14)-C(16) 124.0(7) C(37)-C(38) 1.474(9) Q(13)-C(14)-C(16) 114.7(6) C(38)-C(39) 1.366(9) 0(14)-0(16)-0(3) 109.8(6) C(38)-C(52) 1.527(10) 0(14)-0(16)-0(17) 109.3(6) C(39)-C(40) 1.529(9) 0(3)-0(16)-0(17) 113.7(6) C(40)-C(41) 1.603(9) C(12)-0(22)-Si(23) 127.0(4) C(41)-C(42) 1.468(9) 0(22)—Si(23)-C(24) 100.0(3) C(42)-C(43) 1.325(9) 0(22)-Si(23)-C(30) 109.8(3) C(42)-C(53) 1.535(9) C(24)-Si(23)-C(30) 119.0(4) C(43)—C(44) 1.489(9) O(22)-Si(23)-C(27) 110.8(3) C(44)-0(54) 1.443(7) C(24)-Si(23)-C(27) 107.7(3) C(45)—C(46) 1.458(9) 0(30)-31(23)-0(27) 109.1(3) C(46)-C(47) 1.261(8) 0(26)-0(24)-0(25) 100.0(6) 233 Table 3 (cont’d) 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) 0(32)-0(30)-s1(23) C(31)-C(30)-Si(23) 0(45)-0(33)-0(34) 0(45)-0(33)-0(44) 0(34)-0(33)—0(44) 0(51)-0(34)-0(33) 0(51)-0(34)-0(35) 0(33)-0(34)-0(35) C(50)-C(35)-C(36) C(50)-C(35)-C(48) C(36)-C(35)-C(48) 0(50)-0(35)-0(34) 0(36)-0(35)-0(34) C(48)-C(35)-C(34) C(35)-C(36)-C(37) 0(38)-0(37)-0(36) C(39)-C(38)—C(37) 0(39)-0(38)-0(52) C(37)—C(38)-C(52) C(38)—C(39)-C(40) 0(39)-0(40)-0(41) 0(42)—0(41)-0(40) 0(43)-0(42)-0(41) 115. 115. 110. 113. 110. 107. 117. 111. 124. 114. 121. 124. 120. 115. 110. 109. 107. 112. 110. 105. 118. 112. 118. 125. 115. 126. 105. 110. 119. 8(5) 1(5) 4(5) 4(5) 6(5) 8(5) 3(5) 5(5) 1(5) 8(5) 2(5) 1(5) 4(5) 5(5) 6(5) 2(5) 6(5) 5(5) 9(5) 7(5) 9(5) 8(5) 6(5) 7(7) 7(5) 5(7) 7(5) 5(5) 0(7) 0(43)-0(42)-0(53) 0(41)-0(42)-0(53) 0(42)-0(43)-0(44) 0(54)-C(44)-C(43) O(54)-C(44)-C(33) 0(43)-0(44)-0(33) C(33)—C(45)-C(46) 0(47)-C(46)-C(45) O(47)-C(46)-C(48) C(45)-C(46)-C(48) 0(46)-0(48)-0(35) C(46)—C(48)-C(49) C(35)—C(48)-C(49) 0(44)-0(54)—si(55) 0(54)-51(55)-0(59) O(54)-Si(55)-C(56) C(59)-Si(55)-C(56) O(54)-Si(55)-C(62) C(59)-Si(55)-C(62) 0(56)-si(55)-0(62) C(57)-C(56)-C(58) C(57)-C(56)-Si(55) C(58)-C(56)—Si(55) 0(61)-0(59)-0(60) C(61)-C(59)-Si(55) C(60)-C(59)-Si(55) C(64)—C(62)-C(63) C(64)—C(62)-Si(55) C(63)-C(62)-Si(55) 121 119. 127 111 107. 112 121 121 121 116. 110 106. 114. 127. 110. 110. 107. 100. 110. 117. 111. 114. 114. 108. 112. 114. 119. 112. 114. .0(7) 9(6) .2(7) .0(6) 4(5) .6(5) .4(7) .9(7) .3(7) 5(5) .4(5) 8(5) 2(5) 3(4) 2(3) 7(3) 7(3) 2(3) 4(3) 5(3) 0(6) 4(5) 0(5) 3(5) 9(5) 0(5) 6(5) 6(5) 1(4) Symmetry transformations used to generate equivalent atoms: 234 Table 4. Anisotropic displacement parameters (A 2 x 102) for 307 011 022 033 023 013 012 0(1) 30(4) 20(3) 20(3) -8(3) 6(3) -9(3) 0(2) 40(4) 25(3) 9(3) 2(2) 4(3) -7(3) 0(3) 36(4) 27(3) 21(3) -6(3) 9(3) -11(3) 0(4) 38(4) 26(4) 43(4) 17(3) 5(3) 12(3) 0(5) 88(6) 34(4) 36(4) -11(3) 33(4) -1(4) 0(6) 48(5) 38(4) 49(5) -3(4) 26(4) -11(4) 0(7) 50(5) 21(3) 38(4) 5(3) 10(4) -12(3) C(8) 62(6) 39(5) 47(5) 0(4) 11(4) —22(4) 0(9) 27(4) 43(4) 33(3) -2(3) 0(3) -7(3) 0(10) 21(4) 26(4) 57(5) -6(3) 13(3) -3(3) 0(11) 30(4) 20(4) 24(4) 3(3) 4(3) 3(3) 0(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) 0(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) 0(16) 41(5) 31(4) 39(4) 2(3) 13(4) 8(3) 0(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) 0(19) 48(5) 38(5) 28(4) -12(3) 5(4) 4(4) 0(20) 45(4) 67(5) 81(6) 48(4) 30(4) 30(4) 0(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) 0(24) 79(5) 25(4) 67(5) 1(3) 44(4) 4(3) 0(25) 71(5) 75(5) 59(5) 28(4) 28(4) 30(4) C(26) 231(11) 68(6) 49(4) 25(4) 74(6) 41(6) 0(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) -11(3) 0(29) 50(5) 42(4) 52(5) -16(3) 33(4) -1(3) 0(30) 55(5) 35(4) 36(4) 1(3) 16(4) -9(4) 0(31) 72(6) 26(3) 70(6) -25(4) 13(5) -21(3) 0(32) 23(4) 77(6) 79(6) -2(5) 8(4) 3(4) 0(33) 23(4) 20(3) 35(4) 10(3) 9(3) 7(3) 0(34) 16(3) 21(3) 43(4) -4(3) 7(3) 2(3) 0(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) 0(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) 0(39) 39(4) 43(4) 36(4) -17(3) 14(4) -12(3) 0(40) 31(4) 37(4) 47(5) -4(3) 20(4) -4(3) 0(41) 39(4) 35(4) 63(5) 1(3) 34(3) 1(3) 0(42) 37(4) 37(4) 23(3) —4(3) 13(3) 2(3) 0(43) 21(4) 38(4) 43(5) -7(4) 2(3) 6(3) 0(44) 36(4) 17(3) 35(4) 6(3) 20(3) 11(3) 0(45) 28(4) 27(4) 53(4) -5(3) 16(3) -1(3) 0(46) 32(4) 27(4) 31(4) 0(3) -4(3) -6(3) 0(47) 36(3) 51(4) 47(4) 7(3) -3(3) 5(3) 0(48) 16(4) 35(4) 38(4) 0(3) 5(3) 6(3) 0(49) 43(4) 43(4) 55(5) -4(3) 29(4) 9(3) 0(50) 36(4) 31(4) 71(5) -7(3) 14(4) -1(3) 0(51) 36(4) 33(4) 31(4) -2(3) -1(3) 8(3) 0(52) 99(7) 46(4) 63(5) -3(4) 40(5) 3(4) 235 Table 4 (cont’d) 0(53) 0(54) Si(55) C(56) C(57) C(58) C(59) C(60) C(61) C(62) 0(63) 0(64) 52(4) 37(3) 34(1) 26(4) 50(6) 56(6) 40(5) 57(5) 51(5) 47(4) 83(4) 76(5) 61(4) 18(2) 19(1) 32(4) 95(6) 53(5) 29(4) 60(5) 48(5) 30(4) 23(3) 91(5) 43(4) 32(3) 34(1) 60(5) 73(7) 84(7) 25(4) 35(4) 54(5) 13(3) 67(4) 36(4) 12(3) 3(2) 2(1) -10(4) -14(5) -13(5) -7(3) 23(3) -5(4) 11(2) 13(3) -11(3) 29(4) 0(2) 10(1) 6(3) 19(5) 23(5) 12(3) 19(4) 11(4) 10(3) 9(3) 40(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) 236 The anisotropic displacement factor exponent takes the form: -2 pi2 [h2 a'2 U11 + + 2 h k a* b‘ U12] Table 5. Hydrogen coordinates (x 10“), isotropic displacement parameters (A 2 x 103), and occupancies for 307 U(eq) Occ. H(4A) -1428 4940 1950 45 1 H(4B) -2097 5334 2635 45 1 H(SA) 378 5169 3879 59 1 H(SB) -291 5762 3390 59 1 H(7A) 2247 4984 3381 44 1 H(BA) 3611 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(18B) -1844 4398 4959 61 1 H(18C) —2288 5019 4459 61 1 H(19A) 370(30) 4099(14) 5110(30) 9(9) 1 H(19B) 1230(50) 3620(30) 4380(50) 70(20) 1 H(ZOA) 817 5723 940 93 1 H(ZOB) 102 6142 1553 93 1 H(ZOC) -617 5576 967 93 1 H(ZlA) 320 3809 314 85 1 H(ZIB) 1530 3991 -78 85 1 H(21C) 735 4468 341 85 1 H(24A) 1829 2016 4624 63 1 H(25A) 229 1855 5526 99 1 H(ZSB) -908 1823 4388 99 1 H(ZSC) -195 2419 4799 99 1 H(26A) 1279 1075 5034 164 1 H(ZGB) 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(ZBB) 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(29C) 920 1973 543 66 1 H(30A) -1130 2243 1085 50 1 H(31A) -1968 1274 737 87 1 H(3lB) -1088 1076 1921 87 1 H(31C) -420 1257 1025 87 1 H(32A) -3088 2041 1472 92 1 H(3ZB) -2307 2522 2301 92 1 H(32C) -2301 1873 2700 92 1 H(36A) 6989 1855 7879 43 1 H(37A) 4446 1835 6089 38 1 H(37B) 5150 1247 6568 38 1 237 Table 5 (cont’d) H(39A) H(40A) H(4OB) H(41A) H(4lB) H(43A) H(44A) H(45A) H(48A) H(49A) H(49B) H(49C) H(SOA) H(SOB) H(SOC) H(SlA) H(SlB) H(SZA) H(52B) H(520) H(53A) H(53B) 0(530) H(57A) H(57B) H(57C) H(58A) H(SBB) H(SBC) H(59A) H(GOA) H(6OB) H(6OC) H(61A) H(GIB) H(61C) H(63A) H(63B) H(63C) H(64A) H(64B) H(64C) 2765 2642 1377 1253 1289 2688 4826 6810 8663 8465 9303 7818 6817 5837 7371 4260(50) 4060(30) 4288 5705 4944 4683 4212 3457 7036 5513 6026 8071 7241 7280 3074 2523 4065 3227 1066 1675 1550 3624 4364 2863 4935 4999 5982 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 5057 4508 5100 5957 6053 5874 5126 4528 5032 6636 8821 7789 7307 8555 6903 8498 9067 7399 6006 7179 6669 5102 5081 5570 4960(50) 5530(30) 9075 9003 8400 9645 9777 10067 9234 9087 8106 8526 7274 7850 7840 9256 9500 9011 7421 7020 6372 4907 6174 5779 4497 5114 5667 47 44 44 50 50 43 33 43 36 66 66 66 70 7o 70 80(20) 5(8) 99 99 99 73 73 73 110 110 110 96 96 96 38 74 74 74 78 78 78 91 91 91 94 94 94 HHI—ii—IHHi—IHHHHHHI—IHHI—Ii—IHHHHHHHi—IHHHHi—ni—Ii—Ii—IHHHI—IHI—IHH 238 10. 11. 12. 13. 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