LIBRARY Michigan“. State Uniwrsity 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 6/07 p1/CIRCIDaleDue indd-p.1 STEREOSELECTIVE CONSTRUCTION OF CYCLIC ETHER RINGS VIA CYCLIC ORTHOESTERS AND KINETIC RESOLUTION OF RACEMIC ALKENES BY ASYMMETRIC DIHYDROXYLATION USING PEPTIDE-BASED LIGANDS By Tao Zheng A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PI-HLOSOPHY Department of Chemistry 2006 ABSTRACT STEREOSELECTIVE CONSTRUCTION OF CYCLIC ETHER RINGS VIA CYCLIC ORTHOESTERS AND KINETIC RESOLUTION OF RACEMIC ALKENES BY ASYMMETRIC DIHYDROXYLATION USING PEPTIDE-BASED LIGANDS By Tao Zheng The Lewis acid catalyzed intramolecular ring opening of epoxides by alcohols is one of the most popular methods for constructing oxarings stereospecifically. The potential synthetic utility of this reaction is considerable, given the stereospecific nature of the cyclization and the ease of establishing the absolute stereochemistry of the epoxides through various methods. However, the structural requirment of the most popular Sharpless asymmetric epoxidation, and the Jacobsen-Katsuki and Shi epoxidations limits the synthetic strategy. Compared with the asymmetric epoxidation, Sharpless asymmetric dihydroxylation reaction is less limited by the choice of substrate. Namely, a parental allylic alcohol is not necessary. Therefore, it was deemed beneficial to develop methodology, that could utilize the flexibility of dihydroxylation by equating the reactivity of diols and epoxides. This prompted us to develop a protocol to cyclize 1,2,n-triols to cyclic ether rings with complete stereochemical fidelity established by Sharpless asymmetric dihydroxylation reaction. This protocol was successfully used in the total synthesis of Mucoxin. Compared with Sharpless asymmetric epoxidation, the kinetic resolution of racemic alkenes and desymmetrification of meso olefins by osmium mediated asymmetric dihydroxylation has been successful only in a handful of examples. The development of peptide based ligands for the asymmetric reaction has attracted attention in recent years due to various advantages of peptide chemistry. Our approach is mainly focused on reengineering existing scaffolds by tethering short peptide chains to chincona alkaloids. A small library has been synthesized and tested for the kinetic resolution of racemic alkenes. A better enantioselectivity than the original Sharpless ligand was achieved using one of our peptide-based ligand. For My Parents iv ACKNOWLEDGEMENTS This dissertation would be incomplete without those people who have encouraged and helped me during my Ph.D career. I always believe it is my luck brought me to Babak Borhan’s lab. He has been a perfect advisor ever since, not only guided me through my career but also my life. He has always been supportive on my decisions and believed my abilities. I also need to thank Dr. Baker, Dr. Wulff, and Dr. Geiger who served as my committee members, and gave me a lot of valuable suggestions during the past five years. My labmates are all helpful and friendly. I would like to especially thank Jun and Chrysoula, also my best friends, who have given me unconditional support during these years. I also enjoyed those time spent with Stewart, Dan, Ben, Radha and Marina, who have been close with me in the lab. My friends, Yana, Ying, Zhenjie, Yu, Feng, Chunrui and Lei, have endrosed me friendship. I really enjoyed the time we sepent together. Finally, I would like to thank my parents and my sister. They are everything to me. TABLE OF CONTENTS LIST OF TABLES ............................................................................. x LIST OF FIGURES ........................................................................... xii LIST OF SCHEMES ........................................................................... xiv LIST OF ABBREVIATIONS ................................................................ xxii CHAPTER I Cis-Dihydroxylation of alkenes mediated by osmium tetraoxide: a brief review. 1 1.1 Introduction ........................................................................ l 1.2 History .............................................................................. 2 1.3 Noncatalytic cis dihydroxylation of alkenes .................................. 4 1.4 Catalytic cis dihydroxylation of alkenes ....................................... 7 1.4.1 Catalytic cycles ...................................................... 7 1.4.2 Chiral ligands ........................................................ 1 1 1.4.3 Ligand structure-activity studies and mnemonic device ....... 12 1.4.4 Ligand scope and limitations ...................................... 14 1.4.5 The “AD-mixes” .................................................... 16 1.5 Oxidative cleavage of olefins ................................................... 16 1.6 Mechanism-[[3+2] versus [2+2] addition of 0304 across C=C bond. 18 1.7 Conclusion ........................................................................ 22 Reference ............................................................................... 24 CHAPTER H Oxidative cyclization of 1,4-dienes .......................................................... 31 2.1 Introduction ........................................................................ 31 2.1.1 Arachidonic acid metabolism ........................................ 31 vi 2.1.2 Oxidative cyclization of isolated diols mediated by high valent metal oxide ..................................................... 2.2 Characteristic modification of 1,4—dienes ..................................... 2.2.1 Heteroatoms incorporated 1,4-dienes ............................... 2.2.2 Gem-dimethyl group incorporated 1,4-diene ...................... 2.3 Regiochemical control in the oxidative cyclization of 1,4-dienes ......... 2.4 Conclusion ........................................................................ 2.5 Experimental ...................................................................... Reference ............................................................................... CHAPTER HI One-pot cyclization of 1,2,n-triols via orthoesters ......................................... 3.1 Introduction ........................................................................ 3.1. 1 Annonaceous acctogenins ............................................ 3.1.2 Synthetic strategies for the construction of THF core in total synthesis of Annonaceous acetogenins ................................ 3.1.2.1 Intramolecular epoxide opening cyclization ............ 3.1.2.2 Intramolecular Williamson reaction ..................... 3.1.2.3 Oxidative cyclization of 1,5-dienes ...................... 3.1.2.4 Asymmetric dihydroxylation-haloetherification ....... 3.1.3 Asymmetric epoxidation vs. dihydroxylation ..................... 3.1.4 Transformation of 1,2-diols into epoxides or epoxide-like synthons ................................................................ 3.2 One-pot cyclization of 1,2,n-triols via orthoesters ........................... 3.2.1 Optimization of reaction conditions ................................. 3.2.2 Synthesis of 1,2,5-triol substrates ................................... vii 35 43 51 52 61 62 76 8O 8O 80 83 83 86 87 88 89 90 93 96 99 3.2.3 Cyclization of 1,2,5-triols ............................................ 109 3.2.4 Synthesis of 1,2,4-, 1,2,6-, and 1,2,7-triols and their one-pot cyclization via orthoester intermediates ............................ 114 3.2.5 One-pot cyclization of 1,2,n-triols to construct bicyclic systems .................................................................. 120 3.2.6 Some improvements of the cyclization of 1,2,n-triols via orthoesters .............................................................. 125 3.2.7 Stereospecificity ....................................................... 127 3.3 Extention of substrate scope ..................................................... 129 3.3.1 Lactonization ........................................................... 129 3.3.2 Pyrolidine formation .................................................. 131 3.3.3 Lactam formation ...................................................... 132 3.3.4 Formation of cyclic thioether ........................................ 134 3.4 Conclusion ........................................................................ 135 3.5 Experimental ...................................................................... 135 Reference ............................................................................... 191 CHAPTER IV Intermolecular nucleophilic substitution of orthoesters ................................... 195 4.1 Introduction ........................................................................ 195 4.2 Intermolecular nucleophilic substitution of orthoesters ..................... 200 4.3 Conclusion ........................................................................ 217 4.4 Experimental 217 Reference ............................................................................... 227 CHAPTER V Kinetic resolution of racemic alkenes by asymmetric dihydroxylation using peptide-based ligands .......................................................................... 229 viii 5.1 Introduction ........................................................................ 229 5.1.1 Kinetic resolution ...................................................... 229 5.1.2 Kinetic resolution of racemic alkenes by catalytic asymmetric dihydroxylation ........................................................ 23 1 5.1.3 Peptide-based catalysts for asymmetric organic synthesis ....... 236 5.1.4 Kinetic resolution of racemic alkenes by catalytic asymmetric dihydroxylation by peptide-based catalysts ........................ 241 5.2 Synthetic approaches of designed peptide-based ligand ..................... 243 5.3 Kinetic resolution of racemic olefins by 0304 mediated 275 dihydroxylation using peptide-based ligand .................................. 5.4 Stereochemical effect of proline ................................................ 280 5.5 Other ligand structures ........................................................... 283 5.6 Solvent effect on kinetic resolution using peptide-based ligand ............ 287 5.7 Conclusion ........................................................................ 289 5.8 Experimental 289 Reference ............................................................................... 344 ix Table 1-1 Table I-2 Table II-l Table II-2 Table II-3 Table II-4 Table 111-1 Table HI-2 Table III-3 Table IH-4 Table 111-5 Table IV-l Table IV-2 Table V-l Table V-2 Table V-3 Table V-4 Table V-5 LIST OF TABLES Osmium tetraoxide promoted oxidative cleavage of olefins ............ The recommended ligands for each olefin classes ........................ Oxidative cyclization of 1,4-diene methyl linoleate ..................... Regioselective mono-dihydroxylation of dienes with AD-mix......... The influence of steric effects on the regioselectivity of polyenes ..... Oxidative cyclization of deca-2,5-dienoic acid ethyl ester II-55 ....... One-pot cyclization of decane-l,4,5-triol with various acid promoters ....................................................................... One-pot cyclization of 1,2,5-triols via orthoesters ........................ One-pot cyclization of aromatic 1,2,5-triols .............................. Optimization of one-pot cyclization of octadecane-1,6,7-triol III- 105 .............................................................................. One-step cyclization of 1,2,n-triols to oxan'ngs via orthoester intermediates ................................................................... Optimization of nucleophilic addition of cyclic orthoesters ............ Triphenyl orthobenzoate mediated intermolecular nucleophilic addition of cyclic orthoester ................................................. Summary of kinetic resolution experiments with exocyclic olefins. .. Kinetic resolution of sec-allylic acetates via AD with (DHQD)2TP. .. Kinetic resolution of allylic 4-methoxybenzoate esters using specifically designed DHQD-PYDZ—(S)-anthryl catalyst ............... The optimization of SNAr reaction of difluoropyridazine with dihydroquinadine ............................................................. Attempts of coupling reaction between carboxylic acid V-29 and valine methyl ester ............................................................ 15 41 54 55 58 98 110 113 119 126 208 214 233 234 235 257 260 Table V-6 Kinetic resolution of (i)-3-buten-2-yl 4-methoxybenzoate ............. 276 Table V-7 Kinetic resolution of (i)-or-vinyl benzyl alcohol .......................... 277 Table V-8 Kinetic resolution of (:t)-acetic acid l-phenyl-allyl ester under standard reaction conditions ................................................. 278 Table V-9 Kinetic resolution of (:)—Acetic acid l-phenyl-allyl ester under standard reaction conditions using peptide-based ligand V-95 and V- 96 ................................................................................ 282 Table V-lO Kinetic resolution of acetic acid l-phenyl-allyl ester using peptide- based ligands without pyridazine linker .................................... 287 Table V-11 Solvent effect of kinetic resolution by AD using peptide-based ligand ........................................................................... 288 xi Figure I-1 Figure I-2 Figure 1-3 Figure I-4 Figure I-5 Figure I-6 Figure I-7 Figure II—l Figure II—2 Figure H—3 Figure III-1 Figure III-2 Figure III-3 Figure III-4 Figure III-5 Figure IV -1 Figure V-l Figure V-2 LIST OF FIGURES Typical osmate ester structures and IR stretching datas ................. Typical osmate ester structure and IR stretching band in the presence of tertiary amines .............................................................. Asymmetric dihydroxylation ligands using quinine derivative. . . . Representative ligands for AD reaction other than duinine derivative ....................................................................... Relationship between ligand structure and binding and ceiling rate constants ....................................................................... Mnemonic device for predicting the enantiofacial selectivity in AD reaction ......................................................................... Structure of the bis-OsO4 complex of (DHQD)2PHAL based on molecular mechanics calculations and NOE experiments ............... Structures of AA-THF-diols ................................................ Structure of Monensin, Ionomycin and Salinomycin ..................... 3-D projections of oxidative cyclization of 1,5- and 1,4-dienes ........ General structure of acetogenins ............................................ Representative Annonaceous acetogenins ................................. Structure of Mucoxin ......................................................... (+)-Rolliniastatin 1 ............................................................ Proposed structure of Mucoxin ............................................. The proposed structures of none nucleophilic orthoesters ............... Transition state model proposed for Peptide-based catalyst for Ti- catalyzed asymmetric Strecker reaction .................................... Proline-based catalyst for asymmetric dihydroxylation of olefins. xii 10 11 l2 14 19 35 36 44 80 82 83 85 94 210 240 242 Figure V-3 Figure V-4 Figure V—5 Figure V-6 Figure V-7 The initial design of peptide-based ligand for asymmetric hydroxylation .................................................................. 242 Peptide-based ligand V-l .................................................... 243 Energy minimization of compound V-l .................................... 244 Structure motif of peptide-based ligand without pyridazine linker. . . .. 283 3D projection of compound V-101 ......................................... 286 xiii Scheme I—l Scheme I-2 Scheme I-3 Scheme I-4 Scheme I-5 Scheme I—6 Scheme H-l Scheme II-2 Scheme II-3 Scheme [14 Scheme II-5 Scheme II-6 Scheme II-7 Scheme II-8 Scheme II-9 Scheme 11-10 Scheme II-l 1- Scheme II-12 Scheme II- 13 LIST OF SCHEMES Two catalytic cycles for the asymmetric dihydroxylation using NMO as cooxidant ..................................................... Catalytic cycle of AD reaction with K3Fe(CN)(, as the cooxidant ................................................................ Osmium mediated oxidative cleavage of olefins .................. Proposed mechanism of oxidative cleavage ........................ Concerted vs stepwise pathway ...................................... Proposed CCN pathway for the production of Os(VI) ester of styrene and (DHQD)2PYDZ-OSO4 .................................. AA metabolites via three enzymetic pathways ..................... Proposed biosynthesis of AA-THF—diols ........................... Oxidative cyclization of 1,5-diene ................................... Cr03 mediated oxidative cyclization of 1,5-diene ................. Ru mediated oxidative cyclization of 1,5-dienes .................. OsO4 mediated oxidative cyclization of 1,5-dienes ............... Proposed mechanism for 0504 promoted oxidative cyclization of 1,5-diene ............................................................. Proposed mechanism pathways for oxidative cyclization of 1,4-dienes ............................................................... The alternative 2+2 rearrangement .................................. Attempts of oxidative cyclization of dimethyl distyryl silane. .. Synthesis of dihept-l-enyl dimethyl silane ......................... The attempted oxidative cyclization of dihept-l-enyl dimethyl silane II-33 ............................................................. Oxidative cyclization of sulfur atom incorporated 1,4-diene. . xiv 17 17 18 21 32 33 36 37 37 38 39 42 43 46 47 47 48 Scheme II—l4 Scheme H-15 Scheme II-16 Scheme II-17 Scheme 11- l 8 Scheme II-19 Scheme H-2O Scheme II-21 Scheme II-22 Scheme III-1 Scheme III-2 Scheme III-3 Scheme III-4 Scheme III-5 Scheme III-6 Scheme III-7 Scheme III-8 Scheme III-9 Scheme III-10 Scheme III-11 Synthesis of distyrylsulfoxide and dihept-l—enyl sulfoxide ...... Attempts of oxidative cyclization of distyryl sulfoxide II-36 and dihept-l-enyl sulfoxide 11-37 .................................... Synthesis of gem-dimethyl 1,4-diene II-44 ......................... The attempt to oxidatively cyclize gem-dimethyl 1,4-diene II- 44 ........................................................................ Regioselectivity of oxidative cyclization of 1,4-diene ............ Synthesis and oxidative cyclization of 5-methyl-hepta-2,5- dienoate .................................................................. Synthesis of deca-2,5-dienoic acid ethyl ester II-55 .............. Synthesis of 1-(1-but-3-enylidene-hexyl)-4-methoxy-benzene II-60 ..................................................................... Oxidative cyclization and dihydroxylation of II-60 ............... Intramolecular epoxide opening cyclization ........................ Sequential synthesis of oligo-THF rings by intramolecular epoxide openings ....................................................... General scheme for Williamson reaction ........................... Total synthesis of Asimicin ........................................... Oxidative cyclization of 1,5-dienes .................................. Total synthesis of cis-Solamin using a permanganate-mediated oxidative cyclization ................................................... Total synthesis of Mosin B ........................................... Selective arenesulfonylation .......................................... Cyclic sulfates act as epoxide-like synthons ....................... Stereospecific transformation of 1,2-diols into epoxides via orthoester intermediates .............................................. Retrosynthetic analysis of Mucoxin ................................. XV 48 49 51 52 53 56 57 59 61 83 84 86 86 87 88 89 91 92 93 94 Scheme III-12 Scheme III— 13 Scheme III- 14 Scheme III-15 Scheme III-16 Scheme H1- 17 Scheme HI-18 Scheme III-19 Scheme HI—20 Scheme III-21 Scheme [[1-22 Scheme HI—23 Scheme III-24 Scheme III-25 Scheme III-26 Scheme III-27 Scheme III—28 Scheme III-29 Scheme III-30 Scheme III-31 Scheme III-32 Cyclization of 1,2,n-triols via orthoester intermediate ............ Cyclization of 1,4,5-decantn'ol via orthoester intermediate ...... Epoxidation-cyclization of cis-4-decen-1-ol ........................ Synthesis of cis-1,4,5-decanetriol III-26 ........................... Synthesis of 1-cyclohexyl—9-(4-methoxy-benzyloxy)-nonane- 1,4,5-triol III-33 ........................................................ Synthesis of tetradecan-5,8,9—triol III-36 ........................... Synthesis of 2-methyl-undecane-2,5,6-triol III-41 ................ Synthesis of l-phenyl-decane-1,4,5-tn'ol III-43 ................... Synthesis of 1-(1-hydroxy-cyclohexyl)-butane-1,4-diol III-48.. Synthesis of 2,3,6-trihydroxy-hexanoic acid ethyl ester III-54.. Synthesis of trans-l-phenyl-pentane-l,2,5-triol III-59 ........... Synthesis of cis-l-phenyl-pentane-l,2,5-triol III-64 ............. Synthesis of 1-(4-methoxy-phenyl)—pentane-1,2,5-tn'ol III-69... Attempt to synthesize cis-5-(4-nitro-phenyl)-pent-4-en-l-ol III-70 ..................................................................... Synthesis of l-(4-nitro-phenyl)-pentane- l ,2,5-triol III-76 ....... Intermediates of one-pot cyclization to form tetrahydropyran products .................................................................. Synthesis and cyclization of 1,3,4-octanetriol III-94 .............. Synthesis and cyclization of 1,5,6-nonanetriol III-101 ............ Synthesis of octadecane-1,6,7-triol III-105 ......................... Epoxidation cyclization of cis-octadec—6-en-l-ol III-104. . . . . One-pot cyclization to form acetic acid chroman-3-yl ester [11- 111 ........................................................................ xvi 96 97 98 99 100 101 102 103 103 104 105 106 107 108 109 114 115 116 117 119 121 Scheme III-33 Scheme III-34 Scheme III-35 Scheme III-36 Scheme III-37 Scheme IH-38 Scheme III-39 Scheme III-40 Scheme III-41 Scheme III-42 Scheme III-43 Scheme III-44 Scheme III-45 Scheme IV—l Scheme IV-2 Scheme IV-3 Scheme IV-4 Scheme IV-5 Synthesis and cyclization of 1-hydroxymethyl-cyclooctane- 1,5-diol III-115 ......................................................... Synthesis of l-(2-hydroxy-ethyl)-cyclohexane-l,2-diol 111-121 and 1-(3-hydroxy-propyl)-cyclohexane-1,2-diol III-127 ......... One-pot cyclization of l-(2-hydroxy-ethyl)-cyclohexane-1,2- diol 111-121 and 1-(3-hydroxy—propy1)-cyclohexane-1,2-diol III-127 ................................................................... Proposed mechanism for the formation of Acetic acid 2-(2- oxo-cyclohexyl)-ethyl ester III-129 ................................. Orthobenzoate mediated cyclization of 1,2,n-triols ............... Stereospecific nature of cyclization .................................. Scheme of orthoester mediated lactonization ....................... Attempts of orthoester mediated lactonization ..................... Orthoester mediated cyclization of amino vicinal diol ............ Synthetic pathway to access 1-cyclohexylamino—decane-4,5- diol III-46 ............................................................... Formation of lactam by orthoester mediated cyclization ......... Synthesis of 4,5-dihydroxy-decanoic acid amide III-149. . . . . . Synthesis and cyclization of 1-mercapto-decane-4,5-diol III- 152 ........................................................................ The initial retrosynthetic analysis of Mucoxin ..................... Regiochernically controlled intermolecular union of two advanced intermediates towards the synthesis of Mucoxin ....... The proposed mechanism of 1,2-hydride migration of vinyl epoxide ................................................................... Novel stereocontrolled approach to syn- and anti- oxepe'ne— cyclogeranyl trans-fused polycyclic systems ...................... Construction of small and medium sized oxarings by xvii 122 123 124 125 127 128 129 130 .131 1.32 133 133 134 195 196 196 197 Scheme IV-6 Scheme IV-7 Scheme IV-8 Scheme IV-9 Scheme IV—10 Scheme IV-1 1 Scheme IV-12 Scheme IV-13 Scheme IV-14 Scheme IV-15 Scheme IV-16 Scheme IV-17 Scheme IV-18 Scheme IV-l9 Scheme V-l Scheme V-2 Scheme V-3 intermolecular addition of alcohols to vinyl epoxides coupled with RCM ............................................................... Lewis acid catalyzed intermolecular nucleophilic substitution of cyclic orthoesters coupled with ring closing metathesis to synthesize cyclic ether rings .......................................... Synthesis of orthoesters IV-7 and IV-9 ............................. Intermolecular nucleophilic substitution reaction of cyclic orthoester and nucleophilic alcohol catalyzed by BF3'OEt2. . . .. A two—component catalyst system for allylic alkylations with alcohol pronucleophiles ................................................ Attempts of using alcohol pronucleophiles ......................... Intermolecular nucleophilic addition of alcohol to aliphatic cyclic orthoester ........................................................ Nucleophilic addition of cyclic orthobenzoate ..................... TMSOTf acting as the Lewis acid promoter for the nucleophilic addition of cyclic orthoacetate ........................ Nucleophilic addition of cyclic orthoester by alcohols promoted by Lewis acid TMSOTf ................................... General procedure of synthesis of orthoesters ..................... Synthesis of vinyl orthobenzoate .................................... Acid catalyzed reaction of vinyl orthobenzoate and diol ......... Attempt to synthesize triphenyl orthobenzoate from dithioester and dialkoxydibutylstannane .......................................... Synthesis of triphenyl orthobenzoate from (1,01,01- trichlorotoluene ......................................................... Kinetic resolution of allylic alcohol as reported by Sharpless and co-workers ......................................................... Kinetic resolution of chiral fullerenes by asymmetric osmylation .............................................................. Intrinsic diastereoselection in the dihydroxylation of exocyclic xviii 198 200 201 202 202 203 204 206 206 207 210 210 211 212 213 230 231 Scheme V-4 Scheme V-5 Scheme V-6 Scheme V-7 Scheme V-8 Scheme V-9 Scheme V-10 Scheme V-ll Scheme V- 12 Scheme V- l 3 Scheme V- 14 Scheme V-15 Scheme V-16 Scheme V-17 Scheme V-18 Scheme V-l9 Scheme V-20 Scheme V-21 Scheme V-22 olefins ................................................................... Kinetic resolution by acyl transfer reaction using peptide-based catalyst .................................................................. Peptide-based catalyst for Ti-catalyzed asymmetric Strecker reaction .................................................................. Asymmetric allylic substitution using peptide-based ligands. Retrosynthesis of ligand V-l .......................................... Synthesis of tripeptide V-2 ............................................ Synthesis of compound V-3 .......................................... The attempts of Pd catalyzed C-N coupling ........................ Synthesis of peptide-based ligand V-l .............................. Kinetic resolution of (:)-3-buten-2-yl 4-methoxybenzoate by asymmetric dihydroxylation using ligand V-l ..................... Pd-catalysed C-N coupling of aryl chloride and proline .......... Synthesis of aryl iodide V-22 ......................................... Attempts of Pd-catalyzed C-N coupling using aryl iodide ........ SNAr and Cu(I) mediated coupling of aryl iodide with proline derivatives. . .' ............................................................ the alternative route commenced with amination of dihalopyridazine with proline derivative ............................ Synthesis of 1,3-difluoropyridazine ................................. Synthesis of compound V-29 ........................................ The attempt of coupling of V-29 with C-terminal protected peptides .................................................................. Attempt of coupling reaction between valine methyl ester and compound V-32 ......................................................... Synthesis of B-D-proline ............................................... xix 232 238 240 241 244 246 247 248 249 250 251 252 253 254 255 256 258 259 ' 261 262 Scheme V-23 Scheme V-24 Scheme V-25 Scheme V-26 Scheme V-27 Scheme V-28 Scheme V-29 Scheme V-30 Scheme V-31 Scheme V-32 Scheme V-33 Scheme V-34 Scheme V-35 Scheme V-36 Scheme V-37 Scheme V—38 Synthesis of compound V-37 ......................................... Synthesis of DHQD—PYD-B-(D)-Pro-(L)-Trp~(L)-Val-OMe V- 40 ........................................................................ Synthesis of DHQD-PYD-B—(D)-Pro-(L)-Ser-(L)-Val—OMe V- 44 ........................................................................ Synthesis of DHQD-PYD-B-(D)-Pro-(L)-Met-(L)-Val-OMe V- 47 ........................................................................ Synthesis of DHQD-PYD-B-(D)-Pro-(L)—Tyr-(L)-Val-OMe v- 51 ......................................................................... Synthesis of DHQD-PYD—B-(D)-Pro—(L)—Lys-(L)-Val-OMe V- 55 ......................................................................... Synthesis of DHQD-PYD-B-(D)-Pro-(L)-Asn-(L)-Val-OMe V- 58 ......................................................................... Synthesis of DHQD-PYD-B-(D)-Pro-(L)-His-(L)-Val-OMe V- 61 ......................................................................... Synthesis of DHQD-PYD-B-(D)—Pro-(L)-Asn-(L)-Phe-OMe V- 65 ......................................................................... Synthesis of DHQD-PYD-B-(D)-Pr0-(L)—Asn-(L)-Trp-OMe V- 70 ......................................................................... Synthesis of DHQD-PYD-B-(D)-Pro-(L)—Asn-(L)—t-BuGly-(L)- Val-OMe V-75 ......................................................... Synthesis of DHQD-PYD-B-(D)-Pro-(L)-Val-(L)-Asn(Trt)- OMe V-80 ............................................................... Synthesis of DHQD-PYD-B-(D)-Pro-(L)-Asn(Trt)-(L)-Val- OMe V-83 ............................................................... Synthesis of DHQD-PYD—B-(D)—Pro-(D)—Asn—(L)-Val-OMe V- 86 ......................................................................... Synthesis of DHQD-PYD-B-(D)—Pro-(L)-Asn-(D)-Val-OMe V- 89 ........................................................................ Synthesis of peptide-based ligand DHQD-PYZ-B-(L)—Pro-(L)- XX 263 264 265 266 267 268 269 269 270 271 272 273 274 274 276 Trp-(L)-Val-OMe and DHQD-PYZ—B-(L)-Pro-(L)-Asn-(L)- Val-OMe ................................................................. 28 1 Scheme V-39 Synthesis of peptide-based ligand without pyridazine linker. 284 xxi AA Ac ACN AD Ar aq Bp Boc cbz CH2C12 CI CSA Cy DBU DCC DCM de DI DIC DIAD DIB AL LIST OF ABBREVIATIONS angstrom arachidonic acid acetyl acetonitrile asymmetric dihydroxylation Aryl aqueous dihydrobispyrazolylborate tert-butoxycarbonyl carbobenzyloxy dichloromethane chemical ionization camphorsulfonic acid cyclohexyl 1,8—diazabicyclo[5.4.0]undec-7-ene dicyclohexylcarbodiimide dichloromethane diasteromeric excess deionized diisopropylcarbodiimide diisopropyl azodicarboxylate diisobutylaluminum hydride xxii DIPEA DMAP DMDO DME DMF DMP DMSO 131350 ee EI eq equiv FAB Fmoc GC HMPA HRMS HWE IBX KHMDS LiHMDS mCPBA diisopropylethyl amine 4-(dimethylamino)pyridine dimethyl dioxirane dimethoxyethane N ,N-dimeth ylforrnamide dess-martin periodinane dimethyl sulfoxide Effective Dose to 50 percent enantiomeric excess electric ionization equation equivalent fast atom bombardment 9-fluorenylmethoxycarbonyl gas chromatography hour hexamethyl phosphoramide high resolution mass spectrometry Homers-Wadsworth-Emmons reaction 2-iodoxybenzoic acid potassium bis(trimethylsilyl)amide lithium bis(trimethylsilyl)amide m-chloroperbenzoic acid xxiii Mes mmol MS NaHMDS NMO NMR NOE 0304 Ph PMB PPT S PTSA RT TBAF TB A-OX TBS THF THP mesityl milliliter methyl lineolate millimole mass spectrometry sodium bis(trimethylsilyl)amide N -bromosuccinimide n-methylmorpholine n-methylmorpholine-n-oxide nuclear magnetic resonance N-methyl-2-pyrrolidinone nuclear Overhauser effect osmium tetroxide phenyl p-methoxybenzyl pyridinium para-toluenesulfonate p-toluenesulfonic acid room temperature tetrabutylammonium fluoride tetra-n-butylammonium peroxymonosulfate t-butyldimethylsilyl tetrahydrofuran tetrahydropyran xxiv TMEDA tetramethylethylenediamine TMS trimethylsilyl Z carbobenzylox y XXV Chapter I Cis-Dihydroxylation of alkenes mediated by osmium tetraoxide: a brief review 1.1 Introduction Discovery of new reactions and methodologies is central to the progress of organic chemistry. It is obviously that oxidations and reductions are key reactions for organic chemist. The importance of these reactions can not be overestimated. In particular, we were interested in oxidation processes which are essential to the success of organic synthesis, including chromium oxidations of alcohols and aldehydes (Jones, PCC, PDC ect.),"2 hydroxylations, bishydroxylations,3‘4 aminohydroxylations?‘7 8-12 l3-15 epoxidations, aziridinations, metal-assisted oxidative cleavage of alkenes and 16‘” oxidative cleavage of diols,18 and ozonolysis.19 There is no need to alkynes, emphasize the great effort organic chemists put on these subjects. Although a great number of manuscripts have already been published in this area, more efficient, general oxidation methods with unique properties are always desired. This prompted us to develop a number of stereoselective oxidation reactions in hope of increasing the repertoire of tools available to organic chemists to tackle syntheses of complex molecules on both laboratory and industrial scale for high valued commodities and pharmaceuticals. Inspiration for discovery is fueled from many sources, especially biology and biologically active natural products, biological pathways, synthesis, and serendipity. Our discovery of a new class of fatty acid oxide metabolites with a tetrahydrofuran core in common has piqued our interest in new methodologies to synthesize this motif. On the way to develop a series of methods to construct the THF core, the reagent 0304 has drawn our attention. This high valent metal oxide has unique properties and has been studied extensively. Several synthetic strategies utilizing this metal oxide, including oxidative cyclization of 1,4-dieneszo, oxidative cleavage of olefins18 and lactonization via oxidative cleavage of alkenolszl, were already developed by our group. 0504 is also an essential element to this Ph. D. research. Understanding the reaction properties of this reagent, especially those reactions involving oxidation of alkenes, was fundamental to the projects described in this thesis. Therefore, a brief review of this metal oxide, particularly dealing with its use as a catalytic cis- dihydroxylation reagent, will be detailed in the rest of this chapter. 1.2 History Osmium tetraoxide (0304) is the most reliable reagent available for cis- dihydroxylation of olefins to the corresponding diols and is also widely used in electron 12 microscopy as a staining and fixative agent for biological tissues. The reduction of q j . . . 2 osmium tetraoxide by unsaturated specres has been known for over a century. It was Hofmann who first discovered 0504 could be used catalytically in the presence of 24.25 sodium or potassium chlorate for the cis-dihydroxylation of alkenes. Milas extended his work by reporting the osmium tetraoxide catalyzed oxidation of alkenes by hydrogen 7 peroxide?“2 In the late 1930’s, Cricgce developed the amine ligand-assisted 2839 In 1980, Hentges and Sharpless employed chiral amines as dihydroxylation reaction. ligands, thus achieving asymmetric dihydroxylation. The importance of this reaction is demostrated by the fact that the 2001 Nobel Prize in Chemistry was awarded for the development of chirally catalyzed oxidation reactions.30 This breakthrough led to a number of developments, contributing from the Beller,31 B'ackvall,32 Choudary,33 Jacobs,34 and Sharpless35 laboratories, ranging from an improvement of catalytic oxidation chain to catalyst immobilization. Table I-1. Osmium tetraoxide promoted oxidative cleavage of olefins11 entry Substrate Product Yield (%) 0 COOH / (j 1 O 95 H "2 HOOC\/W\/ 2 / 93 l-3 M mow ACOMCOOH 3 93 l-5 I-6 C>J< CH0 4 2, 3, 80 OBn OBn I-7 I-8 O 5 /U\/\/\COOH 80% |_9 I-10 3All reactions were performed with olefin (1 eq.), oxone (4 eq.) and 0304 (0.01 eq.) in DMF (0.2 M) for 3 h at rt. Noteworthy, a recent highlight of catalytic oxidative carbon-carbon double bond cleavage using 0504 was reported by our group.18 Before the invention of this strategy, the standard pathways for the oxidative cleavage of olefins could be characterized into two categories: transformation of olefins into vincinal diols followed by cleavage with NaIO4 or other oxidants (Lemieux-Johnson reaction)36 and direct ozonolysis37. Drawbacks of these two methods including limited solubilities of the inorganic oxidants and the safty concerns of ozone. Osmium tetraoxide promoted catalytic oxidative C leavage of olefins could be deemed as an organometallic ozonolysis. Simple alkyl and aromatic olefins with different substitution patterns can be oxidatively cleaved into ketones or carboxylic acids using catalytic 0304 and oxone in DMF.18 In most cases, a yield of 80% or greater of desired product could be obtained following simple workup . . 18 procedure. Some representative results are shown 1n Table H. 1 .3 Noncatalytic cis dihydroxylation of alkenes The cis dihydroxylation of unsaturated hydrocarbons by osmium tetraoxide is a well established process.27 The reaction takes place via the formation of an osmium (VI) intermediate which upon reductive or oxidative hydrolysis yields the corresponding cis— diol - The reaction process was thoroughly studied through the dihydroxylation of alkenes usin g stoichiometric osmium tetraoxidezg‘38 The intermediate osmium(VI) complex is usually written as a tetrahedral species. However, structure I-ll, although it might exist as a transient species in solution, would b6 unlikely to exist in the solid state since tetrahedral (12 complexes of third-row transition metals are rare. Criegee29'38‘39 has reported the reaction of stoichiometric amount of 0504 with alkenes in nOnreducing solvent yields dark green to black products OsOr-R and OSOS'Rz. These osmium(VI) intermediates has been formulated as dimeric monoester COmplexes syn- and anti-[OszO4(OgR)g] (I-12 and I-13) and monomeric diester complexes [OsO(OgR)3] 1-14 respectively.38 These diamagnetic products have been observed by X—ray crystallographic studies'fi‘s‘39 The infrared spectra of these complexes show bands near 980 cm‘1 assigned to the Os:O stretching vibration, \'(Os:O). Bands n ear 580 cm'] were assigned to the Os—O stretching vibration, \'(Os-O'). while bands near 630 cm'1 for the dimeric monoester conrplexcs are assigned to the stretching vibration, \’ (08303), of the oxygen bridge system. These latter bridge bands are signature for the d imeric monoester complexes. which are not observed for the monomeric diesters (Figure I-l)4() H + 0304 ——’ OS \ O 630 cm'1 980 cm" E05221? ,oj Cos .10] / S\ / Sx / S\ S\ O o o o o .. o k580 '1 O I—12 cm l-13 0 one [0.05.01 r-14 Figure I-I. Typical osmate ester structures and IR stretching datas. The rate of formation of osmium(Vl) ester complexes could be dramatically merearsed by the addition of an excess of tertiary amine, such as pyridine, to solutions of - . 40 . . g . OSmIUm tetraoxrde and alkenes. Brown diamagnetic products could be isolated and characterized as diolatodioxobis(amirre)osmium(Vl) ester complexes l-15. The infrared spectra of these species show bands near 840 cm'1 assigned to the asymmetric stretching vibration V(Ost) of the trans O=Os=O moiety40 (Figure I-2). 840 cm'1 0: 'SxL E .o, . O L l-15 Figure I-2. Typical osmate ester structure and IR stretching band in the presence of tertiary amines The high volatility and toxicity of OsO4 have been considered a great hazard. Os(VI) complexes.“ The anionic osmium(Vl) species, such as potassium osmate, are unreactive toward alkenes but readily react with cis diols.42 Thus they can not be used directly as cis dihydroxylating agents, although they may be used as a source of osmium tetraoxide when treated with co-oxidant. OsO4 adducts of polydentate and monodentate tertiary amines retained the integrity of the 0304 entity and in the case of hexamethylenetetramine complex can be used as a stabillized, nonvolatile form of osmium tetraoxide.28 Osmium(VI) ester complexes can be hydrolyzed either reductively or oxidatively. Reductive hydrolysis is generally carried out by using sodium or potassium sulfite or 43‘44, or hydrogen sulfide“ to yield the bisulfitezg‘zg, lithium aluminum hydride cor‘resPonding cis-diols together with lower forms of osmium which are removed by filtration.3 Oxidative hydrolysis of osmium(VI) ester complexes is generally carried out by uSin g metal chlorates, N-methylmorpholine-N—oxide, hydrogen peroxide, or tert-butyl hydroperoxide. The cis-diol is formed together with osmium tetroxide, which can react further with alkenes, thus rendering the process catalytic." 1.4 Catalytic Cis Dihydroxylation of Alkenes For reasons of cost and convenience, it is more usual to use osmium tetraoxide catalytically for cis dihydroxylation of alkenes. This can be achieved by using catalytic amount of osmium tetraoxide in the presence of a secondary oxidant which hydrolyzes t he intermediate osmium(Vl) ester complex oxidatively to regenerate osmium tetraoxide. A variety of oxidants have been used in conjunction with osmium tetraoxide, including h ydrogen peroxide (Milas’ reagent)3(”37, N-methylmorpholine N-oxide (Upjohn 4 24 - 47.4 - - . 49 process) 6, oxygen, metal chlorates , tert-butyl hydroper'oxrde 8, sodium perrodate , sodium hypochloriteso, and potassium t'en'ocyzrnide4. 1.4. 1 Catalytic Cycles In 1980, the initial efforts by Sharpless and Hentges to induce enantioselectivity in the osmylation with chiral quinuclidine derivatives allowed isolation of diols with moderate to good enantiomeric excesses, but the reaction had to be performed under 5‘ In 1988, Marko and Sharpless found that in the preccnce of stoichiometric conditions. N-methylmorpholine N-oxide, the asymmetric cis dihydroxylation could be catalytic, although with lower enantioselectivity.52 The origin of this discrepancy was found to be the presence of a second catalytic cycle, which exhibited only low or no enantioselectivity (Scheme H)- Scheme I-I. Two catalytic cycles for the asymmetric dihydroxylation using NMO as cooxidant high 99 R R, R H20 ‘“\— R HO OH (I? ,0 83030 37: l- 17 ' NMM T L O 40 primary NMO secondary :IO—IOS 9 '0} 03:08:. cycle cycle 0 n 408 (high enantioselectivity) 5 (low enantioselectivity) L R\_\ R HO OH low 69 The evidence of this secondary catalytic cycle has been provided by the isolation and characterization of monoglycolate ester I-16 and bisglycolate ester I-18 by performing the dihydroxylation process in a stepwise manner under stoichiometric conditions. Upon reductive hydrolysis, this bisglycolate ester I-18 precisely yielded 2 equiv of diol. The low enantioselectivity of this secondary catalytic cycle is due to the involvement of a putative intermediate, osmium(VHI) trioxoglycolate complex I-17. To minimize the effect of the second cycle, the reaction was performed with slow addition of the Olefin. As predicted, ee value was increased dramatically, simply due to giving I-17 SUffiCient time to hydrolyze so that the osmium catalyst does not get trapped into the sec0nd cycle by reacting with olefin.53 To eliminate this secondary catalytic cycle, a breakthrough discovery was reported by performing the reaction under two-phase conditions with K3Fe(CN)(, as the stoichiometric reoxidant.S4 Under these condtions there is no oxidant other than 0304 in the organic layer, in contrast to the homogeneous NMO conditions. Since the formation of osmate ester takes place in this layer, the resulting osmium(VI) monoglycolate ester Lindergoes hydrolysis, releasing diol and ligand to the organic layer and anionic osmium(VI) species to the aqueous layer before the oxidation could occur. Therefore, I: he osmium monoglycolate entry to the second cycle is prevented (Scheme I-2).54 Scheme I-2. Catalytic cycle of AD reaction with K3Fe(CN)(, as the cooxidant R ‘ R organic aquesous 2 OH' (I? 2' I? o 2‘ 2 OH' 2 H o HO~ ’OH HO~ 4 2 HO’ ”S‘OH H0’?,S=o o o 2 OH' 2 H20 2 Fe(CN)53' 2 Fe(CN)54' Quinine Derivative OMe MeO Dihydroquinidine (R=H) Dihydroquinine (R=H) DHQD DHQ Second Generation Ligands Ph N=N NfN Ph Phthalazine (PHAL) Diphenylpyrimidine (PYR) Ligands Ligands First Generation Ligands O O O-A|k* \ O-A|k* / o N O-A|k* CI Chlorobenzoate (CLB) Phenanthryl Ether (PHN) 4-Methyl-2-quinolyl Ether (MEO) Ligands Ligands Ligands Figure I-3. Asymmetric dihydroxylation ligands using quinine derivative (Alk*= DHQD or DHQ) 10 1.4.2 Chiral Ligands The initial ligands developed by Hentges and Sharpless are acetate esters of cinchona alkaloids, which yield moderate to good enantioselectivities in cis— dihydroxylation of olefins.“ The first generation ligands contain one cinchona alkaloid.55 The discovery of ligands with two independent cinchona alkaloid units attached to a heterocyclic spacer has led to a considerable increase in both the enantioselectivity and the scope of the reaction (Figure I-3).5(”58 Representative Monodentate Ligands for AD KN ZNJQOTBDPS OTBDPS Murahashi Hirama Representative Bidentate Ligands for AD “‘NMeZ Ph N N cm (1 (I L: M 1”“ 1Ph L1. NM92 Snyder Hanessian FUji Figure I-4. Representative ligands for AD reaction other than quinine derivative Apart from cinchona alkaloids catalyzed asymmetric dihydroxylation, there are few other catalytic systems, such as a monodentate l,4-diazabicyclo[2.2.2]octane ll (DABCO) derivative developed by Hirama59 and chiral isoxzaolidines developed by Murahashif’O A number of chiral diamine ligands have been employed by different groups (Figure I-4).°"63 Although good to excellent enantioselectivities can be achieved with diamine ligands, a serious drawback results from their bidentate nature. They tend form very stable chelated complexes with osmium(VI) glycolate, which can not be hydrolyzed. As a consequence, the regeneration of the osmium tetraoxide and ligand is inhibited."4 1.4.3 Ligand Structure-Activity Studies and Mnemonic Device 1 Its presence has a small effect on the rates; however, it increases the binding '\ The nature of R has a very large effect on the rates, but only a small influence _ on the binding R 0’0, 9 The configuration is important: only erythro allows high rates and binding Oxygenation is essential to allow 0% Increases binding to 0504, a carbon su bstituent is too bulky binding to 0304 as well \ N J as rate Y The presence of a flat, aromatic ring system increases binding and rates; the nitrogen has no influence Figure I-5. Relationship between ligand structure and binding and ceiling rate Constants. 12 The origin of the enantioselectivity in Sharpless asymmetric dihydroxylation reactions have been studied extensively by ligand structure-activity studies.4 The enzyme-like binding pocket present in the dimeric cinchona alkaloid ligands is demonstrated to be ideal for providing high ligand acceleration as well as enantioselectivity. The relationship between ligand structure and binding and ceiling rate constants is shown in Figure I—5. In the course of ligand optimization studies, more than 300 cinchona alkaloid derivatives were tested, and it became evident that the enantioselectivity was chiefly influenced by the nature of the O9 substituent of the cinchona alkaloid (R group in Figure I-5). Additionally, the binding constant for 0504 and ligand can be regarded as an approximate measurement of the steric hindrance in the vincinity of the ligand-binding site (tertiary amine in Figure 1-5). The noncorrelation between the binding constant and the saturation rate constant suggests that the rate enhancement is not a ground-state effect, but is rather caused by a stabilization of the transition state due to aromatic stacking interaction. Thus, there is almost a perfect match between the phthalazine ligands and the aromatic olefins with respect to rates and enantioselectivities. The transition-state was stabilized by offset-parallel interactions between the aromatic substituent of the olefin and the phthalazine floor of the ligand, as Well as favorable edge-to—face interations with the ‘bystander’ methoxyquinoline ring.4 ligand structure and More detailed discussion of the relationship between enantioselectivity will be provided later. A mnemonic device for predicting the enantiofacial selectivity in the reaction was built based on the above ligand structure-activity studies and numerous experimental data 13 (Figure L6). The southeast quadrant and to a much less extent the northwest quadrant of this device present steric barriers, whereas the northeast quadrant is relatively open for olefin substituents of moderate size. The southwest quadrant is regarded as being an attractive area, especially well-suited to accommodate flat, aromatic substituents or, in their absence, large aliphatic groups. An olefin positioned according to these criteras will be attacked from top face (,B-face) by dihydroquinidine (DHQD) derivatives (AD-mix-B) or from bottom face (a—face) by dihydroquinine (DHQ) derivatives (AD-mix-or).65 Dihydroquinidine Derivative IIHO OH" I fl-face NE SW T a-face IIHO OH“ Dihydroquinine Derivative Figure I-6. Mnemonic device for predicting the enantiofacial selectivity in AD reaction 1-4.4 Ligand Scope and Limitations A great number of cinchona—based ligands have been tested for the AD reaction in recent years.(’(”67 It was found that the enantiofacial selectivity is chiefly influenced by 14 the nature of the O9 substituents of the cinchona alkaloids. By far, three different classes of ligands developed by Sharpless when taken together can accomodate the 56.58.68 dihydroxylation of almost any olefin. The recommended ligand for each of the six ( . . . . . 2.6) Notrceably, frve out of srx olefin classes are well olefin classes are shown on Table I- served by PHAL and PYR ligands, and only cis-olefins require a unique ligand IND to achieve a good enantiofacial selectivity. Table I-2. The recommended ligands for each olefin classes Olefin A k fi JV \ Class A/ \ Preferred PYR PHAL IND PHAL PHAL PYR ligand PHAL PHAL ee range 30-97 % 70—97 % 20—80 % 90-998 % 90—99 % 20—97 % Ph N_N * at» O *Alk'o / \ O-Alk" Alk'OWO'Alk YO'Alk“ ‘ “r“ Cc“; Ph PHAL-class PYR-class IND-class The phthalazine ligands are recommended for the 1,1- and 1,2-disubstitutcd Olefins as well as trisubstituted olefins as shown in Table L2. The diphenylpyrimidine ligands complement the phthalazines, and they are the ligands of choice for the r 15 g monosubstituted terminal olefins, especially those with branching in the substituent. The PYR ligands give best stereofacial selectivities with aliphatic olefins, while PHAL ligands perform better with olefins bearing aromatic susbtituents. Among the six classes of olefins, cis-disubstituted olefins remain problematic. Even when IND ligands are employed, the enantiomeric excess for the cis—diol products is normally less than 90% for aromatic olefins, while aliphatic substrates give even lower selectivities.68 1.4.5 The “AD-Mixes” The standard substrates, terminal, 1,1-disubstituted, trans-1,2-disubstituted, and trisubstituted olefins, require very similar reaction conditions for AD reaction. A premix of all the reactants is convenient for small scale asymmetric dihydroxylation. The currently commerially available AD-mix recipe is as follows: 1 kg of AD-mix are composed of K3Fe(CN)(, 699.6 g, K2CO3 293.9 g, (DHQD)2-PHAL (AD-mix-B) or (DHQ)2-PHAL (AD-mix-or) 5.52 g and K30803(OH)4 1.04 g. The standard AD PYOCEdUFC calls for 1.4 g of AD—mix per millimole of olefin.“ l -5 Oxidative Cleavage of Oleflns The oxidative cleavage of olefins is one of the paramount reactions developed in Organic chemisty. General oxidative cleavage pathways can be divided into two . . . 3 . 37 Categories, namely Lemreux-Johnson reactron 6 and ozonolysrs. Our group has developed an alternative method using catalytic osmium tetraoxide and Oxone® as Ox idams.18 The general scheme of this reaction is shown on Scheme I-3. One equivalent of olefin was treated with 1 mol% 0504 and 4 equivalent of Oxone® in DMF. In most cases a yield of 80% or greater of the desired ketone or carboxylic acid was obtained. It should be noted that this reaction is not the typical Lemieux-Johnson oxidative cleavage in which a diol intermediate is involved. This conclusion is supported by the fact that a 1,2- diol can not be cleaved under similar reaction conditions. Based on the above observation, the reaction mechanism was proposed as shown on Scheme I-4, in which osmium (VI) ester I-19 is oxidized to osmium (VIII) I-20, followed by immediate attack of Oxone to yield intermediate I-21. The following fragmentation of I-21 furnished two aldehydes and regenerated 0504. The carboxylic acids were obtained by the independent oxidation of aldehydes by Oxone®. This reaction mechanism was further verified by either buffering the reaction with KHC03 or using 1 equiv of Oxone® to yield aldehydes as final products.18 Scheme I-3. Osmium mediated oxidative cleavage of olefins 0304 (1 mol%) Oxone (4 eq.) R/ — ‘R > R1C02H + RQCOQH 1 2 DMF, 3 h, rt Scheme I-4. Proposed mechanism of oxidative cleavage 0° 40 x9: 9A ,08. ,Os O R to 0304 o o [O] ‘o K02803H R RI — ‘R ———>— —————> ————> R R l-19 1-20 0990(OSO3H [O] ,Osl O O 0) O r —* )k R H R OH R R 1-21 17 1.6 Mechanism-[3+2] versus [2+2] addition of 0804 across C=C bond The reaction of 0304 with a double bond is the initial step in the osmium- catalyzed cis-dihydroxylation of olefins. Given the common use of the cis- dihydroxylation in state-of—the-art chemical synthesis, it is interesting to note that the mechanism of the addition of osmium tetraoxide across C=C bonds has been debated for years. Early work indicated a [3+2] addition,70 and later kinetic studies suggested an initial [2+2] addition,71 whereas recent quantum-chemical calculations showed the [3+2] addition to be favorable.72 Experimental and theoretical data have now become reconciled. Scheme I-5. Concerted vs stepwise pathway [3+2] Obs"? 0804 + = ———> O O I-23 [2+2] rearrangement 0,9,0 93’) O\) l-22 It was Boeseken who first postulated the concerted [3+2] mechanism where an =Os=O moiety adds across the C=C bond.70 The formal product of the [3+2] C33’Cloaddition, a five—member ring metallacycle (osma-2,5-dioxolane) I-23, was experimentally isolated and characterized (Scheme 1-5). The hydrolysis of this Compound yields the 1,2—diol. 18 v“ E Figure I-7. Structure of the bis-OsO4 complex of (DHQD)2PHAL based on molecular mechanics calculations and NOE experiments. This [3+2] mechanism was challenged in 1977 by Sharpless and co-workers.“ They postulated a stepwise mecharrrism via a cyclic organometallic intermediate (metalla-2-oxetane) in the reaction of chromyl chloride (CrOzClz) with olefins as well as in the related reaction of osmium tetraoxide. As shown on Scheme I-5, the reaction involves the formation of a four—member metallacycle I-22 via a [2+2] cycloaddition of osmium tetraoxide across the C=C bond. Then, the intermediate rearranges to the five- membered metallacycle I-23. This mechamism was supported by the observation of a non-linear Eyring plot of enantioselectivity as a function of the reciprocal of temperature for asymmetric dihydroxylations. It can be explained by a reaction pathway with at least tW0 enantioselectivity-determining steps weighted differently according to temperature, OWing to their different activation parameters, AHIE and ASL73 Molecular mechanics 19 ‘ calculations as well as NMR experiments with both the free ligand and its bis—osmium complex suggest that (DHQD)2PHAL adopts a solution conformation as shown on Figure 1-7.4 The NMR spectrum shows only one set of signals for the alkaloid moieties, both in the absence and in the presence of 0304. This would suggest an average Cz-symmetry with respect to an axis through the plane of the phthalazine ring system. A series of nOe experiments carried out on the ligand and its bis-OsO4 complex support this conclusion, and the results are consistent with the relative orientation of the aromatic rings and the quinuclidine units. Molecular mechanics calculations and several X-ray crystal structures of osmium diolate complexes provide evidence of the substituents of the glycolate lying right over the O9 substituent (PHAL), consistent with the approach of the olefin along with [2+2] pathway, which requires the coplanarity of the C=C double bond with the equatorial Os=O bond.4 74’” and others supported a Michaelis-Menten kinetics with an However, Corey initial metal coordination of the olefin and subsequent [3+2] cycloaddition. They supported the sandwich-like transition state, designated as CCN (Criegee-Corey-Noe) model. The CCN [3+2] cycloaddition pathway for the enantioselective dihydroxylation is shown for the case of styrene in Scheme I-6. Compared with Sharpless [2+2] model, CCN pathway has the following characteristics: (1) a preference for the U-shaped conformation of the catalyst and 0304 complex, which has the ability to bind olefins in a binding pocket composed of two parallel methoxyquinoline units, N—coordinated 0304 and the pyridazine spacer, (2) [3+2] cycloaddition goes through an initial complexation between olefin and osmium, which adds an additional binding contact between the Catalyst and substrate (I-24), (3) the proximity of one axial oxygen (03) and one 20 equatorial oxygen (03) to the olefinic carbon of the bounded substrate (I-25), (4) a direct [3+2] cycloaddition produces the pentacoordinate osmium (VI) ester in the energetically most favorable geometry.74 Scheme I-6. Proposed CCN pathway for the production of Os(Vl) ester of styrene and (DHQD)2PYDZ-OsO4 OMe OO \‘1 L’ub _ l-25 The controversy about the reaction mechanism of the 0504 addition to olefins was finally resolved with the help of quantum chemical analysis. The improved calculation methods and steadily increasing computational resources allowed the Calculation of geometric structures and energies of transition states. Not only the rate- limiting step but also the entire profile of a multistep mechanism can be deduced. In 1996 and 1997, three independent groups presented quantum chemical analyses about the 21 reaction mechanism of the 0304 with ethylene. Based on Frenking,76 Morokuma,77 Ziegler78 and co-workers’ results, the activation energy of the [2+2] addition (>39 kcal/mol) is calculated to be much higher than [3+2] pathway (<10 kcal/mol), indicating t hat the reaction favors the [3+2] pathway. Recently, the comparison of a large set of high—precision experimental kinetic i sotope effects (KIEs) with high-level transition structure/KIE caculations was demonstrated to be an extremely powerful tool for defining the mechanism and transition state geometry of organic reaction.”80 This method has been applied to asymmetric dihydroxylations and provided a striking support for a rate—limiting [3+2] cycloaddition process. The 13C and 2H KIEs for asymmetric dihydroxylation of rerI—butylethylene were determined combinatorially at natural abundance by Singleton.81 The calculated theoretical KIEs based on the [3+2] transition structures are in evident qualitative and quantitative agreement with the observed values. In contrast, the KIEs predicted for the transition structures for two possible rate-limiting steps along the stepwise [2+2] pathway do not match with the experimental data at all.” These results provided a stong evidence for the concerted reaction course. 1 -‘7 Conclusion The understanding of 0504 promoted cis-dihydroxylation reaction of olefins is Crucial to the projects of this Ph. D. research, especially for the content in chapter 11 and chapter V. Oxidative cyclization of 1,4-diene, the reaction described in chapter 11, could be considered as a deviation of cis-dihydroxylation. Both of these two reactions have OSmylation and hydroxylation steps. Only due to the existence of a second double bond i It 1,4—diene, a rearrangement occurs during the oxidative cyclization process, which results a cyclic product. Moreover, because of the similarity of these two processes, dihydroxylation is always a side-reaction in the oxidative cyclization reaction. Therefore, t hese two processes is highly related to each other. There is no need to emphasize the i rnportance of understanding the dihydroxylation process before we developed a ligand system, which could achieve the kinetic resolution of racemic olefins as we described in Chapter V. Other than this brief review of osmium promoted cis-dihydroxylation of olefins, a detailed introduction will be provided before each chapter. To prevent repetition, some of the materials and references in this chapter will be refered by the rest of this thesis. 23 (1) (3) (4) (5) (6) (7) (8) (9) (1m (1D (12) (13) Reference Millar, J. G.; Oehlschlager, A. C.; Wong, J. W. Journal ofOrganic Chemistry 1983, 48, 4404-4407. Newman, M. S.; Arkell, A.; Fukunaga, T. Journal oft/re American Chemical Society 1960, 82, 2498-2501. Schroder, M. Chemical Reviews 1980, 80, 187-213. Kolb, H. C.; Andersson, P. G.; Sharpless, K. B. Journal oft/re American Chemical Society 1994, 116, 1278-1291. Reiser, O. Angewandte Chemie-International Edition in English 1996, 35, 1308— 1309. Muniz-Femandez, K., Weinheim, Germany, 2004; p 326-336. Bodkin, J. A.; McLeod, M. D. Journal of the Chemical Society-Perkin Transactions 1 2002, 2733-2746. Frohn, M.; Shi, Y. Synthesis-Stuttgart 2000, 1979-2000. Pfenninger, A. Synthesis-Stuttgm't 1986, 89-116. Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1-299. Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, 1., Ed.; VCH: NY, 1993; Vol. 4.2. Johnson, R. A. a. S., K. B. In Catalytic Asymmetric Syntl'zesis; Ojima, 1., Ed; VCH Publishers, Inc., 1993; Vol. 4. Aggarwal, V. K. Synlett 1998, 329—+. 24 (14) (15) ( l6) ( 17) C 18) ( 19) (20) (22) (23) Li, A. H.; Dai, L. X.; Aggarwal, V. K. Chemical Reviews 1997, 97, 2341—2372. Osborn, H. M. I.; Sweeney, J. Tetrahedron-Asymmetry 1997, 8, 1693-1715. Amey, B. E.; Wilcox, K.; Campbell, E.; Gutierrez, M. O. Journal of Organic Chemistry 1993, 58, 6126-6128. Lee, D. G.; Chang, V. S. Journal of Organic Chemistry 1979, 44, 2726—2730. Travis, B. R.; Narayan, R. S.; Borhan, B. Journal oft/2e American Chemical Society 2002, 124, 3824-3825. Griffith, W. P. Coordination Chemistry Reviews 2001, 219, 259-281. Travis, B.; Borhan, B. Tetrahedron Letters 2001, 42, 7741-7745. Schomaker, J. M.; Travis, B. R.; Borhan, B. Organic Letters 2003, 5, 3089-3092. Riemersm.Jc Biochimica Et Biophysica Acta 1968, 152, 718-&. Makowka, O. Berichte Der Deutschen Chemischen Gesellschaft 1908, 41, 943— 944. Hofmann, K. A. Berichte Der Deutschen Chemisehen Gesellschafi 1912, 45 , 3329-3336. Hofmann, K. A.; Ehrhart, O.; Schneider, 0. Berichte Der Deutschen Chemischen Gesellschaft 1913, 46, 1657-1668. Milas, N. A.; Sussman, S. Journal of the American Chet-nical Society 1937, 59, 2345-2347. Milas, N. A.; Sussman, S. Journal ofthe American Chemical Society 1936, 58, 1302-1304. 25 (28) (29) ( 30) (31) (:32) ( 33) ( 34) (35) (36) (37) (38) (39) (40) (41) Criegee, R.; Marchand, B.; Wannowius, H. Justus Liebigs Annalen Der Chemie 1942, 550, 99-133. Criegee, R. Justus Liebigs Annalen Der Chemie 1936, 522, 75-96. Sharpless, K. B. Angewandte Chemie-International Edition 2002, 41, 2024—2032. Dobler, C.; Mehltretter, G. M.; Sundermeier, U.; Beller, M. Journal of the American Chemical Society 2000, .122, 10289-10297. Jonsson, S. Y.; Farnegardh, K.; Backvall, J. E. Journal oft/re American Chemical Society 2001, 123, 1365-1371. Choudary, B. M.; Chowdari, N. S.; J yothi, K.; Kantam, M. L. Journal of the American Chemical Society 2002, 124, 5341-5349. Severeyns, A.; De Vos, D. E.; Fiermans, L.; Verpoort, F.; Grobet, P. J .; Jacobs, P. A. Angewandte Chemie-International Edition 2001, 40, 586-589. Andersson, M. A.; Epple, R.; Fokin, V. V.; Sharpless, K. B. Angewandte Chemie- International Edition 2002, 41, 472-475. Shing, T. K. M. In Comprehensive Organic Synthesis; Trost, B. M., Flemming, I., Eds.; Pergamon Press: Oxford, 1991. Criegee, R. Angewandte Chemie-Internalional Edition in English 1975, I4, 745- 752. Criegee, R. Angewandte Chemie 1937, 50, 0153-0155. Criegee, R. Angewandte Chemie 1938, 51, 0519-0520. Collin, R. J.; Jones, J.; Griffith, W. P. Journal oft/re Chemical Society—Dalton Transactions 1974, 1094-1097. Brunot, F. R. Journal of Industrial Hygiene 1993, 15, 136-143. 26 (42) (43) (44) (45) (46) (47) (48) (49) (50) (51) (52) (53) (54) Griffith, W. P.; Jolliffe, J. M. Journal ofthe Chemical Society-Dalton Transactions 1992, 3483-3488. Barton, D. H. R.; Ives, D. A. J.; Thomas, B. R. Journal ofthe Chemical Society 1954, 903-907. Castells, J.; Meakins, G. D.; Swindells, R. Journal ofthe Chemical Society 1962, 2917-&. Barton, D. H. R.; Elad, D. Journal ofthe Chemical Society 1956, 2085-2090. Vanrheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Letters 1976, 1973-1976. Byers, A.; Hickinbottom, W. J. Journal ofthe Chemical Society 1948, 1328-1331. Mccaslan.Ge; Furuta, 8.; Durham, L. J. Journal of Organic Chemistry 1968, 33, 2835-2841. Wiesner, K.; Santroch, J. Tetrahedron Letters 1966, 5939-&. Foglia, T. A.; Barr, P. A.; Malloy, A. J.; Costanzo, M. J. Journal ofthe American Oil Chemists Society 1977, 54, A870-A872. Hentges, S. G.; Sharpless, K. B. Journal ofthe American Chemical Society 1980, 102, 4263-4265. Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroder, G.; Sharpless, K. B. Journal of the American Chemical Society 1988, 110, 1968-1970. Wai, J. S. M.; Marko, I.; Svendsen, J. S.; Finn, M. G.; Jacobsen, E. N.; Sharpless, K. B. Journal of the American Chemical Society 1989, 111, 1123-1125. Kwong, H. L.; Sorato, C.; Ogino, Y.; Hou, C.; Sharpless, K. B. Tetrahedron Letters 1990, 31, 2999-3002. 27 (55) (56) ( 57) (58) ( 59) ( 60) (61) (62) (63) (64) (65) (66) (67) Sharpless, K. B.; Amberg, W.; Beller, M.; Chen, H.; Hanung, J.; Kawanami, Y.; Lubben, D.; Manoury, E.; Ogino, Y.; Shibata, T.; Ukita, T. Journal ofOrganic Chemistry 1991, 56, 4585-4588. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M.; Xu, D. Q.; Zhang, X. L. Journal of Organic Chemistry 1992, 57, 2768-2771. Amberg, W.; Bennani, Y. L.; Chadha, R. K.; Crispino, G. A.; Davis, W. D.; Hartung, J.; Jeong, K. S.; Ogino, Y.; Shibata, T.; Sharpless, K. B. Journal of Organic Chemistry 1993, 58, 844-849. Crispino, G. A.; Jeong, K. S.; Kolb, H. C.; Wang, Z. M.; Xu, D. Q.; Sharpless, K. B. Journal of Organic Chemistry 1993, 58, 3785-3786. Oishi, T.; Hirama, M. Tetrahedron Letters 1992, 33, 639-642. Imada, Y.; Saito, T.; Kawakami, T.; Murahashi, S. I. Tetrahedron Letters 1992, 33, 5081-5084. Tokles, M.; Snyder, J. K. Tetrahedron Letters 1986, 27, 3951—3954. Hanessian, S.; Meffre, P.; Girard, M.; Beaudoin, S.; Sanceau, J. Y.; Bennani, Y. Journal ofOrganic Chemistry 1993, 58, 1991-1993. Fuji, K.; Tanaka, K.; Miyamoto, H. Tetrahedron Letters 1992, 33, 4021-4024. Hanker, J. S.; Romanovicz, D. K.; Padykula, H. A. Histochemistry 1976, 49, 263- 291. Norrby, P. 0.; Kolb, H. C.; Sharpless, K. B. Journal of the American Chemical Society 1994, 116, 8470-8478. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, 1., ELL; VCH Publishers: New York, 1993. Lohray, B. B. Tetrahedron-Asymmetry 1992, 3, 1317-1349. 28 (68) (69) (70) (71) ( '72) (73) ('74) (75) (76) (77) (7 8) (79) (80) Wang, L.; Sharpless, K. B. Journal ofthe American Chemical Society 1992, 114, 7568-7570. Kolb, H. C.; Vannieuwenhze, M. S.; Sharpless, K. B. Chemical Reviews 1994, 94, 2483-2547. Boeseken, J. Recueil Des Travaux Chimiques Des Pays-Bas 1922, 41, 199-207. Sharpless, K. B.; Teranishi, A. Y.; Backvall, J. E. Journal ofthe American Chemical Society 1977, 99, 3120-3128. DelMonte, A. J.; Haller, J.; Houk, K. N.; Sharpless, K. B.; Singleton, D. A.; Strassner, T.; Thomas, A. A. Journal of the American Chemical Society 1997, 119, 9907-9908. Gobel, T.; Sharpless, K. B. Angewandte Chemie—International Edition 1993, 32, 1329-1331. Corey, E. J .; Noe, M. C. Journal ofthe American Chemical Society 1996, 118, 11038-11053. Corey, E. J.; Noe, M. C. Journal ofthe American Chemical Society 1996, 118, 319-329. Pidun, U.; Boehme, C.; Frenking, G. An gewandte Chemie-lnternational Edition in English 1996, 35, 2817-2820. Dapprich, S.; Ujaque, G.; Maseras, F.; Lledos, A.; Musaev, D. G.; Morokuma, K. Journal of the American Chemical Society 1996, 118, 11660-11661. Torrent, M.; Deng, L. Q.; Duran, M.; 8013, M.; Ziegler, T. Organometallics 1997, 16, 13-19. Beno, B. R.; Houk, K. N.; Singleton, D. A. Journal ofthe American Chemical Society 1996, 118, 9984-9985. Singleton, D. A.; Merrigan, S. R.; Liu, J.; Houk, K. N. Journal ofthe American Chemical Society 1997, 119, 3385-3386. 29 (8 l) Singleton, D. A.; Thomas, A. A. Journal ofthe American Chemical Society 1995, 117, 9357-9358. 30 Chapter II Oxidative cyclization of 1,4-dienes 2.1 Introduction 2.1.1 Arachidonic acid metabolism Our interest in developing new methodologies for regioselective and stereoselective synthesis of heterocyclic rings stems from our interest in fatty acid metabolism. Arachidonic acid (AA) is a C20 polyunsaturated fatty acid that plays an important role in the production of prostanoids (which include prostacyclins, prostaglandins and thromboxanes) and leul z, ' _.\CH2OAC HO OH CHZOAC O OH OH As reported by Sharpless in 1981, a similar reaction occurs with catalytic amounts 5 However the degree of stereoselectivity is of structurally related ruthenium tetroxide.3 much less than the permanganate mediated reaction since a 3:1 mixture of cis-THF II-8 and trans-THF II-9 is obtained. The differences in bond lengths and geometries of comparable intermediates might be responsible for the different outcomes of these two reactions (Scheme II-5).35 Scheme II-5. Ru mediated oxidative cyclization of 1,5-dienes RuCl H O /NalO W 3( 2 )n 4: W14 /OAc + 8““{3—{11/0/“3 OAC CC14'CH3CN'H20 '5‘ é HO Q g OH HO OH H "-8 "'9 geranyl acetate "-6 39% 12% WON: RuCl3(H20)n/Na|04 Won; + a)“, H OAc CCI4-CH3CN-H20 H0 6105 OH HO H i OH neryl acetate "-7 “-8 "_9 34% 12% 37 Osmium tetraoxide is another high-valent metal oxo compound which can mediate this transformation to generate cyclic ether rings. When used in conjunction with sodium periodate (NaIO4) as cooxidant, in DMF, it is capable of inducing the oxidative cyclization of the 1,5—dienes II-6 and II-7 to give stereospecifically the corresponding cis-2,5—bis(hydroxymethyl)tetrahydrofurans II-8 and II-9, respectively. No trace of trans-THF product could be detected under this reaction condition (Scheme 11.6).36 Scheme ”-6. 0304 mediated oxidative cyclization of 1,5-dienes 0304 (5mo|°/o)/Na|04 (4 eq.) H >=/_>:\‘ ~ W 0A0 0A0 DMF,15h,55/o HO 0; OH geranyl acetate "-6 "-3 l K 0 Ac 0504 (5mol%)/Na|O4 (4 eq.) __ _ = WON: DMF, 15 h, 53%: ; O : ' neryl acetate "-7 "-9 These oxidative cyclization reactions are appealing processes that produce four chiral centers from an achiral substrate in a single step and in a predicatable manner. Among all the common strategies, only Diels-Alder reaction could achieve such an efficient and powerful transformation.37 Based on the stereochemical outcome of these metal oxo mediated oxidative cyclization, the reaction mechanism proposed involves a 3+2 rea1rangement. The detailed mechamism for the 0304 promoted oxidative cyclization proposed by Paccilli is 38 shown in Scheme H-7.36 The first event was the addition of 0304 to the C6/C7 double bond of the two geranyl acetate units with the formation of the symmetrical osmium (VI) diester II-10, which adopts a square-pyramidal arrangement. This osmium diester species could be isolated by using stoichiometric amount of 0304 and stopping the oxidative process before its completion. The following 3+2 rearrangement gives II-11 directly. Os(IV) species II-ll then could be oxidized by the co-oxidant to intermediate II-12, which bears an Os=O bond. Thus, the O-OszO portion of II-12 could be engaged in a consecutive 3+2 rearrangement with the double bond of the second geranyl acetate unit to produce Os(IV) species lI-13, which embodies two THF units whose release could occur hydrolytically to generate the final THF product. Scheme ”-7. Proposed mechanism for 0304 promoted oxidative cyclization of 1,5— diene OAc - __ ___’ 0:69;} 0”. rearrangement: OS-/o,,o O O "-10 "-11 :/ NaIO4 (4 eq.), DMF, 4 h (21%) J l [0] : 'I, OAC WHO/X H . : ’/ ’I O A hydrolysrs O\0 )0 rearrangement O\ 88;,0 /O 5 "q/ C4—— 08 4f HO O : OH O/ O ;\O \\ 00’ size—ECO t .3 OAC LWCDAC _ H _ "-13 "-12 39 In order to prove that II-10 was indeed an intermediate in the conversion process, the isolated II-10 was subjected to the exactly same reaction conditions used for the oxidative cyclization of geranyl acetate.36 II-10 had been completely transformed into a mixture of products from which the cis-THF-diol could be isolated in 21% yield. In recent years, 2,3,5-trisubtituted tetrahydrofuran diols have increasingly gained attention among synthetic chemists and biochemists. This structure motif is shown in a number of natural products with interesting biological activities. The invention and development of protocols to stereoselectively construct 2,3,5-trisubstituted THF diols is highly desired. It promoted our group to investigate the feasibility of building this structure sub-unit by oxidative cyclization of 1,4-dienes.38 According to published data,38 the attempt to oxidatively cyclize cis-1,4-diene methyl linoleate II-14 using KMnO4 in aqueous acetone provided the desired 2,3,5-trisubstituted tetrahydrofuran diol products as a 1:1 regioisomeric mixture in a quite modest 20% yield. Further attempts using catalytic amount of 0304 and NaIO4 or RuCl3 with NaIO4 did not show any improvement of the reaction yields (Table II-l). Based on NMR study, the relative stereochemistry of the two regioisomeric products was defined as 2-trans-3,5-cis, which is similar to other 2,3,5-trisubstituted THF diol stereoisomers obtained from linoleic acid oxidation and cyclization reported previously.39 Alternatively, cis-methyl linoleate unambiguously provided the product with all cis relative stereochemistry. Numerous anhydrous solvents (toluene, dichloromethane, T HF, acetonitrile and DMF) and co-oxidants (NMO, tBuOOH, NaIO4, IBX, H202 and Oxone®)were tested to optimize this reaction with 0304. A better yield was obtained when the reaction was performed in polar solvents. Two possible explanations for the better performance of the more polar solvents, such as acetonitrile, 40 THF, and DMF, is that there is a charge stabilizing effect assuming the mechanism involves a charged species. The higher yields could also be due to better solvation of the reagents in the more polar solvents. The best yield was obtained when Oxone®, a mono potassium peroxysulfate salt, was used as co-oxidant with DMF as the solvent. A 30% yield of the cyclized products was attained under our optimized condition. Compared with other conditions, Oxone®-based reactions not only provided desired products in better yield, but also had fewer number of byproducts, making the workup easier. Detailed analysis of the byproducts showed no diol or aldehyde. Instead the reaction only revealed the formation of the carboxylic acids from the oxidative cleavage of the olefin. This observation leads to the discovery of 0504 promoted catalytic oxidative cleavage of olefins with Oxone®.40 Table ”-1. Oxidative cyclization of 1,4-diene methyl linoleate —> COZMG "-14 OH M 0 CC H 0 OH 9 2 7 14'“ CH O ..\C H 5 11 M902CC7H14)\Q 5 11 + HO H "-15 "-160 Oxidant (eq.) Co-oxidant Solvent Yield KMnO4 (6) --- Acetone/1120 20% 0504 (0.05) NaIO4 Acetone/1120 20% Rqu (0.05) NaIO4 EtOAc/ACN/Hg 12% 41 Scheme ”-8. Proposed mechanism pathways for oxidative cyclization of 1,4-d1enes O\O’ZO Ci): O0 Hi to O : O ,‘ M Bioi+ [O] . O 2 "-17 OOS’CVRZ/ Ii- 13 O ,,O O Ols-O-6S03H O I Fig /\ ’1’, "-19 1 H V 2 F12 2 H H O .R 5'0 .R = O .31 \ ‘I \ 1 HO O\ ‘ [O] ‘——-— *— OH 0303 0 0-0 0 O’ ‘5 11 22 "-21 11-20 5 \\ R1 \ R1 \ \\\ / \ 0504 [0] _—'—. I ‘I Fi1 R2 0 C? ‘. R2 O'O\S:O R2 (0310 \1 0 R1 \ \\ 08 “2 die-Ore O’HéJO-OSOaH 1 11 R1 R1 1 H H H I O : I O : R I O :3 R?” OH 1%;ka [O] 2 O / ‘ / HO O 991:0 O 9 O O ‘0 O Our postulated reaction mechanism is shown on Scheme II-8, and was adopted from the Picialli’s concerted 3+2 mechanism proposed for the oxidative cyclization of 1,5-dienes. The first step involves formation of an osmate ester II-17, followed by oxidation to the intermediate II-18. It was postulated that a 3+2 rearrangement would form the osmate II-20. Upon oxidation, the 2,3,5-trisubstituted THF diol was released by hydrolysis, and the 0504 was regenerated. An alternative route was also possible. This involves the further activation of the intermediate II-18 by Oxone®. The mechanism well explained the stereochemical outcome of this reaction. Although we cannot completely eliminate the possibility of the alternative 2+2 followed by a rearrangement proccss (Scheme II-9), the congested conformational arrangement makes this process less plausible. Further experimental and theoretical evidence also supported the 3+2 pathway.41 Scheme "-9. The altemative 2+2 rearrangement 1, 0‘0st R2 F11 I ‘Q C.) O H O 1 [2+2] O‘O/é-O rearrangement O r 0 ..\R1 I -———> R1 1 > We \ / x 2 O‘—Os 0 R2 ’1’ ‘6) “-18 "-20 2.2 Characteristic modification of 1,4-dienes The oxidative cyclization of 1,4-dienes generally gives a much lower yield than 1,5-dienes under the same reaction condition, which makes this method unlikely to be applied in natural product synthesis and limits its application to great extend. As we discussed before, the optimization of reaction conditions based on methyl linoleate by 43 varying solvents, additives, and co-oxidants was unable to improve the reaction yield over 50%. Therefore, another approach based on the characteristic modification of 1,4- dienes was used. 2.2.1 Heteroatoms incorporated 1,4-dienes Figure II—3 illustrates the three dimensional projections of the intermediate II-18 and its counterpart in oxidative cyclization of 1,5-dienes. The approach of the olefinic carbons to the osmate ester oxygen in II-18, which will eventually become the oxygen atom in the THF ring, is hindered by the neighboring alkyl group. The restricted rotation about the carbon-carbon bond in the osmaoxetane increased the strain energy of the oxidative intermediate. However, this is not the case with the 1,5-diene, in which the presence of one more methylene group greatly released the strain energy of the intermediate. Therefore, compared with 1,5-diene, the modest yield of the cyclized product could be well explained by the structure of the relatively conjested intermediate in oxidative cyclization of 1,4-diene. 1.5-diene 1.4-diene Figure ”-3. 3-D projections of oxidative cyclization of 1,5- and 1,4-dienes Based on this postulation, we designed a series of experiments to improve the efficiency of the oxidative cyclization of 1,4-dienes, and hopefully to provide more evidence for the proposed mechanism. Considering that the strain energy was mainly 44 caused by the steric interaction between the neighboring alkyl group and the olefinic carbons, one solution is to position those two components farther apart from each other. Therefore, the most straightforward solution will be placing a larger heteroatom between the two double bond instead of the methylene group. The silicon atom was the first choice because its electronic property is similar to that of carbon. Furthermore, by incorporating a silicon atom into the 1,4-diene, we could expand our methodology to the synthesis of the new structural motif, silaheterocycles. Dimethyl distyryl silane II-25 was synthesized as shown in Scheme II-lO. Transmetallation of commercially available trans-B-bromo-styrene II-23 with 2 equivalents of tert-butyl lithium in ether generated vinyl lithium II-24, which upon addition to dichlorodimethyl silane fonned the desired compound II-25. Various oxidative conditions were tested in order to cyclize substrate II-25 without success. When Oxone® was used as the co-oxidant, the reaction only resulted in the decomposition of the starting material. A milder reaction condition involving hydrogen peroxide as the co-oxidant was tested for the same substrate. The reaction was performed in acetonitrile at low temperature. However, under this reaction condition, only starting material was recovered. The same reaction condition oxidatively cyclized methyl linoleate to 2,3,5-trisubstituted THF rings in about 50% yield. It is obvious that the reactivity of compound II-25 toward the oxidative cyclization had decreased. One of the possible explanation for this diminished reactivity is the lower electron density of the conjugated double bond. Since the formation of the osmate is an electrophilic cycloaddition, the decreased electron density will hinder the reaction (Scheme II-lO). 45 Scheme ”-10. Attempts of oxidative cyclization of dimethyl distyryl silane M8281C12 \ ./ \ Br 2 eq. tBuLi \ Li SI > ———> \ / @V ether UV 650/0 ©/\/ \/\© "-23 "-24 "-25 \Si/ l°o \ / 1 mo / 0804 2; Starting material decomposed 4 eq. Oxone "_25 DMF, rt \\Si// 1 mol% 0304 ; N. R. (:l/V \/\© H202 (3 9C1-) "_25 CchN, 000-400 To eliminate this possibility, an aliphatic 1,4-diene incorporating a silicon atom, compound II-33, was synthesized from 1-heptyne II-26. Vinyl iodide II-28 was synthesized from 1-heptyne II-26 via hydroalumination with DIBAL-H following reported procedure.42 However, the product was isolated as an inseparable mixture of the desired product 1-iodo-l-heptene II-28 and its over-reduced product .l-iodoheptane II-29 in a 3 : 1 ratio. Different reaction conditions were screened but lead to no avail. To eliminate undesired product, bromine was used instead of iodine. A 95 : 5 ratio between l-bromo-l-heptene (II-30) and l-bromoheptane (II-31) was achieved following the same procedure. A metal-halogen exchange of compound II-30 followed gave vinyl lithium II-32, which treated with MeZSiClz produced the desired compound II-33 (Scheme 11). 46 Scheme ”-11. Synthesis of dihept-l-enyl dimethyl silane DIBAl-H | // _____> WA11’8U12 _:__> ml hexanes ether + "'26 3 h, 56 °C "'27 -78-rt,12 h "'23 WI "-29 "-28 : "-29 = 3 : 1 DIBAl-H Br ¢ ______’ WAKEUE ___2__, WEI hexanes ether + "-26 2 h, 56 °C "-27 73"“ 2 h "'30 650/0 NW Br "-31 "-30 : "-31 = 95 2 5 B 2eq. tBuLi L' M92902 \8 / /\/\/\/ I' > NW I —’ i \ -78 °C, 15 min 1 \ 1 -78 °C- rt CsH11/\/ wCan ll-3O ether "-32 8 h "-33 57% Scheme ”-12. The attempted oxidative cyclization of dihept-l-enyl dimethyl silane II-33 C5H11/\/Sl\/\C5H11 1 mol% 0804 ,5 Starting material decomposed 4 eq. Oxone ll-33 DMF, rt \ ./ 1 l% O C H /\/S'\/\C H m0 804 > N. R. 5 11 5 11 H202 (3 911-) CH3CN, O °C-4 °C "-33 Unfortunately, the attempts to oxidatively cyclize Il-33 did not work. The results were consistent with the aromatic case, which gave the decomposed starting material 47 when Oxone® was used as co-oxidant. No reaction occured when hydrogen peroxide was employed along with 0504 (Scheme II—12). Another attempt to introduce a heteroatom within the 1,4-diene system was made by incorporating a sulfur atom. The reaction would generate 3,3-dioxide-l,3-oxathiolane derivative II-35 as product (Scheme II-13). This structural motif is an analogue of sugar and has been studied extensively.43 Scheme ”-13. Oxidative cyclization of sulfur atom incorporated 1,4-diene C_)H R \/\ s /\/ R Oxndatlve cyclization> :YR o’"‘o 3‘0 HO ('5 “-34 "-35 Scheme ”-14. Synthesis of distyrylsulfoxide and dihept-l-enyl sulfoxide \ Br tBULi Li $0012 (>/\/—_'> ether Ovfi 400/0 Q/Vg l\/\© "-23 "-24 "-36 18 L SOCI 9 NWBF ——->u I WU 2 NS¢\ ether 20% C51"11 C'51‘111 "-30 "-32 "-37 48 We utilized the synthetic strategies similar to the synthesis of compound II-25 and “-33 to synthesize the aromatic substrate II-36 and the aliphatic substrate II-37. The reaction pathways are shown on Scheme II-14. The first attempt was to synthesize 1,4- diene with a sulfonyl group inselted between two olefins. However, the reaction of vinyl lithium II-24 and sulfonyl chloride did not generate any desired product. Therefore, we switched the strategy to using thionyl chloride. The resulted sulfoxide functionality would be converted to sulfone by the co-oxidant concurrently during the oxidative cyclization process. For the aromatic sulfoxide compound II-36, the attempt to oxidatively cyclize it under previously optimized condition, 4 equiv Oxone® and 1 mol% 0304 in DMF, did not generate any cyclized product. The major product was isolated as compound II-38, which comes from the oxidation of sulfoxide. To further prove the inertness of this substrate toward the oxidative condition the isolated compound II-38 was subjected to the same reaction conditions. After stirring for 12 hours at rt, no detectable compound other than the starting material could be found. The same results were obtained for the aliphatic substrate II-37 (Scheme II-lS). Scheme ”-15. Attempts of oxidative cyclization of distyryl sulfoxide II-36 and O dihept-l-enyl sulfoxide II-37 ll O\\ /,O \ S / 1 mol% OSO4 \ S / ©/\/ V\© 4eq.Oxone 7 \/\© DMF, rt “-36 67% "-38 ('8') 1 mol% 0304 O\ ,0 \ / > ‘ ’ CSHHA/ \/\CSH11 4eq. Oxone C5H11/\/S\/\CSH11 DMF, rt "-37 75% 11-39 49 The failure to perform oxidative cyclization of the above substrates could be explained by both electronic and steric effects. By investigating the reaction mechanism, it is obvious that the reactivity of this reaction was controlled by the formation of the osmate ester. As soon as the osmate was formed, different reaction pathways were possible, including oxidative cyclization, dihydroxylation, and oxidative cleavage of the olefin. Thus the sole recovery of the starting material was a clear sign that the problematic step of the reaction was the osmate formation. Otherwise, the side products such as diols or carboxylic acids would be the major products instead of unreacted olefin. Osmate formation is an electrophilic reaction. The higher the electron density of the double bond, the easier the osmate formation. As reported by Sharpless, this is the case for osmium mediated dihydroxylation reaction.44 For the sulfone case, electron withdrawing ability of the sulfone will decrease the electron-density of the double bond and hinder the osmate fonnation. However, this is not the case for the silane substrates. The similar electronic characteristics of silicon atom and the carbon atom cannot explain the different reactivity of these two classes of substrates toward oxidative cyclization. This leads us to propose that the steric effect is the major hindrance to the reaction. The geminal dimethyl groups connected with silicon in substrates II-25 and II-33 could pose a steric hindrance for the approach of osmium toward the olefinic carbons. This could also be true for sulfone substrates. Two oxygen atoms present next to the double bond make the it electrons less accessible to 0304. Moreover, for the compound II-25 and II- 33, the proneness of the oxidation of a silicon-carbon bond provides a potential problem for the oxidative cyclization of these substrates. 50 2.2.2 Gem-dimethyl group incorporated 1,4-diene To test the steric effect of the above subtrates, we designed a substrate to mimic the steric environment of the heteoatom incorporated 1,4-dienes. Substrate II-44 was synthesized for this reason. The initial concept to design such a compound was to utilize the Thorpe-Ingold effect45 to accelerate the cyclization reaction. The existence of geminal methyl groups could favor the substrate to adopt the conformation necessary for the cyclization reaction. The angle between two alkenyl chains would be decreased due to the steric repulsion of the geminal methyl groups. The synthetic pathway is shown in Scheme II-16. 3,3-Dimethyl glycol II-42 was synthesized from ethyl malonate II-40 by nucleophilic substitution followed by LAH reduction. Swem oxidation of compound II- 42 generated dialdehyde II-43. Wittig olefination of the resulting aldehyde generated gem-dimethyl 1,4-diene II-44 in 5% yield. The yield was based on ethyl malonate II-40. The low yield of this multi-step reaction was due to the inefficiency of the isolation of 3,3-dimethyl glycol II-42. The attempt to oxidatively cyclize this molecule failed (Scheme II-17). Only starting material was recovered after prolonged reaction time. This result demonstrated that the sterics were the major problem for the oxidative cyclization. Scheme ”-16. Synthesis of gem-dimethyl 1,4-diene II-44 O O LiHMDS O O LAH OH OH Swem Oxiation : . __> > EtO CB 2 equiv Mel EtO QB “-40 "-41 "-42 O O Ph3P(CH2)4CH(CH3)2Br / \ H H BuLi 7 5% over 4 steps "-43 11-44 51 Scheme ”-17. The attempt to oxidatively cyclize gem-dimethyl 1,4-diene II-44 / \ 1 mol% 0504 > No Reaction 6 equiv H202 CH3CN-DMF-CHZCIZ "'44 (2:1 :2) Summary of the above reaction results: Our approaches to improve the osmium mediated oxidative cyclization by characteristic modification of 1,4-dienes was not successful. The major problem of the reaction was the steric hindrance caused by the additional substitution at C3 in 1,4-dienes. 2.3 Regiochemical control in the oxidative cyclization of 1,4-dienes Contrary to the oxidative cyclization of 1,5-dienes, in which case it is only possible to deliver one regioisomer, the oxidative cyclization of 1,4-dienes will result in a mixture of two regioisomeric 2,3,5-trisubstituted tetrahydrofuran diols. Due to the similar polarity of this type of regioisomers, it is normally difficult to separate them by chromatography. Therefore, the confusion brought by regiochemical properties of oxidative cyclization of 1,4-dienes limited its application in synthetic chemistry to great extent. In this part of the research project, our objective is to achieve regiochemical control in the oxidative cyclizaiton of 1,4-dienes and hopefully make this protocol more useful in synthetic chemistry. 52 Scheme ”-18. Regioselectivity of oxidative cyclization of 1,4-diene 01‘0st 01‘0st 0304 O O O 0 F11 R2 R1 R2 + R1 R2 11-45 "-46 l [O] l [0] OH OH , O], 3 I \\O \ HO OH "-47 "-48 Oxidative cyclization of non-symmetrical 1,4-dienes lead to the formation of regioisomeric THF-diols. Based on our proposed mechanism, this is due to the fact that during the first step, two regioisomeric osmates II-45 and II-46 can be produced. Regioisomeric TI-IF-diols II-47 and II-48 were generated from these two osmates, respectively (Scheme II-18). Therefore, it would be desirable to direct the osmylation of one olefin in order to obtain a single regioisomeric product. We plan to attain this control by directing the first osmylation to electron-rich olefins in non-symmetrical 1,4-dienes. 53 Table ”-2. Regioselective mono-dihydroxylation of dienes with AD-mix1‘3‘4 entry substrate products ratio %yield OH )\'/\ 3 \\ 1 M OH ; 48 OH O 17 WOCOPh W 2 \ \ OCOPh OHOH WOCOPh 1 O OH \ \ t OE OH HM 4 W \ \ \ 73 OH \ HO 5 \ \ 94 0A0 OH OAc OH W 13 6 /W OH : 56 OH Electronic factors greatly influence the regioselectivity of osmylation of the unsymmetrical polyenes. The osmylation preferentially occurs at the more electron-rich double bond. This is true for both isolated and conjugated polyenes. Several examples of regioselective outcome of osmium mediated dihydroxylation of polyenes are shown in 54 Table II-2.l’3‘4 Oxidative cyclization should follow the same trend as dihydroxylation reaction. Other than the electronic properties, steric effects may also play a decisive role in systems with electronically similar double bonds. The sterically more accessible site is osmylated preferentially in general cases. Examples are shown on Table II—3 as reference."2 2 Table ”-3. The influence of steric effects on the regioselectivity of polyenesl‘ entry substrate products ratio yield .c----q-----o-----—-.1----_------_-_-_---------------------------_-—--.---------_-_-_------_-—--__--_-----_-----. “‘030H 2 + ‘1 >20: 1 84 HOHO“‘ .-----------—-o-------------------—----—--—-———--_-------------------_-----------_---_-_-_-____----_-----------. OH + : 40 OH \ \ 002Me 55 Therefore, control of these two factors, namely electronics and sterics, will lead us to the regiochemical control of the oxidative cyclization of 1,4-dienes. Compound 11- 51 is a simple example of non-symmetrical 1,4-dienes that contain olefins with dissimilar electronic behavior. It was synthesized based on Uchida’s protocol.46 Coupling of isoprene and ethyl acrylate mediated by Fe(acac)3 in the presence of Lewis acid AlEt3 generated II-Sl, although in low yield. Two olefins presented in this molecule are well differentiated by their electronic properties. We were pleased to find that the oxidative cyclization of this molecule afforded only one of the regio isomers. This regioisomer II- 52 came solely from the osmate derived from the more electron-rich double bond. However, the yield of this oxidative cyclization reaction is much lower than we expected, only 9%, which lead us to optimize the reaction condition to make this protocol more amiable to synthetic chemistry (Scheme II-l9). Scheme ”-19. Synthesis and oxidative cyclization of 5-methyl-hepta—2,5-dienoate 0.25 equiv. AlEt3 / + /\n/OEt > \ / CB 0 cat. Fe(acac)3, Toluene O 8% “-49 "-50 "_51 OH MOEt 0304 (1mOl°/0) 1,," O : 0E1 0 H202 (3 equiv), DMF(20 equiv) 111m ACN, 9% HO This preliminary result shows a promising regiochemical control of the oxidative cyclization by electronic effect. To further prove this theory, a series of experiments were designed aimed at improving the yield and regioselectivity of the reaction. Since 56 compound “-51 was generated in low yield, another substrate with similar structure that could be easily obtained with satisfactory yield was desired in order to optimize the reaction conditions. Therefore, deca-2,S-dienoic acid ethyl ester II-55 was synthesized in two steps as shown on Scheme 11-20. Scheme ”-20. Synthesis of deca-2,5—dienoic acid ethyl. ester II-SS WOH ‘7‘ M14 "_53 CH2Cl2, r1 0 11-54 PPhacHCOzEt > _ / OEt THF, 55% WY O "-55 Different oxidative conditions were screened for substrate II-55, and the result is shown on Table II-4. The major by-products were identified as a-hydroxyketone “-58 and diol II-59. First, various solvents and additives were tested while hydrogen peroxide was employed as the co-oxidant. Acetonitrile was the best solvent according to the data shown on Table II-4. Under this reaction condition, the cyclization products II-56 and II-57 were obtained in 43% and 28% yield, respectively. The over-oxidized product 11- 58 and dihydroxylation product II-59 were trifling. Unfortunately, the regiochemical control was lost conpared with our initial result of oxidative cyclization of compound II- 51. Only a 3:2 ratio was obtained for regioselective oxidative cyclization. Other reaction conditions including our original condition using DMF as solvent did not improve the ratio of the two regioisomers. The reaction was completely shut down when pyridine was employed as additive. 57 Table ”-4. Oxidative cyclization of deca-2,5-dienoic acid ethyl ester II-55a C4H9 WW0 OH OH 0 Et C H ,, O ' OEt O —" 4 9 ‘ + C4H9 DB 0 O HO OH "-55 "-56 "-57 OH O OH O C4H9M0Et .1, C4H9WOE1 O OH 11-53 1159 entry Solvent 11-55 (S.M.) II-56 11-57 Il-58 11-59 1 CAN, 20 eq. DMF" 50% 16% 12% 20% 2% 2 ACNb 29% 43% 28% . . 3 DMFb 72% 9% 7% 13% - 4 131po 60% 9% 5% 10% 6% 5 Isopropanolb 71% 6% 8% 9% 3% 6 Dioxanec 41% 4% 2% 27% 6% 7 THF" 17% 5% 11% 64% — 8 Pyn'dineb 100% - - - _ 9 Acetoneb 19% 7% 7% 13% 8% 10 THF, 1 eq. pyridineb 100% - - - - ll THF, 2 eq. pyridineb 100% - - - - 12 DMF“ 20% - - - - 13 ACNd 47% - - - - a. The yield was based on GC analysis. b. 3 eq. H203, 0°C-rt. c. 3 eq. H202, 11. d. 4 eq. Oxone, rt. 58 However, the investigation of the byproducts of this reaction leads us to an explanation of this disappointing regioselectivity. After closer inspection, we find that both the major byproducts II-58 and II-59 came from the osmylation of the electron-rich double bond. Their regioisomers were not detected at all. This observation suggested that the osmate formation was still favoring the electron-rich double bond as we expected, but the side reaction, namely hydrolysis of the osmate, was considerably faster for the osmate of the electron-rich double bond than the osmate of the electron-deficient double bond. On the other hand, since the [3+2] rearrangement is also an electrophilic process, this step of the oxidative cyclization could be considerably slow for the electron-deficient olefin. Thus, the competition between the cyclization and hydrolysis lowers the regioselectivity of the oxidative cyclization process. Another substrate studied was compound II-60, which is equipped with a monosubstituted olefin as well as a trisubstituted electron-rich olefin. This substrate was synthesized readily from l-heptyne II-26 by Rawal’s one-pot procedure (Scheme 11- 21).47 Scheme ”-21. Synthesis of l-(1-But-3-enylidene-hexyl)-4-methoxy-benzene II-60 1) aIIyI bromide (1eq.) PdBr2(PhCN)2 (3m0|%) THF, 0 °C to rt, 6 h C5H11—E__H > C5H11 2) 4-MeOCSH4B(OH)2(2eq) / \ ll-26 P‘Bua (6mol%) 032003 (2 eq.) rt, 16 h 38% CM, "-60 59 Under our conventional oxidative cyclization conditions, one single isomeric THF-diol compound II-61 was isolated, and its acetylated derivative was characterized as well. Against our expectation, the structure of compound II-61 was identified as a disubstituted THF-d101, which comes from the cyclization of the osmate derived from the monosubstituted olefin. To further prove this observation, a dihydroxylation reaction was performed on this substrate under the biphasic condition. Even though the reaction was considerably slower, diol II-62 was formed exclusively as a single regioisomeric dihydroxylation product. Based on this result, we postulated that the osmylation took place at the monosubstituted double bond preferentially as a result of the steric reason. Molecular modeling of the 1,4-diene II-60 shows a slight dihedral angle between the aromatic ring and the plane of olefinic carbons. This is due to the A13 strain between the aromatic ring and the allylic position. This arrangement greatly decreases the electron density of the conjugated double bond because the electron-donating group on the para position of the phenyl ring cannot donate the electron density toward this double bond, which makes these two olefins have similar electronic properties. When the two double bonds cannot be differentiated by electronic properties, the steric properties will take charge. It is quite obvious that the monosubstituted double bond is more accessible than the trisubstituted double bond. Therefore, the osmylation will prefer to take place at the monosubstituted olefin, then undergo the cyclization to generate THF-diol II-61 instead of the other isomer (Scheme II-22). In conclusion, the regiochemical control of the oxidative cyclization of 1,4-diene can be realized by manipulation of the electronic properties of the 1,4-diene, and steric effect will take charge if the two olefins have similar electronic properties. The 60 regioselectivity of oxidative cyclization agrees with the regioselectivity of osmium mediated dihydroxylation. However, after screening the solvents, additives and oxidants, improving the reaction yield has proved difficult. Scheme ”-22. Oxidative cyclization and dihydroxylation of II-60 / \ C5H11 0504 (1 mol%) H202 3 eq. ACN, 0 °C-rt OMe 17% OMe "-60 "-61 OH K3Fe(CN)6, K2003 HO \ (35H11 MGSOZNHZ 0804 (1 mol%) C51'111 > (BUOH/ H20, 0 OC' rt OMe 20% OMe "-60 "-62 2.4 Conclusion Osmium tetraoxide mediated oxidative cyclizations of 1,4-dienes were investigated. The attempt to incorporate a heteroatom such as silicon and sulfer into the 1,4-diene was not successful due to the unfavorable electronic and steric effects of the heteroatom substituents. The regioselectivity of the cyclization was examined, and the reaction conditions were optimized. For most unsymmetrical 1,4-dienes with electronically differentiated double bonds, the oxidative cyclization gave products in good regioselectivity, albeit in low yield. The electronic properties of the substituent were demostrated to be the major factor in controlling the regioselectivity of the reaction, 61 whereas the steric effect can not be completely ignored. The challenge that remains is to learn how to control the regioselectivity of the osmylation process and at the same time suppress the competitive dihydroxylation. 2.5 Experimental General information All commercially available starting materials were used without further purification. Commercially available starting materials were obtained from Aldrich, Fisher, Nu-Chek-Prep, Lancaster, TCI. ‘H, 13C, gCOSY, gHMBC, DEPT and nOe spectra were recorded on either a 300 MHz NMR spectrometer (VARIAN INOVA) or on a 500 MHz NMR spectrometer (VARIAN VXR). IR spectra were recorded on Nicolet TR/42 spectrometer using NaCl cells. Column chromatography was performed using Silicycle (40-60 um) silica gel. Analytical TLC was done using pre-coated silica gel 60 F254 plates. GC analysis was performed using HP (6890 series) GC system (Column type-AltechSE-54, 30 m x 320 um x 0.25 pm). HPLC analysis was performed using HITACHI LC-ORGANIZER (Column type chiral AD or OD). Unless otherwise mentioned, solvents were purified as follows. THF and 320 were distilled from sodium benzophenone ketyl. CH3C12, toluene, CH3CN and Et3N were distilled from CaHz. DMF, diglyme, and DMSO were stored over 4 A molecular sieves and distilled from CaHz. All other commercially available reagents and solvents were used as received. 62 General procedure for oxidative cyclization (0804, Oxone and DMF) 1,4- diene (1 mol, 1 eq.) was dissolved in DMF (50 mL), and 0804 (0.01 mmol, 0.01 eq, in a benzene or toluene solution) was added and stirred for 5 min. Oxone (4 mol, 4 eq.) was then added to the reaction mixture, and stirred for 3 h or until the reaction went to completion. The reaction was quenched with Na2SO3 (1 g) and stirred for 1 h. CH2C12 (100 mL) was then added to the reaction mixture, and subsequently filtered through a pad of celite to remove the salt. The celite was further washed with CH2C12 (25 mL x 3). The combined organic layers were washed with H2O, 1N HCl and brine, then dried over anhydrous Na2SO4. The solution was then filtered and evaporated under reduced pressure. The residue was purified by column chromatography. General procedure for oxidative cyclization (OsO4, H202 and various solvent) 1,4- diene (1.0 mmol, 1.0 eq.) was dissolved in solvent (50 mL), and 0804 (0.01 mmol, 0.01 eq, in a benzene or toluene solution) was added and stirred for 5 min. 30% H202 (3.0 mmol, 3.0 eq.) aqueous solution was added to the reaction mixture at 0 °C. The reaction temperature was slowly raised to 4 °C and stirred for 12 h. The reaction progress was checked by TLC before it was quenching with saturated Na2SO3 solution. If necessary, another 3.0 eq. of H202 was added. The product was extracted with ethyl acetate (x 3). Combined organic layers were washed with H20 and brine, then dried over Na2SO4. The solution was then filtered and evaporated under reduced pressure. The residue was purified by column chromatography. Dimethyl distyryl silane II-25 63 Trans-B-bromostyrene (1.6 g, 8.7 mmol, 2.1 eq.) was dissolved in anhydrous THF (50 mL). t-BuLi (0.82 M in hexane, 23 mL, 19 mmol, 4.6 eq.) solution was added to the reaction mixture at —78 °C under N2 atmosphere. The reaction mixture was stirred for 10 min. Dimethyldichlorosilane (0.5 mL, 4.1 mmol, 1.0 eq. In 10 mL anhydrous THF) was added to the reaction mixture, and the reaction was stirred at rt for 4 h. The reaction was then quenched with diluted HCl and extracted with diethyl ether (20 mL x 3). The combined organic layers were washed with saturated NaHC03 and brine, then dried over MgS04. After filtration, the solvent was removed under reduced pressure. The residue was purified by column chromatography (100% hexane) to yield 1.09 g of compound II- 25 (65%). 1H—NMR (300MHz, CDCl3) 5 0.30 (s, 6H), 6.50 (d, J = 19.2 Hz, 2H), 6.93 (d, J = 19.2 Hz, 2H), 7.40 (m, 10H). l-Bromoheptene II-30 /\/\/\/Br In a round bottom flask, 1-heptyne (0.5 mL, 3.81 mmol, 1.0 eq.) was dissolved in anhydrous hexanes (10 mL). DIBAL-H (1.0 M in hexane, 3.81 mL, 3.81 mmol, 1.0 eq.) was added to the reaction mixture under N2 atmosphere. The reaction was stirred at rt for 5 min, the temperature was then raised to 56 °C and stirred for another 3 h. Bromine (0.195 mL, 3.81 mmol, 1.0 eq.) in THF (5 mL) was added to the reaction flask at —78 °C. The reaction was stirred at rt for 1 h, then quenched with 20% H2304 aqueous solution, and stirred for 2 h. The product was extracted with diethyl ether (20 mL x 4). The combined organic layers were washed with saturated Na2S2O7 and NaHCO3, and dried 64 over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by column chromatography (100% hexane) to yield 0.44 g 1-bromoheptene II-30 (65%). lH-NMR (300MHz, CDC13) 5 0.87 (m, 3H), 1.30 (m, 6H), 2.02 (q, J = 7.1 Hz, 2H), 6.00 (d, J: 13.7 Hz, 1H), 6.15 (dt, J: 13.7, 7.1 Hz, 1H). GC-MS m/z 176 Di(hept-1-enyl) dimethyl silane II-33 C51'111/\>Si:/\05H11 To a solution of l-bromoheptene II-30 (189 mg, 1.07 mmol, 1.0 eq.) in diethyl ether (6 mL) was added tBuLi (0.80 M in hexanes, 2.94 mL, 2.35 mmol, 2.2 eq.) at -78 °C under N2 atmosphere. The reaction was stirred for 15 min, followed by addition of dimethyl dichlorosilane (0.065 mL, 0.54 mmol, 0.5 eq.). The reaction mixture was stirred at rt for 8 h, then quenched with 3.5 M HCl aqueous solution. THF was removed under reduced pressure, and the product was extracted with diethyl ether (20 mL x 3). The combined organic layers were washed with saturated NaHCO;, (5 mL), and dried over Na2S04. After filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (100% hexane) to yield 78 mg di(hept- l-enyl) dimethyl silane II-33 (57%). lH-NMR (300MHz, CDC13) 5 0.10 (s, 6H), 0.87 (m, 6H), 1.30 (m, 12H), 2.10 (m, 4H), 5.60 (d, J = 18.7 Hz, 2H), 6.05 (dt, J = 18.1, 6.6 Hz, 2H). Distyrylsulfoxide II-36 COSCO 65 To a solution of B-bromostyrene (1.475 g, 8.06 mmol, 2.0 eq.) in anhydrous diethyl ether (10 mL) was added tBuLi (1.7 M in hexanes, 10.4 mL, 17.7 mmol, 4.4 eq.) at —78 °C under N2 atmosphere. The mixture was stirred for 5 min at the same temperature, then thionyl chloride (0.294 mL, 4.03 mmol, 1.0 eq.) was added to the reaction mixture. The reaction temperature was raised to rt and stirred for 12 h. The reaction was then quenched with brine. Two layers were separated, and the aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water and brine, and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (30% EtOAc in hexanes) to yield 0.402 g distyrylsulfoxide II-36 (40%). 1H-NMR (300MHz, CDCl3) 5 6.83 (d, J = 15.4 Hz, 2H), 7.24 (d, J = 15.4 Hz, 2H), 7.30 (m, 6H), 7.40 (m, 4H). Dihept-l-enyl sulfoxide II-37 CsH11/\/ \/\C5H11 To a solution of l-bromo-l-heptene (149 mg, 0.842 mmol, 2.0 eq.) in anhydrous diethyl ether (5 mL) was added tBuLi (0.80 M in hexanes, 2.32 mL, 1.85 mmol, 4.4 eq.) at —78 °C under N2 atmosphere. The mixture was stirred for 15 min at the same temperature, then thionyl chlonde (0.031 mL, 0.421 mmol, 1.0 eq.) was added to reaction mixture. The reaction temperature was raised to rt and stirred for l h. The reaction was then quenched with brine. Two layers were separated, and the aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with 66 water and brine, and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (30% EtOAc in hexanes) to yield 20 mg dihept-l-enyl sulfoxide II-37 (20%). lH-NMR (300MHz, CDCl3) 5 0.85 (t, J = 7.1 Hz, 6H), 1.25 (m, 8H), 1.44 (m, 4H), 2.19 (q, J = 6.9 Hz, 4H), 6.12 (d, J = 15.1 Hz, 2H), 6.42 (dt, J = 15.1, 6.9 Hz, 2H). IR: 2957.25, 2926.39, 2856.94, 1718.79, 1626.20, 1458.37, 1377.35, 1047.48, 958.81, 748.48 cm]. Distyrylsulfone II-38 O\\ 40 ONSCO Distyrylsulfoxide "-36 was oxidized by 0804 and Oxone in DMF following the general procedure described previously to yield distyrylsulfone II-38 in 67% yield. 1H- NMR (300MHz, CDCl3) 5 6.86 (d, J = 15.4 Hz, 2H), 7.45 (m, 10H), 7.63 (d, J = 15.4 Hz, 2H). GC—MS m/z 284. Dihept-l-enyl sulfone II-39 \\// CsH11/\/S\/\C5H11 Dihept-l-enyl sulfoxide 11-37 was oxidized by 0804 and Oxone in DMF following the general procedure described previously to yield dihept-l-enyl sulfone II-39 in 75% yield. lH-NMR (300MHz, CDC13) 5 0.86 (t, J = 7.1 Hz, 6H), 1.28 (m, 8H), 1.44 (p, J = 7.1 Hz, 4H), 2.23 (q, J = 6.6 Hz, 4H), 6.19 (d, J = 14.8 Hz, 2H), 6.85 (dt, J = 14.8, 7.1 Hz, 2H). IR: 2952.25, 2930.24, 2858.87, 1633.91, 1468.02, 1319.48, 1294.40, 1130.43, 983.82, 954.89, 860.36, 829.50 cm". 67 2,2-Dimethyl-malonic acid diethyl ester II-41 O O Howe. To a solution of diethyl malonate (1.52 mL, 10 mmol, 1.0 eq.) in anhydrous THF (10 mL) was added LiHMDS (1.0 M in THF, 11 mL, 11 mmol, 1.1 eq.) at 0 °C under N2 atmosphere. The reaction mixture was stirred at 0 °C for 15 min, then methyl iodide (0.69 mL, 11 mmol, 1.1 eq.) was added. The reaction mixture was stirred at rt for 2 h. Another portion of LiHMDS (1.0 M in THF, 11 mL, 11 mmol, 1.1 eq.) was added to the reaction mixture at 0 °C, followed by methyl iodide (0.69 mL, 11 mmol, 1.1 eq.). The reaction was stirred at 11 for another 12 h. The reaction was quenched with 10% HCl solution. Two layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated NaHC03 solution and brine, dried over Na2S04, and concentrated. The residue was purified by column chromatography (10% EtOAc in hexanes) to yield 1.51 g 2,2-dmethyl-malonic acid diethyl ester Il-41 (80%). lH-NMR (300MHz, CDCl3) 5 1.19 (t, J = 7.1 Hz, 6H), 1.37 (s, 6H), 4.12 (q, J = 6.6 Hz, 6H). neopentyl glycol II-42 OH OH To a suspension of LAH (123.5 mg, 3.25 mmol, 2.0 eq.) in anhydrous diethyl ester (10 mL) was added 2,2-dimethyl-malonic acid diethyl ester II-41 (306 mg, 1.63 mmol, 1.0 eq. in 5 mL anhydrous diethyl ether) at 0 °C under N2 atmosphere over 30 min period. The reaction mixture was stirred at rt for 12 h, then quenched with 3.5 M HCl 68 solution. The two layers were separated and the aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated NaHC03 and brine, and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure and the crude product was subjected to next step reaction without further purification. lH-NMR (300MHz, CDC13) 5 0.86 (s, 6H), 3.00 (8, br, 2H), 3.45 (s, 4H). 2,9,9,16-Tetramethyl-heptadeca-6,1 1-diene-8,10-dione II-44 / \ A solution of oxalyl chloride (0.341 mL, 3.91 mmol, 2.4 eq.) in CH2C12 (5 mL) was cooled to -78 °C, following the dropwise addition of a solution of DMSO in CH2Cl2 (1 mL). The reaction mixture was stirred for 5 min. A solution of neopentyl glycol II-42 (1.63 mmol, 1.0 eq.) in CH2C12 (1.5 mL) was then added to the reaction mixture at the same temperature. After 5 min of stirring, triethylamine (2.27 mL, 16.3 mmol, 10 eq.) was added , and the reaction was warmed to 11. To a solution of triphenylphosphine-isoheptyl bromide (4.30 g, 9.78 mmol, 6.0 eq.) in anhydrous THF (5 mL) was added nBuLi (2.36 M in hexanes, 4.14 mL, 9.78 mmol, 6.0 eq.) at rt under N2 atmosphere. The solution was stirred for 5 min at rt, at which time the solution prepared was added. The reaction mixture was stirred at rt for 18 h. then quenched with water. The reaction mixture was then partitioned between ether and water. The ether layer was washed twice with water, dried over anhydrous Na2S04 and subsequently concentrated under vacuum. The residue was purified by column 69 _— chromatography (5% EtOAc in hexanes) to yield 22.1 mg desired product (5% over 4 steps). lH-NMR (300MHz, CDC13) 5 0.88 (m, 18H), 1.28 (m, 10H), 2.09 (q, J = 6.6 Hz, 4H), 2.08 (q, J = 6.6 Hz, 4H), 5.60 (d, J = 18.7 Hz, 2H), 6.03 (dt, J = 18.1, 6.6 Hz, 2H). S-Methyl-hepta-2,5-dienoic acid ethyl ester II-51 MO E1 0 To a solution of Fe(acac)3 (88.3 mg, 0.25 mmol, 0.01 eq.) and 2,3-dimethyl-1,3- butadiene (2.83 mL, 25 mmol, 1.0 eq.) in toluene (3 mL) was added triethylalumimum (1.9 M in toluene, 3.29 mL, 6.25 mmol, 0.25 eq.) at rt and the mixture was stirred for 5 min. Ethyl acrylate (2.71 mL, 25 mmol, 1.0 eq.) was added to the reaction mixture dropwise at 0 °C. The reaction was stirred at rt for 2 h, then quenched with 10% HCl solution. Two layers were separated and the aqueous layer was extracted twice with diethyl ether (20 mL). The combined organic layers were washed with saturated NaHC03 and water, and dried over Na2S04. Solvent was removed under reduced pressure and the residue was purified by column chromatography (10% EtOAc in hexanes) to yield 5-methyl-hepta-2,5-dienoic acid ethyl ester II-Sl in 8%. 1H-NMR (300MHz, CDC13) 5 1.18 (t, J = 7.1 Hz, 3H), 1.49 (m, 3H), 1.59 (d, J = 14.3 Hz, 3H), 2.80 (d, J = 6.6 Hz, 2H), 4.08 (q, J =7.1 Hz, 2H), 5.28 (q, J = 6.6 Hz, 1H), 5.71 (d, J = 15.4 Hz, 1H), 6.81 (dt, J = 15.4, 6.6 Hz, 1H). Hydroxy-(4-hydroxy-4,5-dimethyl-tetrahydro-furan-Z-yl)-acetic acid ethyl ester 11- 52 70 OH I O ' OEt “'m HO 5-Methyl-hepta—2,S-dienoic acid ethyl ester II-Sl was oxidized by 0304, H202 following the procedure described previously to yield 9% II-52. 1H-NMR (300MHz, CDCl3) 5 1.02 (d, J = 6.6 Hz, 3H), 1.27 (m, 6H), 1.80 (8, br, 1H), 2.05 (dd, J = 13.7, 3.8 Hz, 1H), 2.25 (dd, J = 13.7, 9.9 Hz, 1H), 3.75 (8, br, 1H), 4.00 (q, J = 6.6 Hz, 1H), 4.09 (s, 1H), 4.29 (m, 2H), 4.47 (dd, J = 9.9, 3.8 Hz, 1H). l3C-NMR (75MHz, CDC13) 5 14.1, 17.5, 20.9, 29.7, 41.1, 62.3, 72.6, 78.8, 86.2, 172.6. GC-MS m/z 219. 2,5-Deca-dienoic acid ethyl ester “-55 MOB 0 To a solution of DMP (1.47 g, 3.46 mmol, 1.1 eq.) in CH2Cl2 (10 mL) was added a solution of cis-3-octen-1-ol (0.5 mL, 3.15 mmol, 1.0 eq.) in CH2C12 (5 mL). The reaction mixture was stirred at rt for 10 min. The precipitate was filtered, followed by addition of diethyl ether (20 mL) and saturated NaHC03 and Na2S207 solution, stirred until all the precipitate dissolved. Two layers were separated, and the aqueous layer was extracted with diethyl ether (20 mL x 3). The combined organic layers were washed with sat. NaHC03 and water, and dried over MgS04. The solvent was removed under reduced pressure and the residue was subjected to the next step without further purification. To a solution of the above product in anhydrous THF (10 mL) was added Ph3P=CHCOOEt (1.20 g, 3.46 mmol, 1.1 eq.). The reaction mixture was refluxed for 5 h. The solvent was removed under vacuum. The residue was directly subjected to column 71 chromatography (10% EtOAc in hexanes) to yield 0.339 g of 2,5-deca-dienoic acid ethyl ester lI-55 (55%). lH—NMR (300MHz, CD02.) 5 0.85 (t, J = 7.1 Hz, 3H), 1.25 (m, 7H), 2.00 (m, 2H), 2.90 (t, J = 6.6 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 5.35 (m, 1H), 5.48 (m, 1H), 5.78 (dt, J: 15.4, 1.6 Hz, 1H), 6.91 (dt, J = 15.9, 6.6 Hz, 1H). (5-Butyl-4-hydroxy-tetrahydro-furan-2-yl)-hydroxy-acetic acid ethyl ester II-57 OH 0 0 C4119 0E1 OH 1,4-Diene II-55 was oxidized following the previous procedure to generate II-57 in 12 % yield. lH-NMR (300MHz, CDCl3) 5 0.88 (t, J = 7.1 Hz, 3H), 1.26 (m, 11H), 2.01 (s, 2H), 2.03 (dd, J = 18.7, 10.4 Hz, 1H), 2.18 (t, J = 8.2 Hz, 1H), 3.97 (m, 1H), 4.09 (td, J = 8.2, 2.7 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.57 (d, J = 7.1 Hz, 1H), 5.50 (q, J = 7.7 Hz, 1H). GC-MS m/z 247 3-Hydroxy-5-(l-hydroxy-pentyl)-tetrahydro-furan-2-carboxylic acid ethyl ester 11- 58 OH O O 1,4-Diene II-SS was oxidized following the previous procedure to generate II-58 in 20 % yield. lH-NMR (300MHz, CDCl3) 5 0.88 (t, J = 7.1 Hz, 3H), 1.25 (m, 11H), 1.95 (m, 1H), 2.05 (m, 2H), 2.30 (m, 1H), 4.02 (q, J = 6.0 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 4.50 (d, J = 6.0 Hz, 1H), 5.12 (ddd, J = 3.8, 7.1, 10.4 Hz, 1H), 5.45 (td, J = 6.0, 3.8 Hz, 1H). 72 S-Hydroxy-6-oxo-dec-2-enoic acid ethyl ester II-59 9H 0 C4H9 . \ OH OEt 1,4-Diene II-55 was oxidized following the previous procedure to generate II-59 in 2 % yield. lH-NMR (300MHz, CDCl3) 5 0.92 (t, J = 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.32 (m, 2H), 1.62 (p, J = 7.7 Hz, 2H), 2.49 (m, 3H), 2.75 (m, 1H), 3.65 (br, 1H), 4.19 (q, J = 7.1 Hz, 2H), 4.30 (dd, J = 7.1, 4.4 Hz, 1H), 5.93 (dt, J = 15.4, 1.1 Hz, 1H), 6.90 (dt, J: 15.9, 7.1 Hz, 1H). l3C-NMR (75MHz, CDCI3) 5 13.7, 14.1, 22.3, 25.4, 36.3, 37.7, 60.4, 75.0, 124.6, 142.5, 165.8, 210.8. 1-(1-But-3-enylidene-hexyl)-4-methoxy-benzene II-60l / \ C51'111 OMe To a solution of allylbromide (0.173 mL, 2.00 mmol, 1.0 eq.) in anhydrous THF (50 mL) cooled in an ice bath was added dibromo(bisbenzonitrile)palladium (II) (28.3 mg, 0.06 mmol, 0.03 eq.). A solution of l-heptyne (0.262 mL, 2.00 mmol, 1.0 eq.) in anhydrous THF (5.0 mL) was then added dropwise over 30 min. The reaction solution turned clear during this procedure. The reaction mixture was stirred for another 5.5 h at rt. Tri-t-butylphophine (0.03 mL, 0.12 mmol, 0.06 eq.) was then added and the reaction mixture was stirred for 15 min at rt. Cesium carbonate (1.30 g, 4.00 mmol, 2.0 eq.) was subsequently added followed by the 4-methoxyphenyl boronic acid (0.608 g, 4.00 mmol, 2.0 eq.) The reaction mixture ws stirred for 16 h at rt and then concentrated in vacuo. 73 The mixture was diluted with diethyl ether (100 mL) and the insoluble material was filtered off. The crude product was purified by column chromatography (10% EtOAc in hexanes) to yield 185 mg (38%) l-(l-but-3-enylidene-hexyl)-4-methoxy-benzene II-60. lH-NMR (300MHz, CDC13) 5 0.89 (m, 3H), 1.30 (m, 6H), 2.36 (t, J = 7.1 Hz, 2H), 2.72 (t, J = 6.0 Hz, 2H), 3.80 (s, 3H), 5.05 (m, 2H), 5.45 (m, 1H), 5.95 (m, 1H), 6.88 (m, 2H), 7.12 (m, 2H). GC-MS m/z 244. 5-[1-Hydroxy-l-(4-methoxy-phenyl)-hexyl]-tetrahydro-furan-3-ol II-61 OH O CsH11 HO OMe 1-(1-But-3-enylidene-hexyl)-4-methoxy-benzene II-60 was oxidized by cat. OSO4, H202 in acetonitrile following the procedure described previously to yield 5-[l-hydroxy- 1-(4-methoxy-phenyl)-hexyl]-tetrahydro-furan-3-ol II-6l in 17% yield. lH-NMR (300MHz, CDC13) 5 0.77 (t, J = 6.6 Hz, 3H), 1.20 (m, 6H), 1.58 (m, 1H), 1.81 (m, 2H), 2.08 (m, 1H), 3.66 (s, 1H), 3.70 (dd, J = 9.6, 3.3 Hz, 1H), 3.77 (s, 3H), 3,98 (dd, J = 9.6, 1.6 Hz, 1H), 4.20 (dd, J = 9.6, 3.6 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 9.1 Hz, 2H). 5-(4-Methoxy-phenyl)-dec-4-ene-1,2-diol II-62 74 OH HO C5H11 \ OMe To a well stirred solution of K3Fe(CN)(, (301 mg, 0.915 mmol, 3.0 eq.), K2C03 (127 mg, 0.915 mmol, 3.0 eq.), MeS02NH2 (29 mg, 0.305 mmol, 1.0 eq.), OSO4 (0.00305 mmol, 0.01 eq.) in t-BuOH/H20 (1:1) at 0 °C was added diene II-60 (74.4 mg, 0.305 mmol, 1.0 eq.). After 48 h, the reaction mixture wa diluted with ethyl acetate and the resulting two phases were separated. The aqueous phase was extracted with EtOAc twice and the combined organic phases were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated. The residue was purifed by column chromatography ( 40% EtOAc in hexanes) to yield 15 mg 5-(4-methoxy-phenyl)-dec-4- ene-1,2-diol II-62 (20%). 1H-NMR (300MHz, CDC13) 5 0.82 (t, J = 7.1 Hz, 3H), 1.23 (m, 6H), 2.13 (t, J = 7.7 Hz, 2H), 2.30 (t, J = 7.1 Hz, 2H), 3.36 (dd, J = 11.0, 7.1 Hz, 1H), 3.56 (dd, J = 11.0, 2.7 Hz, 1H), 3.67 (m, 1H), 3.79 (s, 3H), 5.43 (t, J = 7.7 Hz, 1H), 6.85 (d, J: 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H). 75 (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) Reference Becker, H.; Soler, M. A.; Sharpless, K. B. Tetrahedron 1995, 51, 1345-1376. Crispino, G. A.; Sharpless, K. B. Synthesis-Stuttgart 1993, 777-779. Xu, D. Q.; Crispino, G. A.; Sharpless, K. B. Journal of the American Chemical Society 1992, 114, 7570-7571. Vidari, G.; Dapiaggi, A.; Zanoni, G.; Garlaschelli, L. Tetrahedron Letters 1993, 34, 6485-6488. Samuelsson, B. P., R. Advances in prostaglandins, thromboxane, and leukotriene research, 1982. Berti, F. S., B.; Velo, G. P. Prostaglandins and thromboxanes:[lectures], 1977. Samuelsson, B. N. A. T. O. S. A. D. Prostanoids and drugs, 1989. Dubois, R. N.; Abramson, S. B.; Crofford, L.; Gupta, R. A.; Simon, L. S.; Van De Putte, L. B. A.; Lipsky, P. E. Faseb Journal 1998, 12, 1063-1073. Fordhutchinson, A. W.; Gresser, M.; Young, R. N. Annual Review of Biochemistry 1994, 63, 383-417. Smith, W. L.; Mamett, L. J .; Dewitt, D. L. Pharmacology & Therapeutics 1991, 49, 153—179. Mcgiff, J. C. Preventive Medicine 1987, 16, 503-509. Galli, G.; Bosisio, E.; Sautebin, L. Progress in Food and Nutrition Science 1980, 4, 9-11. Hart, T. W. Natural Product Reports 1988, 5, 1-45. Gravierpelletier, C.; Dumas, J .; Lemerrer, Y.; Depezay, J. C. Progress in Lipid Research 1990, 29, 229-276. 76 (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) Mcgiff, J. C. Annual Review of Pharmacology and Toxicology 1991, 31, 339-369. Mcgiff, J. C.; Carroll, M. A. American Review ofRespiratory Disease 1987, 136, 488-491. Gauthier, K. M.; Falck, J. R.; Reddy, L. M.; Campbell, W. B. Pharmacological Research 2004, 49, 515-524. Zhao, X.; Imig, J. D. Current Drug Metabolism 2003, 4, 73-84. Laethem, R. M.; Koop, D. R. Molecular Pharmacology 1992, 42, 958-963. Oliw, E. H.; Guengerich, F. P.; Oates, J. A. Journal ofBiological Chemistry 1982, 257, 3771-3781. Schwartzman, M. L.; Balazy, M.; Masferrer, J.; Abraham, N. G.; Mcgiff, J. G; Murphy, R. C. Proceedings of the National Academy of Sciences of the United States of America 1987, 84, 8125—8129. Cashman, J. R.; Hanks, D.; Weiner, R. I. Neuroendocrinology 1987, 46, 246-251. Proctor, K. G.; Falck, J. R.; Capdevila, J. Circulation Research 1987, 60, 50-59. Capdevila, J. H.; Karara, A.; Waxman, D. J.; Martin, M. V.; Falck, J. R.; Guenguerich, F. P. Journal of Biological Chemistry 1990, 265, 10865-10871. Boutaud, O.; Dolis, D.; Schuber, F. Biochemical and Biophysical Research Communications 1992, 188, 898-904. Moghaddam, M. F.; Motoba, K.; Borhan, B.; Pinot, F.; Hammock, B. D. Biochimica Et Biophysica Acta-General Subjects 1996, 1290, 327-339. Klein, E.; Rojahn, W. Tetrahedron 1965, 21, 2353-&. Powell, K. A.; Sable, H. 2.; Hughes, A. L.; Jerauld, J. F.; Katchian, H. Tetrahedron 1972, 28, 2019-&. 77 (29) (30) (31) (32) (33) (34) (35) (36) (37) (38) (39) (40) (41) (42) Walba, D. M.; Wand, M. D.; Wilkes, M. C. Journal of the American Chemical Society 1979, 101, 4396-4397. Baldwin, J. E.; Crossley, M. J .; Lehtonen, E. M. M. Journal of the Chemical Society-Chemical Communications 1979, 918-920. Walba, D. M.; Edwards, P. D. Tetrahedron Letters 1980, 21, 3531-3534. Spino, C.; Weiler, L. Tetrahedron Letters 1987, 28, 731-734. Brown, R. C. D.; Kocienski, P. J. Synlett 1994, 415-417. Walba, D. M.; Stoudt, G. S. Tetrahedron Letters 1982, 23, 727-730. Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. Journal of Organic Chemistry 1981, 46, 3936-3938. de Champdore, M.; Lasalvia, M.; Piccialli, V. Tetrahedron Letters 1998, 39, 9781-9784. Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angewandte Chemie-International Edition 2002, 41, 1668-1698. Travis, B.; Borhan, B. Tetrahedron Letters 2001, 42, 7741-7745. Borhan, B.; Nouroozzadeh, J .; Uematsu, T.; Hammock, B. D.; Kurth, M. J. Tetrahedron 1993, 49, 2601-2612. Travis, B. R.; Narayan, R. S.; Borhan, B. Journal of the American Chemical Society 2002, 124, 3824-3825. ’ DelMonte, A. J .; Haller, J .; Houk, K. N.; Sharpless, K. B.; Singleton, D. A.; Strassner, T.; Thomas, A. A. Journal of the American Chemical Society 1997, 119, 9907-9908. Zweifel, G.; Whitney, C. C. Journal of the American Chemical Society 1967, 89, 2753-&. 78 (43) (44) (45) (46) (47) Skelton, B. W.; Stick, R. V.; Tilbrook, D. M. G.; White, A. H.; Williams, S. J. Australian Journal of Chemistry 2000, 53, 389-397. Kolb, H. C.; Andersson, P. G.; Sharpless, K. B. Journal of the American Chemical Society 1994, 116, 1278-1291. Sammes, P. G.; Weller, D. J. Synthesis-Stuttgart 1995, 1205—1222. Misono, A.; Uchida, Y.; Saito, T.; Uchida, K. Bulletin ofthe Chemical Society of Japan 1967, 40, 1889-&. Thadani, A. N.; Rawal, V. H. Organic Letters 2002, 4, 4317-4320. 79 Chapter III One-pot cyclization of 1, 2, n-triols via orthoesters 3.1 Introduction 3.1.1 Annonaceous acetogenins Annonaceous acetogenins are a series of natural products isolated from several genera of plant family, Annonaceae species, which are distributed widely in tropical and subtropical regions.M This family of natural products contains over 400 compounds, and a number of new Annonaceous acetogenins are added to the list each year. The common skeleton of the Annonaceous acetogenins is most often characterized by an unbranched C32 or C34 long chain fatty acid ending in a y-lactone. Several oxygenated functional groups, such as tetrahydrofuran (THF), tetrahydropyran (THP), hydroxyl group, ketone, epoxide, and unsaturated double or triple bonds may be present (Figure III-1). Based on the nature of the functional groups present, different types of Annonaceous acetogenins have been characterized. OH OH 32/ 34 Figure III-1. General structure of acetogenins Annonaceous acetogenins exhibit a broad range of biological activities such as antitumor, immunosuppressive, pesticidal, antiprotozoal, antifcedant, anthclmintic and antimicrobial agents.5'8 Mechanistic studies have shown that acetogenins are among the most potent inhibitors of the mitochondrial complex I respiratory chain. The study of the mechanism of actions shows that Amzonaceous acetogenins are potent inhibitors of 80 NADH, ubiquinone oxidoreductase, which is an essential enzyme in complex I of the electron transport system (ETS). The presence of such an inhibitor will eventually halt the oxidative phosphorylation in mitochondria and lead to cell death.9’l3 Another reason Annonaceous acetogenins attracted lots of attention is due to their well-known cytotoxic activities.ll Since they can selectively inhibit the growth of cancerous cells and also inhibit the growth of adriamycin-resistant tumour cells, they have been judged as promising candidates for a future generation of drugs to fight against 9.14 - - - Nevertheless, the1r mechanlsm of selectrve the current chemotherapy-resistant tumors. cytotoxicity, and the factors that modulate the efficiency against cancerous cells are unclear. The structure-activity relationship studies performed by Miyoshi et al.,15 and McLaughlin et al.13'16’17 leads to the following generalizations. (1) The bis-adjacent-TI-[F acetogenins are more active than the rest of the compounds in this family. (2) The 04,8- unsaturated y—lactone at the end of the chain is crucial for the activity. (3) C-35 acetogenins are more potent than the C-37 compounds, and the distance between the 0H- flanked THF and lactone has critical effect for the potency and selectivity. Based on these results and the study of the conformations of Annonaceous acetogenins with liposomes made of dimyristoylphosphatidylcholine (DMPC), the mechanism of actions has been postulatedlg’l9 It has been concluded that the THF rings serve as a hydrophilic anchor in the lipid membrane while the lactone rings, tethered with the THF by spacers with different lengths, penetrate the lipid membrane and interact directly with the protein receptor sites. 81 salzmanolin Figure III-2. Representative Annonaceous acetogenins Two representative Annonaceous acetogenins are shown in Figure III—2. Because of their structural diversity and interesting biological activities, numerous studies have been conducted on the total synthesis of Annonaceous acetogenins in recent yearszo’21 Mucoxin is the first isolated acetogenin that bears a hydroxylated THF ring (Figure III-3). It exhibits potent and selective cytotoxicities against pancreatic cancer cell line (PACA—2) and breast cancer cell line (MCF-7). However, further biological evaluations and the determination of the absolute stereochemistry of Mucoxin has been hampered by its limited access. Only 1.8 mg this compound was isolated from its natural sources.22 Therefore, a total synthesis of this natural product was highly desired and has been pursued in our laboratory. During the course of this total synthesis, a new approach involving the one-pot cyclization of 1,2,n-triols was achieved and the development of this new methodology enabled us to perform a convergent, streamlined synthesis of Mucoxin. The development of this method will be discussed in detail in this chapter. 82 Mucoxin Figure III-3. Structure of Mucoxin 3.1.2 Synthetic strategies for the construction of the THF core in the total synthesis of Annonaceous acetogenins Several representative synthetic strategies for the construction of THF core in total synthesis of Annonaceous acetogenins are summarized in this section. 3.1.2.1 Intramolecular epoxide opening cyclization Scheme III-1. Intramolecular epoxide opening cyclization acid or base catalysis R n = alkyl , R' > HO H O H r III-2 ll HO' ' 'QR' 1) acid catalysis O H R = vinyl or alkynyl R 2) antibody catalysis "1-3 The intramolecular epoxide opening of epoxy alcohols of type III-1 is a well established process for THF-ring formation.”25 Two different products are possible for this reaction. They are five-membered ring THF III-2 or six-membered Iing THP III-3 as shown on Scheme III-1. As predicted by Baldwin’s rules,26 this cyclization reaction selectively gives the five-membered ring THF as the product with the exception of R = vinyl or alkynyl. In these cases, the transition state leading to the six-membered ring is greatly stabilized by the adjacent functionality. Scheme III-2. Sequential synthesis of oligo-THF rings by intramolecular epoxide openings Path A RM epoxidation /_\= H 0 it ’cH "#6 "F7 405 H M F, . _. F1104 F. , ., ., —— H 0 1:. OH H 0 1:1 0 H O F] OH O III-4 III-5 Ill-10 1 Path B M 1 R O i '3 5 M/_\:_\ H H OH oxo 0 O Intramolecular epoxide Ill-8 Ill-9 opening :n O O ll During the total synthesis of Annonaceous acetogenins which contain a bis-THF functionality, a sequential synthesis of oligo-THFs requires the addition of a new THF 84 ring to a preexisting THF ring in a stereocontrolled manner. As shown on Scheme III-2, two strategies could be employed during this process. Path A involves a stereocontrolled addition of a but-3-enyl metallic reagent III-6 to the aldehyde III-5 and subsequent stereocontrolled epoxidation of the resulting olefin III-7. Unfortunately, there are very few examples of this strategy being employed in the total synthesis due to the low degree of stereoselectivity in the epoxidation of the olefin which lacks a directing group.”28 Path B is a more popular protocol than path A in total synthesis of Annonaceous acetogenins. It avoids the troublesome stereocontrolled epoxidation by using an acetonide group as a latent epoxide function. The metallic reagent III-8 can either comes from the chiral reagent such as D- or L- malic acids, or from synthetic enantiopure diols. This method has been applied to the total synthesis of several Annonaceous acetogenins, such as the total synthesis of (+)-Rolliniastatin 1 by Koert (Figure III-4).29 (+)-Rolliniastatin 1 Figure III-4. (+)-Rolliniastatin l 85 3.1.2.2 Intramolecular Williamson reaction The construction of oligo-THFS by an intramolecular Williamson reaction has been used only rarely in the past.30 Only the recent invention of multiple intramolecular Williamson reaction makes this route more popular and an increasingly powerful tool in polyether synthesis (Scheme III-3);“ Scheme III-3. General scheme for Williamson reaction _—> R1flR2 R1/[OLR2 Scheme III-4. Total synthesis of Asimicin BU3SHMOB” C10H21 1) OMOM ; e s CH0 > 2) p-TsCl, py TBAF C10H21 \ _—_> MOMCS 5T3 oRon OTs OMOM C10H21 - - \ —_’ . : o 2 O OBn ———> ; H ———> MOMO H H H OMOM Asimicin 86 A convergent synthesis of oligo-THFs has been realized in Marshall’s total synthesis of both possible C-lO epimers of Asimicin.32 The synthesis relies on the key enantioenriched addition of y-OMOM allylic indium reagents to a core aldehyde, and a Williamson reaction for the THF-ring closing. The key reactions are shown in Scheme HI-4. 3.1.2.3 Oxidative cyclization of 1,5-dienes Scheme III-5. Oxidative cyclization of 1,5-dienes F/‘\=\ [O] Rx/QVR V As discussed in Chapter II, the oxidative cyclization of 1,5-dienes is an efficient strategy for the synthesis of THF-diol fragment in a single step with all the correct stereochemistry (Scheme III-5). The absolute stereochemistry is normally built by utilizing the chiral auxiliary as a directing group. Brown and co-workers have demonstrated the efficiency of this strategy by the total synthesis of cis-Solamin using a 3 By conducting the oxidation under permanganate-mediated oxidative cyclization.3 phase-transfer conditions, a 55% yield was obtained for this pivotal transformation that introduces the C15, C16, C19, and C20 stereocenters present in cis-Solamin in one step. A small amount of diastereomeric THF-diol was observed by NMR (dr 10:1) and fortunately was able to be separated from the desired product by column chromatography (Scheme HI-6). 87 -4 -.. o (I); )10 N. AcOH (8 eq.), + O 04% Adogen 464 (0.1 eq.) EtOAc, -30 °C to 0 °C W 55%, dr10:1 , i O i . N 1° em H OH 4's 0 'I O O . _>' 19 16 I O O N __> 20 O 15 1 1° 04" H OHOZIS 1° orf' H OH 9 0 O cis-solamin 3.1.2.4 Asymmetric dihydroxylation-haloetherification Mootoo’s group developed the strategy of asymmetric dihydroxylation— 5 Conformationally haloetherification to construct trans—THF rings selectively.34'3 restricted isopropylidene derivatives of 5,6-dihydroxyalkenes have been used as templates for stereoselective halocyclization. The existence of the olefin functionality makes this protocol a convergent process. Although the mild reaction condition makes this method more appealing to synthetic chemists, the requirement of an additional hydroxyl group next to the THF ring and trans- stereoselectivity limits the application of this method to some extent. 88 The THF core of Mosin B was synthesized through this route by Tanaka, and Monden.36 The convergency of this stategy was demonstrated by their work as shown in Scheme III-7. Scheme III-7. Total synthesis of Mosin B 1) l(col|idine)ZCIO4 C‘2H25 _ MeCN/HQO, RT : C12H25 ,v 0 O OH O O 2) K2003, MeOH,RT x 80% OH —" OH I o ’ (31sz5 0‘“ OH OH 0 O Mosin B 3.1.3 Asymmetric epoxidation vs. dihydroxylation Among the various methods for the synthesis of THF core in acetogenins, the acid catalyzed expoxidation cyclization turns out to be one of the most popular pathways to construct substituted tetrohydrofuran ring structures. The potential synthetic utility of this reaction is considerable, given the stereospecific nature of the cyclization and the ease of the establishment of the absolute stereochemistry of the epoxides through various methods. Numerous synthetic methods have been developed in the past decades for the asymmetric epoxidation. However, the most popular titanium tartrate catalyzed 37,38 Sharpless asymmetric epoxidation is restricted to allylic and homoallylic alcohols. The hydroxyl group enhances the rate of the reaction, and is also essential for the 89 achievement of asymmetric induction. The need for a hydroxyl group presented in the substrate limits the scope of this asymmetric epoxidation to a fraction of olefins. A number of alternative methods aimed at catalytic asymmetric epoxidation of unfunctionized olefins, where selectivity is determined solely through nonbonded interations, have been developed in the last two dacades. The most prominent methods among these synthetic routes are chiral Mangnese salen complexes catalyzed Jacobson- Katsuki asymmetric epoxidation39 and the chiral dioxirane catalyzed Shi epoxidation.40 However, the former method mainly gives good result for cis-olefins, whereas the latter one is effective for trans- disubstituted and trisubstituted olefins particularly. Other miscellaneous procedures either give unsatisfactory enantioselectivities or utilize stoichiometric amounts of chiral reagents.“42 The shortage of methods available for the direct enantioselective epoxidation of unfunctionalized olefins limits the utility of epoxidation-cyclization processes to some extent. Compared with epoxidation process, the well-defined Sharpless dihydroxylation is much less limited in the choice of substrates. Since its inception in 1988, substantial progress has been attained in the development of ligands that generate higher levels of enantioselectivity from unfunctionalized olefins with different substitution patterns (see Chapter I for details). 3.1.4 Transformation of 1,2-diols into epoxides or epoxide-like synthons Since the Sharpless asymmetric dihydroxylation reaction is superior to asymmetric epoxidation of unfunctionalized olefins in its scope of substrates, a number 90 of protocols which could convert a vicinal diol to an epoxide with complete stereochemical fidelity were invented. The original method involved the selective arenesulfonylation and subsequent base promoted epoxide formation.43 This protocol suffers a lot from the strict requirement of the regioselectivity, since the cyclization of different regioisomers leads to opposite enantiomers and consequently a loss of optical purity. Thus, only terminal 1,2- diols are applicable to this protocol. An synthetic example is shown on Scheme III-8.44 Scheme III-8. Selective arenesulfonylation p-TsCl OH pyridine, OH 0 ° t a: >/’\/OH O C ort > CCOWOTS 0 o 97% ee NaOMe, O O MeOH, CC >/<) reflux, 1 h 0 ‘ 97% ee Cyclic sulfites and sulfates could also be regarded as synthetic equivalents of epoxides and a number of useful synthetic protocols have been invented. Similar with epoxides, they also constitute electrophilic, chiral building blocks with an 1,2-functional group relationship in a cyclic structure, which makes them epoxide-like synthons. Cyclic sulfites are formed easily by the reaction of diols with 80C]; in the presence of an amine base. Whereas the analogous reaction with SOgClg gives unsatisfactory yield, the cyclic sulfate could be easily obtained by oxidation of corresponding cyclic sulfite with NaIO4 in the presence of catalytic amount of RuCl3.45 91 Analogous to epoxides, cyclic sulfates can be opened by nucleophilic attack of either carbon center. A variety of nucleophiles are capable of this ring opening reaction, including halidef’6 azide,47 carbon nucleophiles,45 and hydride.45 The product is a sulfate monoester, which could be easily hydrolyzed to alcohol under acidic conditions (Scheme III-9). Scheme III-9. Cyclic sulfates act as epoxide-like synthons A, n ,0 OH SOCI O 3’0 NaIO4, cat. RUC'a, O 820 Hi R1 0 °C to rt R1 OH Nu- 0/802 0“ cat H so - 2 4 4 R 1 _ 0.5 1 eq. H20 _ Nu THF NU In a recent publication of Sharpless,48 the scope and limitations of the reaction of cyclic orthoacetates, derived from chiral diols, with acetyl halides or TMSCl have been investigated. It was found that the formation of orthoesters by the transorthoesterification of diol and trimethyl orthoacetate and the subsequent nucleophilic opening of a cyclic acetoxonium intermediate, generated from a cyclic orthoester and Me3SiCl, acetyl bromide or acetyl chloride/NaI, give halohydrin ester stereoselectively. And the subsequent base mediated methanolysis to the epoxide can be carried out in the same reaction vessel, making this reaction a convenient ‘one-pot’ procedure (Scheme 111-10). 92 The overall process converts vicinal diols into epoxides with the retention of configuration. Scheme III-10. Stereospecific transformation of 1,2-diols into epoxides via orthoester intermediates OH MeC(OMe)3 XOMG 92 cat.PPTS > O O AcX, or M938IX> DMD R, )_[ OH R1 R2 R1 ’R2 K2003, MeOH ll 0 FHA” R2 The reaction tolerates a wide range of functionalities and even acid sensitive functionalities, such as acetal or TBDMS group, are compatible when the reaction mixture is buffered with triethylamine. There is no epimerization observed even for the benzylic substrates. 3.2 One-pot cyclization of 1,2,n-triols via orthoesters During the process of the total synthesis of Mucoxin (Figure IH-S), an ongoing project in our group, a synthetic challenge appeared, namely stereoselective construction of the second THF functionality. Although a number of synthetic routes have been developed for the construction of the cyclic ether rings, a more convergent and versatile strategy would be desirable. 93 OH OH ”OH Mucoxin Figure III-5. Proposed structure of Mucoxin Scheme III-11. Retrosynthetic analysis of mucoxin "-15 16 _ £33” + 'I, W08” OP I 5 "-14 "-16 Retrosynthetic analysis of mucoxin was shown in Scheme 111-11. The key intermediate bis-THF II-12 could be accessed from bishomoallylic alcohol II-14. This intermediate II-14 already possessed all the required carbons for construction of bis-THF II-12, which makes this strategy a convergent process.49 Stereoselectively construction of the epoxide from alkene is crucial for the success of this pathway albeit challenging. An example of such is the hydroxy-directed, VO(acac)2/tBuOOH-mediated epoxidation- 94 cyclization method pioneered by Kishi.50 A limitation of this methodology, however, is that depending upon the structure of the parent hydroxy olefin the epoxidation may occur with low facial selectivity. In addition, this method lacks versatility that would allow access to other unnatural stereoisomers of the natural product. As we discussed earlier, epoxidation of alkenes without any directing group is difficult. Other asymmetric epoxidation options, such as J acobsen and Shi epoxidation can not be applied to olefin II- 14, because this substrate lacks the specific structural features required for optimal stereoselectivity under the two protocols.40 In view of the above limitations, a route involving transformation of a diol stereospecifically to an epoxide followed by an acid mediated cyclization became more realistic, although multiple steps were envisioned for this process. Close inspection of orthoester mediated transformation of vicinal diols to epoxides lead us to evaluate the possibility of a one-pot process which directly affords the THF ring Without the formation of epoxide. As depicted in Scheme III—12, the overall strategy depends on the in .sztu generation of an orthoester via transorthoesterification of trimethyl orthoacetate with a 1,2-diol The subsequent ionization of the intermediate orthoeSter with 'a Lewis acid leads to a reactive acetoxonium species, which is directly trapped by the pendant hydroxyl group to yield the cyclized oxirane. The 8N2 nature of this protocol will ensure the complete transformation of stereochemical properties. \C ‘J o Scheme III-12. Cyclization of 1,2,n-triols via orthoester intermediates XoMe HO OH MeC(OMe)3 o 0 OH % )—k/\/ R PPTS H OH Lewis Acid ll “‘0 )—K/\/ RJ\_7 R 9H 3.2.1 Optimization of reaction condition Commerically available cis-4-decen-1-ol III-l7 was chosen as the first substrate to test this protocol. Triol III-18 was obtained by dihydroxylation using Upjohn’s procedure. The first attempt was to protect the isolated hydroxyl group by silyl protecting groups to ensure the orthoester formed from the vicinal diol selectively. The subsequent addition of Lewis acid, such as BF3OOEt2, would both function as the orthoester ionization and catalyzing the deprotection of the silyl groups. However, the TMS group did not survive the silica gel during the purification process. Therefore, 1,2,5-triol III-18 was directly subjected to the reaction in hope that the orthoester formation will be selective for the vicinal diol. After the first trial, we were pleased to find that after treatment of III-18 with 1.2 equiv of trimethyl orthoacetate and a catalytic amount of PPT S (0.1 equiv) in dichloromethane, followed by addition of 0.1 equiv of BF3-Et20, the cyclization proceeded to deliver product III-19 as a single diastereomer in excellent yield. After treatment of the starting material with trimethyl orthoester and 96 catalytic PPTS, either stripping off the solvent before the addition of BF3-Et20 or directly adding BF3-EtzO gave comparable yield of the product. The former procedure required less than 5 minutes for the reaction being completed whereas the latter case needed 1. hour. The removal of the methanol generated after the transorthoesterification by vacuum accelerated the cyclization process. (Scheme III-13) Scheme III-13. Cyclization of 1,4,5-decantriol via orthoester intermediate cat. OsO4 NMO HO OH Acetone-H20 (9:1) Ill-17 Ill-18 1) 1.2 equiv MeC(OMe)3 OAC WOH cat. PPTS' CHZCIZ W Ill-18 2) 0.1 equnv BF3'OEt2 I “-1 9 81 °/o To further test the structure and the relative stereochemistry of the product, compound III-19 was synthesized independently form III-17 following epoxidation- cyclization pathway. THF III-20 was directly obtained from epoxidation of III-17 by mCPBA. The acidity of mCPBA was sufficient for the tandem cyclization which led to the tetrahydrofuranol 111-20. The free hydroxyl group was then acetylated by acetic anhydride and base (Scheme III-l4). This compound is identical to compound III-19 by comparison of their respective NMR spectra. 97 Scheme III-14. Epoxidation-cyclization of cis-4-decen-1-ol mCPBA 0” NV—T—WOH = .\\O CHzClz III-1 7 86% III-20 A020 DMAP quantitative OAc .“O Ill-19 Table III-1. One-pot cyclization of decane-l,4,5-tn'ol with various acid promoters entry L.A. equiv time temperature yieldal 1 BF3'OEt2C 0.1 5 min 0 °C \ 81%b 2 3133-032d 0.1 1 h 0 0c 99% 3 TMSOTf 1.2 5 min 0 °C 91% 4 TMSCl 1.2 1 h o 0c 72% 5 AlMe3 1.0 12 h n 12% 6 AcCl 1.2 5 min 0 °C 0 8All the yields are based on GC analysrs. isolated yield. removal of the solvent before addition of LA. d without removal of the solvent before addition of LA. Various Lewis acids other than BF3'OEt2 were tested as shown in Table III-l. TMSOTf and TMSCl also gave good results, although yields are slightly lower than BF3'OEt2. Trimethyl alumina only gave 12% yield for the desired product even for longer period of time, whereas acetyl chloride did not promote the cyclization reaction at 98 all. Therefore, the best reaction condition happened to be the first Lewis acid. we tested, using BF3°OEt2 as the promoter of the cyclization reaction. 3.2.2 Synthesis of 1,2,5-triol substrates Scheme III-15. Synthesis of cis—1,4,5-decanetriol III-26 B O TMSCI B OTMS TEA, THF, rt III-21 58% III-22 l H . 1 1.5 . B L,THF-78 °C /\/\/ ) eq n U I ¥/\/\/\/\OH 2) Ill-22, -78 OC Ill-23 18% 111-24 Na, NH3 (qu) -78 °C OH cat. 0304 < /\/\/\/\/\ WOH NMO, Acetone-H20 \ OH Ill-26 OH 48% over 2 steps Ill-25 After the success of the first trial, various substrates were synthesized and subjected to the optimized conditions in order to investigate the scope of this strategy. trans-4-Decenol III-25 was synthesized from 3-bromo-propanol and l-heptyne following the steps shown in Scheme III-15. l-Heptyne was deprotonated by n-butyllithium, then treated with TMS protected 3-bromo-propanol III-22 at —78 °C to generate 4-decyn-l-ol III-24 in 18% yield. The low yield was due to unstability of the TMS protecting group under the reaction condition. The alkyne III-24 was then reduced by dissolving metal 99 reaction, treated with sodium and liquid ammonia at —78 °C, to produce the trans olefin selectively. Compound III-25 was then oxidized by Upjohn’s procedure to yield cis- 1,4,5-decanetriol III-26. Scheme III-16. Synthesis of l-cyclohexyl-9-(4—methoxy-benzyloxy)-nonane-1,4,5- triol III-33 O NaH PCC N W > W ——-> PMBO H HO OH PMBCI, TBAI PMBO OH 65% 111-27 THF 111-23 111-29 68% Ph3PCH2CH2CHzOHBr KHMDS, TMSCI 20% 1) MsCl, TEA, CH2C|2 W 0 CC /\/\/=\/\ PMBO | < PMBO OH 2) Nal, acetone Ill-31 60% Ill-30 1) tBuLi, MgBr2 2) cyclohexyl carbaldehyde 80% OH PMBO Acetone-H20 (9:1) OH 65% Ill-32 Ill-33 Other than the primary alcohols, secondary and tertiary alcohols were also synthesized individually. As shown on Scheme III-16, compound III-32, an analogue of the intermediate during synthesis of Mucoxin, was synthesized from 1,5—pentanediol III- 27. Mono protection of 1,5-pentanediol III-27 was achieved by treatment of diol with NaH and PMBCl in the presence of a catalytic amount of tetrabutyl ammonium iodide. 100 The free hydroxyl group of III-28 was then oxidized by FCC to generate aldehyde III-29 in 65% yield. Subsequent Wittig olefination of III-29 yielded cis olefin III-30. The hydroxyl group of the ylide reagent was protected in situ by TMSCI, which was removed during the workup to afford the pure cis-alkenol. The hydroxyl group in compound III- 30 was then transformed to the iodide through a mesylate intermediate. The lithiated iodide was reacted with cyclohexyl carbaldehyde in the presence of magnesium bromide led to compound 111-32. The 1,4,5-triol III-33, a mixture of two diastereomers, was finally obtained by dihydroxylation of the olefin III-32. Scheme III-17. Synthesis of tetradecan—5,8,9-triol III-36 OH O nBuLi THF 111-34 90% 111-35 cat. 0504 NMO acetone-H20 (9:1) 62% OH OH AM OH Ill-36 Another linear secondary alcohol was synthesized from trans-4-decenal III-34. n-Butyllithium reacted with aldehyde III-34 in THF solution produced compound III-35 in 90% yield. The following dihydroxylation of the olefin gave the desired product tetradecan-5,8,9-triol III-36 in 62% isolated yield (Scheme 111-17). 101 Scheme III-18. Synthesis of 2-methyl-undecane-2,5,6-tn'ol III-41 WW“ MeLi ._ W O THF, -78 °C OH Ill-37 Ill-38 (CICO)2 DMSO TEA,CH2012 -78 °C, 97% _ A MeLi __ W ‘THF, -78 °C /\/\/—\/\H/ OH o O III-40 71 A Ill-39 HO OH cat. OsO4 NMO, acetone-H20 (9:1) 7 OH 75 % Ill-41 An example of a tertiary alcohol was also synthesized along the route shown in Scheme IH-l8. Starting from aldehyde III-37, methylation of the aldehyde followed by Swem oxidation gave the ketone III-39 in excellent yield. III-39 was reacted with another equivalent of MeLi to produce the tertiary alcohol III-40. Upon OsO4 mediated dihydroxylation, 2-Methyl—undecane-2,5,6-triol III-41 was produced in good yield (Scheme III-18). To test the efficacy of this method on benzylic alcohols, compound III-43 was obtained from aldehyde III-37. Grignard reaction of aldehyde and phenylmagnesiumbromide led to the benzylic alcohol III-42 in quantitative yield. The dihydroxylation of III-42 made the desired triol III-43 as a 1:1 mixture of diastereomers (Scheme III-19). 102 Scheme III-19. Synthesis of l-Phenyl—decane-l,4,5-triol III-43 PhBr’ M9 WWQ W—WH > — Et 0 O 2 . . OH Ill-37 quantltatlve Ill-42 cat. 0504 NMO acetone-H20 (9:1) 89% it HO OH OH Ill-43 A trisubstituted olefin III-47 was synthesized from cyclohexanone along the synthetic pathway as shown in Scheme III-20. A Wittig olefination between cyclohexanone and phosphonium salt generated cyanide III-45. The cyanide was then hydrolyzed under basic conditions to form carboxylic acid III-46. After LAH reduction, the unsaturated alcohol III-47 was obtained in quantitative yield. The desired triol III-48 was obtained by dihydroxylation following conventional procedures (Scheme III-20). Scheme III-20. Synthesis of 1-(1-hydroxy-cyclohexyl)-butane-l,4-diol III-48 G Ph3PCHQCH20HZCNCI 250/3 NaOH 0 . > __ > _ nBuLI,THF OVCN MeOH, reflux O—\/\COOH Sealed tube, reflux 92L—L /\ ,OH NMO, acetone-H20 (9: 1) 111-43 54% 111-47 103 The electronic effect of the olefin was also examined. 0t,B-Unsaturated ester III- 53 was synthesized as shown in Scheme III-21. Mono protection of 1,4-butanediol led to the compound III-50. The free hydroxyl group in this compound was then oxidized to the aldehyde III-51 by PCC. The olefination of aldehyde III-51 generated the or,B- unsaturated ester III-52. Upon deprotection of the PMB group, the desired molecule III- 53 was obtained in excellent yield. The final dihydroxylation reaction produced the triol III-54 in 78% yield. Due to the deactivated a,B-unsaturated ester, the dihydroxylation reaction was performed at elevated temperature. Scheme III-21. Synthesis of 2,3,6-trihydroxy-hexanoic acid ethyl ester III-54 OH PMBCI OPMB PCC JOKA/ > -—-—> OPMB HO/W NaH.TBAl HOW 81% H III-49 94% III-50 III-51 Ph3P=CHCOOEt THF, reflux 70% O O 000 W EtOJK/WOH : EtO / OPMB 98% III-53 III-52 cat. 0504 O OH NMO, acetone-H20 (9:1 ) , EtO)J\‘/‘\/\/OH reflux, 78% OH III-54 Other than III-53, a conjugated double bond with aromatic functionality was also investigated. Cis-olefin III-58 was synthesized from benzaldehyde. The conjugated cis double bond was built by Wittig olefination. The alcoholysis of cyanide III-56 moiety 104 was achieved by reflux with ethanol under acidic conditions. The resulting ethyl ester III-57 was then reduced by LAH to give compound III-58 in 84% yield. This compound was equipped with the desired conjugated double bond and tethered free hydroxyl group. The final dihydroxylation was completed under Upjohn conditions to yield l-phenyl— pentane-1,2,5-triol III-59 was attained in 57% yield (Scheme III-22). Scheme III-22. Synthesis of trans-l-phenyl-pentane-l,2,5-triol 111-59 95% EtOH O Ph3PCHZCH2CH2CNCI H = \ V \ KHMDS H2804, reflux 46% 80% CN COOEt Ill-55 Ill-56 Ill-57 LAH ether 84% OH OH cat. OsO4 \ ‘ NMO, acetone-H20 (9:1) 57% OH OH III-59 III-58 The trans conjugated olefin III-63 was synthesized following a different pathway. Sonogashira coupling reaction of iodobenzene III-60 and 4-pentyn-1-ol III-61 yielded III-62 in quantitative yield (bromobenzene did not yield any product under the same reaction conditions). The alkyne functionality in III-62 was reduced by LAH at reflux in THF. Trans-olefin III-63 was produced selectively. The correspondent triol III-64 was obtained by dihydroxylation of the olefin III-63 (Scheme 111-23). 105 Scheme III-23. Synthesis of cis-l-phenyl-pentane-l,2,5-triol III-64 1 1mol% Pd(PPh3)4 é OH + HOW : H 2mol% Cul ex. NEI3 III-60 "1-51 quantitative "1-52 LAH THF, reflux 89% OH O 0 cat. 3 4 OH :- \ OH NMO, acetone-H20 (9:1) OH 41% Ill-64 Ill-63 Because of the conjugation of the phenyl ring and the olefin, the electronic effect of the double bond could be manipulated quite easily by adjusting the substituent on the aromatic functionality. Therefore, a couple of the substrates with electron-withdrawing or electron-donating substituents on the phenyl ring were synthesized accordingly. Compound III-68, which was equipped with an electron-donating methoxy group on the para position of the phenyl ring, was synthesized following the same pathway as compound III-58. Wittig olefination of para-methoxy benzaldehyde III-65 generated III-66. Basic hydrolysis of the cyanide III-66 generated the carboxylic acid III-67. Upon LAH reduction, compound III-68 was obtained. The following dihydroxylation of olefin III-68 reaction gave the triol 111-69. 106 Scheme III-24. Synthesis of 1-(4-methoxy-phenyl)-pentane-1,2,5-triol 111-69 0 Ph3PCH2CH2CH20NCl m H : — KHMDS Meg/C 57% M90 CN 25% NaOH Ill-65 Ill-66 MeOH, reflux 98% ll \ \ A LAH MeO ‘ ether 0 OC M90 COOH 85% Ill-68 OH III-67 OH cat. 0304 OH NMO, acetone-H20 (9:1) 7 15% M99 OH Ill-69 Compared with the synthesis of electron-donating aromatic substrate, the compound tethered with an electron-withdrawing aromatic substituent was more problematic to synthesize. The same strategy used for the synthesis of III-68 failed to provide compound III-70, which has the same carbon skeleton but an electron- withdrawing nitro group on the para position of the phenyl ring. The Witti g olefination between the para-nitrobenzaldehyde and the phosphonium salt generated the desired cis- olefinic nitrile III-72. Various reductive conditions were attempted to convert the nitrile group to a CHZOH functionality but without any success. The para nitro group in the molecule is not compatible with the reductive conditions, which might cause the 107 decomposition of the compound III-72. Another route which involves the Sonogashira coupling followed by hydrogenation of the alkyne III-74 also failed (Scheme III-24). Scheme III-25. Attempt to synthesize cis-5-(4-nitro-phenyl)-pent-4-en-l-ol III-70 O \ PthCHgCHgCH2CN H = —— KHMDS 02N OZN CN > III-71 III-72 ' Sonogashira / OH 0 — / ><> \ OZN OZN OZN _ - H 111 73 "' 74 111-70 0 Finally, a number of ylides were synthesized, including Ph3P(CH2)4OH'Cl, Ph3P(CH2)4OH'I, Ph3P(CH2)4OTBS'Cl, Ph3P(CH2)4OTHP'Cl, Ph3P(CH2)4OPMB'Cl, and Ph3P(CH2)4OAC'Br. The desired molecule III-70 eventually was obtained from Wittig reaction between para-nitrobenzaldehyde III-71 and Ph3PCH2CH2CH2CH20AC'Br followed by deprotection, albeit in modest yield. The trio] III-76 was then accessed from III-70 uneventfully by an 0804 mediated dihydroxylation reaction (Scheme III-26). 108 Scheme III-26. Synthesis of 1-(4-nitro-phenyl)-pentane-1,2,5-triol III-76 O + OAc - OZN KHMDS 02N OAc 8-1 1% III-71 III-75 OH M cat. 0504 m K2003 ‘ NMO o N OH ‘ MeOH Ill-76 III-7O 3.2.3 Cyclization of 1,2,5-triols A number of 1,2,5-triols with representative structure motifs were synthesized accordingly. The effectiveness of the cyclization via orthoesters intermediate was investigated afterward. The results are shown in Table 111-2. The following details are noteworthy: (1) Comparable results were obtained for the vicinal diols derived from cis and trans olefins (entry 1 and 2). (2) The substitution pattern of the nucleophilic hydroxyl group did not affect the efficiency and stereoselectivity of the cyclization reaction. Substrates with a primary, secondary or tertiary hydroxyl group all afforded good yield of the desired THF products (entry 1-5). It is noteworthy that the PMB group can not fully survive under the reaction conditions, probably due to the acidic nature of the catalyst. (3) This cyclization reaction is also applicable to substrates with a benzylic nucleophilic hydroxyl group. Although partial deacetylation was observed, the problem is easily solved by reprotection of the free hydroxyl group with acetic anhydride. (4) The substitution pattern of the olefin was also investigated. Trisubstituted olefins are also 109 effective in the cyclization reaction. Entry 7 is an example of the cyclization of a trio] derived from a trisubstituted olefin. Although in slightly lower yield than the previous examples, the reaction successfully afforded the desired cyclization product. (5) The substrate derived from 01,B-unsaturated olefin was also compatible with this method. Good isolated yield was observed for the cyclization of III-54 (entry 8). Table III-2. One-pot cyclization of 1,2,5-triols via orthoesters OH R R 3R R2 2 4 1)MeC(OMe)3,cat.PPTS O R R1 OH 5 R1 3 OH 2) cat. BF3'OEt2 R4 - . yield entry 1,2,5 triol product (%) OH OAc 1 3 OH 81 OH Ill-18 Ill-19 OH OAc W O 2 OH 74 OH Ill-26 Ill-77 OAc 9H .0 C PMBO ' OH PMBO ' y 3 OH Ill-78 80 OAc (1:1) .0 III-79 OH OH OAc NW 0 4 OH 82 Ill-36 III-80 110 Cont. Table IH-2 entry 1,2,5-triol product yield (%) OH OH 0 Ac 5 (:DH 80 1u-41 '"'31 OAc At) Ph OH OH 55 WPh 6 : "L82 (DH (DH ,&3 Ph "L43 ’/A\V//\\//L\\L_j7/ 36 "L83 01—9” (DH (3 7 0A 50 "F48 "L84 0 OH QAC (DH EK) ‘ ,(D 8 HOW m 62 (DH C) "L54 "L85 Besides the substrates shown in Table 111-2, a series of aromatic substituted 1,2,5- triols were inspected specifically, and interesting results were obtained (Table HI-3). Compound III-59 was first subjected to the cyclization conditions. To our surprise, a mixture of the desired five-membered ring product III-86 along with an unexpected six- membered ring THP III-87 was generated during the reaction process. To explain this outcome, the electronic effect of the aromatic substitution must be considered. Presumably, the stability of the intermediate carbocation allows nucleophilic attack at the 111 benzylic position (forming a six-member ring) to compete with the expected S-exo process leading to the five-member ring product. To test this postulation, a couple of substrates bearing electron-donating and electron-withdrawing group on the para position of the aromatic substituents were synthesized as discussed previously. As anticipated, . one-pot cyclization of triol III-69, with an electron-rich aromatic substituent, led to the formation of six-membered tetrahydropyran product exclusively. It is notable that epimerization occurred during the process, causing the formation of compound III-89. A detailed analysis of product ratios showed the major product was the ‘unexpected’ trans tetrahydropyran. In fact, treatment of a pure sample of 111-89 or III-90 with BF3°OEt2 gave a mixture of both epimers in a similar ratio as the cyclization of III-69. This observation further proved that the formation of the six-membered ring tetrahydropyran was due to the increased stability of the carbocation intermediate. In contrast to triol III- 69, the cyclization of compound III-76 only generated THF ring products. This could be well explained by the decreased stability of the carbocation intermediate of electron- withdrawing aromatic substituent, which disfavored the formation of the six-membered ring product. A partial deacetylated product was also observed for this reaction, presumably because of the acid catalyzed transesteri fication. 112 Table III-3 One-pot cyclization of aromatic 1,2,5—triols OH OAc R W04 1)MeC(OMe)3.cat.PPTS> m?) + O OH - R 2) BF3 0512 R AC0 entry 1,2,5-trio] product yield (%) OAc .“O OH 48 ; OH Ill-86 1 OH 111-59 " 24 Ill-87 OH OH "“54 Ill-88 MeO 73 OH Ill-89 MeO Ill-69 " 20 0A0 .“O OH 60 OZN 4 5 0” 111-91 OH OH OZN ,o Ill-76 ‘ 8 02N 111-92 113 Another interesting result was obtained for the cyclization of triol III-64, the epimer III-59, which was derived from the trans olefin III-63. The one-pot cyclization of III-64 generated tetrahydropyran III-88 as the only product, as opposed to III-59, which led to a mixture of THF and TIH3 products (see Table 111—3). A possible explanation is illustrated in Scheme III-27. The phenyl group in the anti triol III-59 is axially juxtaposed in the putative transition state. Presumably, the increased steric repulsion counter-balances the greater carbocation stability at the benzylic position, and thus leads to two pathways yielding a mixture of 5- and 6-member ring products. On the other hand, the syn triol III-64 would have its aryl group situated equatorially in the transition state, therefore enjoying both steric relief and electronic stability, which results in the formation of only the six-member ring product. Scheme III-27. Intermediates of one—pot cyclization to form tetrahydropyran products OH 1) MeC(OMe)3 ' W cat. PPTS ; OH > OH 2) 35,-0512 111-59 * 111-a7 OH 1) MeC(OMe)3 W04 cat. PPTS > OH 2) 13133-01512 Ill-64 Ill-88 3.2.4 Synthesis of 1,2,4-, 1,2,6- and 1,2,7-triols and their one-pot cyclization via orthoester intermediates 114 With the success of the cyclization of 1,2,5-trio], other substrates such as 1,2,4-, 1,2,6,- and 1,2,7-triols were also synthesized and their applicability to our one-pot cyclization was investigated. Commercially available cis-3-octen-l-ol III-93 was oxidized. under Upjohn’s condition to produce anti-1,3,4-octanetriol III-94 in moderate yield. The one-pot cyclization of III-94 went smoothly to give the tetrahydrofuran product III-95 in 71% yield. The reaction was selective for the 5-end0 process, and there was no evidence of the formation of a 4-ex0 oxetane, probably due to the high strain energy of the four- membered ring (Scheme III-28). Scheme III-28. Synthesis and cyclization of 1,3,4-octanetriol III-94 OH WOH cat' 0804 > WOH NMO OH 111-93 acetone-H20 (9:1) 111-94 29% 1 MeC OMe 9H )cat. lgPTS)3 O 710/0 ACO Ill-94 Ill-95 As an example of 1,2,6-triol, 1,5,6-nonanetriol 111-101 was acquired from 1,5— pentanediol III-96. The procedure is shown in Scheme III-29, which starts with a mono protection of 1,5-pentanediol by a PMB group. The free hydroxyl group was then oxidized by FCC to produce aldehyde III-98. A cis-olefin III-99 was then generated by a Wittig reaction of the aldehyde with the proper phosphonium salt. After deprotection 115 of the PMB group, a cis-olefin III-100 equipped with the free hydroxyl group four carbons away from the double bond was in hand. The final 1,5,6-nonanetriol III-101 was obtained in 50% yield following the general dihydroxylation procedure. The one-pot cyclization reaction proceeded uneventfully to generate a six-membered ring product III- 102 exclusively via a 6-ex0 process (Scheme III-29). Scheme III-29. Synthesis and cyclization of 1,5,6-nonanetn'ol III-101 NaH W ————> W _ HO OH PM'BCI HO OPMB Ill-96 TBA' 111-97 70% P00 CHZCIZ 68% ll O W Ph3PCHgCH2CH20H38r OPMB < JJ\/\/\OPMB KHMDS H Ill-99 66% Ill- 98 000, CHZCIZ 80% cat. 0804 Afl/WOH OH NMO g actone-HQO (9:1) OH Ill-100 50% Ill-101 OH 1) MeC(OMe)3 OAc /\/’\//\/\/OH cat.PPTS _ Nk‘k‘oj 78% Ill-101 III-102 116 A seven-membered cyclic ether ring was also built via this route. A 1,2,7-triol was accessed from the unsaturated fatty acid octadec-6—enoic acid III-103. The LAH reduction of III-103 afforded unsaturated fatty alcohol III-104, which was equipped with a hydroxyl group five carbons away from the alkene functionality. The simple dihydroxylation generated octadecane-l,6,7-t1iol 111-105 in good yield (Scheme III-30). Scheme III-30. Synthesis of octadecane-l,6,7-triol III-105 H30(H20)10 ___4> H30(H2C)1o O ether 92% III-103 Ill-104 cat. OsO4 NMO acetone-H20 (9:1) 79% ll OH H3C(H2C)10WOH OH III-105 The construction of a seven-membered cyclic ether ring turned to be problematic under the previous reaction conditions. The attempt to cyclize triol 111-105 was unsuccessful. Instead of formation of the seven-membered ring, the reaction gave a mixture of hydrolyzed products. Optimization of the reaction conditions was necessary in order to build a mid-sized ring. Our first attempt was to increase the reaction temperature to promote the cyclization reaction based on the thermodynamic consideration. Gratifyingly, the desired product was obtained when the temperature was 117 raised to 80 °C in toluene, although in quite modest yield (Table III-4). This product was also synthesized independently along the epoxidation cyclization pathway as shown in Scheme III-31. The structure of the product was identified by comparison of the NMRs. The major side products were still the acetates and obviously they come from the competitive hydrolysis of the orthoester intermediate. Different additives were added to the reaction mixture, including bistributyltin oxide, and 3 A molecular sieves. Unfortunately, there was no improvement of the yield of the seven-membered ring product. Even though the reaction was generally performed under a stringent moisture free condition, the hydrolysis byproduct still led us to suspect that the existence of a small amount of moisture was the major cause of the low yield of the cyclization reaction. Most probably this moisture came from the reagent, such as trimethyl orthoacetate and triol, rather than the solvent. Since the competition was between the intramolecular cyclization and the intermolecular hydrolysis, the decrease of the concentration of the reaction might suppress the intermolecular process, and should not affect the intramolecular reaction. Gladly, the yield of the desired product increased to 47% when the reaction was preformed at 0.01 M concentration, whereas the yield was 21% at 0.1 M concentration. The above results are shown in Table III-4. 118 Scheme III-31. Epoxidation cyclization of cis-octadec-6-en-l-ol III-104 OH mCPBA MOH F\/\/\/ H30(H20)1o W H3C(HZC)10 1) (Bu38n)20, Toluene, 90 °C 2) 0.4 eq. Zn(OTf)2 OAC OH \O A020, Py, DMAP \O H30(H20)1o " < H3C(HzC)10 " 66% over two steps Ill-108 III-107 Table III-4. Optimization of one-pot cyclization of octadecane-l,6,7-triol III-105 OH OAc O HSC(H2C)10WOH : quHzChO/KQ) OH Ill-105 III-108 entry reaction conditions yield (%) 1 l) MeC(OMe)3, cat. PPT S, CHzClz. rt 03 2)10% BF3'OEt2, rt 2 1)MeC(OMe)3, cat. PPTS, Toluene, 80 oC, 1 h . 21,. 2)10% BF3°OEt2, 80 °C, 6 h l)MeC(OMe)3, cat. PPI‘ S, Toluene, 80 OC, 1 h 3 2)(BU3Sn)20, 80 °C, 16 h 02! 3)Zn(OTf)2, 80 °C, 16 h l) MeC(OMe)3, cat. PPT S, Toluene, 80 °C, 1 h 4 2) (Bu3Sn)zO, 80 °C, 16 h 21a 3) 10% BF3'OEt2, 80 °C, 16 h 5 1)MeC(OMe)3, cat. PPTS, Toluene, 80 °C, 1 h 47b 2)10% BF3'OEt2, 80 °C, 6 h a Concentration = 0.1 M. ' Concentration = 0.01 M. 119 As an example of 1,2,10-triol, deca-l,2,10-triol was also prepared from 9-decen- l-ol. Various reaction conditions were attempted, however, there was no evidence for the formation of a nine-membered cyclic ether ring. Decomposition of the starting material under current reaction conditions was observed. 3.2.5 One-pot cyclization of 1,2,n-triols to construct bicyclic systems Upon the successful application of this strategy to linear triols, various substrates incorporating a cyclic structure were designed and synthesized to test the scope of this method on the construction of bicyclic systems. 3—(2-Hydroxy-phenyl)-propane-1,2-diol III-110 was accessed from the commercially available 2-allylphenol III-109 by 0304 mediated dihydroxylation. The cyclization of this triol incorporated in a phenyl ring led to the formation of a bicyclic compound III-111 in good yield. It is noteworthy that the newly formed cyclic product is a six-membered ring, instead of the 5-membered ring as we expected (Scheme III-31). This is most likely due to the reversibility in the ring-opening of the anticipated five- member ring product afforded by the presence of the aryl group that eventually leads to the production of the more thermodynamically stable six-member ring. The less steric hindrance of the primary carbon also might contribute to the formation of the tetrahydropyran structure. 120 Scheme III-32. One-pot cyclization to form acetic acid chroman-3-yl ester III-111 OH OH / . cat 0304 > OH NMO OH acetone-H20 (9:1 ) 111-109 quantitative 111-11o OH 1) MeC(OMe) , cat. PPTS OH 3 O; 0 OH 2) BF3'OEt2, 840/0 OAc 111-110 111-111 A 1,2,6-triol incorporated into an eight-member ring was also synthesized from 1,5-cyclooctanediol III-112 as shown on Scheme III-33. The oxidation of 1,5- cyclooctanediol III-112 with one equivalent of FCC generated the ketone III-113 in 76% yield. The alkene III-114 was then accessed by the following Wittig reaction. The dihydroxylation gave the triol III-115 selectively. The diastereoselectivity was the result of the directing effect of the hydroxyl group. The orthoester mediated cyclization of III- 115 afforded the bicyclic acetate III-116 along with the deacetylated product III-117. It should be noted that this is the first example of the cyclization proceeding with the retention of the stereochemistry. An SNl mechanism must play an important role in this case, since the formation of the bicyclic system can not been realized with an 8N2 mechanism. And because of the tertiary carbon center, the cyclization is more plausible via a carbocation intermediate rather than the direct substitution. 121 Scheme III-33. Synthesis and cyclization of 1-hydroxymethyl-cyclooctane-1,5-diol III-115 OH CHZCI2,rt O KHMDS CH2 0 TH F, reflux 76 /° 84% III-112 Ill-113 Ill-114 cat. OsO4 NMO acetone-H20 93% V HO OH 1 MeC(OMe) , cat. PPTS 2) BF3'OEt2 III-117 Ill-116 III-115 18% 33% Two substrates incorporated into a cyclohexane structure were synthesized from 1-cyclohexenylacetonitrile III-118. As shown on Scheme III-34, acid catalyzed alcoholysis of nitrile III-118, followed by LAH reduction yielded alcohol III-120. Dihydroxylation of III-120 produced 1,2,4-triol III-121. One carbon elongation of III- 120 was realized by a sequential mesylation, iodination, substitution and reduction process as shown in Scheme HI-34 to generate compound III-126. Subsequent dihydroxylation generated the 1,2,5-trio] III-127, which was incorporated into a six- member ring system, in 92% yield. 122 Scheme III-34. Synthesis of l—(2-hydroxy-ethyl)-cyclohexane-1,2-diol III-121 and 1- (3-hydroxy-propyl)-cyclohexane-1,2-diol III-127 CN H2804 > COOMe LAH OH MeOH, reflux ether 69% 64% Ill-118 Ill-119 III-120 cat. OsO4 NMO acetone-H20 (9:1) 53% fivOH OH Ill-121 O/VOH MsCl mom Nal Pyridine acetone, reflux> 111- 120 89% III-122 75 /° 111-123 NaCN MeCN OH‘__ LAH COOH KO ether EtOH: H20 (1: 1) 87% III-126 III-125 Ill-124 cat. 0804 NMO acetone-H20 (9:1 ) 92% OH CEW“ OH III-127 123 The one-pot cyclization of tn'ol III-121 turned out to be problemetic and a lot more challenging than we expected. The cyclization reaction was quite sensitive to moisture. The initial trial under conventional conditions led to hydrolysis product exclusively. To prevent the competitive hydrolysis, 3 A molecular sieves were added to the reaction mixture and the products were carefully isolated and characterized by NMR. The results are shown in Scheme III-35. The major products were hydrolysis product III-128 and an unusual ketone III-129 along with 6% recovered starting material. Disappointingly, there is no evidence of the formation of the desired bicyclic system. The mechanism of the formation of ketone III-129 was postulated and is shown in Scheme III-36. It is possible that a 1,2-hydride shift is responsible for the production of ketone III-129. Scheme III-35. One-pot cyclization of 1-(2-hydroxy-ethyl)-cyclohexane-.l,2-diol III- 121 and 1-(3-hydroxy-propyl)-cyclohexane-1,2-diol III-127 OH OH (IVOH 1) MeC(OMe)3, cat. PPTS (INCH OH 2) BFa'OF-t2 OAc III-121 III-128 0“ 1) MeC(OMe)3, cat. PPTS OH > + OH 2) BF3'OEt2 OAC O Ill-121 Ill-123 III-129 21 % 20% OH O (Di/VCH 1) MeC(OMe)3, cat. PPTS; Ct) 52% III-127 III-130 124 One the other hand, the cyclization of 1,2,5-trio] III-127 went smoothly to give the desired Spiro THF 111-130 in 52% yield. Scheme III-36. Proposed mechanism for the formation of acetic acid 2-(2—oxo- cyclohexyl)-ethyl ester III-129 OMe 6') .- OH OH o> OH OH __ OH 4 III-121 (IVOAC O Ill-129 3.2.6 Some improvements of the cyclization of 1,2,n-triols via orthoesters The one-pot procedure employs a Br¢stead acid, PPTS, as the acid catalyst for the orthotransesterification and a Lewis acid BF3'OEt2 to generate the acetoxonium species. Since Lewis acid catalyzed transesterification was a well documented procedure5 1, the reaction scheme could be further simplified with use of BFyOEtz as the sole catalyst to promote both transesterfication and cyclization, and thus improve the transformation by rendering it an essentially one-step process. As a demonstration, triol III-18, 111-26 and 111-101 were converted to corresponding cyclic ether rings using only BF3'OEt2 as the promoter (Table 111-5). The improvement of the reaction yield was achieved to some extent for all three examples. The reaction was also accelerated compared to the one-pot procedure. Therefore, the 125 - procedure of cyclization of 1,2,n-triols to oxiranes via orthoester intermediates was successfully simplified to an one-step process. Table III-5. One-step cyclization of 1,2,n-tr1'ols to oxiranes via orthoester intermediates Ill-26 OH /\/K/\/\/OH OH III-101 V a 1) MeC(OMe)3, cat. PPTS 2)BF3'OEt2 MeC(OMe)3, 13123-0132 78 88 Trimethyl orthobenzoate has been studied as a variant of trimethyl orthoacetate. As a result of an electronic effect, the cyclization reaction occurred even faster than the conventional orthoacetate mediated reaction. The reaction finished in 10 min using trimethyl orthobenzoate, whereas 1 h using using trimethyl orthoacetate. Comparable yields were obtained whereas the product contained a benzoyl group instead of an acetyl group (Scheme 111-37). 126 Scheme III-37. Orthobenzoate mediated cyclization of 1,2,n-triols OH OBz 1) PhC(OMe)3. cat. PPTS 0 OH 2) 1313,0512 Ill-26 86 /° 111-131 3.2.7 Stereospecificity To demonstrate the stereospecific nature of this strategy, an enantiomerically enriched substrate was synthesized and used as a starting material for the cyclization. As shown on Scheme III-38, enantio-rich 1,2,5-trio] III-135 was obtained from trans-4- decen-l-ol III-25. Since the free hydroxyl group diminished the stereoselectivity of the Sharpless asymmetric dihydroxylation (80% ee was obtained in this case), the hydroxyl group was initially protected by the benzyl group. The following Sharpless asymmetric dihydroxylation was performed by AD-mix-(x under standard conditions to yield diol III- 133. The desired enantiomerically enriched triol 111-135 was prepared by hydrogenolysis of the benzyl group in III-133. The ee value of the trio] III-135 was measured as 91% by chiral HPLC analysis of its derivative III-134. The cyclization reaction was then performed following standard procedure to yield THF derivative 111-136. The enantiomeric excess of this product was analyzed by chiral GC analysis of compound III- 137 (92%). Gratifyingly, the stereochemical properties of the starting material were transferred completely to the cyclization product. 127 Scheme III-38. Stereospecific nature of cyclization N H, B B W WOH a n r % \ OBn TBAI, THF Ill-25 84% III-132 AD-mix-a MOSOZNHz tBuOH-HZO (1 :1) 80% X 9“ Q, 0 A (MeO)ZCM92 W08“ W03” acetone, PTSA OH III-134 Ill-1 33 OH OH W H2, Pd/C ? : OBn ———-> AWOH OH EtOH OH Ill-133 Ill-135 OAc OH : .O W 1) MeC(OMe)3, cat. PPTS W ; OH > III-135 III-136 K2C03 MeOH OH Ill-137 128 3.3 Extention of substrate scope After successful development of a cyclization strategy of 1,2,n-triols via orthoester intermediate, a series of experiments were designed in order to broaden the substrate scope. In our original reaction scheme, a cyclic ether ring was formed by the nucleophilic substitution of the acetoxonium intermediate with the tethered hydroxyl group. In this section, a number of nucleophilic variants were synthesized and their compatibility with this cyclization strategy is discussed in detail. 3.3.1 Lactonization Efficient lactonizations compose a major challenge in synthetic chemistry. Great efforts have been applied to develop more efficient and practical strategies to build lactone motifs. The popular lactonization strategies include Yamaguchi lactonization,52 Mistunobo reaction53 and DCC mediated coupling reaction. Scheme III-39. Scheme of orthoester mediated lactonization x> RW —> BMW OAc H/kgifo ( n 129 Based on the mechanism of the cyclization methodology developed by us, a lactonization scheme of vicinal diol carboxylic acid was postulated as shown on Scheme III-39, which involves a formation of orthoester intermediate of the 1,2-diol followed by the Lewis acid promoted nucleophilic substitution by the carboxylate. Scheme III-40. Attempts of orthoester mediated lactonization WCOOB cat. 0804 _ wcooa ' OH NMO Ill-138 Acetone-H20 Ill-139 91 /o H Cl HzO-THF reflux O OH O + M/KQ M/‘fi O OH III-140 Ill-141 HO OH _ cat. OsO4 H3C(H2C)7 (CH2)7COOH NMO T H3C(HQC)7 (CH2)7COOH 111-142 Acemne'HZO 111-143 85% The attempt to synthesize 4,5-dihydroxy-decanoic acid turned out to be fruitless, because of the automatic formation of five of six membered lactone in acidic media. Therefore, our attention was then turned to the development of orthoester mediated macrolactonization. The sample substrate vicinal diol carboxylic acid 111-143 was accessed from unsaturated fatty acid 9-octadecenoic acid III-142. Unfortunately, various procedures involving transorthoesterification followed by Lewis acid treatment, including 130 our standard procedure and a more harsh conditions using THF as solvent under reflux in a sealed tube, failed to generate lactone product. The major product remained to be the acetate resulting from the hydrolysis of the orthoester. The inertness of the carboxylic acid functionality as a nucleophile or the difficulties of forming a large—member ring could be responsible for this failure (Scheme III—40). 3.3.2 Pyrolidine formation Because of the basicity of the amine functionality, it is a better nucleophile than the hydroxyl group. By switching the nucleophilic hydroxyl group to an amine group, a pyrolidine might be formed instead of the tetrahydrofuran ring. We postulated that by switching the nucleophilic hydroxyl group to an amine group the orthoester mediated cyclization of amino vicinal diol would lead to the formation of a pyrolidine motif (Scheme III-41). Scheme III-41. Orthoester mediated cyclization of amino vicinal diol OMe /L OH W MeC(OMe)3_ 0X0 ii. omo R i NH2 cat. PPTS RMNHz RmfiHz l The starting material was synthesized along the pathway shown in Scheme III—42. The hydroxyl group in trans-decenol was converted to a better leaving group by 131 treatment with TsCl and base. The resulted tosylate III-144 was then displaced with the amino group of cyclohexyl amine. Upon dihydroxylation, compound III-146, which was equipped with a vicinal diol and an amine functionality, was obtained. Unfortunately, the attempt to cyclize substrate III-146 led to a futile result. Hydrolysis of the orthoester led to the formation of monoacetate as the major product. Scheme III-42. Synthetic pathway to access l-cyclohexylamino-decane-4,5-diol III- 46 TSCI, DMAP O Et3N, CH20I2 ms 85% cyclohexyl amine EtOH reflux 40% OH WNHC cat. 0304 y = WWNHC OH NMO y acetone-H20 Ill-146 68% 111-145 3.3.3 Lactam formation The less nucleophilic amide substrate was also tested as a substrate for the orthoester mediated cyclization protocol. As shown in Scheme III—43, the product was expected In be a lactam. Scheme III-43. Formation of lactam by orthoester mediated cyclization OMe /L OH o X (MD MeC(OMe)3 O 0 LA. 0 R/kA/IL NH MNHZ ’ MNHZ 2 cat. PPTS V R R ‘3“ 0 W O HN. AcO R The desired substrate was acquired from trans-4-decenoic acid ethyl ester III-138. The ester was hydrolyzed under acidic conditions to generate trans-4-decenoic acid, which was then heated with neat urea to produce the unsaturated amide III-148 (Scheme III-44). Scheme III-44. Synthesis of 4,5-dihydroxy-decanoic acid amide III-149 O HCI 0 ——> W W051 THF-H20 \ OH reflux Ill-138 63% Ill-147 Urea neat A 42% OH O O NM cat. 0804 W i \ OH NH2 NMO NH2 acetone-H20 76% III-149 Ill-148 133 Compound III-149 was then subjected to the orthoester mediated cyclization reaction. However, this trial also lead to the hydrolysis product as well. 3.3.4 Formation of cyclic thioether Due to the similar reactivities of thiols and alcohols, the orthoester mediated cyclization of mercapto vicinal diol was also inspected carefully. The desired substrate was synthesized from trans-4-decenol as shown on Scheme III-45. The Mitsunobo reaction of trans-4-decenol with thioacetic acid installed the thioacetate on the molecule. The direct hydroxylation of compound III-150 generated vicinal diol 111-151 in excellent yield. The final product III-152 was obtained by the LAH reduction of 111-151. Scheme III-45. Synthesis and cyclization of 1-mercapto-decane-4,5-diol III-152 O Ph3P, DIAD )K W > W \ 0” CH3COSH \ 8 CH3 III-25 THF Ill-150 quantitative cat. OsO4 NMO acetone-H20 93% OH OH O LAH A SH ‘—th 5 CH3 9 er 0“ 81% OH "1.152 Ill-151 OH 1) MeC(OMela OAc PPTS 3 SH > OH 2) BF3-OEt2 111-152 79 /° 111-153 134 The orthoester mediated cyclization of III-152 was scrutinized. Gratifyingly, the cyclic thioester ring III-153 was obtained in 79% yield. The yield was comparable with the cyclization of 1,2,5-trio]. 3.4 Conclusion In conclusion, a general and practical cyclization to construct THF and THP structures from 1,2,n-triols based on the Lewis acid mediated cyclization of cyclic orthoesters was developed. In this manner, 1,2-diols can be regarded as epoxide surrogates in reactivity, thus increasing the repertoire of transformations available from asymmetric dihydroxylations. Finally, the procedure was further simplified to a single step reaction with even higher yield. The scope of this reaction was then expended to the mercapto vicinal diols as well. 3.5 Experimental General information All commercially available starting materials were used without further purification. Commercially available starting materials were obtained from Aldrich, Fisher, Nu-Chek-Prep, Lancaster, TCI. 1H, 13C, gCOSY, gHMBC, DEPT and nOe spectra were recorded on either a 300 MHz NMR spectrometer (VARIAN IN OVA) or on a 500 MHz NMR spectrometer (VARIAN VXR). IR spectra were recorded on Nicolet IR/42 spectrometer using NaCl cells. Column chromatography was performed using Silicycle (40-60 pm) silica gel. Analytical TLC was done using pre-coated silica gel 60 F254 plates. GC analysis was performed using HP (6890 series) GC system (Column 135 type-AltechSE-54, 30 m x 320 um x 0.25 mm). HPLC analysis was performed using HITACHI LC-ORGANIZER (Column type chiral AD or OD). Unless otherwise mentioned, solvents were purified as follows. THF and Et20 were distilled from sodium benzophenone ketyl. CHzClz, toluene, CH3CN and Et3N were distilled from CaHz. DMF, diglyme, and DMSO were stored over 4 A molecular sieves and distilled from CaHz. All other commercially available reagents and solvents were used as received. 1,4,5-Decan-triol III-18 HO OH OH A round bottom flask was charged with the alcohol III-17 (178.2 mg, 1.142 mmol, 1.0 eq.) and dissolved with acetone / H20 (9 : l, 10 mL). NMO (200.7 mg, 1.713 mmol, 1.5 eq.) was added to the reaction mixture. 030.; (1 mol%) was added, and the reaction mixture was stirred overnight at rt. The reaction was quenched by the addition of saturated sodium sulfite and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over anhydrous NaZSO4, filtered, and concentrated in vacuo. The crude product was dissolved in a minimum amount of acetone, and the solution was heated to reflux. Hexane was added dropwise to the solution until the solution became cloudy. Crystals were formed after the solution was cooled down to rt, yielding 0.127 mg (59%) of 111-18. lH-NMR (300 MHz, CDCl:,) 8 0.87 (t, J = 6.6 Hz, 3H), 1.29 (m, 5H), 1.44 (m, 4H), 1.62 (m, 1H), 1.70 (m, 2H), 2.27 (m, 3H), 3.66 (m, 4H). 136 Acetic acid 1-(tetrahydro-furan-Z-yl)-hexyl ester III-19 OAc The following procedure for substrate III-19 is representative for all cyclization reactions with PPTS and BF3-OEt2. Trimethyl orthoacetate (79 uL, 0.632 mmol, 1.2 eq.) was added to a mixture of triol III-18 (100 mg, 0.526 mmol, 1.0 eq.), PPT S (1.3 mg, 0.00526 mmol, 0.01 eq.) and CHzClz (10 mL) at rt. The mixture was stirred for 15 min, and BF3-OEt2 (6.7 11L, 0.0526 mmol, 0.1 eq.) was added at 0 °C. After TLC showed no orthoester remaining, the reaction was quenched with aqueous acetone. The solvent was removed under reduced pressure, and the product was purified via column chromatography (10% EtOAc in hexane) to yield compound III-19 in 81% (91 mg) yield. 1H-NMR (500 MHz, CDCl3) 5 0.83 (t, J = 7.0 Hz, 3H), 1.25 (m, 6H), 1.52 (m, 3H), 1.85 (m, 3H), 2.04 (s, 3H), 3.70 (m, 1H), 3.79 (m, 1H), 3.85 (m, 1H), 4.84 (m, 1H). l3C-NMR (125MHz, CDCl3) 5 13.9, 21.1, 22.4, 24.9, 25.9, 27.8, 31.0, 31.6, 68.1, 75.2, 79.5, 170.9. The following procedure for substrate III-19 is representative for all cyclization reactions with only BF3-OEt2. Trimethyl orthoacetate (37 uL, 0.292 mmol, 1.2 eq.) was added to a solution of triol III- 18 (46 mg, 0.244 mmol, 1.0 eq.) in CHZCIZ (10 mL), followed by the addition of BFg-OEtz (3 11L, 0.024 mmol, 0.1 eq.) at 0 °C. The reaction mixture was stirred at rt for l h, and quenched with aqueous acetone. The solvent was removed under reduced pressure, 137 and the product was purified via column chromatography (10% EtOAc in hexane) to yield compound III-l9 in 94% (49 mg) yield. 1-(Tetrahydro-furan-Z-yl)-hexan-l-ol III-20 OH W To a solution of cis-4-decenol (0.416 g, 2.67 mmol, 1.0 eq.) in CH2C12 (26 mL) was added mCPBA (0.72 g, 3.2 mmol, 1.2 eq.) at 0 OC. The reaction mixture was stirred for 12 h and then washed with 10% NaHSO3 and brine. The organic phase was dried over anhydrous Na2S04 and evaporated. The crude product was purified by column chromatography (20% EtOAc in hexanes) to yield 0.396 g 1-(tetrahydro-furan-2-yl)- hexan-l-ol III-20 (86%). 1H-NMR (500 MHz, CDC13) 5 0.86 (t, J = 7.1 Hz, 3H), 1.26 (m, 4H), 1.38 (m, 3H), 1.50 (m, 1H), 1.58 (m, 1H), 1.87 (m, 3H), 2.35 (s, 1H), 3.36 (q, J = 6.0 Hz,1H), 3.67 (q, J = 6.4 Hz, 1H), 3.77 (m, 2H). (3-Bromo-propoxy)-trimethyl-silane III-22 BrWOTMS To a solution of TMSCI (3.1 mL, 24.4 mmol, 1.1 eq.) in anhydrous THF (10 mL) was added a solution of 3-bromo-propanol (2 mL, 22.2 mmol, 1.0 eq.) in anhydrous THF (60 mL) and TEA (5.1 mL, 36.4 mmol, 1.6 eq.). The mixture was stirred at rt for 5 h, then poured into brine (300 mL), and extracted with EtOAc (300 mL). The extract was dried over Na2804 and concentrated. The residue was triturated with diethyl ether (15 mL). After filtration, the solvent was removed under vacuum. The product was further 138 purified with Kiigror at 100 °C under reduced pressure to yield 2.73g (3-bromo- propoxy)—trimethyl-silane 111-22 (58%). 1H-NMR (300 MHz, CDC13) 5 0.03 (s, 9H), 2.02 (p, 1: 6.0 Hz, 2H), 3.48 (t, J = 6.0 Hz, 2H), 3.68 (t, J = 6.0 Hz, 2H). 4-Decyn-l-ol III-24 /\/\/\/\OH To a solution of heptyne (5.1mL, 39mmol, 3.0 eq.) in anhydrous THF (60 mL) at —78 °C was added nBuLi solution (9.7 mL 2.0 M, 19.4 mmol, 1.5 eq.). The resulting solution was stirred at —78 0C for 30 min then at 0 0C for 45 min. The mixture was cooled to —78 °C and (3-bromo-propoxy)-trimethyl—silane III-22 (2.73 g, 13.0 mmol, 1.0 eq.) in THF (10 mL) was added via cannula. The reaction was kept at it for 12 h. The reaction was quenched with saturated NH4Cl aqueous solution, and stirred at rt for 10 h. The product was extracted with EtOAc (20 mL x 3), and dried over NaZSO4. After removal of the solvent, the crude product was further purified by column chromatography with 15% EtOAc in hexanes to yield 356 mg (18%) 4—decyn-l-ol III-24. lH-NMR (300 MHz, CDC13) 5 3.66(2H, t), 2.50(1H, s), 2.20(2H, m), 2.06(2H, m), 1.66(2H,p), 1.40(2H, m), l.26(4H, m), 0.82(2H, t) trans-4-Decen-l-ol III-25 WWOH To a solution of sodium (140 mg, 6.1 mmol, 5.0 eq.) in liquid ammonia (40 mL) was added 4-decyn-l-ol (187.7 mg, 1.22 mmol, 1.0 eq.) dissolved in THF (10 mL) dropwise with stirring at —78 °C. After stirring for 2 h at same temperature, excess 139 sodium was decomposed by adding ammonium nitrate until the blue color disappeared, then the temperature was raised to rt for 2 h. The reaction mixture was extracted with EtOAc (20 mL x 3). Combined organic layers were washed with brine, and dried over Na2804. The product was purified by column chromatography (15% EtOAc in hexanes) yield 171 mg trans-4-decen-l-ol III-25. 1H-NMR (300 MHz, CDC13) 8 0.84 (t, J = 7.1 Hz, 3H), 1.25 (m, 6H), 1.58 (p, J = 6.9 Hz, 2H), 1.87 (s, 1H), 1.94 (q, J = 7.1 Hz, 2H), 2.01 (q, J: 4.7 Hz, 2H), 3.59 (t, J = 6.6 Hz, 2H), 5.38 (m, 2H). cis-1,4,5-Decanetriol III-26 OH We. OH Dihydroxylation procedure identical to the preparation of III-18 with alcohol generated above gave the trio] III-26 in 65% yield. 1H-NMR (300 MHz, CDCI3) 8 0.85 (t, J = 6.6Hz, 3H), 1.26 (m, 5H), 1.42 (m, 4H), 1.63 (m, 3H), 3.34 (m, 2H), 3.61 (m, 2H), 4.12 (br, 3H). 5-(4-Methoxy-benzyloxy)-pentan-l-ol III-28 PMBOWOH To a slurry of NaH (3.7 g, 92.7 mmol, 1 eq.) in anhydrous THF (300 mL) 1,5- pentanediol (10 mL, 92.7 mmol, 1 eq.) was added dropwise at 0 °C. The mixture was warmed to rt, stirred for 1 h and cooled back to 0 oC. PMBCl (12.8 mL, 92.7 mmol, 1 eq.) was then added dropwise, followed by addition of TBAI (3.9 g, 10.6 mmol, 0.11 eq.). After stirring at rt for 1 h the reaction was heated to 60 °C. The reaction mixture was 140 poured into saturated NaHCO3 and vigorously stirred. The layers were separated, and the aqueous layer was extracted with EtOAc (20 mL x 3), and dried over NazSO4. The product was purified by column chromatography (30% EtOAc in hexanes) to yield 14.082 g (67.8%) III-28. 1H-NMR (300 MHz, CDC13) 6 1.43 (m, 4H), 1.57 (m, 2H), 3.43 (t, J = 6.6 Hz, 2H), 3.62 (t, J = 6.3 Hz, 2H), 3.78 (s, 3H), 4.41 (s, 2H), 6.87 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H). 5-(4-Methoxy-benzyloxy)-pentanal 111-29 0 PMBO/\\/A\/JkH To a slurry of FCC (20.327 g, 94 mmol, 1.5 eq.) in CHzClz (185 mL), a solution of 5-(4-methoxy-benzyloxy)-pentan-1-ol III-28 in CHzClz (60 mL) was added at rt under nitrogen with vigorous stirring. After 2 h at 11, anhydrous EtzO was added, and the reaction mixture was filtered through a silica get pad. The filtrate was concentrated, followed by flash column chromatography (10% EtOAc in hexanes) to yield 9.126 g 111- 29 (65%). 1H-NMR (300 MHz, CDC13) 8 1.65 (m, 4H), 2.43 (td, J = 7.1, 1.6 Hz, 2H), 3.43 (t, J = 6.3 Hz, 2H), 3.78 (s, 3H), 4.40 (s, 2H), 6.87 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 9.74 (t J = 1.9 Hz, 1H). 8-(4-Methoxy-benzyloxy)-oct-3-en-1-ol III-30 PMBO/\WOH To a slurry of Ph3PCH2CH2CHZOHBr (24.7 g, 61.66 mmol, 1.5 eq.) in anhydrous THF (120 mL), KHMDS (0.5 M in toluene, 147 mL, 123.3 mmol, 3.0 eq.) was added dropwise at —20 °C. The mixture was warmed to rt and stirred for 1 h under N2 and then 141 cooled back to 0 °C. TMSCI (7.83 mL, 61.66 mmol, 1.5 eq.) was added to the reaction, which was stirred for 15 min at 0 0C. After the reaction was cooled to —78 °C, a solution of 5-(4-methoxy-benzyloxy)-pentanal III-29 (9.126 g, 41.1 mmol, 1 eq.) in anhydrous THF (80 mL) was then added dropwise and the reaction was warmed to —20 °C. The reaction was treated with AcOHszOzTI-IF (6:3:1) 800 mL at 0 °C for 12 h. The product was purified with column chromatography to yield 1.072 g (10%) III-30. 1H-NMR (300 MHz, CDC13) 5 1.39 (m, 2H), 1.56 (m, 2H), 2.00 (m, 2H), 2.22 (m, 2H), 3.40 (t, J = 6.3 Hz, 2H), 3.54 (t, J = 6.6 Hz, 2H), 3.73 (s, 3H), 4.38 (s, 2H), 5.36 (m, 1H), 5.44 (m, 1H), 6.83 (d, J: 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H). 1-(8-Iodo-oct-5-enyloxymethyl)-4-methoxy-benzene III-31 PMBO/\WI To a solution of 8-(4-methoxy-benzyloxy)-oct-3-en-1-01 III-30 (1.072 g, 4.06 mmol, 1.0 eq.) in CHzClz (15 mL), triethyl amine (1.70 mL, 12.2 mmol, 3.0 eq.) was added at 0 °C. MsCl (0.94 mL, 12.2 mmol, 3.0 eq.) was added dropwise to the reaction mixture at same temperature. The reaction was stirred at 0 0C for 30 min. After which it was quenched with saturated NH4Cl (6 mL) and H20 (2 mL) and extracted with CH2C12 (3x 17 mL). The crude mesylate was carried forward without further purification. The organic layer was dried over anhydrous NaZSO4, and the solvent was removed under reduced pressure. The crude mesylate was dissolved in acetone (15 mL) and NaI (3.04 g, 20.3 mmol, 5.0 eq.) was added. The reaction mixture was refluxed for 2 h. The reaction was quenched by adding saturated NaZSZO7, and the mixture was stirred until it turned clear. The product was extracted with ether. The combined aqueous layers were washed 142 with brine twice, and dried over Na2804. The product was concentrated and purified by column chromatography (10% EtOAc in hexanes) to yield 1.138 g III-31 (75%). 1H- NMR (500 MHz, CDC13) 6 1.42 (m, 2H), 1.58 (m, 2H), 2.00 (m, 2H), 2.51 (q, J = 7.5 Hz, 1H), 2.59 (q, J = 7.3 Hz, 1H), 3.11 (m, 2H), 3.41 (t, J = 6.6 Hz, 2H), 3.78 (s, 3H), 4.40 (s, 2H), 5.31 (m, 1H), 5.49 (m, 1H), 6.85 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H). GC- MS: m/z 374. 1-CyclohexyI-9-(4-methoxy-benzyloxy)-non-4-en-l-ol III-32 PMBO ’" OH 1H-NMR (300 MHZ, CDCl3) 6 08-18 (m, 17H), 2.04 (m, 4H), 3.33 (m, 1H), 3.42 (m, 2H), 3.77 (s, 3H), 4.40 (s, 2H), 5.37 (m, 2H), 6.85 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H). 1-Cyclohexyl-9-(4-methoxy-benzyloxy)-nonane-1,4,5-triol III-33 OH PMBO ' OH OH Dihydroxylation procedure identical to the preparation of 111-18 with alcohol III- 32 gave the trio] III-33 in 65% yield. 1H-NMR (300 MHz, CDCl3) 8 0.96 (m, 2H), 1.20 (m, 4H), 1.43 (m, 5H), 1.60 (m, 4H), 1.70 (m, 2H), 3.02 (br, 3H), 3.42 (m, 5H), 3.76 ( s, 3H), 4.39 (s, 2H), 6.83 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H). 143 8-Tetradecen-5-ol III-35 OH WV To a solution of trans-4-decenal (136.2 mg, 0.884 mmol, 1.0 eq.) in anhydrous THF (10 mL) at —78 °C was added nBuLi (1.0 mL, 1.8 M solution in hexane, 1.769 mmol, 2.0 eq.). The reaction mixture was stirred at ~78 °C for 10 min and at rt for an additional 8 h. The reaction was quenched with saturated NH4C1, and extracted with EtOAc, followed by washing with brine, and was dried over anhydrous NazSO4. After evaporation of the solvent, the product was purified with column chromatography (10% EtOAc in Hexane) to yield the desired alcohol in 90% yield (168 mg). 1H-NMR (300 MHz, CDCl3) 5 0.85 (m, 6H), 1.20-1.51 (m, 14H), 1.56 (s, 1H), 1.95 (m, 2H), 2.05 (m, 2H), 3.57 (m, 1H), 5.40 (m, 2H). 13C-NMR (300 MHz, CDCl3) 5 14.0, 22.5, 22.7, 27.8, 28.9, 29.2, 31.4, 32.5, 37.1, 71.5, 129.7, 131.0. Tetradecan-5,8,9-triol III-36 W OH Dihydroxylation procedure identical to the preparation of III-18 with alcohol III- 35 gave the trio] III-36 in 62% yield (dr 1 ; 1). 'H-NMR (300 MHz, CD3OD) 5 0.82 (m, 6H), 1.1-1.7 (m, 18H), 3.28 (m, 2H), 3.43 (s, 1H). 13C—NMR (300 MHz, CD3OD) 5 14.5, 23.7, 23.9, 26.8, 29.1, 29.1, 30.0, 30.3, 33.1, 33.9, 34.6, 34.9, 38.2, 38.2, 72.3, 72.7, 75.3, 75.4, 75.7. S-Undecen-Z-ol 111-38 144 W OH To a solution of cis-4-decenal (0.5 mL, 2.22 mmol, 1.0 eq.) in anhydrous THF (5 mL) at -78 °C was added MeLi (1.9 mL, 1.4 M solution in diethyl ether, 2.67 mmol, 12 eq.). The reaction mixture was stirred at —78 °C for 10 min and at rt for an additional 45 min. The reaction was quenched with saturated NH4Cl, and extracted with EtOAc, followed by washing with brine, and was dried over anhydrous NazSO4. The solvent was removed under reduced pressure and the product was used in the subsequent reaction without purification. 1H-NMR (300 MHz, CDC13) 8 0.84 (t, J = 6.6 Hz, 3H), 1.14 (d, J = 6.0 Hz, 3H), 1.25 (m, 6H), 1.46 (m, 2H), 1.84 (s, 1H), 1.99 (m, 2H), 2.08 (m, 2H), 3.75 (m, 1H), 5.33 (m, 2H). 5-Undecen-2-one III-39 /\/\/=\/\n/ O A solution of oxalyl chloride (0.23 mL, 2.66 mmol, 1.2 eq.) in anhydrous CHzClz (5 mL) was cooled to —78 °C, followed by the dropwise addition of a solution of DMSO (0.19 mL, 2.66 mmol, 1.2 eq.) in anhydrous CHzClz (1 mL). The reaction mixture was stirred for 5 min. A solution of the alcohol III-38 (2.22 mmol, 1.0 eq.) in anhydrous CHzClz (4 mL) was then added to the reaction mixture at —78 °C. After 5 min of stirring, NEt3 (1.55 mL, 11.1 mmol, 5.0 eq.) was added. The reaction mixture was warmed to ambient temperature, and was diluted with diethyl ether and water. The layers were separated, and the organic layers were washed with water, brine, and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was 145 purified with column chromatography (10% EtOAc in Hexane) to yield the desired ketone in 97% yield (360 mg). 1H-NMR (300 MHz, CDCl3) 5 0.82 (t, J = 6.6 Hz, 3H), 1.23 (m, 6H), 1.97 (q, J = 6.6 Hz, 2H), 2.08 (s, 3H), 2.25 (q, J = 7.1 Hz, 2H), 2.42 (t, J = 7.4 Hz, 2H), 5.30 (m, 2H). 2-Methyl-S-undecen-2-ol III-4O W OH To a solution of ketone III-39 (360 mg, 2.14 mmol, 1.0 eq.) in anhydrous THF (5 mL) at —78 °C was added MeLi (1.84 mL, 1.4 M solution in diethyl ether, 2.57 mmol, 1.2 eq.). The reaction mixture was stirred at —78 °C for 10 min and at rt for an additional 45 min. The reaction was quenched with saturated NH4Cl, and extracted with EtOAc, followed by washing with brine, and was dried over anhydrous NaZSO4. The solvent was removed under reduced pressure and the product was purified with column chromatography (10% EtOAc in hexane) to yield the desired alcohol in 71% yield (281 mg). 1H-NMR (300 MHZ, CDC13) 5 0.85 (t, J = 6.9 Hz, 3H), 1.19 (s, 6H), 1.25 (m, 6H), 1.50 (m, 2H), 2.00 (m, 4H), 5.33 (m, 2H). 2-Methyl-undecane-2,5,6-triol III-41 HO OH OH Dihydroxylation procedure identical to the preparation of 111-18 with alcohol 111- 40 gave the trio] III-41 in 70% yield. 'H-NMR (300 MHz, CDC13) 8 0.85 (t, J = 6.6 Hz, 146 3H), 1.19 (d, J = 8.0 Hz, 6H), 1.26 (m, 6H), 1.40 (m, 2H), 1.52 (m, 4H), 3.54 (m, 2H), 4.09 (s, 3H). 1-Phenyl-4-decen-1-ol III-42 Mew OH Magnesium tumings (0.5 g, 20.6 mmol, 9.3 eq.) was added to a 100 mL round- bottom flask, which was equipped with a condenser. Benzyl bromide (2.25 mL, 21.3 mmol, 9.6 eq.) was dissolved in anhydrous diethyl ether (10 mL), and one third of it was added into the reaction flask. The reaction was initiated by warming the flask gradually, after which the rest of PhBr solution was added dropwise. The reaction was refluxed at 40 °C for 40 min. cis-4-Decenal dissolved in diethyl ether was then added dropwise at cold water bath temperature. The reaction was stirred for 30 min. The reaction was then quenched with saturated NH4C1. After complete disappearance of magnesium, the product was extracted with diethyl ether (3x). The combined organic layers were washed with brine, and dried over anhydrous NaZSO4. The crude product was further purified by column chromatography with 10% EtOAc in hexane to yield the desired alcohol quantitatively (515 mg). 1H-NMR (300 MHz, CDCl;) 5 0.88 (t, J = 6.6 Hz, 3H), 1.27 (m, 6H), 1.83 (m, 2H), 2.05 (m, 5H), 4.65 (m, 1H), 5.38 (m, 2H), 7.32 (m, 5H). l-Phenyl-decane-1,4,5-triol III-43 W OH 147 Dihydroxylation procedure identical to the preparation of III-18 with alcohol 111- 42 gave the triol III-43 in 89% yield (mixture of diastereomer, dr 1:1). ]H-NMR (300 MHz, CDCl;,) 5 0.85 (t, J = 5.8 Hz, 3H), 1.24 (m, 7H), 1.43 (m, 2H), 1.54 (m, 1H), 1.80 (m, 2H), 3.49 (m, 2H), 3.90 (br), 4.56 (dd, J = 8.8, 3.8 Hz, 0.5H), 4.68 (dd, J = 6.9, 4.9 Hz, 0.5H), 7.26 (m, 5H). 4-Cyclohexylidene-butyronitrile III-45 OWCN In a sealed tube, Ph3P(CH2)3CNCl (1.83 g, 5.0 mmol, 1.0 eq.) was dissolved in anhydrous THF (10 mL), and nBuLi (2 mL, 2.5 M solution in hexane, 5 mmol, 1.0 eq.) was added to the reaction mixture at rt under N2 atmosphere. The solution was stirred for l h at rt. The solution was cooled to 0 0C and cyclohexanone (1.0 mL, 10 mmol, 2.0 eq.) was added and stirred for 1 h at rt. The tube was sealed and heated to 100 °C for 3 h. The reaction was quenched with 10% HCl. The product was extracted with diethyl ether (3x) from the aqueous phase, and the combined organic layers were washed with saturated NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The product was purified by column chromatography with 5% EtOAc in hexane to yield the desired cyanide in 26% yield (190 mg). 1H-NMR (300 MHz, CDC13) 5 1.51 (s, 6H), 2.09 (dd, J = 14.0, 5.8 Hz, 4H), 2.30 (4H), 5.05 (t, 1H). 4-Cyclohexylidene-butyric acid III-46 G‘V‘com 148 A solution of cyanide 111-45 (190 mg, 1.275 mmol, 1.0 eq.) and 25% aqueous sodium hydroxide (8.6 mL) in methanol (29 mL) was stirred at refluxed temperature for 16 h. The reaction mixture was cooled to 11. Water and EtOAc were added to the reaction mixture, and the two layers were separated. The pH of the aqueous layer was adjusted to 3 with 10% HCl, and the product was extracted with EtOAc (3x). The organic layer was washed with brine, and dried over anhydrous NazSO4. The solvent was removed under reduced pressure. The product was used for the next step without further purification. 1H-NMR (300 MHz, CDC13) 5 1.49 (s, 6H), 2.05 (m, 4H), 2.33 (m, 4H), 5.04 (t, 1H), 11.50 (br, 1H). 4-Cyclohexylidene-butan-l-ol 111-47 (3%.... LAH (54 mg, 1.41 mmol, 1.2 eq.) was suspended in dry diethyl ether and an ethereal solution of carboxylic acid 111-46 (197 mg, 1.17 mmol, 1.0 eq.) was added dropwise while cooling the reaction in an ice bath. The reaction mixture was stirred at rt for 3 h. HCl (10%) was added to the reaction mixture to acidify the solution, and the mixture was stirred for 2 h. The two layers were separated and the aqueous layer was extracted with ether (3x). The combined organic layers were washed with saturated NaHCO3 and brine, and dried over anhydrous MgSO4. After removal of the solvent under reduced pressure, the product was purified by column chromatography with 10% EtOAc in hexane to yield the desired alcohol in quantitative yield (180 mg). 1H-NMR (300 MHz, CDC13) 5 1.48 (m, 6H), 1.56 (m, 2H), 1.80 (s, 1H), 2.10 (m, 6H), 3.59 (t, J = 6.6 Hz, 2H), 5.05 (t, J = 7.4 Hz, 1H). 149 1-(1-Hydroxy-cyclohexyl)-butane-1,4-diol III-48 OHOH W014 Dihydroxylation procedure identical to the preparation of III-18 with alcohol 111- 47 gave the trio] III-48 in 65% yield. 1H-NIVIR (300 MHz, CDCl3) 5 1.1-1.7 (m, 17H), 3.35 (d, J: 10.7 Hz, 1H), 3.68 (m, 2H). 4-(4-Methoxy-benzyloxy)-butan-l-ol III-50 HO/\\/~\/OPMB 1,4-Butanediol (1.0 mL, 11.3 mmol, 1.0 eq.) was added dropwise to a slurry of NaH (452 mg, 60 wt% in mineral oil, 11.3 mmol, 1.0 eq.) in anhydrous THF (40 mL) at 0 °C. PMBC] (1.53 mL, 11.3 mmol, 1.0 eq.) was then added dropwise followed by addition of Bu4NI (459 mg, 1.24 mmol, 0.11 eq.). After stirring at rt for 1 h, the reaction was heated to 60 °C for 15 h. The reaction mixture was then poured into a solution of saturated NaHCO3 and vigorously stirred. The two layers were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous Na2SO4. The product was purified by column chromatography (40% EtOAc in hexane) to yield 94% of the desired product (2.225 g). 1H-NMR (300 MHz, CDC13) 5 1.54 (m, 4H), 3.36 (t, J = 6.0 Hz, 2H), 3.45 (t, J = 5.8 Hz, 2H), 3.61 (br, 1H), 3.64 (s, 3H), 4.32 (s, 2H), 6.76 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H). 4-(4-Methoxy-benzyloxy)-butyraldehyde III-51 O HMOPMB 150 To a slurry of PCC (3.425 g, 15.9 mmol, 1.5 eq.) in CH2C12 (30 mL), a solution of alcohol III-50 (2.225 g, 10.6 mmol, 1.0 eq.) in CHzClz (10 mL) was added at rt under N2 with vigorous stirring. After stirring for 4 h at rt, anhydrous diethyl ether was added, and the reaction mixture was filtered through a celite pad. The filtrate was concentrated in vacuo, and the product was purified by column chromatography with 20% EtOAc in hexane to yield the desired aldehyde in 81% yield (1.789 g). 1H-NMR (300 MHz, CDC13) 5 1.79 (p, J = 6.0 Hz, 2H), 2.36 (td, J = 7.1, 1.6 Hz, 2H), 3.34 (t, J = 6.0 Hz, 2H), 3.64 (s, 3H), 4.29 (s, 2H), 6.76 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H) 9.60 (t, J = 1.4 Hz, 1H). 6-(4-Methoxy-benzyloxy)-hex-2—enoic acid ethyl ester III-52 EtOOCWVOPMB To a solution of aldehyde III-51 (1.789 g, 8.6 mmol, 1.0 eq.) in anhydrous THF (40 mL), Ph3P=CH-COzEt (4.49 g, 12.9 mmol, 1.5 eq.) was added, and the reaction mixture was refluxed for 19 h. The solvent was removed, the residue was dissolved in EtzO / Hexane (10 : 90, 50 mL), and the insolubles were filtered. The filter cake was washed with the above mixed solvent. The filtrate was concentrated under reduced pressure and was subjected to column chromatography with 10% EtOAc in hexane to yield the desired alkene in 70% yield (1.669 g). 1H-NMR (300 MHz, CDCl3) 5 1.23 (t, J = 7.1 Hz, 3H), 1.70 (p, J = 7.7 Hz, 2H), 2.24 (q, J = 6.6 Hz, 2H), 3.40 (t, J = 6.3 Hz, 2H), 3.74 (s, 3H), 4.12 (q, J = 7.1 Hz, 2H), 4.37 (s, 2H), 5.77 (dt, J = 15.7, 1.4 Hz, 1H), 6.82 (d, J = 8.5 Hz, 2H), 6.91 (dt, J: 15.7, 6.9 Hz, 1H), 7.20 (d, J = 8.8 Hz, 2H). 151 6-Hydroxy-hex-2-enoic acid ethyl ester III-53 EtOOCMOH To a stirred solution of PMB protected alcohol III-52 (0.770 g, 2.77 mmol, 1.0 eq.) in CHzClz (27 mL) and water (3 mL) was added DDQ (0.754 g, 3.32 mmol, 1.2 eq.) and the reaction mixture was stirred at rt for 1 h. Saturated NaHCO3 aqueous solution was added, and the mixture was extracted with CH2C12 (3x). The extract was washed with saturated NaHCO3 and brine, and dried over anhydrous NaZSO4. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column with 30% EtOAc in hexane to yield the desired alcohol in 98% yield (0.428 g). 1H-NMR (300 MHz, CDCl3) 5 1.15 (t, J = 7.1 Hz, 3H), 1.58 (p, J = 6.9 Hz, 2H), 2.12 (q, J = 6.9 Hz, 2H), 3.04 (br, 1H), 3.50 (t, J = 6.3 Hz, 2H), 4.04 (q, J = 7.1 Hz, 2H), 5.71 (dt, J=15.7, 1.4 Hz, 1H), 6.85 (dt, J=15.7,7.1 Hz, 1H). 2,3,6-Trihydroxy-hexanoic acid ethyl ester III-54 OH EtOOC\‘/'\/\/OH OH Dihydroxylation procedure identical to the preparation of III-18 with alcohol III- 53 gave the trio] III-S4 in 78% yield. 1H-NMR (300 MHz, CD3OD) 5 1.24 (t, J = 7.1 Hz, 3H), 1.64 (m, 4H), 3.59 (m, 2H), 3.85 (m, 4H), 4.03 (d, J = 2.2 Hz, 1H), 4.18 (qd, J = 7.1, 2.5 Hz, 2H). l3C-NMR (300 MHz, CD3OD) 5 13.2, 26.7, 29.4, 60.6, 61.5, 72.2, 73.6, 173.2. cis-S-Phenyl-pent-4-enenitrile 111-56 152 m CN To a slurry of PthCHzCHzCHzCNCl (1.798 g, 4.9 mmol, 1.0 eq.) in anhydrous THF (100 mL) was added KHMDS (10.8 mL, 0.5 M solution in toluene, 5.4 mmol, 1.1 eq.) at 0 °C under N2 atmosphere. The reaction was warmed to rt, stirred for 1 h and cooled back to 0 °C. Benzaldehyde (1.0 mL, 9.8 mmol, 2.0 eq.) in anhydrous THF (15 mL) was added, and the reaction was then stirred at rt for 1 h. The reaction was quenched with 10% HCl, the two layers were separated and the aqueous layer was extracted with diethyl ether (3x). The combined organic layers were washed with saturated NaHCO3 and brine, and dried over anhydrous MgSO4. After filtration, the solvent was removed under reduced pressure, and a 5% ether in hexane solution was added to the concentrated crude product to precipitate the byproduct. After filtration, the filtrate was concentrated in vacuo and purified by silica gel chromatography (10% ether in hexane) to yield 354 mg of the desired product (46%). 1H-NMR (300 MHz, CDC13) 5 2.35 (t, J: 7.4 Hz, 2H), 2.61 (q, J = 6.9 Hz, 2H), 5.62 (dt, J = 11.5, 6.9 Hz, 1H), 6.60 (d, J = 11.5 Hz, 1H), 7.32 (m, 5H). 5-Phenyl-pent-4—enoic acid ethyl ester III-57 \ COOEt To a solution of nitrile 111-56 (480 mg, 3.06 mmol, 1.0 eq.) in 95% ethanol (10 mL) was added concentrated H2SO4 (1.5 mL). The reaction mixture was refluxed for 12 h. After cooled down to 0 °C, ethanol was removed under reduced pressure. Diethyl 153 ether (20 mL) and water (20 mL) was added to reaction. Two layers were separated, and the aqueous layer was extracted with diethyl ether (20 mL x 3). The combined organic layers were washed with saturated NaHCO3 and brine, dried over anhydrous MgSO4. After filtration, the solvent was removed under reduced pressure. The product was purified by column chromatography ( 10% EtOAc in hexanes) to yield 496 mg (80%) desired product. 1H-NMR (300 MHz, CDC13) 5 1.23 (t, J = 7.1 Hz, 3H), 2.42 (t, J = 8.0 Hz, 2H), 2.65 (q, J: 7.1 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 5.62 (dt, J: 11.8, 7.1 Hz, 1H), 6.47 (d, J = 11.5 Hz, 1H), 7.28 (m, 5H). S-PhenyI-pent-4-en-1-ol III-58 \ OH LAH (0.44 g, 11.6 mmol, 1.2 eq.) was suspended in dry diethyl ether (100 mL) and an ethereal solution of 5-phenyl-pent-4-enoic acid ethyl ester III-57 (9.66 mmol, 1.0 eq.) was added dropwise while cooling the reaction in an ice bath. The reaction mixture was stirred at rt for 3 h. HCl (10%) was added to acidify the solution, and the mixture was stirred for 2 h. The two layers were separated and the aqueous layer was extracted with ether (3x). The combined organic layers were washed with saturated NaHC03 and brine, and dried over anhydrous MgSO4. After removal of the solvent under reduced pressure, the product was purified by column chromatography with 20% EtOAc in hexane to yield the desired alcohol in 84 yield (1.317 g). 1H-NMR (300 MHz, CDC‘l3) 5 1.71 (p, J = 6.9 Hz, 2H), 2.44 (m, 3H), 3.62 (t, J = 6.6 Hz, 2H), 5.68 (dt, J = 11.8, 7.4 Hz, 1H), 4.47 (d, J = 11.5 Hz, 1H), 7.30 (m, SH). 154 trans-l-Phenyl-pentane-l,2,5-triol III-59 OH OH OH Dihydroxylation procedure identical to the preparation of III-18 with alcohol III- 58 gave the trio] III-59 in 57% yield. lH-NMR (300 MHz, CDC13) 5 1.31 (m, 1H), 1.53 (m, 3H), 3.47 (m, 2H), 3.71 (m, 4H), 4.61 (d, J = 3.8 Hz, 1H), 7.27 (m, 5H). 5-Phenyl-pent-4-yn-1-ol III-62 é OH Pd(PPh3)4 (21 mg, 0.01 eq.) and CuI (7 mg, 0.02 eq.) were added to the solution of iodobenzene (0.48 mL, 4.3 mmol, 2.0 eq.) and 5-hydroxyl pentyne (0.2 mL, 2.15 mmol, 1.0 eq.) in triethylamine (6.2 mL, 45 mmol, 10 eq.) and THF (1 mL) under N2. The reaction mixture was stirred at rt for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The product was purified by column chromatography (20% EtOAc in hexane) to yield the desired alcohol in 99% yield (340 mg). 1H-NMR (300 MHz, CDCl3) 5 1.82 (p, J = 7.1 Hz, 2H), 2.23 (s, 1H), 2.50 (t, J = 6.9 Hz, 2H), 3.77 (t, J = 6.0 Hz, 2H), 7.30 (m, 5H). trans-5-Phenyl-pent-4-en-l-ol III-63 155 To a THF (20 mL) solution of LAH (0.408 g, 10.75 mmol, 5.0 eq.), the alcohol III-62 (340 mg, 2.13 mmol, 1.0 eq.) was added at 0 °C under N2. The reaction mixture was stirred at 0 °C for 30 min, and then it was refluxed, and kept for 48 h. The reaction was quenched with water and Na, K-tartrate. The product was extracted with diethyl ether (3x), and the combined organic layers were washed with brine, and dried over anhydrous NaZSO4. The concentrated crude product was further purified by column chromatography with 20% EtOAc in hexane to yield the desired alcohol in 90% yield (309 mg). 1H-NMR (300 MHz, CDCl3) 5 1.74 (p, J = 6.9 Hz, 2H), 2.31 (q, J = 6.9 Hz, 2H), 2.31 (s, 1H), 3.68 (t, J = 6.6 Hz, 2H), 6.23 (dt, J = 15.9, 6.9 Hz, 1H), 6.42 (d, J = 15.7 Hz, 1H), 7.30 (m, 5H). cis-l-Phenyl-pentane-l,2,5-triol III-64 OH OH OH Dihydroxylation procedure identical to the preparation of 111-18 with alcohol III- 63 gave the trio] III-64 in 41% yield. 1H-NMR (300 MHz, CDCl3) 5 1.32 (m, 2H), 1.51 (m, 2H), 3.45 (m, 2H), 3.58 (q, J = 6.6 Hz, 1H), 4.20 (br, 3H), 4.32 (d, J = 7.4 Hz, 1H), 7.25 (m, 5H). 5-(4-Methoxy-phenyl)-pent-4-enenitrile III-66 \ MeO CN 156 To a slurry of Ph3PCH2CH2CH2CNCl (1.50 g, 4.11 mmol, 1.0 eq.) in anhydrous THF (100 mL) was added KHMDS (9.1 mL, 0.5 M solution in toluene, 4.52 mmol, 1.1 eq.) at 0 °C under N2 atmosphere. The reaction was warmed to rt, stirred for 1 h and cooled back to 0 °C. p-Anisaldehyde (1.0 mL, 8.22 mmol, 2.0 eq.) in anhydrous THF (15 mL) was added, and the reaction was then stirred at it for 1 h. The reaction was quenched with 10% HCl, the two layers were separated and the aqueous layer was extracted with diethyl ether (3x). The combined organic layers were washed with saturated NaHCO3 and brine, and dried over anhydrous MgSO4. After filtration, the solvent was removed under reduced pressure, and a 5% ether in hexane solution was added to the concentrated crude product to precipitate the byproduct. After filtration, the filtrate was concentrated in vacuo and purified by silica gel chromatography (5% EtOAc in hexane) to yield 439 mg of the desired product (57%). 1H-NMR (300 MHz, CDCl3) 5 2.41 (t, J = 7.1 Hz, 2H), 2.64 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 5.52 (dt, J = 11.5, 7.1 Hz, 1H), 6.50 (d, J = 11.3 Hz, 1H), 6.86 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H). 5-(4-Methoxy-phenyl)-pent-4-enoic acid III-67 \ MeO COOH A solution of cyanide III-66 (0.439 g, 2.35 mmol, 1.0 eq.) and 25% aqueous sodium hydroxide (15 mL) in methanol (53 mL) was stirred at refluxed temperature for 16 h. The reaction mixture was cooled to rt. Water and EtOAc was added to the reaction mixture, and the two layers were separated. The pH of the aqueous layer was adjusted to 3 with 10% HCl, and the product was extracted with EtOAc (3x). The organic layer was 157 washed with brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The product was used for the next step without further purification. 1H-NMR (300 MHz, CDC13) 5 2.48 (t, J = 8.0 Hz, 2H), 2.65 (m, 2H), 3.79 (s, 3H), 5.53 (dt, J: 11.5, 6.9 Hz, 1H), 6.40 (d, J = 11.5 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 9.20 (br, 1H). 5-(4-Methoxy-phenyl)-pent-4-en-l-ol III-68 \ MeO OH To a diethyl ether (10 mL) solution of LAH (0.105 g, 2.77 mmol, 1.2 eq.), the alcohol 111-67 (475 mg, 2.31 mmol, 1.0 eq.) was added at 0 °C under N2. The reaction mixture was stirred at 0 °C for 30 min, and then it was refluxed, and kept for 48 h. The reaction was quenched with water and Na, K-tartrate. The product was extracted with diethyl ether (3x), and the combined organic layers were washed with brine, and dried over anhydrous Na2SO4. The concentrated crude product was further purified by column chromatography with 30% EtOAc in hexane to yield the desired alcohol in 90% yield (377 mg). lH—NMR (300 MHz, CD02) 5 1.67 (p, J = 7.1 Hz, 2H), 2.37 (q, J = 7.4 Hz, 2H), 2.57 (s, 1H), 3.59 (t, J = 6.6 Hz, 2H), 3.76 (s, 3H), 5.54 (dt, J = 11.5, 7.1 Hz, 1H), 6.35 (d, J: 11.5 Hz, 1H), 6.85 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.8 Hz, 2H). 1-(4-Methoxy-phenyI)-pentane-1,2,5-trio] 111-69 158 OH OH MeO OH Dihydroxylation procedure identical to the preparation of III-18 with alcohol 111- 68 gave the trio] III-69 in 15% yield. 1H-NMR (300 MHz, CDCl3) 5 1.65 (m, 4H), 2.6 (br, 3H), 3.60 (m, 3H), 3.78 (s, 3H), 4.59 (d, J = 4.7 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 7.26 (d, J: 8.8 Hz, 2H). S-(4-Nitro-phenyI)-pent-4-enenitrile III-72 \ 0211 CN In a round-bottom flask, Ph3PCH2CH2CH2CN (4.84 g, 13.23 mmol, 2.0 eq.) was dissolved in anhydrous THF (100 mL), KHMDS (0.5 M in toluene, 26.5 mL, 13.23 mmol, 2.0 eq.) was added to the reaction flask at 0 °C, and stirred at rt for 1 h. The 4- nitrobenzaldehyde (1.0 g, 6.62 mmol, 1.0 eq.) solution (in 15 mL THF) was transferred into the reaction flask at 0 0C. The reaction was stirred at 0 0C for 0.5 h and at rt for 12 h. The reaction was quenced with 10% HCl aqueous solution. The two layers were separated and the aqueous layer was extracted with diethyl ether (20 mL x 3). The combined organic layers were washed with saturated NaHCO3 and brine, dried over anhydrous MgSO4. After removing the solvent, the crude product was purified by column chromatography ( 20% EtOAc in hexanes) to yield 782 mg desired product (59%). lH-NIVIR (300 MHz, CDCl3) 5 2.45 (t, J = 6.9 Hz, 2H), 2.59 (q, J = 7.1 Hz, 2H), 159 5.79 (dt, J = 11.5, 7.1 Hz, 1H), 6.58 (d, J = 11.5 Hz, 1H), 7.33 (d, J = 8.2 Hz, 2H), 8.10 (d, J = 8.2 Hz, 2H). 5-(4-Nitro-phenyl)-pent-4—yn-1-ol III-74 // OH OZN Pd(PPh3)4 (42 mg, 0.043 mmol, 0.01 eq.) and CuI (14 mg, 0.086 mmol, 0.02 eq.) were added to the solution of l-iodo-4-nitro-benzene (2.14 g, 8.6 mmol, 2.0 eq.) and 4- pentyn-l-ol (0.4 mL, 4.3 mmol, 1.0 eq.) in the mixture of triethylamine (12.4 mL) and anhydrous THF (20 mL) under N2 atmosphere. The reaction mixture was stirred at rt for 12 h. The mixture was filtered and filtrate was concentrated to dryness. The product was purified by column chromatography (30% EtOAc in hexanes) to yield 736 mg desired product (84%). 1H-NMR (300 MHz, CDC13) 5 1.81 (p, J = 6.4 Hz, 2H), 2.51 (t, J = 7.0 Hz, 2H), 2.55 (s, 1H), 3.73 (t, J = 6.2 Hz, 2H), 7.41 (d, J = 9.1 Hz, 2H), 8.05 (d, J = 9.1 Hz, 2H). Acetic acid 5-(4-nitro-phenyl)-pent-4-enyl ester III-75 m 02N OAC To a slurry of Ph3P(CH2)4OAcBr (1.372 g, 3.0 mmol, 1.0 eq.) in anhydrous THF (20 mL) was added KHMDS (12 mL, 0.5 M solution in toluene, 6.0 mmol, 2.0 eq.) at 0 °C under N2 atmosphere. The reaction was warmed to 11, stirred for 1 h and cooled back to 0 °C. 4-Nitrobenzaldehyde (0.452 g, 3.0 mmol, 1.0 eq.) in anhydrous THF (15 mL) 160 was added, and the reaction was then stirred at It for 20 h. The reaction was quenched with 10% HCl, the two layers were separated and the aqueous layer was extracted with diethyl ether (3x). The combined organic layers were washed with saturated NaHCO3 and brine, and dried over anhydrous MgSO4. After filtration, the solvent was removed under reduced pressure, and a 5% ether in hexane solution was added to the concentrated crude product to precipitate the byproduct. After filtration, the filtrate was concentrated in vacuo and purified by silica gel chromatography (10% EtOAc in hexane) to yield 60 mg of the desired product (8%). 1H-NMR (300 MHz, CDCl3) 5 1.77 (m, 2H), 1.96 (s, 3H), 2.37 (qd, J = 7.3, 1.9 Hz, 2H), 4.04 (t, J = 6.4 Hz, 2H), 5.81 (dt, J = 11.7, 7.5 Hz, 1H), 6.46 (d, J = 11.6 Hz, 1H), 7.36 (d, J = 8.6 Hz, 2H), 8.14 (d, J = 8.9 Hz, 2H). 13C- NMR (300 MHz, CDC13) 5 20.8, 25.1, 28.4, 63.5, 123.4, 128.0, 129.3, 135.1, 144.0, 146.2, 170.9. 5-(4-Nitro-phenyl)-pent-4-en-l-ol 111-70 0% 0211 "OH To a solution of acetic acid 5-(4-nitro-phenyl)-pent-4-enyl ester 111-75 (60 mg, 0.242 mmol, 1.0 eq.) in methanol (10 mL) was added K2CO3 (1.0 g). The reaction mixture was stirred at rt for 2 h. Water and EtOAc were added. Two layers were separated and the aqueous layer was extracted with ethyl acetate (3x). The cbmbined organic layers were dried over anhydrous Na2SO4 and filtered. After removal of the solvent under reduced pressure, the product was purified by flash chromatography with 30% EtOAc in hexane to yield the desired alcohol in 92% yield (46 mg). 1H-NMR (500 MHz, CDC13) 5 1.58 (s, 1H), 1.71 (p, J = 7.1 Hz, 2H), 2.40 (qd, J = 7.5 Hz, 1.8 Hz, 2H), 161 3.65 (t, J = 6.4 Hz, 2H) 5.84 (dt, J = 11.7 Hz, 7.5 Hz, 1H), 6.45 (d, J = 11.7 Hz, 1H), 7.38 (d, J = 8.8 Hz, 2H), 8.13 (dd, J = 6.8 Hz, 2.0 Hz, 2H). l3C-NMR (500 MHz, CDC13) 5 25.1, 32.4, 62.1, 123.5, 127.6, 129.3, 136.0, 144.2, 146.2. 1-(4-Nitro-phenyl)-pentane-1,2,5-trial III-76 OH 0*(‘1 O2N OH Dihydroxylation procedure identical to the preparation of III-18 with alcohol 111- 70 gave the trio] III-76 in 86% yield. 1H-NMR (500 MHz, CDCl;,) 5 1.40 (m, 1H), 1.56 (m, 1H), 1.70 (m, 2H), 3.63 (m, 1H), 3.74 (m, 1H), 3.90 (d, J = 9.8 Hz, 1H) 4.89 (d, J = 3.9 Hz, 1H), 7.57 (d, J: 8.8 Hz, 2H), 8.22 (d, J = 8.8 Hz, 2H). Acetic acid 1-(tetrahydro-furan-Z-yI)-hexyl ester III-77 OAc M Conversion of 111-26 to III-77 under general cyclization conditions described for III-19 led to 74% product. 'H-NMR (300 MHz, CDCl3) o 0.81 (t, 3H), 1.22 (m, 6H), 1.51 (m, 2H), 1.64 (m, 1H), 1.82 (m, 3H), 2.00 (s, 3H), 3.70 (m, 1H), 3.75 (m, 1H), 3.84 (m, 1H), 4.88 (dt, J = 8.0 Hz, 4.9 Hz, 1H). l3C-NMR (300 MHz, CDCl:,) 5 13.9, 21.0, 22.4, 24.9, 25.6, 27.1, 30.5, 31.6, 68.5, 74.9, 79.8, 170.6. IR: 1024.33, 1074.49, 1240.39, 1371.56, 1462.23, 1743.87, 2862.73, 2932.17, 2957.25 cm'l. Acetic acid 5-(4-methoxy-benzyloxy)-1-(tetrahydro-furan-Z-yl)-pentyl ester 111-78 162 OAc oo PMBOW Conversion of III-33 to III-78 under general cyclization conditions described for III-19 led to 80% product (111-78 and III-79). 1H-NMR (500 MHz, CDC13) 5 0.92 (m, 1H), 1.18 (m, 4H), 1.37 (m, 3H), 1.60 (m, 10H), 1.88 (m, 3H), 2.04 (d, 3H), 3.40 (t, J = 6.4 Hz, 2H), 3.54 (m, 1H), 3.78 (s, 3H), 3.88 (m, 1H), 4.40 (s, 2H), 4.86 (m, 1H), 6.85 (d, J = 8.6 Hz, 2H), 7.23 (d, J :86 Hz, 2H). Acetic acid l-(5-butyl-tetrahydro-furan-2-yl)-hexyl ester III-80 OAc /\/\/'\<:7/\/\ Conversion of 111-36 to III-80 under general cyclization conditions described for III-19 led to 82% product (dr 1 : 1). 1H-NMR (500 MHz, CDC13) 5 0.85 (m, 6H), 1.18- 1.60 (m, 15H), 1.70 (m, 1H), 1.80-2.00 (m, 2H), 2.02 (s, 3H), 3.78-3.98 (m, 2H), 4.50 (m, 1H). l3C-NMR (500 MHz, CDCl3) 5 13.9, 14.0, 21.2, 22.5, 22.7, 25.0, 27.0, 27.7, 28.2, 28.3, 30.7, 30.8, 31.6, 31.7, 31.7, 35.4, 35.6, 75.1, 75.5, 79.4, 79.9, 80.0, 80.0, 170.7, 170.7. Acetic acid 1-(5,5-dimethyl-tetrahydro-furan-2-yl)-hexyl ester III-81 OAc Conversion of 111-41 to III-81 under general cyclization conditions described for III-19 led to 80% product. 1H-NMR (300 MHz, CDCl3) 5 0.84 (t, J = 6.6 Hz, 3H), 1.20 163 (d, J = 8.0 Hz, 6H), 1.25 (m, 6H), 1.52 (m, 2H), 1.68 (m, 2H), 2.00 (m, 2H), 2.06 (s, 3H), 4.00 (q, J = 5.2 Hz, 1H), 4.84 (q, J = 5.2 Hz, 1H). l3c-NMR (300 MHz, CDCl;) 5 14.0, 21.2, 22.5, 25.1, 27.9, 28.2, 28.4, 30.9, 31.7, 38.2, 75.7, 79.0, 81.1. 170.9. IR: 1024.33, 1059.05, 1142.00, 1244.24, 1367.70, 1462.23, 1740.01, 2864.66, 2932.17, 2964.97 cm". HRMS: MH+243.1963 (FAB) (ca. 243.1961). Acetic acid 1-(5-phenyl-tetrahydro-furan-Z-yl)-hexyl ester III-82 1-(5-Phenyl-tetrahydro-furan-Z-yl)-hexan-l-ol III-83 Conversion of 111-43 to III-82 under general cyclization conditions described for III-19 led to 55% product III-82 (dr 1 : 1) along with 36% deacetylated product III-83 (dr 1 t 1). lH--Nl\/IR (300 MHz, CDC13) 5 0.87 (m, 3H), 1.3 (m, 6H), 1.7 (m, 5H), 2.18 (3H), 2.3 (1H). 4.12 (m, 0.5H), 4.23 (m, 0.5H), 4.95 (m, 2H), 7.3 (m, 5H). W131} 1H-NMR (300 MHZ, CDCl3) 5 0.88 (m, 3H), 1.3 (m, 4.5H), 1.45 (m, 3.5H), 1.9 (m, 3.5H), 2.3 (0.5H), 3.86 (1H), 3.98 (m, 0.5H), 4.14 (m, 0.5H), 4.84 (t, J = 7.7 Hz, 0.5H), 4.98 (dd, J = 8.5, 6.3 Hz, 0.5H), 7.31 (m, 5H). Acetic acid l-(tetrahydro-furan-2-yl)-cyclohexyl ester 111-84 164 ACO Conversion of III-48 to III-84 under general cyclization conditions described for III-19 led to 50% product. 1H—NMR (300 MHz, CDC13) 5 1.1-1.9 (m, 12H), 2.01 (s, 3H), 2.20 (m, 2H), 3.76 (m, 2H), 4.57 (t, J = 6.9 Hz, 1H). l3C-NMR (300 MHz, CDC13) 5 21.3, 21.5, 22.2, 25.5, 26.1, 26.2, 29.0, 30.1, 68.8, 80.8, 85.9, 170.5. IR: 1018.54, 1070.63, 1138.15, 1232.87, 1263.54, 1367.70, 1736.16, 2860.80, 2934.10 cm". HRMS: M+ 212.1413 (EI) (ca. 212.1412). Acetoxy-(tetrahydro-furan-2-yl)-acetic acid ethyl ester III-85 OAc EtO ' ,.\O m Conversion of III-54 to III-85 under general cyclization conditions described for III-l9 led to 62% product. 1H-NMR (300 MHZ, CDCl;,) 5 1.22 (t, J = 7.1 Hz, 3H), 1.90 (m, 4H), 2.09 (s, 3H), 3.74 (m, 1H), 3.81 (m, 1H), 4.16 (q, J = 7.1 Hz, 2H), 4.24 (m, 1H), 5.04 (d, J = 3.6 Hz, 1H). 13c—NMR (300 MHz, CDC13) 5 14.0, 20.6, 25.7, 26.7, 61.4, 69.1, 74.1, 77.5, 168.0, 170.2. IR: 1074.49, 1115.00, 1203.73, 1230.74, 1271.25, 1375.42, 1446.80, 1747.73, 2876.23, 2984.26 cm". HRMS: MH+ 217.1075 (FAB) (ca. 217.1077). Acetic acid phenyl-(tetrahydro-furan-Z-yl)-methyl ester III-86 Acetic acid 2-phenyl-tetrahydro-pyran-3-yl ester 111-87 165 OAc ::/ \J‘O; Conversion of III-59 to III-86 under general cyclization conditions described for III-l9 led to 48% product III-86 along with 24% product III-87. 1H-NMR (300 MHz, CDC13) 5 1.55 (m, 1H), 1.64 (m, 1H), 1.81 (m, 2H), 2.08 (s, 3H), 3.85 (m, 2H), 4.20 (q, J = 7.4 Hz, 1H), 5.60 (d, J = 7.7 Hz, 1H), 7.32 (m, 5H). 13C- NMR (500 MHz, CDC13) 5 21.2, 25.7, 28.3, 68.6, 78.0, 80.6, 127.4, 128.3, 128.4, 137.8, 170.2 AcO‘“ 1H-NMR (500 MHZ, CDC13) 5 1.48 (m, 1H), 1.85 (s, 3H), 1.91 (m, 1H), 2.00 (m, 1H), 2.10 (m, 1H), 3.66 (td, J = 11.5, 2.2 Hz, 1H), 4.21 (dt, J: 11.5, 2.4 HZ, 1H), 4.52 (s, 1H), 5.13 (s, 1H), 7.25 (m, 5H). 13C-NMR (500 MHZ, CDC13) 5 20.4, 20.8, 28.2, 68.5, 69.6, 80.1, 126.0, 127.4, 128.0, 139.1, 170.2. IR: 704.11, 1022.40, 1093.78, 1240.39, 1373.49, 1452.58, 1736.16, 2851.15, 2955.32 cm'l. HRMS: M+ 220.1100 (EI) (ca. 220.1099). Acetic acid 2-phenyl-tetrahydro-pyran-3-yl ester III-88 AcO Conversion of 111-64 to III-88 under general cyclization conditions described for III-19 led to 83% product. 1H-NMR (300 MHZ, CDCl3) 5 1.60 (m, 1H), 1.74 (m, 1H), 166 1.79 (s, 3H), 1.86 (m, 1H), 2.24 (m, 1H), 3.51 (td, J = 11.5, 2.5 Hz, 1H), 4.05 (m, 1H), 4.15 (d, J = 9.6 Hz, 1H), 4.79 (m, 1H), 7.30 (m, 5H). 13C-NMR (300 MHZ, CDC13) 5 20.9, 25.2, 29.8, 68.2, 72.4, 82.3, 127.1, 128.1, 128.1, 138.9, 169.6. IR: 700.25, 758.12, 898.94, 956.81, 1039.76, 1089.92, 1238.46, 1263.54, 1307.90, 1439.08, 1454.51, 1495.02, 1743.87, 2856.94, 2949.53, 3034.41 cm". HRMS: [M+H]+ 221.1177 (FAB) (ca. 221.1179). Acetic acid 2-(4-methoxy-phenyl)-tetrahydro-pyran-3-yl ester III-89 Acetic acid 2-(4-methoxy-phenyl)-tetrahydro-pyran-3-yl ester III-90 MeO AcO“' Conversion of III-69 to III-89 under general cyclization conditions described for III-l9 led to 73% product III-89 along with 20% product III-90. 1H-NMR (300 MHz, CDC13) 5 1.58 (m, 1H), 1.76 (m, 1H), 1.80 (s, 3H), 1.85 (m, 1H), 2.23 (m, 1H), 3.50 (td, J = 11.5, 2.5 Hz, 1H), 3.76 (s, 3H), 4.03 (m, 1H), 4.10 (d, J = 9.6 Hz, 1H), 4.78 (td, J = 9.9, 4.7 Hz, 1H), 6.82 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H). l3C-NMR (300 MHZ, CDCl3) 5 20.9, 25.3, 29.9, 55.2, 68.3, 72.4, 82.0, 113.5, 128.4, 131.1, 159.3, 169.7. IR: 829.50, 956.81, 1037.83, 1087.99, 1176.73, 1248.10, 1304.05, 1373.49, 1516.24, 1614.62, 1738.08, 2851.15, 2953.39 cm". HRMS: [M+H]+ 251.1285 (FAB) (ca. 251.1285). MeO 167 lH-N1\/IR (300 MHZ, CDCl3) 5 1.46 (m, 1H), 1.88 (S, 3H), 2.0 (m, 3H), 3.64 (t, J = 11.8 HZ, 1H), 3.75 (s, 3H), 4,18 (m, 1H), 4.46 (s, 1H), 5.05 (s, 1H), 6.81 (d, J = 6.9 HZ, 2H), 7.22 (d, J = 7.1 HZ, 2H). l3C-NIVIR (500 MHZ, CDCI3) 5 20.4, 20.9, 28.1, 55.1, 68.6, 69.7, 79.8, 113.4, 127.2, 131.3, 158.8, 170.3. IR: 1024.33, 1091.85, 1248.10, 1373.49, 1516.24, 1738.08, 2856.94, 2957.25 cm". HRMS: M)r 250.1205 (El) (ca. 250.1205). Acetic acid (4-nitro-phenyl)-(tetrahydro-furan-Z-yl)-methyl ester III-91 (4-Nitro-phenyl)-(tetrahydro-furan-Z-yl)-methanol III-92 Conversion of 111-76 to III-91 under general cyclization conditions described for III-19 led to 60% product III-91 along with 8% product III-92. OAc 02N lH-NIVIR (500 MHZ, CDCI3) 5 1.56 (dq, J = 7.3 Hz, 1H), 1.80 (m, 3H), 2.12 (s, 3H), 3.83 (m, 2H), 4.18 (q, J = 6.6 Hz, 1H), 5.71 (d, J = 6.4 Hz, 1H), 7.51 (d, J = 8.6 HZ, 2H), 8.18 (d, J = 8.8 HZ, 2H). l3C-NMR (500 MHz, CDCl3) 5 21.0, 25.7, 28.0, 68.8, 76.6, 80.0, 123.6, 128.1, 145.0, 147.6, 170.6. IR: 703.67, 839.13, 858.45, 1022.69, 1071.52, 1105.93, 1233.42, 1349.48, 1371.44, 1535.45, 1605.85, 1741.60, 2873.26, 2955.85, 2977.55, 3080.29, 3111.62 cm'l. HRMS: [M+H]+ 266.1027 (FAB) (ca. 266.1030). OH OZN 168 1H-NMR (500 MHZ, CDC13) 5 1.51 (m, 1H), 1.83 (m, 3H), 2.64 (s, 1H), 3.81 (m, 1H), 3.92 (m, 1H), 4.08 (m, 1H), 5.04 (d, J = 3.8 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H), 8.19 (d, J = 8.8 HZ, 2H). l3C-NMR (500 MHZ, CDCI3) 5 24.6, 26.0, 69.2, 73.2, 82.5, 123.5, 126.7, 147.2, 147.7. IR: 1047.48, 1242.32, 1373.49, 1741.94, 2849.22, 2916.74, 2984.26 ~l cm . 1,3,4-Octanetriol III-94 OH /\/Y\/\OH OH Dihydroxylation procedure identical to the preparation of 111-18 with cis-3-octen- l-ol gave the trio] III-94 in 70% yield. lH-NIVIR (300 MHZ, CDCl3) 5 0.89 (t, J = 6.9 Hz, 3H), 1.35 (m, 6H), 1.70 (m, 2H), 2.3 (br, 2H), 3.0 (br, 1H), 3.63 (m, 1H), 3.89 (m, 3H). IR: 924.02, 964.53, 1010.83, 1045.55, 1069.28, 1074.49, 1315.62, 1441.01, 1468.02, 1481.52, 2856.94, 2914.81, 1939.89, 2953.38, 3221.53. Acetic acid 2-butyI-tetrahydro-furan-3-yl ester III-95 AA?) AGO Conversion of 111-94 to III-95 under general cyclization conditions described for III-l9 led to 71% product. lH-NMR (500 MHz, CDCl3) 5 7.88 (t, J = 7.5 Hz, 3H), 1.2- 1.6 (m, 6H), 1.94 (m, 1H), 2.06 (s, 3H), 2.27 (m, 1H), 3.68 (m, 1H), 3.75 (m, 1H), 3.99 (q, J = 7.5 Hz, 1H), 5.27 (m, 1H). l3C-N‘MR (300 MHz, CDCl;,) 5 13.9, 21.0, 22.7, 28.5, 28.5, 33.5, 65.7, 74.6, 81.7, 162.8. 169 l-Methoxy-4-non-5-enyloxymethyl-benzene III-99 WOPMB To a slurry of Ph3P(CH2)3CH3Br (0.416 g, 1.04 mmol, 1.0 eq.) in anhydrous THF (20 mL) was added KHMDS (2.29 mL, 0.5 M solution in toluene, 1.14 mmol, 1.1 eq.) at 0 °C under N2 atmosphere. The reaction was warmed to rt, stirred for l h and cooled back to 0 °C. The aldehyde III-98 (0.231 g, 1.04 mmol, 1.0 eq.) in anhydrous THF (5 mL) was added, and the reaction was then stirred at 11 for 12 h. The reaction was quenched with 10% HCl, the two layers were separated and the aqueous layer was extracted with diethyl ether (3x). The combined organic layers were washed with saturated NaHCO3 and brine, and dried over anhydrous MgSO4. After filtration, the solvent was removed under reduced pressure, and a 5% ether in hexane solution was added to the concentrated crude product to precipitate the byproduct. After filtration, the filtrate was concentrated in vacuo and purified by silica gel chromatography (5% EtOAc in hexane) to yield 179 mg of the desired product (66%). lH-I\H\/IR (300 MHz, CDCl3) 5 0.88 (t, J = 7.1 Hz, 3H), 1.36 (m, 4H), 1.61 (m, 2H), 1.99 (m, 4H), 3.43 (t, J = 6.3 Hz, 2H), 3.78 (s, 3H), 4.41 (s, 2H), 5.35 (m, 2H), 6.86 (d, 2H), 7.25 (d, 2H). 5-Nonen-l-ol III-100 WAG.) To a stirred solution of PMB protected alcohol III-99 (0.179 g, 0.687 mmol, 1.0 eq.) in CH2C12 (9.5 mL) and water (0.5 mL) was added DDQ (0.187 g, 0.825 mmol, 1.2 eq.) and the reaction mixture was stirred at rt for 1 h. Saturated NaHCO3 aqueous solution was added, and the mixture was extracted with CH2C12 (3x). The extract was 170 washed with saturated NaHCO3 and brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column with 30% EtOAc in hexane to yield the desired alcohol in 80% yield (77 mg). 1H-NMR (300 MHZ, CDCl3) 5 0.87 (t, J = 7.4 Hz, 3H), 1.35 (m, 4H), 1.53 (s, 1H), 1.55 (m, 2H), 2.03 (m, 4H), 3.61 (t, J = 6.6 Hz, 2H), 5.34 (m, 2H). 1,5,6-Nonanetriol III-101 OH /\/'\/\/\/OH OH Dihydroxylation procedure identical to the preparation of III-18 with the alcohol III-100 gave the trio] III-101 in 50% yield. 1H—NMR (300 MHz, CD3OD) 5 0.94 (t, 3H), 1.36 (m, 4H), 1.56 (m, 6H), 3.36 (m, 2H), 3.56 (t, 2H). l3C-NMR (300 MHz, CD3OD) 5 14.5, 20.1, 23.3, 33.3, 33.7, 35.9, 63.0, 75.7, 75.9. Acetic acid l-(tetrahydro-pyran-Z-yl)-butyl ester III-102 OAc AAROJ Conversion of III-101 to III-102 under general cyclization conditions described for III-19 led to 78% product. lH-NMR (500 MHZ, CDC13) 5 0.88 (t, 3H), 0.4-1.6 (m, 9H), 1.82 (m, 1H), 2.05 (s, 3H), 3.30 (m, 1H), 3.35 (m, 1H), 3.99 (m, 1H), 4.85 (m, 1H). l3C-NMR (125 MHz, CDC13) 5 14.1, 18.9, 21.3, 23.5, 26.1, 27.7, 32.5, 69.2, 75.5, 78.3, 171.1. IR: 1091.85, 1242.32, 1371.49, 1738.08, 2855.01, 2939.89, 2959.18 cm'l. HRMS: M+ 200.1413 (E1) (ca. 200.1412). 171 6-Octadecen-1-ol III-104 W0“ 10 To a diethyl ether (10 mL) solution of LAH (0.134 g, 3.54 mmol, 1.0 eq.), cis- octadec-6-enoic acid (1.0 g, 3.54 mmol, 1.0 eq.) was added at 0 °C under N2. The reaction mixture was stirred at 0 °C for 30 min, and raised temperature to 11, and kept for 12 h. The reaction was quenched with water and Na, K—tartrate. The product was extracted with diethyl ether (3x), and the combined organic layers were washed with brine, and dried over anhydrous Na2SO4. The concentrated crude product was further purified by column chromatography with 10% EtOAc in hexane to yield the desired alcohol in 92% yield (0.873 g). 1H-NMR (300 MHz, CDC13) 5 0.86 (t, J = 6.6 Hz, 3H), 1.2 (m, 22H), 1.56 (m, 2H), 2.00 (m, 4H), 3.63 (t, J = 6.6 Hz, 2H), 5.33 (m, 2H). Octadecane-l,6,7-triol III-105 OH Wop, 10 3 OH Dihydroxylation procedure identical to the preparation of III-18 with the alcohol 111-104 gave the triol 111-105 in 63% yield. 'H—NMR (300 MHz, CDC13) o 0.86 (t, J = 7.2 Hz, 3H), 1.2-1.6 (m, 28H), 3.64 (m, 4H). 5-(3-Undecyl-oxiranyl)-pentan-1-ol III-106 O W011 10 172 To a solution of cis-6—octadecen-1-ol (100 mg, 0.374 mmol, 1.0 eq.) in CH2Cl2 (3.5 mL) was added mCPBA (77%, 101 mg, 0.449 mmol, 1.2 eq.) at 0 °C. The reaction mixture was stirred for 12 h, then washed with 10% NaHSO3 and brine. The organic phase was dried over Na2SO4 and evaporated. The product was purified by column chromatography (20% EtOAc in hexanes) to yield 102 mg desired epoxide III-106 (96%). 1H-NMR (300 MHz, CDC13)5 0.84 (t, J = 7.1 Hz, 3H), 1.23 (s, 16H), 1.28-1.60 (m, 12H), 2.49 (br, 1H), 2.88 (m, 2H), 3.62 (t, J = 6.6 Hz, 2H). Acetic acid l-oxepan-Z-yl-dodecyl ester Ill-10854 OAc ,,tO To a solution of epoxide 111-106 (43 mg, 0.151 mmol, 1.0 eq.) in toluene (2 mL) was added bis(tributyltin)oxide (0.085 mL, 0.167 mmol, 1.1 eq.). The reaction was stirred at 90 °C under N2 for 12 h. Zn(OTf)2 (22mg, 0.061 mmol, 0.4 eq.) was added to the reaction flask, then the reaction mixture was kept at this temperature for another 12 h. The reaction was quenched with water. After extraction with EtOAc (20 mL x 3). The crude product was reacted with AC2O under basic condition. The product was then purified by column chromatography (5 % EtOAc in hexane) to yield 31 mg desired product (66%). Trimethyl orthoacetate (14 11L, 0.110 mmol, 1.2 eq.) was added to a mixture of triol III-105 (28 mg, 0.0914 mmol, 1.0 eq.), PPT S (1 mg, 0.004 mmol, 0.04 eq.) and toluene (10 mL) at rt. The mixture was stirred for 15 min, and BF3'OE12 (14 1.1L, 0.110 mmol, 1.2 eq.) was added at 0 °C. The reaction mixture was then refluxed for 10 h. The 173 reaction was cooled to rt and quenched with aqueous acetone. The solvent was removed under reduced pressure, and the product was purified via column chromatography to yield compound III-108 in 47% (14 mg) yield. 1H-NMR (300 MHZ, CDCl3) 5 0.85 (t, J = 6.3 Hz, 3H), 1.23 (s, 20H), 1.42-1.76 (m, 8H), 2.06 (s, 3H), 3.49 (m, 2H), 3.86 (m, 1H), 4.85 (m, 1H). '3C-N1VIR (300 MHZ, CDC13) 5 14.1, 21.1, 22.7, 25.5, 26.2, 26.6, 29.3, 29.5, 29.6, 30.5, 30.9, 31.7, 31.9, 69.4, 76.2, 79.5, 170.9. IR: 1024.33, 1116.93, 1240.39, 1371.56, 1466.09, 1740.01, 2855.01, 2926.39 cm". HRMS: MH“ 327.2901 (FAB) (ca. 327.2900). 3-(2-Hydroxy-phenyl)-propane-1,2-diol III-1 10 OH OH OH Dihydroxylation procedure identical to the preparation of 111-18 with 2- allylphenol gave the triol 111-110 in 99% yield. 1H-NMR (300 MHz, CDCl3) 5 2.71 (d, J = 5.8 Hz, 2H), 3.37 (dd, J = 11.5, 7.4 Hz, 1H), 3.55 (dd, J = 11.5, 2.5 Hz, 1H), 3.90 (m, 1H), 6.80 (m, 2H), 6.96 (m, 1H), 7.07 (m, 1H). l3C-NMR (300 MHZ, CDC13) 5 34.8, 65.8, 73.4, 116.7, 120.7, 124.4, 128.3, 131.5, 154.7. Acetic acid chroman-3-yl ester III-111 CC) OAc Conversion of 111-110 to III-111 under general cyclization conditions described for III-19 led to 84% product. 1H-NMR (500 MHZ, CDCI3) 5 2.08 (s, 3H), 2.95 (dd, J = 174 15.7, 7.5 Hz, 1H), 3.29 (dd, J = 15.7, 9.5 Hz, 1H), 4.19 (dd, J = 11.7, 7.1 Hz, 1H), 4.32 (dd, J = 11.9, 3.5 Hz, 1H), 4.97 (m, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.84 (td, J = 7.3, 0.9 Hz, 1H), 7.10 (m, 1H), 7.15 (m, 1H). l3c-NMR (300MHz, CDC13) o 20.8, 31.9, 65.9, 79.9, 109.6, 120.7, 124.9, 125.7, 128.2, 159.1, 170.9. IR: 752.33, 1043.62, 1223.02, 1369.63, 1462.23, 1481.52, 1599.19, 1741.94, 2947.61 cm'l. S-Hydroxy-cyclooctanone 111-113 0 To a slurry of PCC (1.474 g, 6.84 mmol, 1.0 eq.) in CH2Cl2 (30 mL), a solution of 1,5-cyclooctanediol (1.006 g, 6.84 mmol, 1.0 eq.) in CH2Cl2 (10 mL) was added at rt under N2 with vigorous stirring. After stirring for 4 h at rt, anhydrous diethyl ether was added, and the reaction mixture was filtered through a celite pad. The filtrate was concentrated in vacuo, and the product was purified by column chromatography with 40% EtOAc in hexane to yield 5-hydroxyl cyclooctanone in 76% yield (0.734 g). 1H- NMR (300 MHz, CDC13) 5 1.50 (m, 2H), 1.70 (m, 4H), 1.89 (m, 4H), 2.06 (m, 2H), 2.89 (br, 1H), 4.30 (m, 1H). S-Methylene-cyclooctanol 111-114 mg To a slurry of Ph3PCH3Br (1.14 g, 3.19 mmol, 2.0 eq.) in anhydrous THF (10 mL) was added KHIVIDS (6.4 mL, 0.5 M solution in toluene, 3.19 mmol, 2.0 eq.) at 0 0C under N2 atmosphere. The reaction was warmed to rt stirred for 1 h and then cooled back to 0 175 °C. The ketone generated above 111-113 (227 mg, 1.595 mmol, 1.0 eq.) in anhydrous THF (5 mL) was added, and the reaction was then stirred at rt for 3 h. The reaction was quenched with 10% HCl, the two layers were separated and the aqueous layer was extracted with diethyl ether (3x). The combined organic layers were washed with saturated NaHCO3 and brine, and dried over anhydrous MgSO4. After filtration, the solvent was removed under reduced pressure, and a 5% ether in hexane solution was added to the concentrated crude product to precipitate the byproduct. After filtration, the filtrate was concentrated in vacuo and purified by silica gel chromatography (5% ether in hexane) to yield 188 mg of the desired product (84%). lH--NMR (300 MHz, CDCl3) 5 1.60 (m, 9H), 2.15 (m, 4H), 3.90 (m, 1H), 4.76 (s, 2H). 13C-NMR (75 MHz, CDC13) 5 24.0, 35.4, 35.6, 71.0, 112.8, 150.6. 1-Hydroxymethyl-cyclooctane-1,S-diol III-115 HO OHOH Dihydroxylation procedure identical to the preparation of 111-18 with alcohol generated above gave the trio] III-115 in 93% yield. 1H-NMR (500 MHz, CDCl3) 5 1.4- 1.8 (m, 13H), 1.93 (m, 2H), 3.41 (s, 2H), 3.80 (tt, J = 9.7, 2.7 Hz, 1H). l3C-NMR (500 MHZ, CDCl3) 5 19.1, 33.4, 38.0, 68.7, 72.0, 74.9. Acetic acid 9-oxa-bicyclo[3.3.1]non-1-ylmethyl ester III-116 (9-Oxa-bicyclo[3.3.l]non-1-yl)-methanol III-117 176 Conversion of III-115 to III-116 under general cyclization conditions described for III-19 led to 33% product III-116 along with 18% deacetylated product III-117. 1H-NIVIR (500 MHZ, CDCl3) 5 1.48 (m, 4H), 1.64 (m, 4H), 1.91 (m, 2H), 2.02 (m, 2H), 2.08 (s, 3H), 3.82 (s, 2H), 4.10 (t, J = 6.0 Hz, 1H). 13C-NMR (125 MHZ, CDCI3) 5 18.6, 21.0, 28.5, 30.4, 68.1, 69.5, 72.0, 171.2. IR: 1033.98, 1230.74, 1244.24, 1367.70, 1456.44, 1745.80, 2936.03 cm". HRMS: [M+H]+ 199.1333 (FAB) (ca. 199.1335). @311 1H-NMR (500 MHZ, CDCl3) 5 1.40 (m, 2H), 1.50 (m, 2H), 1.63 (m, 2H), 1.72 (m, 2H), 1.88 (m, 2H), 2.03 (m, 3H), 3.27 (s, 2H), 4.07 (t, J = 5.7 Hz, 1H). l3C-NMR (125 MHZ, CDC13) 5 18.6, 28.8, 30.2, 68.1, 70.7, 71.6. IR: 800.56, 1028.19, 1452.88, 1466.23, 2858.87, 2926.39. HRMS: [M+H]+ 156.1150 (E1) (ca. 156.1150). Cyclohex-l-enyl-acetic acid methyl ester III-119 @COOMe To a solution of l-cyclohexeneacetonitrile (92%, 1 mL, 7.19 mmol, 1.0 eq.) in methanol (4.7 mL) was added concentrated H2SO4 (0.8 mL). The reaction was refluxed for 72 h. After cooling, the reaction mixture was diluted with water and extracted with diethyl ether (20 mL x 3). The combined organic layers were washed with 10% Na2CO3 and brine. The solvent was removed under reduced pressure, and the product was 177 purified with column chromatography (5% B20 in hexanes) to yield 0.766 g desired product (69%). 1H-NMR (300 MHz, CDC13) 5 1.60 (m, 4H), 2.00 (m, 4H), 2.93 (s, 2H), 3.66 (s, 3H), 5.54 (m, 1H). 2-Cyclohex-l-enyl-ethanol III-120 WOH To a slurry of LAH (0.189 g, 4.98 mmol, 1.0 eq.) in diethyl ether (10 mL) was added compound III-119 (0.766 g, 4.98 mmol, 1.0 eq.) at 0 °C under N2 atmosphere. The reaction temperature was raised to rt and stirred for 3 h. Quench the reaction with 10% HCl. The product was extracted with ether. The combined ether layers were washed with saturated NaHC03 and brine and dried over MgSO4. The product was used without further purification (64%). 1H-NMR (300 MHz, CDC13) 5 1.53 (m, 4H), 1.90 (m, 4H), 2.04 (s, 1H), 2.13 (t, J = 6.0 Hz, 2H), 3.58 (t, J = 6.0 HZ, 2H), 5.44 (m, 1H). 1-(2-Hydroxy-ethyl)-cyclohexane-1,2-diol III-121 OH OH CG Dihydroxylation procedure identical to the preparation of 111-18 with alcohol generated above gave the trio] 111-121 in 53% yield. ‘H-NMR (300 MHz, CDgOD) 5 1.36 (m, 3H), 1.70 (m, 6H), 1.95 (m, 1H), 3.40 (dd, J = 8.2, 5.3 Hz, 1H), 3.77 (m, 2H). 13C-NMR (75 MHZ, CD3OD) 5 20.7, 23.5, 29.5, 35.0, 41.5, 57.4, 72.6, 73.6. 178 Methanesulfonic acid 2-cyclohex-1-enyl-ethyl ester III-122 OA/OMS To a solution of alcohol III-121 (3.01 g, 23.9 mmol, 1.0 eq.) in anhydrous pyridine (30 mL) was added MsCl (2.4 mL, 31.1 mmol, 1.3 eq.) at 0 °C. The resulting reaction mixture was stirred at 4 °C for 16 h. Dilution with CH2C12 and evaporation of the washed (10% HCl until aqueous layer turned pH ~ 3, saturated NaHCO3 and brine) organic solution affored a crude reaction product, which was purified by column chromatography to yield 3.653 g (89%) of the desired product. 1H-NMR (300 MHz, CDC13) 5 1.56 (m, 4H), 1.94 (m, 4H), 2.34 (t, J = 7.0 Hz, 2H), 2.96 (s, 3H), 4.24 (t, J = 7.0 HZ, 2H), 5.48 (m, 1H). l-(2-Iodo-ethyl)-cyclohexene 111-123 0” ' To a solution of compound III-122 (3.653 g, 21.2 mmol, 1.0 eq.) in acetone (50 mL) was added Nal (9.56 g, 63.7 mmol, 3.0 eq.). The reaction mixture was refluxed for 6 h. After cooling, the mixture was diluted with diethyl ether and washed with saturated Na2S2O7 and brine. The organic layer was dried over MgSO4. The solvent was removed, and the crude product was purified with column chromatography (100% hexanes) to yield 3.733 g (75%) desired product. IH-NMR (300 MHz, CDCl3) 5 1.54 (m, 4H), 1.93 (m, 4H), 2.47 (t, J = 7.7 Hz, 2H), 3.20 (t, J = 7.7 HZ, 2H), 5.46 (m, 1H). 3-Cyclohex-l-enyl-propionitrile 111-124 179 O/VCN A solution of iodide III-123 (3.733 g, 15.8 mmol, 1.0 eq.) in anhydrous acetonitrile (20 mL) was added NaCN (3.1 g, 63.3 mmol, 4.0 eq.). The reaction mixture was stirred at 80 °C for 12 h. After cooling, the reaction solution was diluted with ether. The organic layer was washed with saturated NaHCO3 and brine. After evaporation of the solvent, the crude product was subjected to next step reaction without further purification. 1H-NMR (300 MHz, CDCI3) 5 1.50 (m, 4H), 1.83 (m, 2H), 1.91 (m, 2H), 2.15 (t, J = 7.1 Hz, 2H), 2.34 (t, J = 6.6 Hz, 2H), 5.43 (m, 1H). 3-Cyclohex-l-enyl-propionic acid 111-125 To a solution of nitrile 111-124 (15.8 mmol, 1.0 eq.) in a mixture of ethanol and water (1:1, 30 mL) was added KOH (3.9 g, 69.5 mmol, 4.4 eq.). The resulting mixture was stirred at 80-90 °C for 18 h. After cooling, the reaction mixture was diluted with ether and acidified with aqueous HCl. The organic layer was dried over MgSOa. Evaporation of the organic solvent afforded III-125. 1H-NMR (300 MHz, CDC13) 5 1.51 (m, 4H), 1.88 (m, 4H), 2.19 (t, J = 7.7 Hz, 2H), 2.39 (dd, J = 8.8, 6.6 Hz, 2H), 5.37 (m, 1H), 9.78 (s, 1H). 3-Cyclohex-l-enyl-propan-l-ol III-126 W“ 180 To a solution of LAH (0.60 g, 15.8 mmol, 1.0 eq.) in anhydrous diethyl ether (40 mL) was added carboxylic acid (15.8 mmol, 1.0 eq. in 20 mL ether) at 0 °C. The reaction mixture was stirred for 12 h at rt. Water and 10% HCl were added. The product was extracted with diethyl ether. The combined organic layers were washed with saturated NaHCO3 and brine, dried over MgSOa. Evaporation of the organic solvent affored the crude product. It was further purified by column chromatography (20% EtOAc in hexanes) to yield 1.917 g (87% in 3 steps) desired product. 1H-NMR (300 MHz, CDC13) 5 1.60 (m, 4H), 1.94 (m, 8H), 3.57 (t, J = 6.6 HZ, 2H), 5.39 (m, 1H). l-(3-Hydroxy-propyl)-cyclohexane-1,2-diol III-127 OH cm“ OH Dihydroxylation procedure identical to the preparation of 111-18 with alcohol generated above gave the trio] III-127 in 92% yield. 1H-NMR (300 MHZ, CDC13) 5 1.0- 2.0 (m, 12H), 3.34 (dd, J = 8.8, 4.4 Hz, 1H), 3.55 (m, 2H), 3.97 (br, 3H). Acetic acid 2-hydroxy-2-(2-hydroxy-ethyl)-cyclohexyl ester III-128 Acetic acid 2-(2-oxo-cyclohexyl)-ethyl ester III-129 Conversion of 111-116 to III-128 under general cyclization conditions with 3 A MS described for III-l9 led to 21% compound III-128 along with 20% compound III- 129. OH CW” OAc 181 1H-NMR (300 MHZ, CDCl3) 5 1.20-1.80 (m, 8H), 1.92 (m, 2H), 2.07 (s, 3H), 2.63 (br, 1H), 2.73 (br, 1H), 3.75 (m, 1H), 3.89 (m, 1H), 4.65 (dd, J = 9.1, 5.3 Hz, 1H). 13C- NMR (75 MHZ, CDCI3) 5 20.7, 21.2, 23.1, 26.8, 34.1, 39.2, 58.7, 73.2, 77.1, 171.5. mOAC 0 1H-NMR (300 MHZ, CDC13) 5 1.45 (m, 2H), 1.64 (m, 2H), 1.84 (m, 1H), 1.99 (s, 3H), 2.11 (m, 3H), 2.36 (m, 3H), 4.07(m, 2H). l3C-NMR (75 MHZ, CDC13) 5 20.9, 25.1, 28.0, 28.5, 34.1, 42.1, 47.3, 62.5, 171.0, 212.2. Acetic acid 1-oxa-spiro[4.5]dec-6-yl ester III-130 C09 OAc Conversion of III-127 to 111-130 under general cyclization conditions described for III-19 led to 52% product. 1H-NMR (500 MHz, CDCl3) 5 1.2-1.7 (m, 8H), 1.90 (m, 4H), 2.02 (s, 3H), 3.78 (m, 2H), 4.74 (dd, J = 8.4, 3.5 Hz, 1H). l3C-NMR (125 MHz, CDCl3) 5 21.39, 22.24, 23.05, 26.19, 28.97, 31.38, 35.74, 67.99, 75.98, 83.42, 170.40. Benzoic acid l-(tetrahydro-furan-Z-yl)-hexyl ester III-131 082 My To a solution of cis-1,4,5-decanetriol (41.9 mg, 0.221 mmol, 1.0 eq.) in CH2C12 (10 mL) was added trimethyl orthobenzoate (45.4 11L, 0.265 mmol, 1.2 eq.) and catalytic amount of PPTS under N2 atmosphere. The reaction mixture was stirred at rt for 10 min. 182 BF3'OEt2 (3 1.1L, 0.0221 mmol, 0.1 eq.) was added to the reaction mixture at 0 °C. After 30 min, the reaction was quenched with saturated NaHCO3 aqueous solution. The product was extracted with EtOAc (3x). The combined organic layer were washed with brine and dried over Na2SO4. After filtration, the solvent was removed under reduced pressure, and the product was purified by column chromatography (5% EtOAc in hexane) to yield 52.6 mg the desired product (86%). 1H-NMR (500 MHZ, CDCI3) 5 0.83 (t, J = 7.5 Hz, 3H), 1.26 (m, 4H), 1.36 (m, 2H), 1.70 (m, 2H), 1.80-2.00 (m, 4H), 3.74 (m, 1H), 3.80 (m, 1H), 4.01 (q, J = 5.3 Hz, 1H), 5.20 (td, J = 5.3, 7.1 Hz, 1H), 7.42 (t, J = 8.0 Hz, 2H), 7.53 (t, J = 7.1 HZ, 1H), 8.02 (d, J = 7.1 Hz, 2H). 13C-NMR (125 MHz, CDC13) 14.0, 22.4, 25.1, 25.8, 27.3, 31.2, 31.6, 68.7, 75.5, 79.9, 128.2, 129.4, 130.4, 132.9, 166.2. trans-l-Benzoxy-4-decene III-132 WOBn To a THF (50 mL) solution of trans-4—decenol (321 mg, 2.06 mmol, 1.0 eq.), NaH (165 mg, 4.11 mmol, 2.0 eq.) was added at 0 0C at N2 atmosphere. The mixture was warmed to rt, stirred for 1 h and cooled back to 0 °C. Benzyl bromide (0.488 mL, 4.11 mmol, 2.0 eq.) was then added dropwise, followed by addition of TBAI (76 mg, 0.206 mmol, 0.1 eq.). After stirring at rt for 10 h, the reaction mixture was poured into saturated NaHCO; and vigorously stirred. The layers were separated and the aqueous layer was extracted with EtOAc (x3), and dried over Na2SO4. The solvent was removed under reduced pressure and the product was purified by column chromatography (20% EtOAc in hexanes) to yield 241 mg (48%) desired product. 1H-NMR (300 MHz, CDCl3) 5 0.90 (t, J = 7.4 Hz, 3H), 1.30 (m, 6H), 1.69 (p, J = 7.4 Hz, 2H), 1.98 (m, 2H), 2.07 (m, 183 2H), 3.48 (t, J = 6.6 HZ, 2H), 4.50 (s, 2H), 5.41 (m, 2H), 7.34 (m, 5H) 13C-NMR (300 MHZ, CDC13) 5 14.0, 22.5, 29.1, 29.2, 29.6, 31.3, 32.5, 69.7, 72.8, 127.4, 127.6, 128.3, 129.3, 131.0, 138.6. 1-Benzoxy-decan-4, 5-diol III-133 OH WOBD OH To a mixture of tBuOH (5 mL), water (5 mL) and AD-mix-a (1.4 g) was added MeS02NH2 (95 mg). The mixture was stirred at rt until both phases are clear, and then cooled to 0 °C. Whereupon the inorganic salts partially precipitate, the olefin III-132 (241 mg, 0.98 mmol, 1.0 eq.) was added at 0 °C, and the heterogeneous slurry was stirred vigorously at this temperature for 12 h. The reaction was quenched at 0 °C by addition of sodium sulfite (1.5 g) and then warmed to rt and stirred for 45 min. The reaction mixture was extracted three times with EtOAc, and the organic layer was washed with 2M KOH, then dried over MgSO4 and concentrated. The product was purified with column chromatography (40% EtOAc in hexane) to yield 218 mg (80%) desired product. IH- NMR (300 MHZ, CDCI3) 5 0.87 (t, J = 6.1 Hz, 3H), 1.2-1.8 (m, 12H), 3.32 (m, 2H), 3.48 (t, J = 6.0 Hz, 2H), 4.48 (s, 2H), 7.30 (m, 5H) 13C-NMR (75 MHz, CDCl3) 5 13.96, 22.52, 25.26, 25.93, 30.68, 31.79, 33.35, 70.29, 72.90, 73.95, 74.37, 127.55, 127.60, 128.28, 137.95. 4-(3-Benzyloxy-propyl)-2,2-dimethyl-S-pentyl-[1,3]dioxolane 111-134 184 Y 0 W03" The diol generated above 111-133 (38 mg, 0.134 mmol, 1.0 eq.) was dissolved in a solution of acetone (1.5 mL) and 2,2-dimethoxypropane (0.5 mL,4.0 mmol, 30 eq.). To this mixture was added p-toluenesulfonic acid (8 mg, 0.04 mmol, 0.3 eq.) and the reaction mixture was stirred at rt for 12 h. The mixture was then brought to pH 7 with NHaOH. Following this, the acetone was evaporated under vacuum, and the residue was dissolved in EtOAc (10 mL), and this solution was washed with brine (3 x 2.5 mL). The combined organic layers were dried with Na2SO4 and filtered, and the filtrate was concentrated under vacuum to give a crude residue, which was purified by column chromatography to afford 30 mg (70%) desired product. The enantiopurity was 91% ee analyzed by chiral HPLC (CHIRALCEL OD with guard column, flushed with 1% iPrOH in hexane) lH-NMR (300 MHZ, CDC13) 5 0.88 (t, J = 6.9 Hz, 3H), 1.29 (m, 4H), 1.36 (s, 6H), 1.48 (m, 4H), 1.66 (m, 4H), 3.50 (m, 2H), 3.59 (m, 2H), 4.49 (s, 2H), 7.28 (m, 5H). (45, SS )-1,4,S-Decanetriol III-135 OH W0” OH To a solution of diol III-133 (92 mg, 0.33 mmol, 1.0 eq.) in EtOH (10 mL) was added Pd/C (92 mg). The reaction mixture was stirred under H2 atmosphere for 12 h. The mixture was filtered, and the solvent was removed under reduced pressure, and the product was purified by column chromatography (EtOAc) to yield 62 mg (98%) desired 185 product. 1H—NMR (300 MHz, CDCl3) 5 0.85 (t, J = 6.6Hz, 3H), 1.26 (m, 5H), 1.42 (m, 4H), 1.63 (m, 3H), 3.34 (m, 2H), 3.61 (m, 2H), 4.12 (br, 3H). 4,5-Dihydroxy-decanoic acid ethyl ester III-139 OH //\V/~\/1\r/\\/COOEt OH Dihydroxylation procedure identical to the preparation of III-18 with alkene III- 138 gave compound III-139 in 91% yield. lH-NMR (300MHz, CDC13) 5 0.81 (t, J = 6.7Hz, 3H), 1.1—1.5 (m, 10H), 1.70 (m, 2H), 2.42 (m, 2H), 3.10 (s, 1H), 3.32 (s, 3H), 4.05 (q, J = 7.0Hz, 2H). 9,10-Dihydroxy-octadecanoic acid III-143 HO OH OOH 7 7 Dihydroxylation procedure identical to the preparation of 111-13 with alkene III- 142 gave compound III-143 in 85% yield. IH-NMR (300MHz, CD3OD) 5 0.81 (t, 3H), 1.2-1.6 (m, 26H), 2.19 (t, J = 7.3, 2H), 3.23 (m, 4H). l3C-NMR (300MHz, CD3OD) 5 14.4, 23.7, 26.1, 26.96, 27.03, 30.2, 30.40, 30.43, 30.67, 30.74, 30.87, 33.07, 33.55, 33.60, 35.01, 75.97, 75.99, 177.76. Toluene-4-sulfonic acid dec-4-enyl ester III-144 WOT-S 186 To a solution of dec-4-en-1-ol (217.7 mg, 1.396 mmol) in CH2Cl2 (IOmL), triethylamine (0.584 mL), TsCl (798 mg, 4.19 mmol) and catalytical DMAP was added at 0 °C under nitrogen. The reaction mixture was stirred at 0° C for 30 min and at rt for 6 h. The reaction was quenched with saturated NBC] and water. The product was extracted with CH2Cl2 three times. The organic layer was dried over Na2SOa. The crude product was purified with 2.5% EtOAc in hexane to yield 367.3 mg (85%) of the compound III- 144. lH-NMR (500MHz, CDCl3) 5 0.86 (t, J = 7.3Hz, 3H), 1.25(m, 6H), 1.68 (m, 2H), 1.95 (m, 4H), 2.43 (s, 3H), 4.00 (t, J = 6.4Hz, 2H), 5.27 (m, 2H), 7.33 (d, J = 8.0Hz, 2H), 7.77 (d, J = 8.4HZ, 2H). Cyclohexyl-dec-4-enyl-amine III-145 M/WNHCy To a solution of toluene-4-sulfonic acid dec—4-enyl ester III-144 (367.3 mg, 1.184 mmol) in ethanol (5 mL), cyclohexylamine (0.135 mL) was added. The reaction was refluxed for 16 h. The reaction was quenched with water (5 mL). The pH was adjusted to 10 by adding 3 N NaOH. The product was extracted with ethyl acetate, and dried over Na2SO4. The product was purified by column chromatography with 8% MeOH in CHCl3 to yield 126.6 mg of 111-45 (40%). lH-NMR (300MHz, CDC13) 5 0.83 (t, J = 7.1Hz, 3H), 1.0-2.0 (m, 22H), 2.36 (m, 1H), 2.56 (t, J = 7.4Hz, 2H), 5.34 (m, 2H). 1-Cyclohexylamino-decane-4,5-diol III-146 OH WNHCY OH 187 Dihydroxylation procedure identical to the preparation of III-18 with alkene III- 145 gave compound 111-146 in 68% yield. lH-NMR (300MHz, CD3OD) 5 0.76 (t, J = 6.9Hz, 3H), 0.9-1.9 (m, 23H), 2.38 (m, 1H), 2.55 (m, 2H), 2.24 (m, 2H). 13C-NMR (75MHz, CD3OD) 5 14.488, 23.761, 26.098, 26.842, 26.903, 27.024, 31.805, 33.155, 33.793, 47.300, 58.000, 75.089, 75.286. Dec-4-enoic acid amide 111-148 0 WNH Urea (674 mg, 11.22 mmol) and carboxylic acid 111-147 (954 mg, 5.61 mol) 2 were placed in a round-bottom flask. A condenser was attached to the flask and the mixture was heated to 180-220 0C for 4 h. The mixture was then allowed to cool to rt. Sodium carbonate solution (10%, 15 mL) was carefully added through the condenser with vigorous shaking of the flask to yield 395.8mg 111-148 (42%). lH-NMR (300MHz, CDCl3) 5 0.86 (t, 3H), 1.22 (m, 6H), 1.95 (m, 2H), 2.28 (m, 4H), 5.43 (m, 2H). 4,5-Dihydroxy-decanoic acid amide III-149 OH O OH Dihydroxylation procedure identical to the preparation of III-18 with alkene III- 148 gave compound 111-149 in 76% yield. IH-NMR (300MHz, CD3OD) 5 0.80 (t, J = 6.6Hz, 3H), 1.30 (m, 8H), 1.65 (m, 2H), 2.23 (m, 2H), 3.27 (m, 2H). l3C-NMR (75MHz, 188 CD3OD) 5 14.427, 23.731, 26.736, 30.014, 33.080, 33.110, 33.914, 74.664, 75.210, 179.202. Thioacetic acid S-dec-4-enyl ester III-150 O \ SJK PPh3 (1.26 g, 4.8 mmol) was dissolved in THF (20 mL), DIAD (0.93 mL, 4.8 mmol) was added at 0 0C and the solution was stirred for .15 min. A solution of dec-4-en- l—ol (374.4 mg, 2.4 mmol) in 20 mL THF was added to the PPh3 DIAD suspension at 0 °C, followed by thioacetic acid (0.34 mL, 4.8 mmol). The now clear solution was stirred for 2 h while it was warmed to rt, at which time methanol (3 mL) was added, and the solvent was evaporated. The oily product was purified by chromatography (5% EtOAc in hexane) to yield quantitative III-150. ‘H-NMR (300MHz, CDC13) 5 0.84 (t, J = 7.1Hz, 3H), 1.25 (m, 6H), 1.69 (p, J = 7.4Hz, 2H), 1.98 (m, 4H), 2.28 (s, 3H), 2.82 (t, J = 7.1Hz, 2H), 5.35 (m, 2H). Thioacetic acid S-(4,5-dihydroxy-decyl) ester III-151 OH O Wsk OH Dihydroxylation procedure identical to the preparation of III-18 with alkene III- 150 gave compound III-151 in 93% yield. 1H-NMR (300MHz, CDCl3) 5 0.81 (t, J = 6.6Hz, 3H), 1.1-1.8 (m, 12H), 2.24 (s, 3H), 2.82 (m, 2H), 3.14 (s, 2H), 3.29 (m, 2H). 189 l-Mercapto-decane-4,5-diol III-152 OH WSH OH To a suspension of LAH (168 mg, 4.44 mmol, 5.0 eq.) in diethyl ether (10 mL) was added 111-151 (211 mg, 0.887 mmol, 1.0 eq.) at 0 oC. The reaction was stirred at rt for 12 h. The reaction was quenched with 10% HCl. The product was extracted with ether. After combination of the organic layers, the solution was dried with MgSOa. The product was then purified by column chromatography .( 40% EtOAc in hexanes) to yield 148 mg (81%) desired product. lH-NMR (300MHz, CDC13) 5 0.84 (t, J = 6.4Hz, 3H), 1.0-2.0 (m, 13H), 2.51 (q, J = 7.0Hz, 2H), 2.92 (s, 2H), 3.34 (m, 2H). l3c-NMR (75MHz, CDCl3) 5 13.955, 22.515, 24.564, 25.262, 30.028, 31.758, 32.046, 33.397, 73.874, 74.481. Acetic acid l-(tetrahydro-thiophen-Z-yl)-hexyl ester III-153 OAc W) Conversion of III-152 to 111-153 under general cyclization conditions described for III-l9 led to 79% product. lH-NMR (500MHz, CDC13) 5 0.85 (t, J = 6.8Hz, 3H), 1.26 (m, 6H), 1.52 (m, 1H), 1.68 (m, 2H), 1.95 (m, 3H), 2.05 (s, 3H), 2.83 (m, 2H), 3.40 (m, 1H), 4.87 (td, J = 8.8Hz, 3.1Hz, 1H). l3c-NMR (125MHz, CDC13) 5 13.925, 21.043, 22.439, 24.868, 30.119, 31.515, 32.562, 33.321, 51.473, 76.696, 170.687. Reference 190 (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) Alali, P. Q.; Liu, X. X.; McLaughlin, J. L. Journal of Natural Products 1999, 62, 504-540. Zafra-Polo, M. C.; Figadere, B.; Gallardo, T.; Tormo, J. R.; Cortes, D. Phytochemistry 1998, 48, 1087-1117. Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z. M.; He, K.; McLaughlin, J. L. Natural Product Reports 1996, 13, 275-306. Berrnejo, A.; Figadere, B.; Zafra-Polo, M. C.; Barrachina, 1.; Estornell, E.; Cortes, D. Natural Product Reports 2005, 22, 269-303. Cave, A.; Figadere, B.; Laurens, A.; Crotes, D. In Progress in The Chemistry of Organic Natural Products; Herz, W., Kirby, G. W., Moore, R. E., Steglish, W., Tamm, C., Eds; Springer-Verlag: New York, 1997. Gu, Z. M.; Zhao, G. X.; Oberlies, N. H.; Zeng, L.; McLaughlin, J. L. In Recent Advances in Phytochemistry; Plenum Press: New York, 1995; Vol. 29. Fang, X. P.; Rieser, M. J .; Gu, Z. M.; Zhao, G. X.; Mclaughlin, J. L. Phytochemical Analysis 1993, 4, 49-67. Rupprecht, J. K.; Hui, Y. H.; Mclaughlin, J. L. Journal of Natural Products 1990, 53, 237-278. Morre, D. J .; Decabo, R.; Farley, C.; Oberlies, N. H.; Mclaughlin, J. L. Life Sciences 1994, 56, 343-348. Wolvetang, E. J .; Johnson, K. L.; Krauer, K.; Ralph, S. J .; Linnane, A. W. Febs Letters 1994, 339, 40-44. Oberlies, N. H.; Jones, J. L.; Corbett, T. H.; Fotopoulos, S. S.; Mclaughlin, J. L. Cancer Letters 1995, 96, 55-62. Oberlies, N. H.; Croy, V. L.; Harrison, M. L.; McLaughlin, J. L. Cancer Letters 1997, 115, 73-79. 191 (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) Oberlies, N. H.; Chang, C. J .; McLaughlin, J. L. Journal of Medicinal Chemistry 1997, 40, 2102—2106. Holschneider, C. H.; Johnson, M. T.; Knox, R. M.; Rezai, A.; Ryan, W. J .; Montz, F. J. Cancer Chemotherapy and Pharmacology 1994, 34, 166-170. Miyoshi, H.; Ohshima, M.; Shimada, H.; Akagi, T.; Iwamura, H.; McLaughlin, J. L. Biochimica Et Biophysica Acta-Bioenergetics 1998, 1365, 443-452. He, K.; Zeng, L.; Ye, Q.; Shi, G. E.; Oberlies, N. H.; Zhao, G. X.; Njoku, J.; McLaughlin, J. L. Pesticide Science 1997, 49, 372-378. Alali, F. Q.; Kaakeh, W.; Bennett, G. W.; McLaughlin, J. L. Journal of Economic Entomology 1998, 91, 641-649. Shimada, H.; Kozlowski, J. F.; Mclaughlin, J. L. Pharmacological Research 1998, 37, 357-364. Shimada, H.; Grutzner, J. B.; Kozlowski, J. F.; McLaughlin, J. L. Biochemistry 1998, 37, 854-866. Hoppe, R.; Scharf, H. D. Synthesis-Stuttgart 1995, 1447—&. Marshall, J. A.; Hinkle, K. W.; Hagedom, C. E. Israel Journal of Chemistry 1997, 37, 97-107. Shi, G.; Kozlowski, J. F.; Schwedler, J. T.; Wood, K. V.; MacDougal, J. M.; McLaughlin, J. L. Journal of Organic Chemistry 1996, 61, 7988-7989. Harmange, J. C.; Figadere, B. Tetrahedron-Asymmetry 1993, 4, 1711-1754. Boivin, T. L. B. Tetrahedron 1987, 43, 3309-3362. Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321-3408. Baldwin, J. E. Journal of the Chemical Society-Chemical Communications 1976, 734-736. 192 (27) (28) (29) (30) (31) (32) (33) (34) (35) (36) (37) (38) (39) (40) Hashimoto, M.; Harigaya, H.; Yanagiya, M.; Shirahama, H. Tetrahedron Letters 1988, 29, 5947-5948. Hashimoto, M.; Yanagiya, M.; Shirahama, H. Chemistry Letters 1988, 645-646. Koert, U. Tetrahedron Letters 1994, 35, 2517-2520. Sonnewald, U. Acta Chemica Scandinavica Series B-Organic Chemistry and Biochemistry 1988, 42, 567-568. Appel, B.; Saleh, N. N. R.; Langer, P. Chemistry-a European Journal 2006, 12, 1221-1236. Marshall, J. A.; Jiang, H. J. Journal of Organic Chemistry 1999, 64, 971-975. Cecil, A. R. L.; Brown, R. C. D. Organic Letters 2002, 4, 3715-3718. Zhang, H. P.; Mootoo, D. R. Journal of Organic Chemistry 1995, 60, 8134-8135. Zhang, H. P.; Seepersaud, M.; Seepersaud, S.; Mootoo, D. R. Journal of Organic Chemistry 1998, 63, 2049-2052. Maezaki, N.; Kojima, N.; Sakamoto, A.; Torninaga, H.; Iwata, C.; Tanaka, T.; Monden, M.; Damdinsuren, B.; Nakamori, S. Chemistry-a European Journal 2003, 9, 390-399. Johnson, R. A. a. S., K. B. In Catalytic Asymmetric Synthesis; Ojima, 1., Ed.; VCH Publishers, Inc., 1993; Vol. 4. Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1-299. Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, 1., Ed.; VCH: NY, 1993; Vol. 4.2. Shi, Y. Accounts of Chemical Research 2004, 37, 488-496. 193 (41) (42) (43) (44) (45) (46) (47) (48) (49) (50) (51) (52) (53) (54) Bez, G.; Zhao, C. G. Tetrahedron Letters 2003, 44, 7403-7406. Armstrong, A.; Ahmed, G.; Dominguez-Femandez, B.; Hayter, B. R.; Wailes, J. S. Journal of Organic Chemistry 2002, 67, 8610-8617. Rossiter, B. E. In Asymmetric Synthesis; Academic Press: New York, 1986; Vol. 5. Oi, R.; Sharpless, K. B. Tetrahedron Letters 1992, 33, 2095-2098. Gao, Y.; Sharpless, K. B. Journal of the American Chemical Society 1988, 110, 7538-7539. Gao, Y.; Zepp, C. M. Tetrahedron Letters 1991, 32, 3155-3158. Kim, B. M.; Sharpless, K. B. Tetrahedron Letters 1989, 30, 655-658. Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515-10530. Narayan, R. S.; Borhan, B. Journal of Organic Chemistry 2006, 71, 1416-1429. Fukuyama, T.; Vranesic, B.; Negri, D. P.; Kishi, Y. Tetrahedron Letters 1978, 2741-2744. Grasa, G. A.; Singh, R.; Nolan, S. P. Synthesis-Stuttgart 2004, 971-985. Austin, K. A. B.; Banwell, M. G.; Loong, D. T. J.; Rae, A. D.; Willis, A. C. Organic & Biomolecular Chemistry 2005, 3, 1081-1088. Dembinski, R. European Journal of Organic Chemistry 2004, 2763-2772. Matsumura, R.; Suzuki, T.; Sato, K.; Oku, K.; Hagiwara, H.; Hoshi, T.; Ando, M.; Kamat, V. P. Tetrahedron Letters 2000, 41, 7701-7704. 194 Chapter IV Intermolecular nucleophilic substitution of orthoesters 4.1 Introduction During our study toward the total synthesis of Mucoxin, the initial retrosynthetic strategy is shown in Scheme IV-l, which entailed a regiochemically controlled intermolecular union of two advanced intermediates IV-3 and IV-4. The vinyl moiety in compound IV-4 was not only poised to function as a directing group to ensure nucleophilic attack of IV-3 at C9, but also would serve in a double ring closing metathesis to deliver the second THF ring and the butenolide. Unfortunately, utilizing standard Lewis acid promoters, our attempts failed to deliver the desired product IV-2 in no greater than 20% yield( Scheme IV-2). The detailed analysis of the products showed that the major isolated product was the unconjugated enone IV-S, which presumably results from a 1,2-hydride migration upon activation of the epoxide with BF3-OEt2 (Scheme IV-3). A series of Lewis acids were examined, including BF3-OEt2, SnF4, 'ri(oi1>r)4 and Zn(OAC)2. but to no avail. Scheme I V-I. The initial retrosynthetic analysis of mucoxin Tandem RCM-hydrogenation I mucoxin, IV-1 I , op on | 9H 0H ————> = 0., / ‘ 7 0,, 0,, O Regio- and ,6 ‘ 16 ' ’ 5 Stereo— -. + .g \ \ 0 selective ’Qp OH epoxide opening IV-3 IV-4 IV-2 195 Scheme I V-2. Regiochemically controlled intermolecular union of two advanced intermediates towards the synthesis of Mucoxin 9 30¢ lV-2 W4 BFa'OEtz 20% yield ———> o ores OH \ 3 O”. / W0 H3C(H20)16 0 v "ores 1v-5 lV-3 Scheme I V-3. The proposed mechanism of 1,2-hydride migration of vinyl epoxide 1313-01512 H O / _’ ‘_ O > / I ‘. O " v (103’ v 1v _4 — BF3-OEt2 J 0 W0 O (\\“V 196 Scheme I V-4. Novel stereocontrolled approach to syn- and anti— oxepene-cyclogeranyl trans-fused polycyclic systems (2-2.5 eq.) X 3 OP R M? BF3'OE12 (0.1 eq.) ' OP i W 10 M solution in CH2CI2 0 °C, 20-30 min 50-60% o ’ I I Palisadin A Palisadin B 12-hydroxy-Palisadin B Although we have not observed this reaction pathway in the intramolecular cyclizations, it may be a manifestation of the slower rate of the intermolecular reaction. A similar synthetic challenge was also encountered by Couladouros during their synthesis of syn- and anti-oxepene-cyclogeranyl trans-fused polycyclic systems (Scheme IV-4).l Utilization of BF3-OEt2 in a 1 M solution of stoichiometric amounts of the coupling partners resulted in slow decomposition of the epoxide, yet at a slower rate, while a small amount of the desired product was observed in 10-15% yield. Fortunately, the problem was solved by using two fold excess of alcohol and performing the reaction in a 10 M solution. Further studies showed more substituted epoxides required practically solvent- 197 free conditions along with an excess of alcohol. Thus, the desired or-alkoxy alcohol products could be isolated in 50-60% yield, based on the epoxide. It should be noted, that by increasing the concentratibn the two-component coupling reaction would be accelerated, whereas the rate of the undesired 1,2-hydride migration should not be affected. Intermolecular addition of alcohols to vinyl epoxides coupled with ring closing metathesis can be a useful strategy for the construction of small and medium sized oxarings, since excellent methodologies are in place to deliver the epoxide and alcohol in an enantiomerically defined manner (Scheme IV-S). This strategy has been demonstrated by Couladoros in their synthetic approach toward (-)-aplysistatin, (+)-palisadin A, (+)- palisadin B, (+)-12-hydroxy-palisadin B (vide supra).1 Scheme I V-5. Construction of small and medium sized oxarings by intermolecular addition of alcohols to vinyl epoxides coupled with RCM O FHA/ 2A OH However, most of the intermolecular epoxide ring-opening reactions with oxygen nucleophiles involve the use of strongly acidic conditions, stoichiometric amounts of the reagents, extended reaction times, low regioselectivity, unsatisfactory yields and sometimes undesirable side products due to rearrangement or polymerization of starting oxiranes.2 Several examples are listed herein, including the use of Nafion-H3, dehydrated alumina,4 organotinphosphate condensates (OPC),5 000,6 CAN,7 CSA,8"° FeCl3,” metal 198 salts,12 BF3-OEt2,l3 and CBra.I4 It is noteworthy that Trost’s Pd-trialkylborane catalyzed 1,1 56 and dynamic kinetic asymmetric addition of alcohols to racemic vinyl epoxide Schneider’s scandium-bipyridine catalyzed enantioselective addition of alcohols to meso- epoxidesl7 were the two examples of asymmetric version of this reaction. Despite the elegant asymmetric properties of these strategies, only simple vinyl epoxides and less hindered primary alcohols work well. Therefore, there are no reliable methodologies to address the issue using advanced chirally defined vinyl epoxides and more hindered and synthetically precious secondary alcohols. Such a methodology could lead to alternate convergent strategies in the construction of complex molecules. Cyclic orthoesters derived from vicinal diols were demonstrated to react as an epoxide equivalent in our newly developed cyclization strategy of 1,2,n-triols. The success of this intramolecular reaction promoted us to investigate the intermolecular version of this strategy. Should this strategy be proved successful, it would provide a general strategy of transforming a 1,2-diol to an (x-alkoxy alcohol. In addition, the stereochemistry of the product would be dictated by the vicinal diol, allowing the synthesis of or-alkoxy alcohols in a stereocontrolled fashion. Furthemore, since the reaction is mediated by a five-member ring oxonium ion intermediate, the 1,2-hydride shift, which is the major problem for the Lewis acid catalyzed regiospecific opening of vinyl epoxides by alcohols, would be suppressed. Finally, this strategy could also be coupled with ring closing metathesis to furnish the cyclic ether ring. The general scheme of this strategy is shown on Scheme IV-6. 199 Scheme I V-6. Lewis acid catalyzed intermolecular nucleophilic substitution of cyclic orthoesters coupled with ring closing metathesis to synthesize cyclic ether rings. OMe 51013 M6C(OM9)3 X L. A. O 0 R1“ cat.PPTS V h:——> __ OH H1 H1 é: RCM 11 5.“ / 4.2 Intermolecular nucleophilic substitution of orthoesters In order to investigate the intermolecular nucleophilic substitution of cyclic orthoesters by alcohols, the aromatic vicinal diol derived from stilbene was chosen as the sample substrate. Compared with the aliphatic substrate, the cyclic orthoester formed by transesterification of 1,2-diphenyl-ethane-1,2-diol IV-6 with trimethyl orthoacetate is less moisture sensitive. Unlike orthoester IV-9, which was hydrolyzed spontaneously during column chromatography, compound IV-7 could be isolated in 85% yield (Scheme IV-7). 200 Scheme I V-7. Synthesis of orthoesters IV-7 and IV-9 > WO‘AIMe ] ; No Reaction 2 CH2C|2 XOMQ Worms 0 9 > No Reaction F: CH2012, I1 Ph Ph XOM" Worms 0 9 > No Reaction ' Toluene, 80 °C 203 Commercially available (I-hydroxy—allyl)-trimethyl-silane, in which the alkoxy group was already attached to Lewis acidic silane, was tested for the same purpose. However, the same result was obtained, and No reaction occurred during a prolonged reaction time. Presumably the insufficient Lewis acidity of this reagent was the main reason for this outcome. So far, all the attempts to perform intermolecular nucleophilic addition of alcohols to preformed aromatic cyclic orthoester IV-7 were not successful. Thus, we turned our attention to the aliphatic cyclic orthoester IV-9. Although orthoester IV-9 could not be isolated due to its sensitivity toward moisture, it could be generated in situ as we demonstrated in the intramolecular cyclization strategy. As shown in Scheme IV-Il, when the reaction was performed at 0 0C, using BF3'OEt2 as the catalyst, the reaction returned mainly monoacetate IV-12. To increase the reactivity of the alcohol nucleophile, the reaction was heated up, which led to decomposition of the starting material. Scheme I V-I 1. Intermolecular nucleophilic addition of alcohol to aliphatic cyclic orthoester 1) MeC(OMe)3, PPTS OH 2) BF3'OEt2, cyclohexanol OH IV-8 0 °C, 52% IV-12 1) MeC(OMe)3. PPTS OH Toluene > Decomposition OH 2) BF3'OE12, cyclohexanol lV-8 reflux 204 An NMR study of the above reaction was performed. Deuterated benzene was used as the solvent. The cyclic orthoester was formed in the NMR tube as previously described. After the addition of cyclohexanol and Lewis acid, BF3'OEt2, the characteristic acetate peak could not be observed around 2 ppm before the reaction was quenched with water. This observation clearly showed that hydrolysis was not occurring during the reaction process but rather happened after the introduction of water to the reaction system upon quenching. The brief screening of the diol, Lewis acid catalyst, nucleophilic alcohol, solvent and temperature all led to either hydrolysis product or recovery of the starting material. The last resort was obviously to switch the orthoester. Since during our development of the intramolecular cyclization strategy, orthobenzoate was demonstrated to be an even better orthoester than orthoacetate due to the stability of the benzylic carbocation, trimethyl orthobenzoate was therefore tested as a substitute of trimethyl orthoacetate. As shown in Scheme IV-12, the aromatic cyclic orthobenzoate III-14 was produced by transorthoesterification of 1,2-diphenyl-ethane-l,2-diol III-13 with trimethyl orthobenzoate. This cyclic orthoester was stable enough to be isolated by column chromatography. When it was treated with 2 equiv of cyclohexanol and 1 equiv of BF3'OEt2, three major products could be isolated and identified as compound IV-15, IV- 16, and IV-17, respectively. Although none of these compounds was the desired product, the isolation of its dehydration product IV-15 was rather encouraging. B-Elimination of the desired product was expected to be quite facile because of the highly conjugated structure of compound IV-15. Therefore, it is highly possible that the nucleophilic 205 addition of cyclic orthobenzoate occurred and the product then underwent a subsequent elimination reaction to furnish compound IV-lS. Scheme I V-12. Nucleophilic addition of cyclic orthobenzoate Ph OMe HO 0“ PhC(OMe)3 OX0 ph Ph cat. PPTS r H CH20I2 Ph Ph 78% lV-13 IV-14 Ph OMe OX0 2.0 eq.cyclohexanol H _ OCy O HO .982 =’:+Ph)1\oc+l) BF3-OEt2,CHZC|2 Ph P“ Y Ph Ph Ph Ph lV-1 4 IV-15 IV-16 lV-17 29% 49% 20% Utilization of TMSOTf as the Lewis acid promoter improved the reaction outcome. Again, a 37% yield of the dehydration product IV-19 could be obtained when the cyclic orthoacetate was treated with nucleophilic alcohol and TMSOTf (Scheme IV- 13). Scheme I V-13. TMSOTf acting as the Lewis acid promoter for the nucleophilic addition of cyclic orthoacetate M OMe _ H > o o = )=( CH2012 Ph Ph 0 C-rt, 3h 37% 1v-13 1v-18 ”-19 206 To prevent the undesired elimination reaction, we employed decane-1,2-diol IV- 18 instead of aromatic substrate IV-13. The results are shown in Scheme IV-l4. The first trial used the combination of trimethyl orthoacetate and TMSOTf. The desired product IV-21 was isolated in 8% yield, along with 15% deacetalated product III-22. Better results were obtained when orthobenzoate was utilized instead of orthoacetate. Desired product IV-23 was obtained in 55% yield along with 29% of another major product. This compound was later identified as 2-benzoxy-l—methoxy-decane IV-24. After close inspection, we proposed that this side product was possibly derived from the nucleophilic addition reaction between cyclic orthobenzoate and methanol, which evolved from the transorthoesterification of trimethyl orthobenzoate and diol. Scheme I V-14. Nucleophilic addition of cyclic orthoester by alcohols promoted by Lewis acid TMSOTf OAc H30(H2C)7 CW 8% OH 1) MeC(OMe)3. cat. PPTS IV-21 OH > H3C(HZC)7 2) 1.0 eq. TMSOTf allyl alcohol + lV-2O 0 °C to rt OH H30(HZC)7/K/O\/\ 15% IV-22 OBz H30(H20)7 CW 55% OH - OH 1) PhC(OMe)3. cat. PPTS 'V 23 H30(H20)7 > 2) 1.0 eq. TMSOTf + allyl alcohol - 082 IV 20 0 °C to rt 0 HsC(HzC)7 \ 29% IV—24 207 Table I V-1. Optimization of nucleophilic addition of cyclic orthoesters OH 1) PhC(OMe)3, cat. PPTS 47 Product H3C(H2C)7 0“ 2) L. A. allyl alcohol lV-20 entry additive Lewis acid Product Yield (%) IV-23 9 1 511 MS TMSOTf M24 3 a lV-23 32 2 none TMSOTf IV-24 44 b lV-23 38 3 none TMSOTf lV-24 6 082 OH 4 none ZnClz H3C(HZC)7 60 lV-25 082 CI 5 none TiCl4 H3C(H2C)7 62 lV-26 6 none Ti (OfPr)4 lV-25 64 7 (BU3Sn)2O TMSOTf lV-25 71 8 (Bu38n)20 Zn(OTf)2 IV-25 69 a Toluene, O — 65 °C b Vacuum 30 min before the addition of Lewis acid 208 A series of experiments were designed to eliminate the effect of methanol and further optimize the reaction. The results are shown in Table IV -1. First, 5 A molecular sieves were added to the reaction mixture to eliminate methanol (entry 1). However, the yield of both desired product IV-23 and side product IV-24 were decreased dramatically for the reason that molecular sieves are not compatible with the reaction conditions in the presence of Lewis acid. Attempts of removing methanol either by vacuum or heat (entry 2, 3) before the addition of Lewis acid were also in vain. The optimization also included using different Lewis acids such as ZnClz, TiCl4 and Ti(OiPr)4 (entry 4, 5, 6) as the reaction promoter. Except for TiCl4, which generated chloride IV-26 as the major product, the other two Lewis acids only gave the monobenzoate IV-25 as the only product. Based on literature precedent, an alcohol’s nucleophilicity could be increased by reacting with bis(tributyltin) oxide.18 The resultant alkoxy tin reagent was a better nucleophile than the parent alcohol. This protocol was also applied to optimize our intermolecular nucleophilic addition reaction by heating the alcohol and bis(tributyltin) oxide at 80 °C for several hours, with subsequent addition to the mixture of preformed cyclic orthobenzoate and Lewis acid. However, either using TMSOTf or Zn(OTf)2 as a catalyst did not furnish the desired product. The hydrolysis occurred predominantly for these trials (entry 7 and 8). With no luck to get rid of methanol in the reaction system, we turned our attention to some orthoesters derived from none nucleophilic alcohols, such as phenol, trifluoromethanol, tert-butanol or vinyl alcohol. Some of the proposed orthoesters are shown in Figure IV-l. 209 Ph Ph Ph Ph \ l p. l p. B ,- l - l x. 0 OP u 0 C.) O (Bu F300 OCQSFS O O O—\\ tBu ‘\ IV-27 lV-28 lV-29 IV-3O Figure I V-I. The proposed structures of none nucleophilic orthoesters Unluckily, most commercially available orthoesters are methyl or ethyl orthoesters. As such, synthesis of these non-nucleophilic orthoesters was pursued. A number of methods for the preparation of orthoesters that would seem to be of general applicability have been reported to date. The most general procedure that appears in the literature was published by Pinnerl'9 and involves the alcoholysis of an iminoester hydrochloride which is obtained from a nitrile (Scheme IV -15). The major disadvantage of this protocol is the prolong reaction time, requiring 7 days for the synthesis of one orthoester. Thus, a more convenient route to access orthoesters involving the transesterification of commericially available trimethyl orthobenzoate seems more appealing. Scheme I V-15. General procedure of synthesis of orthoesters 9” R'—0H 9” R-CN + R'-OH + HCI —> Fl-C=NH'HCI ———> R-Q-OR' OR' Scheme IV-16. Synthesis of vinyl orthobenzoate PhC(OM6)3 D PhC(OCH2CH2CI)3 > PhC(OCH=CH2)3 PTSA DME, tBuOH 55% lV-31 37% IV-30 210 Vinyl orthobenzoate was synthesized from trimethyl orthobenzoate as shown in Scheme IV-16. It commenced with a transesterification of trimethyl orthobenzoate with 2-chloro-ethanol to furnish tri(2-chloroethyl) orthobenzoate IV-3l in 56% yield. Upon base mediated elimination, vinyl orthobenzoate IV-30 was obtained. Unexpectedly, acid catalyzed transorthoesterification of vinyl orthobenzoate IV- 30 with diol did not furnish the desired cyclic orthoester. Instead, acetal IV-32 was identified as the major product. The mechanism of generation of IV-32 was postulated as shown in Scheme IV-l7. Treatment of vinyl orthobenzoate with acid catalyst resulted the generation of acetaldehyde, which would further compete with orthobenzoate for transesterification to form the five-member ring acetal as the major product. Scheme I V-I 7. Acid catalyzed reaction of vinyl orthobenzoate and diol PhC(OCH=CH2)3 H30 OH 0%H IV-30 H3C(H20)7/'\/ ' H3C(H20)7/|\/ cat. PPTS IV-20 CHZC'Z lV-32 + H+ A O Cl)I-CH=CH2 PhC(OCH=CH2)3 —> Ph?—(60H=CH2)2 —> /lLH + Ph-C-OCH=CH2 IV- H’9_\ 30 \ OH OH H30(H20)7 lV-20 PPTS v H30 0 H o HaC(HzC)7 IV-32 211 Scheme I V-18. Attempt to synthesize triphenyl orthobenzoate from dithioester and dialkoxydibutylstannane 1) HMPA, NaH, DMF, Benzene s/W 130-150 °C. 2 h cat. PTSA Ph 2) Mel 8% 86% lV-33 S Ph/u\SMe IV-34 neat No Reaction < + 70 °C, 36 h BU28n(OPh)2 lV-35 tetralin, reflux 3% BUZSnO + 2PhOH Due to the unwanted side reaction, vinyl orthobenzoate was abandoned and we further inspected the other potential none nucleophilic orthoesters, such as triphenyl orthobenzoate IV-27. Several approaches were pursued in order to obtain this molecule. Firstly, Sakai20 et al. have shown the preparation of orthobenzoates from dithio esters and dialkoxydibutylstannanes, which inspired us to attempt the synthesis of triphenyl orthobenzoate following a similar approach. The two coupling partners, methyl dithiobenzoate and diphenoxydibutylstannane were synthesized separately following reported procedures. Benzaldehyde was converted into its ethylenethioketal IV-33. Treatment of the latter with sodium hydride in DMF containing HMPA, followed by 212 direct reaction with methyl iodide gave methyl dithiobenzoate IV-34.21 Diphenoxydibutylstannane IV-35 was obtained by refluxing dibutyltin oxide and phenol in tetralin. The mixture of IV-34 and IV-35 was then heated to 70 °C without any solvent as instructed. After 36 hours, no reaction had occurred. Since there is no precedent of this protocol being applied to the synthesis of phenoxy orthoesters, the low nucleophilicity of the phenol might be the reason for the failure of this reaction. Synthesis of triphenyl orthobenzoate was also attempted following the procedure published in a patent.22 The patent described a copper (I) mediated coupling reaction of a,a,a-trichlorotoluene and sodium phenoxide to yield triphenyl orthobenzoate. Unfortunately, even though the procedure was strickly followed, the reaction could not be driven all the way to form the orthoester, instead, only partial substituted a,a-dichloro-a— phenoxytoluene was formed. Different copper (I) catalysts, such as CuI and CuCl, were used, and no orthoester product could be observed under either condition. An alternative route, a base mediated coupling reaction of a,a,a-trichlorotoluene with phenol, was then attempted.” The reaction smoothly generated 24% of the desired triphenyl orthobenzoate IV-27 as a white powder after recrystallization (Scheme IV-19). Scheme I V-19. Synthesis of triphenyl orthobenzoate from a,a,a-tiichlorotoluene Cul, PhONa PhCC|3 > PhCCI2(OPh) ACN, 50 °C, 12 h IV-36 CUCI, PhONa PhCCl3 ; PhCCI2(OPh) ACN, 50 °C, 12 h IV-36 PhOH PhCC|3 > PhC(OPh)3 Pyridine 24% IV-27 213 Table I V-2. Triphenyl orthobenzoate mediated intermolecular nucleophilic addition of cyclic orthoester 0H 1) Acid I, PhC(OPh)3 H > Product H3C(H20)7 2) Acid ll, allyl alcohol — entry Acid 1 Acid 11 Solvent 36%;) Product Y(:7:l)d 1 cat. PPTS - CH2Cl2 rt S. M. 0 2 cat. PPT S - CH2C12 50 S M O """""""""""""""""""""""""""""""""""""""""""""""""""""""""" O 82 l.0eq. OH 3 TF A TMSOTf CH2Cl2 rt 7 50 W25 .......................... l.0eq. 4 TF A TMSOTf Toluene reflux Decomp. - ................................................................................. O 82 lOeq. 2.0eq , OH 5 TFA TFA CH2Cl2 ft 7 60 ................................................................................. ' V25 082 O CF3 l.0eq. l.0eq. W 6 TF A 3133.032 CHsz rt 7 \g/ 30 'V37 .......................... l.0eq. 7 PTSA - CHZCIZ rt S M O """"""""""""""""""""""""""""""""""""""""""" OBzOTs . q. 8 PTSA - Toluene 85 7 7 46 ......................................................................... !‘.’:§§--__----_'.\!:§?.-_------------_-- OBZ OTs 10 won 082 . eq 9 PTS A TMSOTf Toluene 85 7 7 37 ....................................................................... !Y:?§..-------l\!:3?._---------------- ' OBz l.0eq. Won 10 BF3-0Et2 - Toluene rt 7 50 214 Cont. Table I V-2 . . Temp. Yiled entry Acrd I ACld II Solvent (0 C) Product (%) 082 1.0 eq. Wow 11 BF3-0Et2 - Toluene 70 7 \ ................................................................................ ”27 082 1.0 eq. O\/\ 12 BF3-0Et2 - Toluene 80 7 \ ................................................................................ ”27 082 13 1'0 eq' - Toluene 90 OW 24-31 BF3'OEI2 7 ................................................................................ ”27 082 1.0 eq. O\/\ 14 3133032 - Toluene 80 7 \ ................................................................................ ”27 082 1.0 eq. O\/\ 15 BF3'OEI2 - Toluene 80 7 \ ................................................................................ 'V27 16 1'0 eq' - THF rt 3. M. o BF3°OEt2 With triphenyl orthobenzoate IV-27 in hand, a series of experiments were performed in order to optimize the reaction. The optimization was mainly focused on the two acid catalysts, one for the transorthoesterfication of triphenyl orthobenzoate and diol, the other for the activation of the cyclic orthoester intermediate. The solvent and reaction temperature were also taken into consideration. The results are shown in Table IV-2. First, using PPTS, the same acid we used in our intramolecular cyclization strategy, as the acid catalyst for the transorthoesterification was not successful. No cyclic orthoester 215 was formed at It or elevated temperature (entry 1 and 2). A stronger acid was reqiured for this transesterification due to the low reactivity of triphenyl orthobenzoate. Thus, we switched to trifluoroacetic acid to promote the transorthoesterification reaction. At room temperature, the transorthoesterification was successful. However, the second step, nucleophilic ring opening of the cyclic orthoester by alcohol, failed to generate the desired product when TMSOTf was used as the Lewis acid promoter, instead only hydrolysis occurred (entry 3). The reaction was also performed at elevated temperature in order to accelerate the second step of the reaction. However, decomposition of the starting material occurred under these conditions (entry 4). Adding 2.0 equiv of additional TFA with the nucleophilic allyl alcohol gave no desired product (entry 5). Thus, it is demonstrated that the addition of a Lewis acid promoter is reqiured for the ring openning of cyclic orthoester. BF3-0Et2 was then tested (entry 6). To our surprise, an unanticipated product IV-37 was isolated in 30% yield. The generation of this product was postulated resulting from the ring openning of the cyclic orthoester by trifluoroacetate. p-Toluene sulfonic acid (PT SA) was also tested as the acid promoter for the transorthoesterification. No reaction occurred at rt (entry 7). However, at 85 °C in toluene solution, compound IV-38 and IV-39 were isolated as the major products (entry 8). Similar to the reaction promoted by TFA, the sulfonic anion acting as the nucleophile competed with allyl alcohol for the nucleophilic reaction. The situation was not improved when a second Lewis acid, TMSOTf, was added (entry 9). In the previous chapter, we have shown that the one-pot intramolecular cyclization reaction of 1,2,n-triol could be further simplified to one-step process by using 216 BF3-0Et2 alone as the catalyst for both transorthoesterification and nucleophilic cyclization. Herein, the same strategy was attempted for the intermolecular reaction. At room temperature, only hydrolysis products were isolated. Fortunately, when the reaction was performed at elevated temperature, the desired product was produced, albeit in quite moderate yields (24-31%). The rest of product was still the monobenzoate, which comes from the hydrolysis of the cyclic orthoester. The delicate temperature change seems to have no effect on the reaction outcome (entry 11, 12, 13) as well as changing the equivalence of the Lewis acid catalyst used (entry 14 and 15). Finally, triethyl borane was tested as the Lewis acid promoter with no luck. 4.3 Conclusion An orthoester mediated coupling reaction of a vicinal diol and a nucleophilic alcohol was investigated. The cyclic orthoester intermediate acts as the epoxide equivalent, taking the advantage of the ease to define the stereochemistry using Sharpless asymmetric dihydroxylation reaction. The major drawback of this strategy is the generation of the side product when trimethyl orthobenzoate was utilized. The competition of nucleophilic ring opening between methanol, a byproduct of transorthoesterification, and the nucleophilic alcohol remains to be a problem. Using a none nucleophilic orthoester, triphenyl orthobenzoate, produces the desired product, albeit in moderate yield. 4.4 Experimental General information 217 All commercially available starting materials were used without further purification. Commercially available starting materials were obtained from Aldrich, Fisher, Nu-Chek-Prep, Lancaster, TCI. 1H, 13C, gCOSY, gHMBC, DEPT and nOe spectra were recorded on either a 300 MHz NMR spectrometer (VARIAN INOVA) or on a 500 MHz NMR spectrometer (VARIAN VXR). IR spectra were recorded on Nicolet IR/42 spectrometer using NaCl cells. Column chromatography was performed using Silicycle (40-60 pm) silica gel. Analytical TLC was done using pre-coated silica gel 60 F254 plates. GC analysis was performed using HP (6890 series) GC system (Column type-AltechSE-54, 30 m x 320 um x 0.25 um). HPLC analysis was performed using HITACHI LC-ORGANIZER (Column type chiral AD or CD). Unless otherwise mentioned, solvents were purified as follows. THF and EtzO were distilled from sodium benzophenone ketyl. CHZCIZ, toluene, CH3CN and Et3N were distilled from CaHz. DMF, diglyme, and DMSO were stored over 4 A molecular sieves and distilled from CaHz. All other commercially available reagents and solvents were used as received 2-Methoxy-2-methyl-4,5-diphenyl-[1,3]dioxolane IV-7 >=< Ph Ph 220 Compound IV-15 was obtained from compound IV-14 following same reaction procedure as described for IV-10. 1H-NMR (300 MHz, CDCl3) 5 1.2-2.0 (m, 10H), 3.83 (m, 1H), 6.57 (s, 1H), 7.25 (m, 8H), 7.45 (m, 2H). Alloxyl stilbene IV-19 H _ O—’/= PhHPh Compound IV-19 was obtained from compound IV-18 following same procedure as described for IV-10. 1H-NMR (300 MHz, CDC13) 5 4.44 (d, J = 5.5 Hz, 2H), 5.29 (dd, J = 1.6, 10.4 Hz, 1H), 5.39 (dd, J = 1.1, 17.0 Hz, 1H), 5.97 (m 1H), 6.52 (s, 1H), 7.25 (m, 10H). l3C-NMR (75 MHz, CDCl3) 5 73.7, 117.9, 120.6, 126.4, 126.5, 127.9, 128.2, 128.4, 129.9, 133.6, 137.6, 140.5, 144.6. Acetic acid lnallyloxymethyl-nonyl ester IV-21 l-Allyloxy-decan-Z-ol IV-22 To a solution of decan-l,2-diol (101 mg, 0.58 mmol, 1.0 eq.) and catalytic amount of PPTS in CH2C12 (5 mL) was added MeC(OMe); (0.088 mL, 0.695 mmol, 1.2 eq.) at rt. The mixture was stirred for 1 h. The solvent was then removed under reduced pressure. Freshly distilled CH2C12 (3 mL) was added. To the above solution, TMSOTf (0.105 mL, 0.580 mmol, 1.0 eq.) was added at 0 °C. After 5 min. allyl alcohol (0.079 mL, 1.16 221 mmol, 2.0 eq.) was added to the reaction mixture at 0 °C. The reaction mixture was then stirred at rt for 16 h. Saturated N aHCO3 was added, and the product was extracted with CH2C12 (20 mL x 3). The combined organic layers were washed with brine and dried over NaZSO4. After filtration, the product was concentrated under vacuum. The residue was purified by column chromatography (10% EtOAc in hexanes) to yield 12.4 mg (8%) compound IV-21 along with 18.2 mg (15%) compound IV-22. 1H-NMR (300 MHz, CDCl3) 5 0.85 (t, J = 6.0 Hz, 3H), 1.23 (s, 12H), 1.56 (m, 2H), 2.05 (s, 3H), 3.47 (d, J = 4.9 Hz, 2H), 3.98 (m, 2H), 4.99 (m, 1H), 5.21 (m, 2H), 5.87 (m, 1H). OW 1H-NMR (300 MHz, CDCl3) 5 0.84 (t, J = 6.6 Hz, 3H), 1.1-1.5 (m, 14H), 2.33 (d, J = 3.3 Hz, 1H), 3.25 (dd, J = 8.2, 9.9 Hz, 1H), 3.43 (dd, J = 3.3, 9.9 Hz, 1H), 3.77 (m, 1H), 4.00 (td, J: 1.6, 5.5 Hz, 2H), 5.23 (m, 2H), 5.90 (m, 1H). Benzoic acid l-allyloxymethyl-nonyl ester IV-23 Benzoic acid l-methoxymethyl-nonyl ester IV-24 082 CW 7 To a solution of decan-1,2-diol (96 mg, 0.553 mmol, 1.0 eq.) and catalytic amount of PPTS in CH2C12 (5 mL) was added PhC(OMe)3 (0.114 mL, 0.664 mmol, 1.2 eq.) at it. The mixture was stirred for 1 h. The solvent was then removed under reduced pressure. Freshly distilled CH2C12 (3 mL) was added. To the above solution, TMSOTf (0.120 mL, 0.664 mmol, 1.2 eq.) was added at 0 °C. After 5 min, allyl alcohol (0.075 mL, 1.106 222 mmol, 2.0 eq.) was added to the reaction mixture at 0 °C. The reaction mixture was then stirred at rt for 16 h. Saturated NaHCO3 was added, and the product was extracted with CH2C12 (20 mL x 3). The combined organic layers were washed with brine and dried over NaZSO4. After filtration, the product was concentrated under vacuum. The residue was purified by column chromatography (10% EtOAc in hexanes) to yield 96 mg (55%) compound IV-23 along with 48 mg (29%) compound IV-24. 1H-NMR (300 MHz, CDCl3) 0.85 (t, J = 6.0 Hz, 3H), 1.23 (m, 12H), 1.71 (m, 2H), 3.60 (t, J = 5.5 Hz, 2H), 4.01 (t, J = 5.5 Hz, 2H), 5.27 (m, 3H), 5.85 (m, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.53 (t, J = 7.1 Hz, 1H), 8.03 (d, J = 7.1 Hz, 2H). l3C-NMR (75 MHz, CDCl3) 5 14.1, 22.6, 25.3, 29.2, 29.4, 29.5, 31.0, 31.8, 71.3, 72.0, 73.5, 117.0, 128.2, 129.7, 130.6, 132.8, 134.6, 166.2. 082 O\ 7 1H-NMR (300 MHZ, CDCl3) 0.84 (t, J = 7.1 Hz, 3H), 1.23 (m, 13H), 1.69 (m, 2H), 3.36 (s, 3H), 3.56 (dd, J = 5.5, 8.2 Hz, 2H), 5.26 (m, 1H), 7.41 (t, J = 7.7 Hz, 2H), 7.53 (t, J = 7.1Hz, 1H), 8.03 (d, J = 7.1 Hz, 2H). Benzoic acid l-chloromethyl-nonyl ester IV-26 082 We 7 The compound IV-26 was obtained from compound IV-20 following the same procedure described for compound IV-23. 1H—NMR (300 MHz, CDCl3) 0.85 (t, J = 6.6 223 Hz, 3H), 1.24 (m, 12H), 1.80 (m, 2H), 3.72 (dd, J = 4.4, 6.0 Hz, 2H), 5.28 (p, J = 5.5 Hz, 1H), 7.43 (t, J =7.7 Hz, 2H), 7.56 (t, J = 7.7 Hz, 1H), 8.05 (d, J = 7.1 Hz, 2H). Tris-(Z-chloro-ethyl) orthobenzoate IV-313 PhC(OCH2CHZCI)3 2-Chloroethanol (11.7 mL, 0.175 mol, 6.0 eq.) was mixed with trimethyl orthoacetate (5 mL, 0.0291 mol, 1.0 eq.) and a trace of pTSA was added. The alcohol liberated was evaporated at reduced pressure. The reaction was neutralized with NaOMe. The product was distilled at reduced pressure using Kugerl to yield 5.322 g (56%) of desired product. 1H-NMR (300 MHz, CDCl3) 5 3.64 (m, 12H), 7.38 (m, 3H), 7.61 (m, 2H). l3C-NI\/IR (75 MHz, CDCl3) 542.8, 63.2, 114.2, 127.3, 128.6, 129.5, 135.9. Trivinyl orthobenzoate IV-30 PhC(OCH=CH2)3 To a suspension of NaH (2.14 g, 0.0536 mol, 3.3 eq.) in DME (5.4 mL), tert- butanol (1.38 mL) was added. Tris-(2-chloro-ethyl) orthobenzoate IV-3l (5.322 g, 0.0162 mol, 1.0 eq.) was added dropwise and the reaction system was then refluxed for 3 h until the evolution of hydrogen gas had stopped. Water and ether were added carefully, and the ether solution was washed several times with water, dried, and purified by column chromatography (hexane) to yield 1.314 g (37%) of the desired product. 1H- NMR (500 MHz, CDC13) 5 4.25 (dd, J = 6.4, 1.3 Hz, 3H), 4.69 (dd, J = 13.9, 1.3 Hz, 3H), 6.36 (dd, J = 13.9, 6.2 Hz, 3H), 7.40 (m, 3H), 7.60 (m, 2H). 224 2-Phenyl-[l,3]dithiolane Iv-334 9p, Ph A solution of the benzaldehyde (10.25 g, 96.6 mmol, 1.0 eq.) and 1,2- ethanedithiol (8.9 mL, 106.2 mmol, 1.1 eq.) in benzene (100 mL) was treated with a catalytic amount of pTSA. After refluxing with a Dean Stark trap for 5 h, the thioketal was isolated by distillation under reduced pressure to yield 15.1 g (86%) of the desired product. 1H-NMR (300 MHz, CDC13) 8 3.36 (m, 2H), 3.50 (m, 2H), 5.61 (s, 1H), 7.29 (m, 3H), 7.53 (m, 2H). Dithiobenzoic acid methyl ester IV-34 S JL Ph SMe To a stirred solution of the thioketal (15.1 g, 83.1 mmol, 1.0 eq.) in DMF (600 mL) containing HMPA (14.6 mL) under N2 was added NaH (3.32 g, 60 wt% in mineral oil, 83.1 mmol, 1.0 eq.), and the temperature of the mixture was raised to 130-150 °C and maintained for approximately 2 h. It was then cooled to rt and treated with methyl iodide (5.2 mL, 83.1 mmol, 1.0 eq.). After stirring for 0.5 h, the mixture was poured into water (1000 mL) and the product was extracted into benzene. The colored organic extract was washed with water and dried with Na2SO4. The residue obtained by evaporating the filtered extract was purified by chromatography on silica (100% hexane) to yield 1.166 g (8.3%) of the desired product with recovered starting material. 1H-NMR (300 MHz, CDC13) 6 2.77 (s, 3H), 7.37 (t, J = 8.2 Hz, 2H), 7.52 (t, J = 7.1 Hz, 1H), 7.98 (t, J = 7.1 Hz, 2H). 225 Triphenyl orthobenzoate IV-27 PhC(OPh)3 Phenol (37.6 g, 0.40 mol, 10 eq.) and anhydrous pyridine (10.5 mL, 0.13 mol, 3.2 eq.) were mixed in a round bottom flask. Benzotrichloride (5.67 mL, 0.04 mol, 1.0 eq.) was added dropwise over the course of 20 min at 53-89 °C. The reaction was allowed to continue for 4 h at an internal temperature of 110 °C and after cooling the mixture was poured onto 100 mL of ice water and extracted with methylene chloride. The organic phase was evaporated and the residue was picked up with ethanol, filtered off and recrystallized from butanol to yield 24% desired product. 1H-NMR (300 MHz, Basic- CDCl3) 5 6.95 (m, 3H), 7.12 (m, 11H), 7.23 (m, 4H), 7 .61 (m, 2H). l3C-NMR (75 MHz, CDCl3) 5 115.8, 120.4, 123.2, 127.8, 128.9, 129.3, 136.3, 152.7. 226 (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) Reference Couladouros, E. A.; Vidali, V. P. Chemistry-a European Journal 2004, 10, 3822- 3835. Rosowoslay, A. Heterocyclic Compounds with Three- and F our- Membered Rings, Part I; Wiley-Interscience: New York, 1964. Olah, G. A.; Fung, A. P.; Meidar, D. Synthesis-Stuttgart 1981, 280-282. Posner, G. H.; Rogers, D. 2.; Kinzi g, C. M.; Gurria, G. M. Tetrahedron Letters 1975, 3597-3600. Otera, J.; Yoshinaga, Y.; Hirakawa, K. Tetrahedron Letters 1985, 26, 3219-3222. Iranpoor, N.; Baltork, I. M. Tetrahedron Letters 1990, 31, 735-738. Iranpoor, N.; Baltork, I. M. Synthetic Communications 1990, 20, 2789-2797. Nicolaou, K. C.; Duggan, M. E.; Hwang, C. K.; Somers, P. K. Journal of the Chemical Society-Chemical Communications 1985, 1359-1362. Nicolaou, K. C.; Duggan, M. E.; Hwang, C. K. Journal of the American Chemical Society 1989, I 1 I, 6676-6682. Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C. K. Journal of the American Chemical Society 1989, 111, 5330-5334. Iranpoor, N.; Salehi, P. Synthesis-Stuttgart 1994, 1152-1 154. Chini, M.; Crotti, P.; Gardelli, C.; Macchia, F. Synlett 1992, 673—676. Prestat, G.; Baylon, C.; Heck, M. P.; Mioskowski, C. Tetrahedron Letters 2000, 41, 3829-3831. Yadav, J. S.; Reddy, B. V. S.; Harikishan, K.; Madan, C.; Narsaiah, A. V. Synthesis-Stuttgart 2005, 2897-2900. 227 (15) (l6) (17) (18) (19) (20) (21) (22) (23) Trost, B. M.; Tenaglia, A. Tetrahedron Letters 1988, 29, 2931-2934. Trost, B. M.; McEachem, E. J .; Toste, F. D. Journal of the American Chemical Society 1998, 120, 12702-12703. Schneider, C.; Sreekanth, A. R.; Mai, E. Angewandte Chemie-Intemational Edition 2004, 43, 5691-5694. Matsumura, R.; Suzuki, T.; Sato, K.; Oku, K.; Hagiwara, H.; Hoshi, T.; Ando, M.; Kamat, V. P. Tetrahedron Letters 2000, 41 , 7701-7704. Pinner Ber. 1883, 16, 1644. Sakai, 8.; Fujinami, T.; Kosugi, K.; Matsnaga, K. Chemistry Letters 1976, 891- 892. Gonnella, N. C.; Lakshmikantham, M. V.; Cava, M. P. Synthetic Communications 1979, 9, 17-23. Urasaki, T.; Funakoshi, W.; Teijin, Ltd., Japan: JP, 1976. Haupt, H.; Freitag, D.; Vemaleken, H.; Wagner, K.; Findeisen, K.; Bayer A-G: Ger., 1974. 228 Chapter V Kinetic resolution of racemic alkenes by asymmetric dihydroxylation using peptide-based ligands 5.1 Introduction 5.1.1 Kinetic resolution The history of kinetic resolution can be traced back to the mid nineteenth century. In 1858, Pasteur discovered that fermentation of racemic ammonium tartrate with Penicillium glaucum selectively destroys the dextrorotatory isomer.l By 1890, several enzymatic resolutions in the carbohydrate series were observed by Fischer, including the resolution of racemic hexose upon fermentation with brewer’s yeast.2 This work was part of his monumental studies that defined relative and absolute configuration of monosaccharides. The first example of kinetic resolution with non-enzymatic reagents was reported by Marckwald and McKenzie in 1899,3’4 in which an enantioselective esterification of racemic mandelic acid by (-)-menthol was described. A small amount of the less reactive l-mandelic acid could be recovered in pure form after multiple crystallizations. According to the 1996 IUPAC recommendation, the definition of kinetic resolution is as follows: “The achievement of partial or complete resolution by virtue of unequal rates of reaction of the enantiomers in a racemate with a chiral agent (reagent, catalyst, solvent, etc.)”.5 In kinetic resolution process, two diastereomeric transition states are generated during the interaction of the substrate enantiomers with a chiral reagent or catalyst. The different free energies of these transition states cause the different rate constants between the two enantiomers. The ratio k,2,.,./k,.,0,,. (equal to k,,.,) 229 controls the products distribution. ee’s of the reactants can be correlated to the conversion (C) of the substrates through an equation shown below. ln[(l-C)(l-ee)l ln[(l-C)(l+ee)] rel = The efficiency of non-enzymatic kinetic resolution has been improved dramatically in recent years since the milestone discovery of the kinetic resolution of racemic allylic alcohol substrates by Sharpless asymmetric epoxidation.6 One of the best example is shown in Scheme V—l. A high selectivity km, above 100 was observed. Within several years after Sharpless’s discovery a great number of non-enzymatic kinetic resolutions have been developed to serve the needs of synthetic chemists, and a number of reviews have been published since then?"lo Scheme V-I. Kinetic resolution of allylic alcohol as reported by Sharpless and co- workers : E0H 0): O OH \ OH + t-BuOOH fast “(Clam erythro 98:2 threo L-(+)-DIPT SIOW \“ if... t O ’ O + O (F?) kre = kfast/ kslow = 104 erythro 38362 threo 230 5.1.2 Kinetic resolution of racemic alkenes by catalytic asymmetric dihydroxylation 6,11-14 14,15 Kinetic resolution and desymmetrization of racemic allylic alcohols using asymmetric epoxidation methods have been fully investigated and have demonstrated a high degree of utility.”19 The asymmetric catalyst system is sensitive to the stereogenic center at the allylic position. The generally superior chiral discrimination for the Sharpless asymmetric dihydroxylation over the asymmetric epoxidation leads one to expect the osmium mediated SAD (Sharpless Asymmetric Dihydroxylation) will exhibit excellent discrimination in kinetic resolution when presented with a racemic chiral olefin. To date, however, only limited success has been obtained with SAD as a 20'23. The difficulty with kinetic resolution is not well strategy for kinetic resolution. understood at present. Nevertheless, the coordination of the oxygen atom of an allylic alcohol to titanium limits the possible transition state geometries and facilitates the ligand to differentiate the two stereoisomers. The absence of such a restricting tether in the SAD reaction might be implicated in the difficulty of achieving kinetic resolution. Several important examples of kinetic resolution using SAD reaction will be presented. Scheme V-2. Kinetic resolution of chiral fullerenes by asymmetric osmylation DHQ-PHN > ('l'C76 + C76(OSO4L) / 0304 (i)'Cn, ”:76, 78, 84 \ DHQD-PHN = (+)'C76 + C76(OSO4L) 0804 231 Hawkins had kinetically resolved chiral fullerenes C76, C73 and C84 using asymmetric osmylation, thus providing the first known example of an enantiomerically pure allotrope of an element (Scheme V-2).20 The Sharpless group also investigated the kinetic resolution of racemic olefins with an axial chirality element.24 An intriguing result was realized upon analysis of the diol products obtained from the kinetic resolution experiments. When the dihydroxylation was carried out in the absence of a chiral ligand, the major product arose from equatorial dihydroxylation in both instances (Scheme V-3). However, the fastest forming diol in each set of kinetic resolution experiments was that arising from axial dihydroxylation (Table V-l). This seems to be one of the rare exceptions to the general rule encountered in double diastereoselective synthesis, namely matched double 25 In this case, the fast dihydroxylation is one that would be asymmetric reaction. predicted to be mismatched by application of the principles of doule asymmetric synthesis. While the substrate used in this perticular paper are of limited synthetic utility, the results nevertheless demonstrated the kinetic resolution of racemic alkenes using SAD reaction is possible. Scheme V-3. Intrinsic diastereoselection in the dihydroxylation of exocyclic olefins R K2003 HO R Hon, R K3Fe(CN)6 , I K2OsO2(OH)4 HO HO " r + M9302NH2 t-BuOH-H2O t-Bu quinuclidine t-Bu t-Bu R=Ph 1 6 R = C02Et 1 3 1-3 232 Table V-1. Summary of kinetic resolution experiments with exocyclic olefins [1.5] olefin ligand km. Recovered olefin Ph P“ I l (DHQD)2-PHAL 9.7 t-Bu t-Bu Ph P“ l | (DHle-PHAL 5.0 t-Bu t-Bu CO2Et CO2Et I . | 6 (DHQD)2-PHAL 32.0 t-Bu t'BU | I (S (DHQ)2-PHAL 26.5 Lohray and coworkers have also investigated the utility of asymmetric dihydroxylation in the kinetic resolution of racemic allylic acetates.26 The substrate to catalyst ratio varies from 100 to 500 affording a respectable level of kinetic resolution (km; = 3 — 25). Reaction temperature and olefinic substitution patterns were systematically examined as well. Each of the reactions was carried out using the bis(dihydroquinidinyl) terephthalate (DHQD)2-TP as the chiral ligand. The best results 233 were obtained with l-acetoxy-1-cyclohexyl-3-phenyl-2—propene. summarized in Table V-2. The data are Table V-2. Kinetic resolution of sec-allylic acetates via AD with (DHQD)2TP [16] OH OAc R R O O , DHQD TP 1 2 S 4 ( )2 9’: OH do 3 K3F9(CN)6, K2003 R1 R2 OAc t-BuOH-H2O (1 :1 ) + OH 0 Ac recovered (S)- ? ? allyl acetate coonoD R1/\,/\R2 OH COZDHQD (DHQD)2TP entrL R1 R2 Subs/Cat. conv.(%) ee (%) km. 1 MC C-C6H11 100 60 47 6.7 2 250 83 98 12.0 3 500 75 84 9. 5 4 Ph c-C6Hn 500 60 88 24.5 5 100 70 98 25.0 6 Ph Me 500 40 25 6.4 7 500 80 82 7.6 8 500 90 98 8.8 9 MC n-Can 250 70 61 6.8 10 250 88 >98 9. 7 11 Ph Ph 250 70 15 4. 8 12 250 92 33 3.0 secondary allylic 4-methoxybenzoate esters using a mechanistically designed cinchona alkaloid DHQD-PYDZ-(S)-anthryl catalyst. Thus, (:)-3-buten-2-yl 4-methoxybenzoate and (1)-1-phenyl-2-propen-1-yl 4-methoxybenzoate have been kinetically resolved with relative rate constants of 20 and 79, respectively. It is stated that these values are among 234 the best reported for the kinetic resolution of racemic compounds by a non-enzymatic catalyst (Table V-3). Table V-3. Kinetic resolution of allylic 4-methoxybenzoate esters using specifically designed DHQD-PYDZ-(S)-anthryl catalyst [13] O R AD > O/IW Kinetic Resolution /[D/lL l H3CO DHQD-PYDZ-(S)-anthryl DHQD-PYDZ-(S)-anthryl Substrate Ligand ' krel 0 CH3 film/W DHQD-PYDZ-(S)-anthryl 20 H3CO o E DHQD-PYDZ-(S)-anthryl 79 o I: :l | H3CO 235 It is noteworthy that the design of this resolution process was accomplished under mechanistic guidance using the transition state model proposed for the asymmetric dihydroxylation process by their own group. The detailed descriptions of this mechanistic model were already discussed in chapter I. As they proposed, the ligand DHQD-PYDZ-(S)-anthryl processes a U—shape binding pocket with both the methoxyquinoline and the 1-anthryl walls projecting rearward of the pyridazine linker at the floor. The initial mechanistic guidance indicated that this specially designed ligand would bind the extended binding groups of allylic 4-methoxybenzoate into its deep binding pocket. Therefore, the transition state geometry would be able to accommodate the allylic substituent R for only one enantiomer of the substrate. This catalyst system not only renders an example of efficient kinetic resolution by asymmetric dihydroxylation, but also provides strong evidence for the guiding mechanistic model. In summary, the performance of the AD reaction in kinetic resolutions is generally not well behaved. However, with the few exceptions stated above, it is appears unlikely that the AD in kinetic resolution will remain underdeveloped. The scope of the AD is enormous compared to that for the asymmetric epoxidation, which is restricted for allylic alcohols only. Therefore, the kinetic resolution using asymmetric dihydroxylation will prove to be a fast route to a chiral olefin in the near future. 5.1.3 Peptide-based catalysts for asymmetric organic synthesis The development of peptide-based catalysts for asymmetric organic synthesis 27-35 consists of a fast moving area over the past decade. It is evolved from the observation of an intersection of organic synthesis and enzymology. As a chemist, we 236 are more familiar with organic synthesis, which is mainly concerned with natural product synthesis, especially those molecules with biological functions. Nevertheless, nature rivals us in this field by employing enzymes. Within the field, both target- and diversity- oriented synthesis have benefited greatly from understanding enzyme-mediated biosynthesis, so called biomimetic synthesis.36 Catalytic processes also have a tremendous impact on organic synthesis, which make reactions more atom economical and efficient. Before the introduction of peptide-based ligands, asymmetric catalysis mainly focused on the development of rigid aromatic chiral molecules which could bind to the a metal catalyst. Nevertheless, a ligand pool consisting of a great number of man- made small molecules was built and is expanded every year. On the other hand, the scope of small molecule ligands has been extending greatly in the field of biomimetic chemistry. The inclusion of simple organic molecules, especially simple amino acids and 37.38 small peptides, has resulted in a rich literature. Among these examples, a single amino acid proline has let to tremendous contributions and has remarkably extended the scope of asymmetric catalysis.39“”0 The discovery of peptide-based catalysts for asymmetric organic synthesis has not only broadened the scope of chiral ligands, but also has accelarated the ligand screening process by introduction of diversity-based combinatorial approach. Most often, the discovery of an efficient catalysis system relies on a small mutation of a novel molecule, and a subtle variant sometimes may result in a great improvement of the asymmetric outcome. Regularly, the searches for asymmetric catalysis relied on interactive approaches wherein a single compound is designed and synthesized, then tested.“ This sequence would be repeated until the catalyst reaches the desired level of stereoselectivity. 237 On the other hand, combinatorial chemistry brings together rational design and high- throughput evaluation and is especially beneficial to those reactions with little 42,43 mechanistical data available. A considerably large number of candidates are synthesized in parallel, and tested for asymmetric catalysis.”48 Peptide-based ligands are generally prepared with great ease. Various methods have been developed for peptide synthesis, including solid phase techniques, which ”'52 Because the peptides are enable one to obtain over fifty peptides in a single day. synthesized from simple amino acids, it makes the peptide-based ligands more attractive for economical considerations. Scheme V-4. Kinetic resolution by acyl transfer reaction using peptide-based catalyst[21] A020 NHAc Toluene AcQ NHAc HO NHAc H? 20 mol% Catalyst O O > + AcOH NH‘~~- 0 O NH ' "i-Pl’. \\" HN lPr O 0 """ HN i-Pr Me\ I N NH """" O Q \Boc’ OMe krel = 51 238 The examples of peptide-based catalyst in asymmetric organic synthesis including enantioselective acylation[44], phosphorylation”, conjugate addition“, allylic 5 . 5 . A representative substitution”, aldol reaction33 and Morita-Baylis-Hillman reactions kinetic resolution by acyl transfer reaction using peptide-based catalyst is shown in Scheme V456 Miller’s group described an octapeptide B-hairpin containing a modified histidine residue that exhibits appreciable enantioselectivity (km; = 51) in acylation reactions. Kinetic evaluation of this peptide unambiguously indicated that enantioselectivities are due to specific acceleration of reaction for one substrate enantiomer. And the mechanistic study revealed that the selectivity is possibly the result of enantiomer-specific hydrogen-bonding interation in the stereochemistry determining step. An efficient Ti-catalyzed enantioselective reaction of TMSCN with a variety of imines was discovered by Hoveyda’s group.57’58 The optimum ligands was identified by high-throughput screening methods. Illustrative example is shown in Scheme V-5. The resulting amino nitriles can be recrystallized to optical purity (>99% ee). A transition state model has been reported based on mechanistic and kinetic studies as well (Figure V- l).59 The phenol and imine group in the terminal of the peptide ligands acted as a handle to coordinate with Ti. Similar strategy allowed the same group developed a number of peptide-based catalysts for enantioselective additions to imines and carbonyls, including Zr-catalyzed alkylation of iminesm’m, Al-catalyzed cyanide addition to ketones62, Ag- catalyzed enantioselective Diels-Alder and Mannich reactions63’64. 239 Scheme V-5. Peptide-based catalyst for Ti-catalyzed asymmetric Strecker reaction t-Bu O PhY Ph H Ph Ph \N NNdLN/Wl/OMG Y N\ H o H o HNVH OH /\Ot-Bu i 10 mol% 10 mol% Ti(Oi-Pr)4. TMSCN, i-PrOH, V toluene, 4°C, 22 h, 0M9 hexanes >98% ee, 96% Figure V-I. Transition state model proposed for Peptide-based catalyst for Ti- catalyzed asymmetric Strecker reaction Noteworthy, Gilbertson’s group has been actively involved in the development of parallel approaches for the discovery of phosphine ligands. Their approaches based on the incorporation of phosphine-containing amino acids into peptide sequences that are designed to have stable secondary structures.32 The functions of the peptide secondary structures were demonstrated through the synthesis of a series of peptide ligands and their contribution to the selectivity of the allylation reaction were examined. An 88% ee could be achieved by a Pd-catalyzed allylic substitution reaction using the selected ligand as 240 shown in Scheme V-6. Notably, the results also demonstrated the importance of B-turn secondary structure in controlling catalyst selectivity. Scheme V-6. Asymmetric allylic substitution using peptide-based ligands OAc O O Pd-Ligand O O M 2 mol /0 Pd + t MeO OMe BSA, TB AF MeO OMe E i 88% ee, 91% yield H ' C02Me Ligand 5.1.4 Kinetic resolution of racemic alkenes by catalytic asymmetric dihydroxylation by peptide-based catalysts Corey et al has reported a proline-based catalyst which accomplished the catalytic asymmetric dihydroxylation of olefins with high enantioselectivity.65 Based on guidance from the mechanistic model, the ligand shown in Figure V-2 was designed and synthesized. An (R)-proline amide was connected by a pyridazine linker with cinchona alkaloid DHQD to form the U-shaped structure as they predicted. This ligand dramatically accelerated the dihydroxylation of a series of olefins under the same 241 conditions that have been employed previously for catalytic reactions with the biscinchona alkaloid-OsO4-K3Fe(CN)6-t-BuOH-H2O system. Figure V-3. The initial design of peptide-based ligand for asymmetric hydroxylation Based on this proline derived ligand, we postulated a peptide-based ligand for osmium mediated asymmetric hydroxylation. As shown in Figure V-3, the initially designed ligand composed of a short peptide chain that was attached to the pyridazine linker with a proline unit. The rest of the molecule still composed of the regular cinchona alkaloid DHQD. Due to the unique structure of proline, the molecule should still be a U- shaped structure with one arm that contains the binding site of 0504. Because of the ease at which peptides could be assembled, a large number of such ligands could be easily 242 prepared and tested. We hope by developing a series of peptide-based ligands, eventually achieve kinetic resolution by asymmetric dihydroxylation. 5.2 Synthetic approaches of designed peptide-based ligand Ligand V-l was designed based on our proposed model (Figure V-4). It is constituted with a tripeptide, which is attached to the pyridazine linker by an (5)-proline. The phenylalanine was chosen for its relatively rigid aromatic substituent. A modeling study using MM2 force field calculation was performed. The energy minimized structure is shown in Figure V-5. It seems plausible that the U-shaped binding pocket is retained by the quinoline ring of the cinchona alkaloid and the peptide chain with the pyridazine ring acting as the floor. Figure V-4. Peptide-based ligand V-1 243 Figure V-5. Energy minimization of compound V-l Scheme V-7. Retrosynthesis of ligand V-l. V-12 . .. V-13 244 H.., HN V-2 The retrosynthesis of ligand V-l is shown in Scheme V-7. The key step of the synthesis is relied on a Pd-catalyzed C-N coupling reaction of fragments V-2 and V-3. Compound V-3 could be accessed easily from dihydroquinidine V-12 and 3,6- dichloropyridazine V-l3 by a nucleophilic aromatic substitution reaction. 245 Scheme V-8. Synthesis of tripeptide V-2 CbZHNvCOOH Me20(OMe)2 CbZHNvCOOMe Pd/C. H2 HngCOOMe ' w _ : ——-—-—> _ ' ' 53% V-4 quantltatlve V-5 V-6 NHCbz DCC . CszN CH2Cl2/dioxane(1:1) “ COOH H rt 12 h ‘9‘ NVCOOMB ’ O /:\ 87'890A) V-7 H2N H Pd/C, H2 NVCOOMB EtOAc r O /\ 86% V-8 ' I, 4’ . 'l 75% Boc V-9 v-1o 0 Z ) HZN H DCC Z ). H N "’COOH + vkrNVCOOMe » N 'oerxi/lku 0M9 ‘ 0 \Ph 0 \\ l _ CH2CI2/dioxane (1 :1 ) l Boc O A rt, 12 h Boc quantitative v-1o v-a v-11 Z ) H O TFA I I N .”’|]/N\./ILN 0M9 ‘ H a H CH2C|2/MeOH, 5:1 0 \ 0 PH quantitative V-2 246 The two fragment pieces V-2 and V-3 were synthesized as shown in Scheme V-8 and Scheme V-9. The tripeptide V-2 was synthesized from protected amino acids. The amide bond was formed by solution-phase DCC coupling. After a series of coupling and deprotection steps, compound V-2 was obtained in good overall yield. The other piece, 5 Conversion of compound V-3, was obtained following Corey’s procedure.6 dihydroquinidine V-12 to the sodium salt with NaH in dimethylformamide followed by reaction with 1 equiv of 3,6-dichloropyridazine V-l3 afforded the cross-coupling product V-3. Scheme V-9. Synthesis of compound V-3 M o 9 MeO 0' NaH,DMF H /l + l\'l' ”“000 2 ? .. N 7 ti N7\l N / 13122:” N7\\“ /|NN N o.H Cl % o <, \> Cl v-12 v-13 _ v-3 Unfortunately, the initial attempt of the Pd catalyzed C-N coupling of compound V-2 and V-3, using 5mol% Pd2(dba)3 as catalyst, 10mol% rac-BINAP as ligand, as well as 3 equiv Cs2C03 as base, did not generate any desired coupling product. A model study using proline methyl ester V-14 instead of valuable tripeptide V-2 was conducted. Under same reaction condition, the coupling reaction was not achieved either. Only starting material V-3 was recovered after 30 hours (Scheme V-lO). 247 Scheme V-10. The attempts of Pd catalyzed C-N coupling MeO H ,. / I H o N7\l NN_N + ( >, N\/U\ OMe / \ Cl N l/ ; N O — H 5 = H o \Ph v.3 v.2 5 mol% Pd2(dba)3CHCl3 10 mol% rac-BlNAP 3 eq. CSQCO3 dioxane 55-60 °C. 30 h V N. R. 11 M90 5 mol% Pd2(dba)3CHCl3 10 mol% rac-BINAP 3 eq. 082003 H dioxane N ? ,. /IN 7 j 55-60°C,30h ‘ — + n, %7\\ /N N N COOMe 0 Cl H — v-3 V-14 Generally, the participation of secondary amines in C-N coupling reaction was not 66 Thus, increasing the amount of as facile as primary amines due to the steric reasons. catalyst and ligand was attempted in order to push the reaction toward the desired direction. Finally, the desired coupling product V-l was obtained in 24% yield at 70 °C, when 30% Pd2(dba)3 and 60% ligand was used. (Scheme V-l 1). 248 Scheme V-11. Synthesis of peptide-based ligand V-l N \ w 30 mol% Pd2(dba)3CHC13 : OMe + 0 Z 5 H 60 mol% rao-BINAP Nfl N—N N 'IIII/N\l/ILNI’(OM9 — | i H 3 eq. 032C03 H O 0 \Ph 0 V0 dioxane ’/___ 55'60 °C, 24 h 70 °C, 24 h V-3 V'2 24°/o 0 Ph ” OMe NH O H,,, o \ Although the reaction yield was quite moderate, access to this ligand promoted us to run a kinetic resolution experiment to test our proposition. The 0304 catalyzed asymmetric dihydroxylation of (:)-3-buten-2-yl 4-methoxybenzoate was performed under the standard asymmetric dihydroxylation conditions. Our newly synthesized ligand V-l was subjected to the reaction vessel as the chiral ligand to induce the enantioselectivity. Two enantiomeric isomers of (.t)-3-buten-2-yl 4-methoxybenzoate could be separated on chiral HPLC column. After 6 hours, the unreacted alkene was analyzed by chiral HPLC, and the ee was calculated to be less than 7%. A 14% ee 3- buten-2-yl 4-methoxybenzoate could be isolated from the reaction mixture at 55% 249 conversion after 17 hours. The rate ratio between two enantiomers was then deduced to be 1.4 based on these results (Scheme V-12). Scheme V-12. Kinetic resolution of (:)-3-buten-2-yl 4-methoxybenzoate by asymmetric dihydroxylation using ligand V-l O 3 eq. K3F9(CN)5 O O 3 eq. K CO OJKQOW 2 3 d” OQ’OMe + 9W0” 1 mol% Iigan / / A/ tBuOH-HgO 1:1 A/ MO” 0.5 mol% 0504 OH V-15 0 °C - rt V-16 v-17 6 h, < 7°/o 66 17h, 14% ee krel = 1 .4 Based on the result of the above trial, the rate differece between the two enantiomeric isomers of the racemic olefin looks promising. Our goal for this project was to access a great number of peptide-based ligands in a short period time and achieve kinetic resolution of racemic olefins by asymmetric dihydroxylation based on the screening of the ligand pool. Such an objective required us to build a fast and easy route to the ligand. However, the latter route was less than optimum due to its low reliability and moderate yield. For example, the coupling of aryl chloride V-3 and a tetrapeptide V- 18 failed under the same reaction condition. No desired product could be isolated. Thus, we were more interested in installation of the proline first, which makes the final step of the synthesis to be a reliable and easy DCC coupling of the peptide and the C-terminal of the proline tethered to pyridazine and cinchona alkaloid. Pd-catalyzed C-N coupling of proline t—butyl ester with aryl chloride V-3 furnished about 20% of the desired product V- 250 20. This was not a satisfactory result because compound V-20 and starting material V-3 have similar polarity, therefore coelute on column chromatography (Scheme V-13). Scheme V-13. Pd-catalysed C-N coupling of aryl chloride and proline / Nfl N=N + _ /\ OVCI NH "’ 30 mol% Pd2(dba)3CHCl3 V-3 V-18 60 mol /0 rao-BINAP 3 eq. C82C03 dioxane 55-60 °C, 24 h V S. M. recovered N\ I 30 mol% Pd2(dba)3CHCl3 .__/ 0M9 D 60 mol% rao-BINAP Nfl N=N + %_O\C N 3 eq. 052003 0 \ / Cl ('5 H HCI dioxane ,I_ 55-60 °C, 24 h V-3 V-19 OMe OtBu ”, N_N HI” 0 N o ’ \ N \ V-20 ~20°/o by NMR inseparable with SM. 251 For the Pd catalyzed cross coupling reaction, it is a general rule that the aryl iodide is more reactive than aryl chloride. The relatively weak bond strength of C-1 bond makes it a better reactant in oxidative addition processes. Thus, the synthetic route of aryl iodide V-22 was designed as depicted in Scheme V-14. It commenced with 1,3- dichloropyridazine V-13, which was heated with 47% HI and 1C] to yield 1,3- diiodopyridazine V-21 in 16% yield after recrystallization. Compound V-21 was then reacted with the sodium salt of dihydroquinidine to furnish the desired aryl iodide V-22 smoothly in 90% yield. Scheme V-14. Synthesis of aryl iodide V-22 CIflCI HI (47%) 7» lfll N=N N=N ICI, 70 °C 16% after recrystallization V-13 V-21 N N I ‘ 03L f OMe f OMe : 1 NaH, DMF, 1h : ”A + lfl—I ) > N7\ N=N ”’I— 900/0 .0, V-12 V-21 V-22 However, the Pd-catalysed cross-coupling reaction of aryl iodide V-22 and proline t-butyl ester V-19 only yielded reductive product V-23. To optimize the reaction, Buchwald’s bulky phosphine ligand V-24, which was reported to give better yields in Pd- catalyzed amination of aryl iodides“, was used instead of racemic BINAP. Since 252 moisture sensitivity in this type of reactions is common, the experiment was performed in a drybox to exclude any possible moisture. Disappointingly, still no desired product could be isolated under this condition (Scheme V-15). Scheme V-15. Attempts of Pd-catalyzed C-N coupling using aryl iodide N \ CE) OMe O Pd2(dba)3 CHC|3 ._. OMe N=N > 2 _ N N N_N H U COO’B“ BINAP, 052003 v-22 v-19 v-23 .... \ [z O? \ / ' HHCl <12 0? dioxane, 55-60 °C I” ll ‘ e l ) Pd (db ) N i _ ., 2 a 3 A N_N + N .0008“ MR. 0 / H \ HCI O PCYZ M92N ] V-24 K3PO4, DME, rt - 60 °C in dry box The cross-coupling of aryl iodide V-22 and proline derivative V-l9 was also attempted under Pd-free conditions, including base catalyzed SNAr reaction and Cu(I) mediated C-N coupling“. Unfortunately, the results were not encouraging either as shown in Scheme V-16. 253 Scheme V-16. SNAr and Cu(I) mediated coupling of aryl iodide with proline derivatives N\ l / 052003 § OMG i j Dioxane N7\o N=N l + N WCOO’B“ ldt be 150 °C> S'M' v HHCI seae u , V-22 V-19 N I \ =/ OMe i j Cul N t _ ., = \ / HHCl WA, 90 oC V-22 Because of the failure of the Pd-catalyzed cross-coupling, an alternative route commenced where amination of dihalopyridazine with proline derivative was investigated. In the presence of Cs2CO3, dichloropyridazine reacted with proline t-butyl ester at elevated temperature in a sealed tube to furnish compound V-25 in 69% yield. This aryl chloride then reacted with the sodium salt of dihydroquinidine. However, no nucleophilic aromatic substitution reaction occurred because of the electron-donating property of the amino group on the para- position of the chloride. The same result was obtained for the aryl iodide V-26 (Scheme V-17). 254 Scheme V-17. The alternative route commenced with amination of dihalopyridazine with proline derivative N‘“ 082003 N-N Cl-—<_>—CI + Z > Ot-Bu > / \ dioxane, sealed tube Cl N O HCI 150 C, reflux 16 h V-13 V-19 69% V-25 N\ O Ot-Bu @OMQ /N-'\{ 1. NaH, DMF, 3 I'l‘ S M : + r ' ' OH 2.18h "’1... V-12 V-25 O Ot-Bu N—N CSzCO3 N-N |/\|+z>-.,’Ot-Bu >|/\N — l-hl‘ n/ dioxane, sealed tube — Q o HCI 150 C, reflux 16h v-21 we 80% V'26 I N\ O Ot-BU _ 1.NaH,DMF,3h :/ OMe + N N\ T I / N r s. M. Nfl 2.18h OH ll,— V-12 V-26 255 Because of the strong electronegativity of fluorine atom, aryl flouride is generally considered to be a better reactant in an SNAr reaction. Therefore, a synthetic route was revised to include an aryl fluoride in the nucleophilic aromatic substitution reaction. 1,3- difluoropyridazine was accessed from 1,3-dichloropyridazine by a halogen exchange reaction. 1,3—dichloropyridazine was heated to 150 °C in a tetramethylene sulfone solution containing potassium fluoride and catalytic amount of 18-crown-6. The desired product 1,3-difluoropyridazine was isolated in 22% yield, eventhough the conversion of the reaction was quantitative based on GC analysis. The high volatility of 1,3- difluoropyridazine was the major cause for the low isolated yield (Scheme V-18). Scheme V-18. Synthesis of 1,3-difluoropyridazine N-N KF N-N Cl / \ CI = F / \ F — tetramethylene sulfone — 18-crown-6 V-13 150 °C V-27 22% The nucleophilic aromatic substitution reaction of dihydroquinidine V-12 and difluoropyridazine V-27 was investigated and the reaction conditions were optimized as shown in Table V-4. Adopting the previous reaction conditions, 3 equiv of NaH in DMF generated 30% of the desired product. The unreacted starting material dihydroquinadine was recovered (entry 1). Utilizing different polar solvents, such as DMSO (entry 2) and dioxane (entry 3) did not help the reaction achieve better yield, neither increasing the reaction temperature led to any improvements (entry 3). The recovery of the starting material led us to suspect the low yield of the reaction was due to the sluggishness of the nucleophilic aromatic substitution. Thus, an excess amount of NaH was employed in 256 hope to accelerate the reaction. As shown on entry 4 (Table V-4), 10 equiv of NaH was added to the solution of dihydroquinadine in DMF. Unexpectedly, no reaction occurred under this condition. The above observation led us to believe that the excess amount of base (NaH) does harm the reaction yield. Due to the ease of the SNAr reaction with aryl fluorides, the excess hydride in the reaction system might compete with the alkoxide for the nucleophilic aromatic substitution. Therefore, as shown in entry 5, decreasing the amount of NaH to 1 equiv increased the yield of the desired product V-28 to 62%. Table V-4. The optimization of SNAr reaction of difluoropyridazine with dihydroquinadine N\ N 03 / : 0M9 N—N 1.NaH _/ 0M9 N” F / \ I: ———> Nfl N N OH + — 2.12h % o \‘/ F I’ ‘III V-12 V-27 V-28 entry reaction condition yield (%) 1 3.0 equiv NaH, DMF, rt 30 2 3.0 equiv NaH, DMSO, rt 30 3 3.0 equiv NaH, dioxane, reflux 27 4 10.0 equiv, NaH, DMF, rt 0 5 1.0 equiv, NaH, DMF, rt 62 257 With aryl fluoride V-28 in hand, it was subjected to the nucleophilic aromatic substitution reaction with D-proline. Potassium carbonate was used as the base, and the reactants were heated at 100 °C in a 1:1 mixture of water and DMSO. The reaction went smoothly to afford 76% desired product V-29 (Scheme V-19). Scheme V-19. Synthesis of compound V-29. 1 N‘ / OH N § N N OMe + K2003 = Z > "I a I”, Hu, 0 o F N COOH DMSO - H20 1 : 1 N-N , 100 °C, 12 h _ — 76% \ V-28 V-29 With compound V-29 in hand, we expected the rest of the molecule could be assembled easily through a DCC coupling reaction. However, the DCC coupling reaction between carboxylic acid V-29 and a C-terminal protected peptide H-Tyr(Me)-Ser(bzl)— Val-OMe V-30 did not yield any desired ligand, but a deep green compound with high polarity was formed that could not be isolated and identified. N,N’- Diisopropylcarbodiimide was utilized as the coupling reagent to connect a different peptide H-Trp(Boc)-Cha-Gly-0Me V-3l and carboxylic acid V-29. Similar result was obtained for this trial, no desired product could be detected after 3 days (Scheme V-20). 258 Scheme V-20. The attempt of coupling of V-29 with C-terminal protected peptides OH H o DCC’ CHZCIZ no desired + H-Tyr(Me)-Ser(le)-Val-OMe 48h r product N \ v-29 v-3o OH DIC, DMF . 0 + H- Trp (Boc)-Cha-GIy-OMe 3 d > “0 des'red product \ V-29 V-31 Since the failure of these trials, we did a series of experiments to test various amidation reagents, which are common coupling reagents used in peptide synthesis. In order to save precious peptides, which were accessed from simple amino acids by multistep processes, a simple amino acid derivative valine methyl ester was used instead of the peptide chain. The results have been summerized in Table V-S. None of these coupling reagents, DCC, CDI, EDC, BOP, HATU and EEDQ, could furnish the desired product (entry 1-6). Furthermore, the mixed anhydride method and acid chloride mediated amidation also failed. 259 Table V-5. Attempts of coupling reaction between carboxylic acid V-29 and valine methyl ester OH ., H O Coupling reagent ’ N-N + H-Val-OMe > N o ’ \ N \ V-29 entry reaction condition yield (%) l DCC, CHZCIZ 0 CD1, CH2C12 EDC, CH2C12 BOP, HOBt, TEA, ACN HATU, HOAt EEDQ, EtOH—Benzene (1:1) NMM, ClCOzEt, DMF NMM, ClCOzEt, THF \qummhww 1oooooooo SOC12 Proline’s unique turn structure makes the carboxylate in compound V-29 not quite accessible. The compound V-29 was relatively congested sterically. Therefore, compound V-32 was synthesized, which was equipped with a glycine instead of a proline. However, DCC coupling between compound V-32 and valine methyl ester failed also as 260 previous trials (Scheme V-21). This led us to believe that the failure of the coupling reaction was not a direct result of the sterics of compound V-29. Scheme V-21. Attempt of coupling reaction between valine methyl ester and compound V-32 OMe N . 0M9 K2003 7\ N:~ + HZNVCOOH-HCI > o / F DMSO - H20 N-N Nfi—coorr 1:1 NO-U— 100 °C, 12 h V-28 V-32 OMe I, H DCC " N-N /—COOH + H-Val-OMe. —> no desired product V-32 It is a bit surprising that all of these efforts to connect a simple amide bond met with failure, since cross-coupling reaction of a carboxylic acid and an amine was generally quite facile. This challenge did not stop us but rather prompted us to investigate the mechanism behind the failure of these coupling reactions. There is one common phenomenon of all of these reactions, that is the formation of a substance with dark color. The formation of this dark colored compound might be the problem for all of 261 these coupling reactions. It suggested that during the coupling reaction, a highly conjugated intermediate was formed which interrupted the condensation reaction. Due to the high polarity of this substance, it can not be isolated nor identified through common procedure. Although without solid evidence, we made a bold proposition that this undesired highly conjugated system could be disrupted by using a B—amino acid in place Scheme V-22. Synthesis of B-D-proline O 1)NMM, EtO/U\Cl Boc 3°C 0 THF,-5 °C, 10min N TsCl, TEA, cat. DMAP > OH OH 2) NaBH4, 12, THF,0°C (f CH2C|2, 000,311 12“ 81 % v-1o 70% v-33 v m “0' 12 N HCI - AcOH Boc Boc (5:1) N KCN 3e . N reflux DMSO, 90 oC quant. V-36 v-35 v-34 76% B-Proline was synthesized according to a reported procedure”. The synthesis commenced from Boc protected D-proline. A mixed anhydride was formed by NMM catalyzed reaction with ClCOzEt. The following NaBH4 reduction gave Boc protected amino alcohol V-33 in 70% yield. The free hydroxy group was then converted to its tosylate V-34, which was subsequently substituted by a cyano group to generate compound V-35 in 76% yield. Finally, an acid catalyzed hydration of cyanide V-35, and removal of the Boc protecting group at the same time, furnished fi-proline as its hydrogen chloride salt V-36. No further purification was necessary (Scheme V-22). 262 B-Proline HCI salt V-36 was reacted with aryl fluoride V-28 in the presence of excess potassium carbonate to yield compound V-37 in excellent yield (Scheme V-23). Scheme V-23. Synthesis of compound V-37 OMe ., H H HCI K2003 COOH I’ N-N + (fCOOH . > N o , \ F DMSO-H20 (1.1) N — 100 °C — s 96 % \ \ V-28 V-36 V-37 Gratifyingly, DCC coupling of compound V-37 with peptides went on smoothly to furnish the desired peptide-based ligands. A series of ligands were synthesized; the synthetic efforts for the preparation of these ligands are shown in Scheme V-24 to Scheme V-37. All the peptides were synthesized by DCC coupling along with necessary protections and deprotections, the details of which will be discussed in the experimental section. Although we use multi-step solution phase synthesis to access short peptide chain, it might be more productive and efficient to use solid phase methods. Herein, we just intend to show a demonstration of kinetic resolution of racemic olefins by osmium mediated asymmetric dihydroxylation using peptide-based ligands. A larger ligand pool would appear in the future. 263 Scheme V-24. Synthesis of DHQD-PYD-B-(D)-Pro-(L)-Trp—(L)-Val-OMe V-40 O o O 7' i ——> i \ + /\ DCM \ 0 EtOH NH 92 % NH 75 % V-38 o H2N o o v-37, occ \AN‘Il/ \ H - H O \ ‘ o /"'\ 68 % NH \ V-40 V-39 264 Scheme V-25. Synthesis of DHQD-PYD-B-(D)-Pro-(L)-Ser—(L)-Val~0Me V-44 O o O ._ DCC — z HN\;/1LOH H2N\.)LOM z NH/lLNH o\ _ ‘ 5 CH CI = t—Bu-O/ /\ quzanf t8 -0/ O v.41 Pd/C, H2 EtOH 88 % l t-Bu\O ‘ H 0 J1 N VLO/ v-37,occ 11...; M. o\ H s < = O /\ CH20|2 f-BU-O/ O 76% v-42 265 Scheme V-26. Synthesis of DHQD-PYD-B-(D)-Pro-(L)-Met-(L)-Val-OMe V-47 o z o Z-HN\:)L OH 0 HN\;/‘LNH o\ Hqu/KOMG 000 O l/ + ———> —* /S /\ CH2Cl2 /S Pd/C, H2 87 °/o EtOH v-45 .0 \S 12 / V o o H N N\./u\o/ H Ni 0 N H 5 v-37, occ 2 ; NH \ O /\ <—————— : O / N CH2012 K 67 % /S v-47 V-46 266 Scheme V-27. Synthesis of DHQD-PYD-B-(D)—Pro-(L)-Tyr-(L)-Val-OMe V-Sl 0 0 z—HN\)LOH o z—NHl/lLNH 0\ O; +H2N\3/U\OMGDC _.__> ; O _ CH20|2 t'BU\O /\ (“BU\O Pd/C, H2 92 % V-48 EtOH t-Bu—O 80 °/o V-37, DCC o o N\_/U\O / CH20|2 HzNi/U‘NH O /\ 75 °/o /©/. 0 N t” \ @— Bu 0 I2 V-49 HO V-50 TFA I > o H o CH2Cl2 N N . O/ 91 % N H o /=\ / N V-51 267 Scheme V-28. Synthesis of DHQD-PYD-B-(D)-Pro-(L)-Lys-(L)-Val-OMe V-55 o g o Z-HN\;/1k HN\;)LNH o\ O OH ——> O —‘ A CH2C|2 Pd/C,H2 Boc/NH Boc,NH v 52 EtOH ' 82 % two steps V BOC\NH J1 H N O 0 H 0 V-37,DCC 2 5 NH \ N N O/ <—— " Q N-N H E CH2C'2 ’ O /\ 81 % N O \ / N ,NH Boc v-53 v-54 NH2 OMe TFA,CHZC|2, MeOH > O H O 79 "/0 I, N N 2 O/ I’ N=N H O /:\ N GUN \ V-55 268 Scheme V-29. Synthesis of DHQD-PYD-B-(D)-Pro-(L)—Asn-(L)«Val-0Me V-58 O O Z-HN HN % J Jim HZNY + g ——> HZNY O —— /\ DMF O 37 % O Pd/C, H2 V'56 EtOH 65% 0 v 0 3H2 0 O /\ CH CI N 2 2 H2N\"/ O 65 % O \ V-58 V-57 Scheme V-30. Synthesis of DHQD-PYD-B-(D)-Pro-(L)-His—(L)—Val-OMe V-61 H O Z,N\:/IL OIt‘ll'ICfOMe ’N\/U\OH z ; + HzNjL N : OMe ——C> (Nj/ (Elf /\ CHZCIZ Pd/C, H2 I 7% Z 5 ZN V-59 MeOH 83% H r“ v \ N / O 0 “JL v-37, DCC HzNgL CROW? u ; OMe o /-\ (sz012 (NJ/ N 0 45/0 HN \ V-61 _ v-so 269 Scheme V-3I. Synthesis of DHQD-PYD-B-(D)-Pro-(L)—Asn—(L)-Phe—OMe V-65 O O H2N\:/U\OH Me2C H2N\;/lk0/ cat. HCI rt 68% V-62 O o H H2N\)]\O/ ,N\/IL DCC H O é Z 2 OH I Z/N N 0\ —— + N : 5, er w - Ho 0 41% I Pd/C, H2 MeOH V-62 was 790/ V H2N 0 o 0 M7. DCC 0 Pk/lk = H2N\/lLN o\ ’1 u ; 0M9 CHzclz H N E H O ” N—N o ; o 2 N O / \ N j 80 /° F \ V-65 V-64 270 Scheme V-32. Synthesis of DHQD-PYD-B—(D)-Pro-(L)-Asn-(L)-Trp-OMe V-70 H O H O : ——> :- o HZN \JLO/ Pd/C, H2 ——> HN \ M90“ HN \ M90” HN \ 62% 86% v.55 V-67 O O H2N\)LO/ H o o \ NH 5 ,N H HN \ + Z 5 OH DCC Z’N\-/U\N O\ H2N ' —-> i H '— \fl/ DMF HZNW/ O O 53% O Pd/C, H2 MeOH V-67 V-68 45% Y ° 0 0 ”Hz 0 N N / O \ NH H i v-37, DCC O / ‘ H2N\/U\N o\ N NH 5 H - 74 % \H/ E\ O v-7o V-69 271 Scheme V-33. Synthesis of DHQD-PYD-B-(D)-Pro—(L)-Asn-(L)-t-BuGly-(L)-Val- OMe V-75 O H2N\/IL0M9+ meHNfiOH—DE» FmocHN\)k Cargo— : CH20|2 /\ ~ . /I\ 83% Piperidine V'" CH2 0:2 4 h, 'rt, 277% N / _ {Hi} filo—EH \__/lol\o ZAsn-OH H N\)L E \”_NH2 0 /\ DCC Pd/C H2 0 CH2C|2, 42% MeOH 73% V-73 V-72 V H2N\/1L OirNEJOLO / v-37 DCC CH CI ,73%> firm" A 2 2 OMe ' Ii \ V-75 272 Scheme V-34. Synthesis of DHQD-PYD—B-(D)-Pro-(L)—Val-(L)-Asn(Trt)-0Me V-80 0 o NH2 triphenyl methanol NH(Trt) TMSCHN2 NH (Trt) $ ———> 0‘32”” OH ”320' °°"°- H2304 CszN OH MeOH. 50% CszN 0M9 AcOH, 50 °C, 1 h 0 O 74% V-76 v.77 Pd/C, H2 MeOH, 91 °/o 1) z Val-OH NH(Trt) DCC, cnzcu2 NH(Trt) HZN/{LN =2) Pd/C, H2, MeOH H2N 0M9 65% two steps 0 V-79 V-78 OMe 0 O V-37, DCC H H Njgf NE/lko/ CH2C|2, 72°/o ’6 N-N H — o ‘ NH(Trt) N lo—§_/)—N \g’ V-80 273 Scheme V-35. Synthesis of DHQD-PYD-B-(D)-Pro-(L)-Asn(Trt)-(L)-Val-0Me V-83 NH(Trt) NWT”) H-Val-OMe Hi Pd/C. H2 OH > N CszN DCC,CHZC|2 CszN é OMe MeOH 31% 0 /\ 98% v-a1 { r ONH(Trt) o YCOOM" v-37 NH(Trt) o N: o H N Oi)— DCC, CH2C|2, es/o HZN NJOMB O A V-82 Scheme V-36. Synthesis of DHQD-PYD-B-(D)-Pro-(D)-Asn-(L)-Val-OMe V-86 o o g o Z-HN HN 0 0” H2N\/U\OM9 DIC NH \ H2N + 5 ———> H2N O —- /\ DMF V'“ EtOH 65% V o j—NHz o o N’firN/iLO / ‘ v-37, DCC H2N NHIKK CHzClz H2N o 65 % o V-85 274 Scheme V-37. Synthesis of DHQD-PYD-B-(D)-Pro-(L)-Asn-(D)-Val-OMe V-89 Z‘HNiJLOH thIkOMe DIC HNgCLNHZrO— H2N ——> H2N WOI/ + DMF \n/ 37 % O Pd/C, H2 V'87 EtOH 65% O NH V O H 2 O \_/ H « meg N O CH2Cl2 HZN \n/z \ / 65 % O \ V-89 V-88 5.3 Kinetic resoultion of racemic olefins by 0804 mediated dihydroxylation using peptide based ligands Kinetic resolution studies using the above peptide-based ligands were performed. First, (1)-3-buten-2-yl 4-methoxybenzoate was chosen as the racemic olefin, since it could be easily separated on chiral HPLC column. Ligand V-40, V-44, V-47 and V-Sl were tested under the same reaction conditions described before; the results are summarized in Table V-6. The resolution experiments were carried out as following procedure. A mixture of K3Fe(CN)6 (0.24 g, 0.73 mmol, 3.0 equiv), K2C03 (0.10 g, 0.73 mmol, 3.0 equiv), Ligand (0.0024 mmol, 0.01 equiv), alkene (0.24 mmol, 1.0 equiv) and internal standard in 3 mL of 1:1 tert-butyl alcohol-water (or the designated solvent system) was stirred for 275 20 min at 0 °C. Approximately 0.01 mL of this mixture (organic layer) was quenched with 0.05 mL of saturated aqueous NaZSO3 and extracted with 0.2 mL EtOAc. The organic layer was analyzed by chiral GC (using undecane as internal standard) or HPLC. The reaction was initiated by the addition of 0304 (0.005 equiv), and organic layers were taken and analyzed as indicated above every 1 h (the interval of the sampling depends on reaction rate). Calculation of km, (kfas/kvlow): the relative rates of reaction of olefin enantiomers, was accomplished using the following equation: km = ln[(l-c)(l-ee)]/1n[(l- c)(1+ee)]. A plot of ln[(l-c)(1-ee)] vs ln[(l-c)(l+ee)] is linear, with slope equal to km. Knowledge of the rate constants for a pair of enantiomers allows one to calculate the extent of conversion necessary to achieve a desired enantiomeric purity. Knowledge of any two of the reaction variables will allow prediction of the third. Table V-6. Kinetic resolution of (1)-3-buten-2-yl 4-methoxybenzoate o 3 eq. K3Fe(CN)6 o 0 3 eq. K CO OJKQ'OMe 2 3 > WOMe + QJKQ'OMG 1 mol% ligand / / OH A/ t—BuOH-HZO 1:1 /\‘/\ 0.5 mol% 0504 OH v-15 0 oC_n v-1s v-17 entry Ligand km 1 V-40 l 2 V-44 1.3 3 V-47 1.8 4 V-51 1-3 276 Although most ligands showed some promise of kinetic resolution, km. values are less than 2 for all of these four ligands. The selectivity between the two enantioisomers are far less than satisfactory. The kinetic resolution of another racemic alkene (1)-a-vinyl benzyl alcohol using ligand V-44, V-47 and V-Sl was examined also. The data obtained was based on chiral GC analysis. Unfortunatedly, the two enantiomeric isomers of (:)-a-vinyl benzyl alcohol can not be differentiated by asymmetric dihydroxylation using these peptide-based ligands. It is worth noting that an allylic hydroxyl group, or other allylic functionalities with acidic hydrogens, can exert an influence on the regio- and stereochemistry of osmium mediated dihydroxylation. It is not uncommon that free allylic alcohol can not achieve good stereoselectivity in osmium mediated asymmetric dihydroxylation reactions. The stereoselectivity could be influenced by the proposed hydrogen bonding interaction between OsO4 and the allylic substituent.”72 Therefore it might expain the data shown on Table V—7 as well. Table V-7. Kinetic resolution of (:)-a-vinyl benzyl alcohol OH K3F6(CN)6 (3 eq.) OH QH K2003 (3 eq.) : / > / + OH 1 mol% ligand OH 0.5 mol% 0304 t-BUOH'H2O (1 11) Entry Ligand km] 1 V-44 l 0 2 V-47 1.0 3 V-51 1.0 277 Table V-8. Kinetic resolution of (:)-acetic acid l—phenyl-allyl ester under standard reaction conditions OAc K3F9(CN)6 (3 GQ-l OAc QAc K2C03 (3 eq.) 7 / > / + OH 1 mol% ligand OH 0.5 ”101%: 0804 t-BuOH-HZO (1 :1 ) Entry Ligand krel 1 AD-mix-B 3.5 2 V-40 3 .7 3 V-44 4. 8 4 V-47 4.0 5 V-S l 3 .9 6 V-SS 5. 1 7 V-58 6.3 8 V-6l N .R. 9 V-65 3 .6 10 V-70 3.5 l 1 V-75 6.6 12 V-80 6.1 13 V-83 5 .4 14 V-86 5 .3 15 V-89 5.8 278 Therefore it is more wise to protect the allylic hydroxy group before subjecting it to the dihydroxylation reaction. Based on this observation, acyl protected allylic alcohol (-_I:)-acetic acid l-phenyl-allyl ester was selected as the racemic olefin. This turns out to be a good substrate for kinetic resolution study because the two enantiomers show two distinct peaks in chiral GC analysis. Furthermore, the rate difference parameter km. falls into good range from 3 to 8, which makes us be able to compare the kinetic resolution abilities of different peptide—based ligands easily and accurately. The data is summarized in Table V-8. Herein, several facts need to be addressed. (1) Sharpless’s AD-mix-B gave a kinetic resolution km. 3.5. Most of our peptide-based ligands afforded a better result than AD-mix-B. (2) The seven initial ligands (entry 2 to 8) have similar structures. The only difference between these ligands was the amino acid directly attached with B-proline. Within these ligands, V-58, which was equipped with an asparagine gave the best result for kinetic resolution. Therefore, the rest of the ligands shown on Table V-8 were structure modifications based on compound V-58. (3) Ligand V-6l, which has a histidine directly attached with the B-proline, shut down the dihydroxylation process completely. The imidazoles in histidine will be osmylated, and thus shutdown the dihydroxylation process. (4) Further manipulation of the C-terminal of the peptide chain did not improve the outcome of the kinetic resoltion (entry 9 and 10). (5) It seems that a bulkier amino acid next to the Asn would improve the kinetic resoltion due to the steric effect, although the improvement was not significant (entry 11). (6) Protection of the amide in asparagine with a trityl group did not affect the kinetic resolution significantly. Therefore, the kinetic resolution is not the direct result of the basicity of the primary 279 amide group (entry 12 and 13). (7) The stereochemistry of the amino acid did not affect the kinetic resolution to a great extent. Some loss of selectivity could be observed when a D-Asn was used instead of L-Asn (entry 14). Little impact could be observed with stereochemical manipulation of the C-terminal of the peptide chain (entry 15). 5.4 Stereochemical effect of proline Initially, we utilized the unnatural proline with a (D) configuration in order to mimic the Sharpless’s AD-mix ligand. And according to Corey’s publication“, the asymmetric dihydroxylation of olefins in the presence of the ligand with an (L)-proline led to poor enantioselectivities. However, careful investigation of DHQD-PYDZ-(S)- anthryl (Table V-3), the ligand which showed good kinetic resolution of allylic 4- methoxybenzoatezz, led us to reevaluate the stereochemical effect of the proline unit. In this kinetic resolution, a U-shape binding pocket with both the methoxyquinoline and the l-anthryl walls projecting rearward is proposed. The transition state geometry would be able to accommodate the allylic substituent for only one enantiomer of the substrate. Thus, an L-proline was employed in order to mimic DHQD-PYDZ-(S)-anthryl ligand. It is postulated that by using an L-proline, the methoxyquinoline and peptide chain would point toward the same direction, therefore, preferentially accommodate one enantiomer over the other. The synthetic process was similar as we discussed in the previous section. B-(L)- Proline was obtained from Boc-protected L-proline. Two representative peptide-based ligands with a B-(L)-proline, DHQD-PYZ-B-(L)-Pro-(L)-Trp-(L)-Val-0Me V-95 and 280 DHQD-PYZ-B-(L)-Pro-(L)-Asn-(L)-Val-OMe V-96 were synthesized as shown in Scheme V-38. Scheme V-38. Synthesis of peptide-based ligand DHQD-PYZ-B-(L)-Pro-(L)—Trp-(L)- Val-OMe and DHQD-PYZ-B-(L)-Pro—(L)-Asn-(L)-Val-OMe 1) NMM, ethyl chloroformate Boc Boc ill THF, _5 °C, 10 min 111 TSC', TEA, DMAP .HCOOH 4’ .\‘\\OH Q 2) NaBH4, l2, THF \/_\/ DCM, 0 °C, 3 h T F, ° , h H 0 C 2 V-90 Y IT! HCl 000 000 N 12NHCI,AcOH N m KCN N M ( 7"“\COOH 4 V 7' \CN< i 7' \OTs reflux DMSO, 90 °C V-93 V-92 v-91 V-28 K2C03 DMSO-H20 (1 :1) 100 °C. 12 h V N I \ COOH :/ OMe E/ : N=N ' CVNfOVN/J V-94 OMe I HN / O N H 000 )L N / V-94 + H-Trp-Val-OMe —> \ H 3 fl 5 0 CH2C12 I N-N . O A N 0 / \ NO \ V-95 281 C out. OMe O N] NHZO N v.94+ H-Asn-Val-OMe ——> \ IH H\/ILO / 0142012 I’ O /:\ N O—<\ =/>—N:::1 V-96 The kinetic resolution of (:)-acetic acid l-phenyl-allyl ester by asymmetric dihydroxylation using these two ligands was examined. Results are shown in Table V-9. The km is lower than the (D)-proline derived peptide-ligand (see Table V-9). These results demonstrated that the configuration of the proline is crucial to the kinetic resolution and generally the ligand with an R- configured B-proline led to better results. Table V-9. Kinetic resolution of (1)-Acetic acid l-phenyl-allyl ester under standard reaction conditions using peptide-based ligand V-95 and V-96 OAc KaFe(CN)s (3 eq.) OAc QAc K2CO3 (3 eq.) 7 / > / + OH 1 mol% ligand OH 0.5 mol% 0504 t-BuOH-HZO (1 :1 ) entry Ligand km. 1 V-95 3. l 2 V-96 3.5 282 5.5 Other ligand structures The peptide chain is more flexible than the rigid aromatic substituent in Corey’s ligand as shown in Figure V—2. To further improve the asymmetric selectivity of the hydroxylation reaction, we proposed to bring the peptide chain closer to the cinchona alkaloid. Therefore, the structural motif shown in Fugure V-6 was postulated. This structural motif is composed of the cinchona alkaloid DHQD and a peptide chain. The peptide chain is directly connected to the DHQD by an ester bond. The peptide C- terminus is composed of a proline. In this structural motif, the distance between the cinchona alkaloid and the peptide chain is much shorter compared with the previous ligands. N \ / OMe $f0\ N,CO-AA-AA... W ’I— Figure V-6. Structure motif of peptide-based ligand without pyridazine linker The synthesis of this type of ligand was easier as compared to previous ligands. The synthetic route commenced with DCC mediated esterification of dihydroquinidine and Boc-protected proline. After deprotection, the rest of the peptide chain was connected with the proline unit by an amidation process. The ligands with either configured proline were synthesized. The synthetic routes are shown in Scheme V-39. 283 Scheme V-39. Synthesis of peptide-based ligand without pyridazine linker IN‘ N : '_/ U NfOH + N "COOH D_CC_, o—o W300 go, DMAP [WM/:51) \ OMe CH2Cl2 ”' quant. .,,’ TFA V'97 CHZCIZ 20% after recrystallization N \ | N OMe (g / + OH 1 mol% V-58 OH 0.5 mol% OsO4 t-BuOH-HZO (1 :1) entry Solvent km, l tBuOH-HZO (1:1) 6.3 288 5.7 Conclusion A peptide-based system for OsO4 mediated asymmetric dihydroxylation was investigated and its application in the kinetic resolution of racemic olefins was evaluated. Racemic acetic acid l-phenyl-allyl ester was resolved by AD using various peptide-based ligands. Among these ligands, DHQD-PYD-B-(D)—Pro-(L)-Asn-(L)-Val-OMe V-58 was demonstrated to be the most effective ligand for the kinetic resolution. And the resolution outcome was further improved by employing the toluene-water solvent system. An 11.7 km, value was achieved under the optimized conditions. A larger ligand pool could be built and evaluated using more efficient synthetic strategies. The investigation of kinetic resolution of racemic olefins using other peptide-based ligands containing different structure motifs will be conducted in the near future. 5.8 Experimental General information All commercially available starting materials were used without further purification. Commercially available starting materials were obtained from Aldrich, Fisher, Nu-Chek-Prep, Lancaster, TCI. lH, l3c, gCOSY, gHMBC, DEPT and nOe spectra were recorded on either a 300 MHz NMR spectrometer (VARIAN INOVA) or on a 500 MHz NMR spectrometer (VARIAN VXR). IR spectra were recorded on Nicolet IR/42 spectrometer using NaCl cells. Column chromatography was performed using Silicycle (40-60 pm) silica gel. Analytical TLC was done using pre—coated silica gel 60 F254 plates. GC analysis was performed using HP (6890 series) GC system (Column 289 type-AltechSE-54, 30 m x 320 um x 0,25, pm)."I-IPLC analysis was performed using HITACHI LC-ORGANIZER (Column type chiral AD or CD). - Unless otherwise mentioned, solvents were purified as follows. THF and EtZO were distilled from sodium benzophenone ketyl. CH2C12, toluene, CH3CN and Et3N were distilled from CaHz. DMF, diglyme, and DMSO were stored over 4 A molecular sieves and distilled from CaHz. Allbther commercially available reagents and solvents were used as received. General procedure for kinetic resolution A mixture of K3Fe(CN)6 (0.24 g, 0.73 mmol, 3.0 eq.), K2CO3 (0.10 g, 0.73 mmol, 3.0 eq.), ligand (0.0024 mmol, 0.01 eq.), alkene (0.24 mmol, 1.0 eq.) and internal standard in 3 mL of 1:1 tert-butyl alcohol-water was stirred for 20 min at 0 °C. Approximately 0.01 mL of this mixture (organic layer) was quenched with 0.05 mL of saturated Na2S03 and extracted with 0.2 mL EtOAc. The organic layer was analyzed by chiral GC or HPLC. The reaction was initiated by the addition of 0304 (0.005 eq.), and organic layers were taken and analyzed as indicated above every 1 h. Calculation of km], the relative rates of reaction of olefin enantiomers, was accomplished using the following equation: km. = ln[(l-c)(1—ee)]/ln[(l-c)(1+ee)]. A plot of ln[(l-c)(1-ee)] vs ln[(l-c)(l+ee)] is linear, with slope equal to krel. Cbz-Val-OMe v-s73 CszNvCOOMe /\ 290 Cbz-Val-OH (0.251 g, 1.0 mmol, 1.0 eq.) was suspended in 2,2- dimethoxypropane ( 15 mL) and to the suspension was added concentrated HCl (1 mL). The mixture was allowed to stand at rt for 3 h. EtOAc (50 mL) was added, and the organic layer was washed with saturated NaHCO3, Na2C03 and brine, and dried over Na2804. After filtration, the solvent was removed under reduced pressure. The residue was purified by column (20% EtOAc in hexanes) to yield quantitative Cbz-Val-OMe V-S. 1H-NMR (300 MHz, CDCl3) 5 0.89 (dd, J = 21.4, 6.6 Hz, 6H), 2.12 (m, 1H), 3.69 (s, 3H), 4.27 (dd, J: 9.3, 4.9 Hz, 1H), 5.08 (s, 2H), 5.39 (d, J = 8.9 Hz, 1H), 7.32 (m, 5H). H-Val-OMe V-6 H2N VCOOMB /\ To a solution of Cbz-Val-OMe V-5 (0.9697 g, 3.66 mmol, 1.0 eq.) in EtOAc (30 mL) was added Pd/C (366 mg). The reaction mixture was stirred under H; atmosphere for 12 h. The mixture was filtered and the filtrate was concentrated and purified by column chromatography to yield 252 mg desired product (53%). H-NMR (300 MHz, CDCl3) 8 0.91 (dd, J = 20.9, 7.1 Hz, 6H), 1.43 (3, br, 2H), 1.99 (m, 1H), 3.27 (d, J = 4.9 Hz, 1H), 3.70 (s, 3H). Cbz-Phe-Val-OMe V-7 CszN N VCOOMe “v 0/5\ A solution of L-valine methyl ester (120.7 mg, 0.921 mmol, 1.0 eq.) and Cbz- Phe-OH (275.5 mg, 0.921 mmol, 1.0 eq.) in CH2C12 (5 mL) and dioxane (5 mL) was 291 treated with DCC (228 mg, 1.11 mmol, 1.2 eq.) in CH2C12 (2.5 mL). After 12 h at rt, the precipitated urea was removed by filtration and the filtrate was concentrated at reduced pressure. A solution of the residue in methylene chloride was washed thoroughly with 5% HCI, 5% NaHC03 and water, and dried over Na2SO4. After concentration in vacuo, the crude product was purified by column chromatography with 30% EtOAc in hexane to yield the desired product in 87% yield (330 mg). lH-NMR (300MHz, CDC13) 5 8.20 (dd, J = 7.1, 11.5 Hz, 6H), 2.06 (m, 1H), 3.02 (m, 2H), 3.64 (s, 3H), 4.48 (dd, J = 5.5, 8.8 Hz, .1H), 4.60 (dd, J = 7.1, 14.3 Hz, 1H), 5.03 (m, 2H), 5.83 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 7.25 (m, 5H). H-Phe-Val-OMe V-8 H2N H \,.-‘\[vaCOOMe 0/-\ To a solution of Z-Phe-Val-OMe (330 mg, 0.800 mmol, 1.0 eq.) in EtOAc (20 mL) was added Pd/C (100 mg). The reaction mixture was stirred under a H2 atmosphere for 12 h. After gravity filtration, the filtrate was washed with 10 mL saturated Na2C03, and dried over sodium sulfate. The solvent was removed under reduced pressure, and the product was purified by column chromatography] with 2% triethylamine in ethyl acetate to yield 191 mg product (86%). 1H-NMR (300MHz, CDC13) 5 0.86 (t, J = 6.6 Hz, 6H). 1.36 (s, br, 2H), 2.12 (m, 1H), 2.68 (dd, J = 9.3, 13.7 Hz, 1H), 3.21 (dd, J = 3.8, 13.7 Hz, 1H), 3.68 (s, 3H), 4.47 (dd, J = 4.9, 8.8 Hz, 1H), 7.20 (m, 5H), 7.79 (d, J = 8.8 Hz, 1H). 292 Boc-(D)-Pro-OH V-lO QWCOOH | Boc D-Proline (2.30 g, 0.02 mmol, 1.0 eq.) was added to a 10% solution (30 mL) of TEA in methanol. To this mixture, di-t-butyl dicarbonate was added with vigorous stirring. The mixture is then heated to 45 °C for 2 h. After the reaction was complete, the solvent was then evaporated under reduced pressure, and the residue was stirred for 10 min with ice—cold dilute HCI (pH 2.5, 10 mL) and extracted immediately with EtOAc (100 mL x 5). The organic extract was dried over MgSO4, filtered, and evaporated. The remaining product is crystallized from EtOAc and hexanes to yield 3.45 g desired product (75%). Boc-(D)-Pro-Phe-Val-0Me V-ll H O ‘I,’ N\.)LN 0M9 (~51; H é“ \Ph 0 A solution of V-8 (93 mg, 0.334 mmol, 1.0 eq.) and V-10 (144 mg, 0.668 mmol, 2.0 eq.) in CH2C12 (5 mL) and dioxane (5 mL) was treated with DCC (83 mg, 0.401 mmol, 1.2 eq.) in CH2C12 (2.5 mL). After the disappearance of the starting material on TLC, the precipitated urea was removed by filtration and the filtrate was concentrated at reduced pressure. A solution of residue in CH2C12 was washed with 10% HC1 and 5% NaHCO3, dried over NaZSO4, and concentrated in vacuo. The residue was purified by column chromatography (40% EtOAc in hexanes) to yield 163 mg desired product (quantitative). lH—NMR (300MHz, CDCl3) 5 0.77 (t, J = 7.7 Hz, 6H), 1.37 (s, 9H), 1.80 293 (m, 2H), 2.06 (m, 2H), 3.06 (m, 2H), 3.35 (m, 2H), 3.62 (s, 3H), 4.17 (m, 1H), 4.36 (m,1H), 4.62 (m, 1H), 6.22 (m,1H), 6.65 (m, 1H), 7.20 (m, 5H). H- (D)-Pro-Phe-Val-0Me V-2 Q OHDLNIJOM. A mixture of Boc-D-Pro-Phe-Val-OMe (158 mg, 0.334 mmol, 1.0 eq.), dichloromethane (5 mL), trifluoroacetic acid (4 mL), methanol (0.75 mL) was stirred at rt for 12 h. Saturated sodium carbonate was added to the reaction mixture to increase pH to 10. The product was extracted with dichloromethane five times, and dried over sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography with MeOH:CHCl3:TEA (10:88:2) to yield 146 mg desired product (quantitative). lH-NMR (300MHz, CD3OD) 5 0.92 (dd, J = 2.7, 6.6 Hz, 6H), 1.61 (m, 4H), 2.12 (m, 1H), 2.88 (m, 3H), 3.13 (dd, J = 5.5, 13.7 Hz, 1H), 3.56 (dd, J = 5.5, 9.3 Hz, 1H), 3.69 (s, 3H), 4.31 (d, J = 6.0 Hz, 1H), 4.70 (dd, J = 5.5, 8.8 Hz, 1H), 7.23 (m, 5H). DHQD-Pyz-Cl v-3 M90 5 /| N ' ’ NN—N Z%?57\1}—H<_;>—CI ”_ 294 Sodium hydride (60% in mineral oil, 120 mg, 3.0 mmol, 3.0 eq.) and DMF (5 mL) were charged into a flame-dried flask under a nitrogen atmosphere at 10 °C. A solution of hydroquinidine (326 mg, 0.95 mmol,1.0 eq.) in DMF (5 mL) was slowly added to the vigorously stirred suspension by syringe. The mixture was stirred at rt for another 3 h followed by addition of solution of 3,6-dichloropyridazine (150 mg, 1.0 mmol, 1.0 eq.) in DMF (5 mL). The resultant mixture was stirred at rt overnight. The solvent was removed under reduced pressure and the residue was extracted with diethyl ether (3 x 20 mL). The organic extracts were washed with brine and dried with N a2SO4. The solvent was removed and the residue was purified by flash chromatography (2% TBA in EtOAc) to generate 275 mg product (66%). lH-NMR (300MHz, CDCl3) 5 0.82 (t, J = 6.6 Hz, 3H), 1.42 (m, 6H), 1.67 (m, 1H), 1.86 (m, 1H), 2.68 (m, 4H), 3.29 (m, 1H), 3.88 (s, 3H), 6.96 (dd, J = 3.8, 8.8 Hz, 2H), 7.27 ( m, 3H), 7.43 (d, J = 2.7 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 8.59 (d, J = 4.4 Hz, 1H). l3C-NMR (75 MHz, CDC13)5 11.8, 14.0, 23.1, 25.3, 25.8, 27.0, 31.2, 36.3, 37.1, 49.9, 50.9, 55.4, 59.6, 76.6, 101.5, 118.4, 119.8, 121.7, 127.0, 131.0, 131.5, 143.6, 1445,1471, 151.2,157.7, 1632,1804)55 DHQD-PYZ-(D)-Pro-Phe-Val-0Me V-l 295 Aryl chloride (47.7 mg, 0.109 mmol, 1.0 eq.), D-Pro-Phe-Val-OMe (40.8 mg, 0.109 mmol, 1.0 eq.), Pd2(dba)3CHC13 (34 mg, 0.033 mmol, 0.3 eq.), rac-BINAP (41 mg, 0.065 mmol, 0.6 eq.), CSzCO3 (107 mg, 0.327 mmol, 3.0 eq.) and dioxane (2 mL) were mixed in a flame-dried Schlenk flask. The mixture was degassed, refilled with nitrogen and stirred at 55-60 °C for 40 h. The mixture was cooled to rt and poured onto ethyl acetate. The organics were washed with brine and dried with sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography with 1% TEA in ethyl acetate to yield 19 mg product (24%). lH-NMR (500MHz, CDCl;) 5 0.76 (dd, J = 6.8, 9.8 Hz, 6H), 0.88, (t, J = 6.8 Hz, 3H), 1.50 (m, 6H), 1.73 (m, 1H), 1.93 (m, 3H), 2.05 (m, 2H), 2.26 (m, 1H), 2.72 (m, 1H), 2.82 (m, 2H), 2.91 (m, 2H), 3.05 (dd, J = 5.9, 14.6 Hz, 1H), 3.24 (m, 1H), 3.33 (m, 1H), 3.56 (t, J = 8.8 Hz, 1H), 3.67 (s, 3H), 3.90 (s, 3H), 4.26 (d, J = 8.8 Hz, 1H), 4.40 (dd, J = 4.9, 8.8 Hz, 1H), 4.51 (m 1H), 6.53 (d, J = 9.8 Hz, 1H), 6.67 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 4.9 Hz, 1H), 6.95 (m, 2H), 7.01 (m, 3H), 7.33 (dd, J = 2.9, 9.8 Hz, 1H), 7.40 (d, J = 4.9 Hz, 1H), 7.52 (m, 1H), 7.98 (d, J = 8.8 Hz, 1H), 8.65 (d, J = 4.9 Hz, 1H). 13C- NMR (125 MHz, CDCl3) 5 12.0, 17.5, 18.7, 22.6, 26.1, 27.3, 29.7, 31.0, 36.8, 37.4, 48.7, 50.1, 50.9, 52.1, 53.4, 54.4, 55.6, 57.0, 59.6, 61.9, 77.3, 117.7, 119.7, 121.6, 126.7, 127.0, 128.4, 129.1, 131.7, 136.3, 144.7, 147.3, 155.8, 157.6, 158.7, 170.7, 171.9, 173.0. 3,6-Diiodopyridazine V-21 .——. N=N A mixture of 3,6-dichloro-pyridazine (1.0 g, 6.7 mmol, 1.0 eq.), hydriodic acid (47%, 5 mL) and iodine monochloride (0.55g, 3.38 mmol, 0.5 eq.) were reacted for 24 h 296 at 70 °C. After cooling to rt, the mixture was poured into ice water (30 mL) with stirring. The solution was neutralized by aqueous potassium hydroxide (20%, 12 mL). After the precipitate was filtered, the resulting residue was washed with water (100 mL), with aqueous sodium thiosulfate (10%, 5 mL) and with hexane (1 mL). The residue was recrystallized from ethyl acetate to give 363.2 mg product (16%). lH-NMR (300MHz, CDC13) 5 7.48 (s, 2H)". DHQD-PYZ-I V-22 (”fit I fl/ OMe N : N=N Cw 0V. Sodium hydride (60% in mineral oil, 120 mg, 3.0 mmol, 3.0 eq.) and DMF (5 mL) were charged into a flame-dried flask under a nitrogen atmosphere at 10 °C. A solution of hydroquinidine (326 mg, 1.0 mmol, 1.0 eq.) in DMF (5 mL) was slowly added to the vigorously stirred suspension by syringe. The mixture was stirred at rt for another 3 h, followed by addition of a solution of 3,6-diiodopyridazine (332 mg, 1.0 mmol, 1.0 eq.) in DMF (5 mL). The resulting mixture was stirred at rt for 12 h. Diethyl ether and water were added to the reaction mixture and two layers were separated. The aqueous layer was extracted with diethyl ether (3 x 20 mL). The organic extracts were washed with brine and dried with MgSO4. The solvent was removed and the residue was purified by flash chromatography (2% TBA in EtOAc) to yield 478 mg desired compound (90%). 1H-NMR (500MHz, CDC13) 5 0.89 (t, J = 6.6 Hz, 3H), 1.48 (m, 6H), 1.73 (m, 1H), 1.92 (m, 1H), 2.74 (m, 3H), 2.89 (dd, J = 9.3, 13.7 Hz, 1H), 3.35 (q, J = 8.4 Hz, 1H), 3.93 (s, 297 3H), 6.73 (d, J = 9.3 Hz, 1H), 6.99 (d J = 6.6 Hz, 1H), 7.34 (m, 2H), 7.47 (d, J = 2.7 Hz, 1H), 7.62 (d, J = 9.3 Hz, 1H), 7.97 (d, J = 9.3 Hz, 1H), 8.66 (d, J = 4.4 Hz, 1H). 1-(6-Chloro-pyridazin-3-yl)-pyrrolidine-2-carboxylic acid tert-butyl ester V-25 Ot-Bu o N-N CI-—<_>—N To a solution of 3,6-dichloro-pyridazine (60 mg, 0.4 mmol, 2.0 eq.) and H-Pro- O'Bu-HC] (41.5 mg, 0.2 mmol, 1.0 eq.) in dioxane (1 mL) was added C32C03 (260.7 mg, 0.8 mmol, 4.0 eq.) in a sealed tube. The reaction was heated at 150 °C for 16 h. After cooling the reaction to rt, ethyl acetate and water was added, two layers were separated and the organic layer was dried over sodium sulfate. After filtration the crude product was purified by column chromatography on silica gel (20% EtOAc in hexane) to yield 39 mg product (69%). lH-NMR (300MHz, CDC13) 5 1.40 (s, 9H), 2.12 (m, 3H), 2.29 (m, 1H), 3.48 (m, 1H), 3.64 (m, 1H), 4.51 (m, 1H), 6.61 (d, J = 9.3 Hz, 1H), 7.16 (d, J =9.3, 1H). 1-(6-iodo-pyridazin-3-yl)-pyrrolidine-Z-carboxylic acid tert-butyl ester V-26 Ot-Bu o N-N In a sealed tube, to a solution of 3,6-diiodopyridazine (133 mg, 0.4 mmol, 1.0 eq.) and V-19 (41.5 mg, 0.2 mmol, 1.0 eq.) in dioxane (2 mL) was added CS2C03 (261 mg, 0.8 eq. 4.0 eq.). The reaction was heated at 150 °C for 16 h. After cooling the reaction mixture to rt, EtOAc (20 mL) and water (10 mL) were added. Two layers were separated 298 and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over anhydrous N32804, and concentrated in vacuo. The residue was purified by column chromatography (20% EtOAc in hexanes) to yield 55 mg desired product (74%). 1H-NMR (300MHz, CDC13) 5 1.40 (s, 9H), 2.11 (m, 3H), 2.26 (m, 1H), 3.46 (m, 1H), 3.60 (m, 1H), 4.50 (d, J = 7.1 Hz, 1H), 6.37 (d, J = 9.3 Hz, 1H), 7.42 (d, J = 9.3 Hz, 1H). 3,6-Difluoropyridazine V-27 N-N F/\F To a solution of 3,6-dichloropyridazine (7.45 g, 50 mmol, 1.0 eq.) in tetramethylene sulfone (100 mL) was added potassium fluoride (14.5 g, 0.25 mol, 5.0 eq.) and catalytic amount of 18-crown-6. The reaction was heated up to 150 °C for 12 h. After the reaction mixture was cooled to rt, water (100 mL) was added, and the product was extracted with diethyl ether (3x). The combined organic layers were washed with water and brine, dried over sodium sulfate, then concentrated under reduced pressure. The residue was purified by column chromatography (100% hexane) to yield 1.246 g of product (22%). lH-NMR (300MHz, CDCl3) 5 7.35 (s, 2H). DHQD-PYZ-F V-28 N 03L 3/ OMe N=N \/ F {2 O? "’1— 299 Sodium hydride (20 mg, 0.500 mmol, 60% in mineral oil, 1.0 eq.) was charged into a flame-dried flask under a nitrogen atmosphere at 10 °C. A solution of hydroquinidine (163.2 mg, 0.500 mmol, 1.0 eq.) in DMF (3 mL) was slowly added to the vigorously stirred suspension by syringe. The mixture was stirred at rt for another 2 h followed by addition of the solution of 3,6-difluoropyridazine (58 mg, 0.500 mmol, 1.0 eq.) in DMF (1 mL). The resultant mixture was stirred at rt for 12 h. The reaction was quenched with water, and the product was extracted with EtOAc (20 mL x4). The organic extracts were washed with brine and dried over Na2S04. The solvent was removed and the residue was purified by column chromatography on silica gel (2% TBA in EtOAc) to yield 130.4 mg (62%) desired product as a white solid. lH-NMR (500 MHz, CDCl3) 5 0.86 (t, J = 7.3 Hz, 3H), 1.36-1.56 (m, 6H), 1.70 (s, 1H), 1.91 (m, 1H), 2.70 (m, 3H), 2.86 (dd, J = 8.8, 13.7 Hz, 1H), 3.34 (dd, J = 8.8, 15.6 Hz, 1H), 3.91 (s, 3H), 6.96 (d, J = 6.8 Hz, 1H), 7.04 (dd, J = 2.0, 8.8 Hz, 1H), 7.11 (dd, J = 5.9, 9.8 Hz, 1H), 7.31 (dd, J = 2.9, 9.8 Hz, 1H), 7.35 (d, J = 4.9 Hz, 1H), 7.47 (d, J = 2.9 Hz, 1H), 7.94 (d, J = 9.8 Hz, 1H), 8.63 (d, J = 4.9 Hz, 1H). l3c-NMR (125 MHz, CDCl3) 5 11.9, 23.2, 25.4, 26.0, 27.2, 37.3, 50.0, 51.0, 55.5, 59.7, 77.2, 101.7, 118.5, 119.1, 119.4, 121.7, 122.8, 122.9, 127.1, 131.6, 143.8, 144.6, 147.2, 157.7, 162.2, 162.9, 164.1. DHQD-PYZ-(L)-Pro-OH V-29 300 To a solution of the fluoride V-28 (100 mg, 0.237 mg, 1.0 eq.) in DMSO (10 mL) was added D-proline (27.3 mg, 0.237 mmol, 1.0 eq.), K2C03 (32.7 mg, 0.237 mmol, 1.0 eq.) and H20 (10 mL). The mixture was stirred at 100 °C for 12 h. The solvent was distilled out under reduced pressure. The residue was dissolved in EtOH, and filtered. The solvent was removed under reduced pressure to afford 93.2 mg (76%) of the desired product. 1H-NMR (500 MHz, CDgOD) 5 0.82 (t, J = 6.8 Hz, 3H), 1.18 (m, 1H), 1.36- 1.58 (m, 6H), 1.64 (s, 1H), 1.76 (m, 1H), 1.86 (m, 1H), 1.97 (m, 1H), 2.11 (m, 1H), 2.18 (m, 1H), 2.69 (m, 1H), 2.83 (m, 2H), 2.94 (m, 1H), 3.18 (m, 1H), 3.28 (dt, J = 10.7, 6.8 Hz, 1H), 3.44 (ddd, J = 10.7, 7.8, 4.9 Hz, 1H), 3.88 (s, 3H), 3.96 (dd, J = 7.8, 3.9 Hz, 1H), 6.77 (d, J = 9.8 Hz, 1H), 6.87 (s, 1H), 6.98 (d, J = 9.8 Hz, 1H), 7.28 (dd, J = 8.8, 2.9 Hz, 1H), 7.38‘(d, J = 4.9 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.80 (d, J; 9.8 Hz, 1H), 8.44 (d, J = 3.0 Hz, 1H). l3c-NMR (125MHz, CD3OD) 5 12.3, 22.1, 25.0, 26.3, 27.3, 27.6, 32.5, 38.2, 48.8, 51.0, 51.9, 56.6, 60.3, 64.1, 76.6, 102.7, 119.6, 120.5, 120.8, 123.6, 128.3, 131.4, 145.0, 146.7, 148.0, 156.8, 158.2, 159.8, 180.8. DHQD-PYZ-Gly-OH V-32 .301 To a solution of V-28 (92.1 mg, 0.218 mmol, 1.0 eq.) in DMSO (1 mL) and H20 (1 mL) was added glycine hydrochloride (24.3 mg, 0.218 mmol, 1.0 eq.) and K2C03 (60.2 mg, 0.436 mmol, 2.0 eq.). The reaction mixture was heated to 100 °C for 12 h. Another eq.alent of glycine hydrochloride and K2C03 were added to the reaction mixture, stirred at 100 °C for another 24 h. The solvent was removed under reduced pressure. The residue was triturated by ethanol. After filtration, ethanol was removed under reduced pressure. The crude product was purified by column chromatography on silica gel (CHCl3zMeOH2TEA 85: 10:5) to give 52 mg of the desired product. (D)-2-Hydroxymethyl-pyrrolidine-l-carboxylic acid tert-butyl ester V-33 (EACH A mixture of Boc-D-Pro-OH (0.75 g, 3.5 mmol, 1.0 eq.), N-methylmorpholine (0.46 mL, 4.2 mmol, 1.2 eq.), ethyl chloroformate (0.40 mL, 4.2 mmol, 1.2 eq.), and THF (4 mL) were stirred at —5 °C. After 10 min the mixture was filtered over celite, and the precipitate was washed with THF. In a round-bottom flask a solution of NaBI-I4 (0.16 g, 4.2 mmol, 1.2 eq.) in dry THF (10 mL) was stirred at 0 °C under an inert atmosphere. Iodine (0.44 g, 1.7 mmol, 0.48 eq.) was slowly added over 30 min, and after an additional 302 10 min the collected organic layers containing the Boc-D-Pro mixed anhydride were added with stirring. After 30 min at 0 °C. the temperature was allowed to reach to rt, and the mixture was stirred for 12 h. The solvent was evaporated at reduced pressure, the residue was diluted with EtOAc, and the mixture was washed with water (5 mL). The water layer was extracted twice with EtOAc, and the organic layers were collected and dried over NaZSO4. Solvent was evaporated at reduced pressure. The residue was purified by flash chromatography over silica gel (30% EtOAc in hexane) giving 0.79 g of the product. 1H-NMR (300 MHz, CDCl3) 5 1.37 (s, 9H), 1.6-2.0 (m, 4H), 3.23 (m, 1H), 3.35 (m, 1H), 3.51 (m, 2H), 3.86 (m, 1H).69 2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-l-carboxylic acid tert-butyl ester V-34 Soc (N7/\OTS \_ ~A mixture of (R)-N—Boc-prolinol, TEA, catalytic DMAP, and tosylchloride in CH2Cl2 (20 ml) was stirred at 0 °C for 3 h, and at rt for another 10 h. The mixture was washed with saturated Na2C03, and the water layer was extracted twice with dichloromethane. Organrc layers were. collected and dried over NaZSO4, and the solvent was evaporated at reduced pressure. The resulting crude oil was purified by flash chromatography over silica gel (10% ‘EtOAc in hexanes) giving (R)-N-Boc-2- tosyloxymethylpyrrolidine 0.706g (81%). lH-NNIR (300 MHz, CDCl3) 5 1.31 (d, J = 11.5 Hz, 9H), 1.6-2.0 (m, 4H). 2.38 (5,311), 3.20 (m, 2H), 3.84 (m, 1H), 4.03 (m, 2H), 7.28 (m, 2H), 7.70 (d, J = 8.2 Hz, 2H). 303 2-Cyanomethyl-pyrrolidine-l-carboxylic acid tert-butyl ester V-35 To a solution of (R)-N-Boc-2-tosyloxy methylpyrrolidine V-34 (0.706 g, 2.105 mmol, 1.0 eq.) in DMSO (10 ml) was added KCN (0.41 g, 6.31 mmol, 3.0 eq.), and the mixture was stirred at 90 °C for 12 h, then ethyl acetate was added, and the organic layer was washed three times with small portions of water. The organic layer was dried over NazSO4, and the solvent was evaporated at reduce pressure. The residue was purified by flash chromatography over silica gel (30% EtOAc in hexanes) giving (R)-N-Boc- pyrrolidylacetonitrile 0.324 g (76%). 1H-NMR (300 MHz, CDCl3) 5 1.40 (s, 9H), 1.7-2.2 (m, 4H), 2.69 (m, 2H), 3.35 (m, 2H), 3.95 (m, 1H). Pyrrolidin-Z-yl-acetic acid hydrochloric acid V-36 i' N “00% A mixture of (R)-N-Boc-pyrrolidy1 acetonitrile (0.324 g, 1.54 mmol, 1.0 eq.), 12 N HCI (15 mL) and glacial acetic acid (3 mL) was refluxed for 12 h. The reaction was then allowed to reach rt, and it was washed twice with diethyl ether. Water was evaporated at reduced pressure, giving (R)-B-pro as hydrochloric salt. 1H-NMR (300 MHz, D20) 5 1.56 (m, 1H), 1.88 (m, 2H), 2.10 (m,1H), 2.67 (dd, J = 8.8, 17.6 Hz,1H), 2.74 (dd, J = 4.4, 18.1 Hz, 1H), 3.18 (t, J: 7.1 Hz, 2H), 3.74 (m, 1H). DHQD-PYz-(D)-B-Pro-0H v-37 304 COOH To a solution of compound V-28 (96 mg, 0.227 mmol, 1.0 eq.) and (R)—B-pro hydrochloric salt V-36 (38 mg, 0.227 mmol, 1.0 eq.) in DMSO (1 mL) and water (1 mL) was added potassium carbonate (63 mg, 0.454 mmol, 2.0 eq.). The reaction was stirred at 100 °C for 12 h. The solvent was removed under reduced pressure, and the residue was dissolved in ethanol, and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography over silica gel (CHC13 : MeOH : TEA = 85 : 10 : 5) giving 94 mg of the desired product (78%). 1H-NMR (300MHz, CDC13) 5 0.91 (t, J = 6.8 Hz, 3H), 1.60 (m,6H), 1.83 (m, 6H), 2.02(dd, J = 10.3, 13.7 Hz, 1H), 2.22 (t, J = 10.7 Hz, 1H), 2.42 (d, J = 13.7 Hz,1H), 3.16 (m, 4H), 3.39 (m, 2H), 3.71 (m, 1H), 3.93 (s, 3H), 4.85 (q, J = 9.3, 2H), 7 .03 (s, 1H), 7.26 (dd, J = 2.9, 9.3 Hz, 1H), 7.31 (d, J = 4.4 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 9.3 Hz, 1H), 8.56 (d, J = 4.4 Hz, 1H). 13c—NMR (75 MHz, CDCl3) 5 8.8, 20.2, 22.9, 24.8, 25.0, 25.7, 31.1, 35.9, 40.7, 44.9, 47.3, 48.7, 56.2, 56.3, 58.0, 74.3, 101.4,117.8, 117.9, 118.5, 122.1, 126.1, 131.4, 142.5, 144.5, 146.9, 155.0, 156.9, 158.2, 177.4. Z-(L)-Trp-(L)-Val-0Me v-3s 305 o Z-HN\)J\NH o\ O \ NH DCC coupling of Z—Trp-OH and H-Val-OMe similar to the reaction procedure described for V-7 afforded compound V-38 in 92% yield. lH-NMR (300MHz, CDC13) 5 0.75 (dd, J = 7.1, 11.5 Hz, 6H), 2.00 (m, 1H), 3.20 (m, 2H), 3.59 (s, 3H), 4.41 (dd, J = 4.9, 8.2 Hz, 1H), 4.59 (m, 1H), 5.08 (s, 2H), 5.70 (d, J = 7.8 Hz, 1H), 6.48 (d, J: 7.7 Hz, 1H), 6.9-7.2 (m, 3H), 7.30 (m,5H), 7.62 (d, J = 7.1 Hz,1H), 8.52 (s, 1H). H-(L)-Trp-(L)-Val-0Me V-39 o HZNQLEO\ i H \ 0 NH Hydrogenation of compound V-38 catalyzed by Pd/C similar to the reaction procedure described for V-8 gave compound V-39 in 75% yield. lH-NMR (300MHz, CDCl3) 5 0.87 (dd, J = 3.8, 7.1 Hz, 6H), 1.55 (3, br, 2H), 2.13 (m, 1H), 2.86 (dd, J = 4.9, 9.3 Hz, 1H), 3.38 (dd, J = 3.3, 14.3 Hz, 1H), 3.69 (s, 3H), 3.72 (dd, J = 3.8, 9.3 Hz,1H), 4.51 (dd, J = 4.9, 8.8 Hz, 1H), 7.06 (m, 2H), 7.16 (t, J = 8.2 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 9.3 Hz, 1H), 8.82 (s, 1H). DHQD-PYD-B-(D)-Pro-(L)-Trp-(L)-Val-0Me V-40 306 HN/ o H , u :0/ 1’ _ O: No/\N A \ DCC coupling of compound V-37 and V-39 similar to the reaction procedure described for V-7 gave compound V-40 in 68% yield. lH-NMR (500MHz, CDC13) 5 0.33 (d, J = 6.8 Hz, 3H), 0.60 (d, J = 6.8 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H), 1.23 (m, 1H), 1.58 (m, 5H), 1.72 (m, 1H), 1.81 (s, 1H), 1.9-2.1 (m, 4H), 2.21 (dd, J: 8.8, 12.7 Hz, 1H), 2.31 (t, J = 12.7 Hz, 1H), 2.66 (d, J = 12.2 Hz, 1H), 2.94 (m,overlap, 4H), 3.05 (m, 3H), 3.17 (q, J: 8.8 Hz, 2H), 3.31 (t, J = 8.8 Hz, 1H), 3.44 (m, 1H), 3.53 (dd, J: 4.9, 15.1 Hz, 1H), 3.63 (s, 3H), 4.27 (dd, J = 4.9, 7.8 Hz, 1H), 4.31 (t, J = 6.8 Hz, 1H), 4.61 (td, J = 5.4, 6.8 Hz, 1H), 6.48 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 9.3 Hz, 1H), 6.98 (t, J = 7.3 Hz, 1H), 7.07 (m, 3H), 7.12 (d, J = 7.3 Hz, 1H), 7.17 (dd, J = 2.4, 9.3 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 7.52 (d, J = 4.4 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.87 (d, J = 9.3 Hz, 1H), 8.06 (s, 1H), 8.65 (d, J: 4.9 Hz, 1H), 11.2 (8, br, 1H). 13C-NMR (125 MHz, CDC13) 5 12.0, 17.5, 18.1, 20.2, 23.4, 25.2, 26.0, 26.9, 27.2, 30.9, 31.6, 37.2, 41.6, 47.2, 50.4, 51.0, 51.9, 53.4, 54.4, 56.4, 57.2, 59.2, 75.3, 77.3, 100.0, 109.3, 110.7, 117.7, 118.2, 118.9, 119.4, 119.6, 121.6, 122.4, 125.0, 126.4, 127.8, 131.6, 136.8, 144.2, 144.4, 147.1, 155.1, 157.4, 158.1, 170.9, 171.9, 172.1. Z-(L)-Ser(OtBu)-(L)-Val-OMe V-41 307 DCC coupling of Z—Ser(OtBu)-OH and H-Val-OMe similar to the reaction procedure described for V-7 afforded compound V-4l in quantitative yield. lH-NMR (300MHz, CDCl3) 5 0.87 (dd, J = 7.1, 12.1 Hz, 6H), 1.18 (s, 9H), 2.12 (m, 1H), 3.36 (t, J = 8.2 Hz, 1H), 3.67 (s, 3H), 3.38 (m, 1H), 4.25 (m, 1H), 4.51 (dd, J = 4.9, 8.8 Hz, 1H), 5.07 (dd, J = 12.6, 15.9 Hz, 2H), 5.76 (d, J = 4.9 Hz, 1H), 7.31 (m, 5H). H-(L)-Ser(OtBu)-(L)-Val-0Me V-42 Hydrogenation of compound V-4l catalyzed by Pd/C similar to the reaction procedure described for V-8 gave compound V-42 in 88% yield. 1H-NMR (300MHz, CDC13) 5 0.83 (dd, J = 6.6, 10.4 Hz, 6H), 1.10 (s, 9H), 1.62 (3, br, 2H), 2.08 (m, 1H), 3.46 (m, 3H), 3.64 (s, 3H), 4.45 (dd, J: 4.9, 9.3 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H). DHQD-PYZ-(D)-B-Pl'o-(L)-Ser(OtBu)-(L)-Val-0Me V-43 308 DCC coupling of compound V-37 and V-42 similar to the reaction procedure described for V-7 gave compound V-43 in 76% yield. lH-NMR (300MHz, CDC13) 5 0.88 (m, 9H), 1.13 (s, 9H), 1.48 (m, 6H), 1.69 (s, 1H), 2.0 (m, 5H), 2.13 (m, 1H), 2.32 (dd, J = 8.8, 14.3 Hz, 1H), 2.61 (dd, J = 3.8, 14.3 Hz, 1H), 2.80 (m, 4H), 3.24 (m, 3H), 3.53 (m, 1H), 3.67 (dd, J = 4.4, 8.2 Hz, 1H), 3.69 (s, 3H), 3.93 (s, 3H), 4.33 (m, 1H), 4.39 (m, 1H), 4.46 (dd, J = 4.9, 8.8 Hz, 1H), 6.56 (d, J = 6.0 Hz, 1H), 6.85 (m, 3H), 7.28 (dd, J = 2.7, 9.3 Hz, 1H), 7.36 (d, J = 4.9 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 2.7 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 8.61 (d, J = 4.4 Hz, 1H). DHQD-PYZ-(D)-B'Pro-(L)-Ser-(L)-Val-0Me V-44 :LWNJ’L / OMe 635- «45 Deprotection of Boc group in V-43 generated compound V-44 in 72% yield. 1H- NMR (500MHz, CDC13) 5 0.87 (m, 9H), 1.2-1.6 (m, 6H), 1.71 (s, 1H), 1.92 (m, 4H), 2.07 (m, 2H), 2.25 (dd, J = 7.8, 14.2 Hz, 1H), 2.72 (m, 1H), 2.82 (m, 4H), 3.17 (m, 1H), 3.24 (m, 1H), 3.41 (m, 2H), 3.67 (s, 3H), 3.82 (dd, J = 4.4, 11.2 Hz, 1H), 3.94 (s, 3H), 4.29 (m, 1H), 4.35 (q, J = 5.4 Hz, 1H), 4.42 (dd, J = 4.9, 8.3 Hz, 1H), 6.72 (d, J = 9.8 Hz, 1H), 6.88 (m, 2H), 7.20 (d, J = 8.8 Hz, 1H), 7.30 (dd, J: 2.4, 9.3 Hz, 1H), 7.34 (d, J = 4.9 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 6.8 Hz, 1H), 7.92 (d, J = 9.3 Hz, 1H), 8.59 (d, J = 4.4 Hz, 1H). 13C-NMR (125 MHz, CDC13) 5 11.4, 12.0, 17.7, 18.9, 22.1, 23.3, 25.3, 309 26.1, 27.2, 30.9, 31.6, 37.4, 41.2, 46.1, 47.7, 50.1, 50.9, 52.1, 54.5, 55.6, 55.7, 57.3, 59.6, 61.8, 102.0, 118.1, 118.4, 119.7, 121.7, 126.9, 131.5, 144.5, 147.3, 155.0,157.7, 157.8, 171.0,172.1. Z-(L)-Met-(L)-Val-0Me V-45 2 O HNEJLNH o\ {/- O /S DCC coupling of Z-(L)-Met-OH and H-(L)-Val-0Me similar to the reaction procedure described for V-7 gave compound V-45 in 87% yield. lH-NMR (300MHz, CDC13) 5 0.86 (dd, J = 7.1, 9.9 Hz, 6H), 1.8-2.2 (m, 6H), 2.54 (t, J = 7.1 Hz, 2H), 3.68 (s, 3H), 4.46 (m, 2H), 5.06 (s, 2H), 5.82 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 7.28 (m, 5H). H-(L)-Met-(L)-Val-0Me V-46 0 H2N\,/ILNH o\ '/ O /S Hydrogenation of compound V-45 catalyzed by Pd/C similar to the reaction procedure described for V-8 gave compound V-46 in 12% yield. lH-NMR (300MHz, CDC13) 5 0.89 (dd, J = 6.6, 8.2 Hz, 6H), 1.54 (3, br, 2H), 1.77 (m, 1H), 2.08 (s, 3H), 2.04- 2.20 (m, 2H), 2.59 (dt, J = 1.6, 6.6 Hz, 2H), 3.52 (dd, J = 4.9, 7.7 Hz, 1H), 3.70 (s, 3H), 4.47 (dd, J = 4.9, 9.3 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H). 310 DHQD-PYZ-(D)-B-Pro-(L)-Met-(L)-Val-0Me V-47 DCC coupling of compound V-37 and V-46 similar to the reaction procedure described for V-7 gave compound V-47 in 67% yield. lH-NMR (300MHz, CDCl3) 5 0.85 (m, 9H), 1.2-1.4 (m, 6H), 1.76 (m, 3H), 1.86 (s, 3H), 1.7-2.17 (m, 6H), 2.23 (dd, J = 7.8, 14.2 Hz, 1H), 2.31 (m, 1H), 2.5-2.9 (m, 6H), 3.20 (m, 2H), 3.43 (m, 1H), 3.69 (s, 3H), 3.95 (s, 3H), 4.19 (m, 1H), 4.46 (m, 2H), 6.78 (d, J = 9.3 Hz, 1H), 6.82 (d, J = 4.9 Hz, 1H), 6.92 (d, J = 9.8 Hz, 1H), 7.32 (m, 2H), 7.44 (d, J = 2.9 Hz, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 8.58 (d, J = 4.4 Hz, 1H). l3c-NMR (75 MHz, CDC13) 5 12.0, 14.7, 17.6, 18.9, 22.2, 23.4, 25.3, 26.2, 27.3, 29.8, 30.9, 31.8, 37.4, 41.6, 47.5, 50.3, 51.0, 51.6, 52.0, 55.7, 56.1, 57.2, 59.6, 76.9, 101.8, 118.0, 118.3, 119.7, 121.7, 126.9, 131.5, 144.5, 144.9, 147.3, 154.7, 157.6, 157.7, 171.3, 172. Z-(L)-Tyr(tBu)-(L)-Val-0Me V-48 o z—NHJLNH o\ 0r ° t-BU\O DCC coupling of Z-(L)-Try(tBu)-OH and H-(L)-Val-0Me similar to the reaction procedure described for V-7 gave compound V-48 in 92% yield. 'H—NMR (300MHz, 311 CDCl3) 5 0.79 (dd, J = 7.1, 12.6 Hz, 6H), 1.28 (s, 9H), 2.04 (m, 1H), 2.99 (d, J = 7.1 Hz, 2H), 3.65 (s, 3H), 4.46 (m, 2H), 5.05 (s, 2H), 5.52 (d, J = 8.2 Hz, 1H), 6.52 (d, J = 7.7 Hz, 1H), 6.84 (d, J = 8.2 Hz, 2H), 7.04 (d, J = 8.2 Hz, 2H), 7.29 (m, 5H). H-(L)-Tyr(tBu)-(L)-Val-0Me V-49 o HZNJNH o\ 13 ° t-Bu\O Hydrogenation of compoUnd V-48 catalyzed by Pd/C similar to the reaction procedure described for V-8 gave compound V-49 in 80% yield. lH-NMR (300MHz, CDC13) 5 0.82 (dd, J = 7.1, 8.8 Hz, 6H), 1.26 (s, 9H), 1.31 (s, br, 2H), 2.11 (m, 1H), 2.67 (dd, J = 9.3, 13.7 Hz, 1H), 3.10 (dd, J = 4.4, 13.7 Hz, 1H), 3.56 (dd, J = 4.4, 8.8 Hz, 1H), 3.66 (s, 3H), 4.44 (dd, J = 4.9, 8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 7.7.7 (d, J = 8.8 Hz, 1H). DHQD-PYZ-(D)-B-Pro-(L)-Tyr(tBu)-(L)-Val-OMe V-50 t-Bu-O \ / O H 10 H O : 312 DCC coupling of compound V-37 and V-49 similar to the reaction procedure described for V-7 gave compound V-50 in 75% yield. lH-NMR (300MHz, CDC13) 5 0.81 (dd, J = 7.1, 11.0 Hz, 6H), 0.89 (t, J = 7.1 Hz, 3H), 1.20 (s, 9H), 1.49 (m, 6H), 1.66- 1.96 (m, 5H), 2.08 (m, 2H), 2.56 (dd, J = 3.3, 13.7 Hz, 1H), 2.69 (dd, J = 8.8, 13.7 Hz, 2H), 2.78 (m, 1H), 2.88 (m, 4H), 3.11 (q, J = 8.8 Hz, 1H), 3.26 (m, 1H), 3.38 (m, 1H), 3.67 (s, 3H), 3.90 (m, 1H), 3.94 (s, 3H), 4.41 (dd, J = 4.9, 8.2 Hz, 1H), 4.45 (m, 1H), 6.56 (d, J = 8.2 Hz, 2H), 6.65 (d, J = 8.2 Hz, 1H), 6.74 (dd, J = 6.6, 9.3 Hz, 3H), 6.85 (d, J = 4.9 Hz, 1H), 6.92 (d, J = 9.3 Hz, 1H), 7.24 (dd, J = 2.7, 9.3 Hz, 1H), 7.35 (d, J = 4.4 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.65 (d, J = 7.1 Hz, 1H), 7.84 (d, J = 9.3 Hz, 1H), 8.58 (d, J = 4.9 Hz, 1H). DHQD-PYZ-(D)-B-PrO-(L)-Tyr-(L)-Val-0Me V-51 HO A solution of tert-butyl protected ligand V-50 (49 mg, 0.0567 mmol,1.0 eq.) in anhydrous TFA (5 ml) was stirred at 0 °C for 5 min. The reaction was then warmed to rt, and stirred for another 12 h. TFA was removed at reduced pressure. Saturated sodium carbonate solution was added to the residue, and the product was extracted with dichloromethane three times. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure. The 313 residue was purified by column chromatography on silica gel (EtOAc : Hexanes : MeOH : TEA = 34 : 51 : 10 : 5) to yield 41.6 mg (91%) desired product. lH-NMR (300MHz, CDCl3) 5 0.84 (t, J = 7.3 Hz, 6H), 1.04 (t, J = 6.8 Hz, 3H), 1.22 (dd. J = 5.9, 7.3 Hz, 1H), 1.60 (m, 5H), 1.80 (m, 2H), 2.01 (m, 4H), 2.26 (m, 2H), 2.76—3.10 (m, 8H), 3.20 (m, 3H), 3.55 (m, 1H), 3.69 (s, 3H), 3.95 (s, 3H), 4.10 (m, 1H), 4.45 (dd, J = 5.4, 8.3 Hz, 1H), 4.52 (q, J = 7.3 Hz, 1H), 5.94 (d, J = 7.3 Hz, 1H), 6.58 (d, J: 8.3 Hz, 2H), 6.73 (t, J: 8.3 Hz, 3H), 6.86 (d, J = 9.8 Hz, 1H), 6.96 (d, J = 9.3 Hz, 1H), 7.07 (s, 1H), 7.31 (m, 2H), 7.43 (d, J = 2.4 Hz, 1H), 7.94 (d, J = 9.3 Hz, 1H), 8.57 (d, J = 4.4 Hz, 1H). l3C-NMR (75 MHz, CDC13) 5 11.9, 18.0, 18.8, 20.0, 23.5, 25.1, 25.8, 26.4, 31.0, 31.2, 35.7, 36.9, 39.5, 45.9, 48.7, 50.0, 51.1, 52.1, 53.2, 55.9, 57.3, 58.4, 76.5, 101.1, 115.8, 117.2, 118.2, 119.0, 122.3, 125.5, 126.3, 130.2, 131.4, 143.7, 144.5, 147.0, 155.7, 156.5, 157.5, 158.1, 171.3, 172.1. H-(L)-Lys(Boc)-Val-0Me V-53 o HZNJNH o\ O NH Boc’ Hydrogenation of compound V-52 catalyzed by Pd/C similar to the reaction procedure described for V-8 gave compound V-53 in 82% yield over two steps. 1H- NMR (300MHz, CDC13) 5 0.83 (dd, J = 6.9, 8.0 Hz, 6H), 1.34 (s, 9H), 1.45 (m, 6H), 1.76 (m, 1H), 2.10 (m, 1H), 3.03 (q, J = 6.0, 12.1 Hz, 1H), 3.30 (dd, J = 3.8, 7.7 Hz, 1H), 3.64 (s, 3H), 4.41 (dd, J = 4.9, 9.3 Hz, 1H), 4.68 (m, 1H), 7.74 (d, J = 8.8 Hz, 1H). 314 DHQD-PYZ-(D)-B-gg‘:-(L)-Lys(Boc)-(L)-Val-0Me V-54 DCC coupling of compound V-37 and V-53 similar to the reaction procedure described for V-7 gave compound V-54 in 81% yield. lH-NMR (300MHz, CDC13) 5 0.85 (m, 9H), 1.05 (m, 4H), 1.36 (s, 9H), 1.2-1.6 (m, 8 H), 1.70 (s, 1H), 1.8-2.2 (m, 7H), 2.25 (dd, J =6.6, 14.3 Hz, 1H), 2.57 (m, 1H), 2.84 (m, 4H), 3.23 (m, 2H), 3.46 (m, 2H), 3.69 (s, 3H), 3.94 (s, 3H), 4.14 (m, 2H), 4.43 (dd, J = 4.9, 8.8 Hz, 1H), 4.69 (m, 1H), 6.83 (m, 3H), 6.93 (d, J = 9.9 Hz, 1H), 7.33 (m, 3H), 7.51 (d, J = 6.0 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 8.59 (d, J =4.9 Hz, 1H). DHQD-PYZ-(D)-B-PrO-(L)-Lys-(L)-Val-0Me V-SS Deprotection of Boc group in V-54 generated compound V-SS in 79% yield. 1H- NMR (300MHz, CDC13) 5 0.85 (dd, J = 2.0, 6.8 Hz, 6H), 0.90 (t, J = 6.8 Hz, 3H), 1.28 315 (m, 3H), 1.56 (m, 8H), 1.7-2.3 (m, 10H), 2.60 (dd, J = 7.3, 13.2 Hz, 1H), 2.8-3.1 (m, 5H), 3.26 (m, 2H), 3.49 (t, J = 8.8 Hz, 1H), 3.67 (s, 3H), 3.92 (s, 3H), 3.96 (m, 1H), 4.36 (dd, J = 5.4, 8.3 Hz, 2H), 6.33 (5, br, 2H), 6.90 (s, 1H), 6.98 (d, J = 9.8 Hz, 1H), 7.04 (d, J = 9.8 Hz, 1H), 7.32 (m, 3H), 7.41 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 9.3 Hz, 1H), 8.14 (d, J = 7.3 Hz, 1H), 8.57 (d, J = 4.9 Hz, 1H). ”GM (75 MHz, CDCl;,) 5 17.7, 18.9, 20.9, 213,227, 25.1, 25.8, 26.3, 27.0, 29.7, 30.8, 31.0, 36.7, 38.8, 40.6, 45.7, 47.1, 50.1, 50.8, 52.0, 53.7, 55.6, 55.9, 57.2, 59.4, 75.6, 101.1, 117.8, 119.7, 120.0, 122.3, 126.4, 131.5, 143.9, 144.3, 147.0, 155.3, 157.0, 158.3, 171.7, 172.2, 172.5. Z-(L)-Asn-(L)-Val-0Me V-56 z o HN\;/U\NH o\ Hme/2 o O DIC coupling of Z-(L)-Asn-OH and H-(L)-Val-OMe similar to the reaction procedure described for V-7 gave compound V-56 in 37% yield. lH--NMR (300MHz, CDCl3) 5 0.84 (dd, J = 6.6, 10.4 Hz, 6H), 1.22 (m, 2H), 2.11 (m, 1H), 2.84 (m, 2H), 3.69 (s, 3H), 4.48 (dd, J = 4.9, 8.8 Hz, 1H), 4.61 (m, 1H), 5.10 (s, 2H), 4.12 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 7.30 (s, 5H). H-(L)-Asn-(L)-Val-0Me V-57 o H2N\/ILNH o\ 1+4,ij o O 316 Hydrogenation of compound V-56 catalyzed by Pd/C similar to the reaction procedure described for V-8 gave compound V-57 in 65% yield. 1H-NMR (300MHz, CDC13) 5 0.90 (dd, J = 6.6, 9.3 Hz, 6H), 1.38 (dd, J = 2.2, 7.1 Hz, 1H), 1.76 (3, br, 2H), 2.17 (m, 1H), 2.80 (dd, J = 7.1, 17.0 Hz, 1H), 2.88 (dd, J = 4.4, 17.0 Hz, 1H), 3.69 (m, 1H), 3.71 (s, 3H), 4.45 (dd, J = 4.9, 9.3 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H). DHQD-PYZ-(D)-B-Pro-(L)-Asn-(L)-Val-0Me V-58 DCC coupling of compound V-37 and V-57 similar to the reaction procedure described for V-7 gave compound V-58 in 65% yield. 1H-NMR (500MHz, CDC13) 5 0.81 (t, J = 6.8 Hz, 6H), 0.90 (t, J = 7.3 Hz, 3H), 1.27 (m, 1H), 1.4-1.6 (m, 5H), 1.72 (s, 1H), 1.96 (m, 4H), 2.09 (m, 2H), 2.29 (dd, J = 6.8, 14.6Hz, 1H), 2.36 (dd, J = 4.4, 17.1 Hz, 1H), 2.40 (dd, J = 9.8, 17.1 Hz, 1H), 5.56 (s, 2H), 2.62 (dd, J = 3.4, 14.6 Hz, 1H), 2.74 (m, 1H), 2.85 (m, 1H), 2.91 (d J = 8.8 Hz, 2H), 3.14 (q, J = 8.3 Hz, 1H), 3.22 (m, 1H), 3.40 (m, 1H), 3.69 (s, 3H), 3.98 (s, 3H), 4.21 (m, 1H), 4.38 (dd, J = 4.9, 8.8 Hz, 1H), 4.46 (m, 1H), 6.79 (d, J = 9.8 Hz, 2H), 6.97 (d, J = 9.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 4.9 Hz, 1H), 7.35 (dd, J = 2.4, 8.8 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.98 (d, J = 9.3 Hz, 1H), 8.60 (d, J = 4.4 Hz, 1H), 9.68 (s, 1H). l3C-NMR (125 MHz, CDCl3) 5 12.0, 17.5, 18.4, 18.9, 21.7, 23.6, 25.3, 25.6, 26.2, 27.2, 30.9, 33.0, 37.4, 40.9, 43.2, 47.6, 317 49.8, 50.4, 51.2, 52.1, 55.7, 56.6, 57.4, 59.4, 101.5, 116.8, 117.9, 118.3, 120.2, 121.8, 126.7, 131.7, 144.5,-147.3, 154.5, 157.6, 157.9, 168.8, 171.7, 173.4. Z-(L)-His(Z)-(L)-Val-0Me V-59 H O Z,N\£)J\n OMe N ' O <4 I Z DCC coupling of Z-(L)-His(Z)-OH and H—(L)-Val-0Me similar to the reaction procedure described for V-7 gave compound V-57 in 57% yield. 1H-NMR (300MHz, CDCl3) 5 0.71 (d, J = 6.6 Hz, 6H), 2.02 (m, 1H), 2.90 (dd, J = 14.8, 6.0 Hz,1H), 3.12 (dd, J = 14.8, 4.4 Hz, 1H), 3.63 (s, 3H), 4.40 (dd, J = 8.8, 4.9 Hz, 1H), 4.54 (q, J = 5.5 Hz, 1H), 5.10 (d, J = 4.9 Hz, 2H), 5.36 (s, 2H), 6.48 (d, J = 6.6 Hz, 1H), 7.20 (m, 1H), 7.33 (m, 5H), 7.38 (s, 6H), 8.04 (d, J: 1.6 Hz, 1H). H-(L)-His-(L)-Val-0Me V-60 o H2N dL N OMG i H N o if Hydrogenation of compound V-59 catalyzed by Pd/C similar to the reaction procedure described for V-8 gave compound V-60 in 83% yield. lH-NMR (300MHz, CDCl3) 5 0.82 (dd, J = 7.1, 3.3Hz, 6H), 2.11 (m, 1H), 2.97 (ddd, J = 26.9, 14.3, 4.4 Hz, 2H), 3.62 (dd, J = 7.1, 4.4 Hz, 1H), 3.69 (s, 3H), 4.41 (dd, J = 8.8, 4.9 Hz, 1H), 6.81 (s, 1H), 7.53 (s, 1H), 7.98 (d, J: 8.8 Hz, 1H). 318 DHQD-PYZ-(D)-B'Pro-(L)-His-(L)-Val-0Me V-61 DCC coupling of compound V-37 and V-60 similar to the reaction procedure described for V-7 gave compound V-6l in 45% yield. lH-NMR (500MHz, CDC13) 5 0.82 (dd, J = 6.8, 3.9 Hz, 6H), 0.90 (t, J = 7.3 Hz, 3H), 1.18 (t, J = 7.3 Hz, 1H), 1.22 (s, 1H), 1.31 (ddd, J = 13.7, 9.8, 4.4 Hz, 1H), 1.54 (m, 5H), 1.79 (s, 1H), 1.93 (m, 4H), 2.08 (m, 1H), 2.19 (m, 1H), 2.26 (dd, J = 14.2, 7.8 Hz, 1H), 2.55 (dd, J = 14.2, 3.4 Hz, 1H), 2.81 (m, 1H), 2.94 (m, 4H), 3.18 (q. J = 8.3 Hz, 1H), 3.31 (td, J = 9.3, 3.9 Hz, 1H), 3.42 (td, J = 6.8, 2.0 Hz, 1H), 3.67 (s, 3H), 3.83 (s, 3H), 4.22 (m,1H), 4.38 (dd, J: 8.3, 5.4 Hz. 1H), 4.48 (q, J = 6.8 Hz, 1H), 6.72 (s, 1H), 6.82 (d, J = 9.8 Hz, 1H), 6.95 (d, J = 9.3 Hz, 1H), 7.13 (s, 1H), 7.28 (dd. J = 9.3, 2.9 Hz, 1H), 7.38 (m, 3H), 7.71 (s, 1H), 7.90 (d, J = 9.3 Hz, 1H), 8.60 (d, J = 4.4 Hz, 1H). 13CNMR (125 MHz, CDC13) 5 11.9, 14.8, 17.8, 18.9, 21.2, 23.3, 25.2, 25.9, 26.6, 29.7, 30.9, 31.4, 36.9, 41.0, 45.9, 47.5, 50.1, 50.8, 52.0, 53.5, 55.6, 55.7, 57.5, 59.4, 75.8, 101.3, 118.1. 119.5, 122.1, 126.6, 131.6, 134.8, 143.9, 144.5. 147.2, 155.1, 157.5, 158.0, 171.3, 171.9, 172.1. H-Phe-OMe V-62 319 o Hsz/‘LO/ G To a suspension of phenylalanine (165 mg, 1.0 mmol, 1.0 eq.) in 2,2- dimethoxypropane (15 mL) was added concentrated HCl (1 mL). The reaction mixture was stirred at rt for 14 h. The solvent was evaporated under reduced pressure. Saturated N32CO3 solution was added. The product was extracted with CH2C12 (20 mL x 3). The combined organic layers were washed with brine, and dried over NaZSO4. The solvent was removed under reduced pressure, and the product was purified by column chromatography (100% EtOAc) to afforded 121 mg desired product (68%). lH-NMR (300MHz, CDC13) 5 1.47 (2, 2H), 2.84 (dd, J = 13.7, 7.7 Hz, 1H), 3.07 (dd, J = 13.7, 5.5 Hz, 1H), 3.69 (s, 3H), 3.71 (m, 1H), 7.24 (m, 5H). Z-(L)-Asn-(L)-Phe-0Me V-63 H o Z,N\:/U\N o\ H o Hsz; O DCC coupling of Z-(L)-Asn-OH and H-(L)-Phe-0Me V-62 similar to the reaction procedure described for V-7 gave compound V-63 in 41% yield. lH-NMR (300MHz, CDC13) 5 2.80 (m, 2H), 3.07 (ddd, J = 29.1, 13.7, 5.5 Hz, 2H), 3.71 (s, 3H), 4.49 (m, 1H), 4.82 (q, J = 6.0 Hz, 1H), 5.09 (s, 2H), 5.59 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 7.1 Hz, 1H), 7.05 (dd, J = 7.7, 2.7 Hz, 2H), 7.21 (d, J = 6.6 Hz, 3H), 7.34 (m, SH). 320 H-(L)-Asn-(L)-Phe-0Me V-64 0 K ; H2N\/LI\N o\ - H o Hsz O Hydrogenation of compound V-63 catalyzed by Pd/C similar to the reaction procedure described for V-8 gave compound V-64 in 79% yield. lH-NMR (300MHz, CDCl3) 5 1.65 (s, 2H), 2.61 (dd, J = 17.1, 7.8 Hz, 1H), 2.89 (dd, J = 17.1, 4.4 Hz, 1H), 3.09 (dd, J = 13.7, 6.3 Hz, 1H), 3.20 (dd, J = 13.7, 5.9 Hz, 1H), 3.64 (dd, J: 7.8, 3.9 Hz, 1H), 3.76 (s, 3H), 4.85 (q, J = 6.3 Hz, 1H), 7.15 (d, J = 7.3 Hz, 2H), 7.30 (m, 5H), 7.74 (d, J = 7.3 Hz, 1H). DHQD-PYZ-(D)-B-Pl‘o-(L)-Asn-(L)-Phe-0Me V-65 DCC coupling of compound V-37 and V-64 similar to the reaction procedure described for V-7 gave compound V-65 in 80% yield. lH-NMR (500MHz, CDCl3) 5 0.91 (t, J = 7.3 Hz, 3H), 1.22 (t, J = 7.3 Hz, 3H), 1.40-1.62 (m, 10H), 1.74 (s, 1H), 1.86-2.12 (m, 7H), 2.30 (dd, J = 15.1, 9.8 Hz, 1H), 2.59 (dd, J = 17.1, 7.8 Hz, 1H), 2.86 (m, 3H), 3.09 (dd, J = 14.2, 6.8 Hz, 1H), 3.19 (dd, J = 13.7, 5.9 Hz, 1H), 3.32 (m, 2H), 3.51 (m, 1H), 3.63 (m,1H), 3.75 (s, 3H), 3.97 (s, 3H), 4.10 (q, J = 321 6.8 Hz, 2H), 4.37 (m, 1H), 4.83 (dt, J = 8.3, 6.3 Hz, 1H), 6.76 (d, J = 9.8 Hz, 1H), 6.89 (d, J = 5.4 Hz, 1H), 6.91 (d, J = 9.8 Hz, 1H), 7.13 (m, 2H), 7.24-7.36 (m, 4H), 7.40 (d, J = 4.4 Hz, 1H), 7.53 (d, J = 2.9 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 9.3 Hz, 1H), 8.64 (d, J = 4.4 Hz, 1H). l3C-NMR (125 MHz, CDC13) 5 12.0, 14.1, 23.0, 24.2, 24.9, 25.3, 26.2, 27.4, 30.8, 33.9, 37.5, 37.7, 37.9, 47.5, 50.2, 50.9, 51.7, 52.4, 53.0, 54.6, 55.6, 59.6, 60.4, 102.3, 117.4, 117.5, 119.3, 121.5, 127.0, 127.2, 128.6, 129.2, 131.5, 135.6, 144.6, 147.3, 154.9, 157.5, 157.8, 170.6, 171.5, 171.6. Z-Trp-OMe V-66 H O Z’NE/ILO/ HN\ To a solution of Z-Trp-OH (388 mg, 1.0 mmol, 1.0 eq.) in methanol (10 mL) was added TMSCHzNz (2.0 M in diethyl ether, 1.0 mL, 2.0 mmol, 2.0 eq.) dropwise at 0 °C. The reaction mixture was stirred at rt for 3 h, then quenched with water. The solvent was removed under reduced pressure. The product was extracted with diethyl ether (20 mL x 3). The combined organic layers were washed with brine and dried over MgSO4. After filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (40% EtOAc in hexanes) to yield 218 mg desired product (62%). lH-NMR (300MHz, CDCl3) 5 3.30 (d, J = 5.5 Hz, 2H), 3.66 (s, 3H), 4.72 (dt, J = 8.2, 5.5 Hz, 1H), 5.11 (dd, J = 17.0, 12.1 Hz, 2H), 5.36 (d, J = 7.7 Hz, 1H), 6.90 (s, 1H), 7.09 (td, J: 7.1, 1.1 Hz, 1H), 7.18 (td, J: 7.1, 1.1 Hz, 1H), 7.33 (s, 5H), 7.52 (d, J = 7.7 Hz, 1H), 8.21 (s, 1H). 322 H-Trp-OMe V-67 o H2N\./u\0/ HN\ Hydrogenation of compound V-66 catalyzed by Pd/C similar to the reaction procedure described for V-8 gave compound V-67 in 86% yield. 1H-NMR (300MHz, CDCl3) 5 1.59 (s, br, 2H), 3.04 (dd, J = 20.9, 14.3 Hz, 1H), 3.26 (dd, J = 14.3, 4.4 Hz, 1H), 3.70 (s, 3H), 3.84 (dd, J = 7.7, 4.9 Hz, 1H), 7.00 (d, J = 2.2 Hz, 1H), 7.10 (td, J = 8.2, 1.1 Hz, 1H), 7.18 (td, J = 7.1, 1.1 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 8.40 (s, 1H). Z-(L)-Asn-(L)-Trp-0Me V-68 !\ NH H o Z,N\:/U\N o\ .. H O H2N\n/' O DCC coupling of Z-(L)-Asn-OH and H-(L)-Trp-0Me V-67 similar to the reaction procedure described for V-7 gave compound V-68 in 53% yield. 'H-NMR (300MHz, CDC13) 8 2.71 (d, J = 5.5 Hz, 2H), 3.26 (d, J = 3.8 Hz, 2H), 3.65 (s, 3H), 4.48 (q, J = 7.1 Hz, 1H), 4.86 (q, J = 5.5 Hz, 1H), 5.03 (s, 2H), 5.81 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 2.2 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H), 7.06 (m, 2H), 7.32 (s, 5H), 7.44 (d, J = 7.7 Hz, 1H), 8.29 (s, 1H). 323 H-(L)-Asn-(L)-Trp-0Me V-69 !\ :NH 0 HZNJN o\ 2 H O H2N\"/' O Hydrogenation of compound V-68 catalyzed by Pd/C similar to the reaction procedure described for V-8 gave compound V-69 in 45% yield. 1H-NMR (300MHz, CDC13) 5 2.42 (dd, J = 16.5, 7.7 Hz, 1H), 2.74 (dd, J = 17.0, 3.8 Hz, 1H), 3.30 (m, 2H), 3.49 (m, 1H), 3.70 (s, 3H), 4.85 (dt, J = 8.2, 6.0 Hz, 1H), 7.00 (d, J = 2.2 Hz, 1H), 7.08 (t, J = 7.1 Hz, 1H), 7.15 (t, J = 6.6 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 8.52 (s, 1H). DHQD-PYZ-(D)-B-Pro-(L)-Asn-(L)-Trp-0Me V-70 O 0 ”H2 0 u “= O/ O - / N NH DCC coupling of compound V-37 and V-69 similar to the reaction procedure described for v.7 gave compound v.70 in 74% yield. lH-NMR (500MHz, CDCl;,) 8 0.96 (t, J = 7.3 Hz, 3H), 1.04 (t, J = 7.3 Hz, 1H), 1.21 (m, 1H), 1.52-1.68 (m, 5H), 1.72 (dd, J = 17.1, 11.7 Hz, 1H), 1.83 (m, 2H), 1.96 (m, 3H), 2.15 (m, 2H), 2.32 (dd, J = 12.2, 10.7 Hz, 1H), 2.49 (dd, J = 14.6, 2.4 Hz, 1H), 2.57 (q, J = 6.8 Hz, 1H), 2.94 (m, 1H), 324 2.99 (dd, J = 14.6, 8.8 Hz, 1H), 3.12 (m, 3H), 3.22 (dd, J = 12.7, 7.8 Hz, 1H), 3.28 (t, J = 9.3 Hz, 1H), 3.37 (m, 2H), 3.38 (s, 3H), 3.69 (s, 3H), 4.06 (m, 1H), 4.34 (ddd, J = 11.2, 7.3, 3.9 Hz, 1H), 4.73 (td, J = 8.8, 3.9 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6.83 (d, J = 9.3 Hz, 1H), 6.94 (m, 3H), 7.95 (s, 1H), 7.10 (dd, J = 19.0, 7.8 Hz, 3H), 7.24 (d, J = 4.4 Hz, 1H), 7.29 (dd, J = 8.8, 2.4 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.98 (d, J = 9.3 Hz, 1H), 8.58 (d, J = 4.4 Hz, 1H), 9.60 (s, 1H), 11.55 (s, 1H). l3C-NMR (125MHz, CDC13) 5 11.9, 18.8, 20.3. 23.8, 25.3, 25.6, 26.1, 26.9, 27.5, 33.7, 37.1, 46.1, 47.4, 49.7, 50.5, 51.2, 52.4, 53.3, 55.0, 57.0, 58.6, 100.9, 109.5, 111.4, 116.8, 117.4, 118.6, 119.0, 120.2, 121.1, 121.4, 123.1, 126.1, 127.6, 132.0, 136.3, 143.1, 144.2, 147.3, 154.2, 157.1, 158.1, 168.6, 171.9, 173.3. Fmoc-(L)-tBuGly-(L)-Val-OMe V-71 o FmocHNdLHIrO\ i H o r DCC coupling of Fmoc-(L)-tBuGly-OH and H-(L)-Val-0Me V-71 similar to the reaction procedure described for V-7 gave compound V-70 in 83% yield. lH-NMR (300MHz, CDC13) 5 0.86 (dd, J = 12.1 7.1 Hz, 6H), 1.00 (s, 9H), 2.11 (m, 1H), 3.66 (s, 3H), 4.16 (m, 2H), 4.31 (dd, J = 10.4, 7.1 Hz, 1H), 4.44 (dd, J = 10.4, 7.1 Hz, 1H), 4.53 (dd, J = 8.2, 4.9 Hz, 1H), 5.62 (d, J = 9.3 Hz, 1H), 6.53 (d, J = 8.8 Hz, 1H), 7.27 (m, 2H), 7.36 (t, J = 7.1 Hz, 2H), 7.57 (d, J = 4.9 Hz, 2H), 7.73 (d, J = 7.7 Hz, 2H). H-(L)-tBuGly-(L)-Val-0Me V-72 325 o H2N\/U\Nj:'(0\ H o r To a solution of compound V-71 (387 mg, 1.0 eq.) in CH2C12 (15 mL) was added piperidine (1 mL). The reaction mixture was stirred at rt for 4 h. The solvent was removed under reduced pressure. The residue was purified by column chromatograpy ( EtOAczHeszeOHzTEA 35.2:52.8:10:2) to yield 156 mg desired product (77%). 1H- NMR (300MHz, CDCl3) 5 0.89 (dd, J = 12.6, 7.1 Hz, 6H), 0.97 (s, 9H), 1.45 (s, br, 2H), 2.15 (m, 1H), 3.12 (s, 1H), 3.69 (s, 3H), 4.48 (dd, J = 93,49 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H). Z-(L)-Asn-(L)-tBuGly-(L)-Val-0Me V-73 H O H O Cbz’N\;/ILN N O/ : H O : \n—NHz /\ O DCC coupling of Z-Asn-OH and compound V-72 similar to the reaction procedure described for V-7 gave compound V-73 in 42% yield. lH-NMR (300MHz, CDCl3) 5 0.83 (dd, J = 8.8, 7.1 Hz, 6H), 0.91 (s, 9H), 2.06 (m, 1H), 2.52 (dd, J = 15.9, 5.5 Hz, 1H), 2.88 (dd, J = 15.9, 4.9 Hz, 1H), 3.67 (s, 3H), 4.48 (m, 2H), 6.61 (m, 1H), 5.07 (s, 2H), 5. 93 (s, 1H), 6.55 (s, 1H), 6.72 (s, J = 8.2 Hz, 1H), 7.28 (m, 5H), 7.55 (d, J = 9.3 Hz, 1H). H-(L)-Asn-(L)-tBuGly-(L)-Val-0Me V-74 326 1"12N\:)J\u H - O/ \"_NH20 /\ O Hydrogenation of compound V-73 catalyzed by Pd/C similar to the reaction procedure described for V-8 gave compound V-74 in 73% yield. lH-NMR (300MHz, CDC13) 5 0.83 (dd, J = 9.3, 7.1 Hz, 6H), 0.95 (s, 9H), 2.07 (m, 3H), 2.53 (dd, J = 14.8, 7.7 Hz, 1H), 2.70 (dd, J = 14.8, 3.3 Hz, 1H), 3.64 (dd, J = 7.7, 3.3 Hz, 1H), 3.69 (s, 3H), 4.52 (dd, J = 8.8, 5.5 Hz, 1H), 4.56 (d, J = 9.9 Hz, 1H), 5.95 (s, 1H), 6.72 (s, 1H), 7.50 (d, J = 8.8 Hz, 1H), 8.29 (d, J = 9.9 Hz, 1H). DHQD-PYZ-(D)—B-Pro-(L)-Asn-(L)-tBuGly-(L)-Val-0Me V-75 DCC coupling of compound V-37 and V-74 similar to the reaction procedure described for V-7 gave compound V-75 in 73% yield. lH-NMR (500MHz, CDC13) 5 0.87 (m, 9H), 0.92 (s, 9H), 1.29 (m, 1H), 1.48 (m, 4H), 1.72 (s, 1H), 1.91 (m, 4H), 2.10 (m, 2H), 2.25 (dd, J = 14.6, 7.8 Hz, 1H), 2.31 (dd, J = 15.1, 5.9 Hz, 1H), 2.54 (m, 2H), 2.59 (q, J = 7.3 Hz, 1H), 2.72 (m, 1H), 2.87 (m, 3H), 3.22 (m, 2H), 3.44 (m, 1H), 3.67 (s, 3H), 3.94 (s, 3H), 4.24 (d, J = 8.8 Hz, 2H), 4.46 (dd, J = 8.3, 4.9 Hz, 1H), 4.68 (q, J = 6.3 Hz, 1H), 5.45 (s, 1H), 6.25 (s, 1H), 6.83 (d, J = 9.8 Hz, 1H), 6.86 (s, 1H), 6.91 (d, J = 9.8 327 Hz, 1H), 7.32 (m, 3H), 7.45 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 8.21 (d, J = 6.8 Hz, 1H), 8.58 (d, J = 4.4 Hz, 1H). l3C-NMR (125MHz, CDC13) 5 12.0, 17.9, 18.9, 23.2, 25.3, 25.6, 26.1, 26.6, 31.1, 31.9, 34.3, 36.3, 37.3, 41.4, 46.1, 47.5, 50.21, 50.23, 51.0, 52.0, 55.6, 55.8, 57.1, 59.5, 61.3, 101.7, 118.3, 119.7, 121.9, 126.8, 126.9,128.4, 131.6, 144.5, 147.3, 155.0, 157.7, 157.8, 170.3, 170.9, 171.8, 172.4, 173.1. Z-Asn(Trt)-OH v.7675 O NH(Trt) CszN OH O Z-Asn-OH (5.32 g, 0.02 mol, 1.0 eq.), Ph3COH (10.4 g, 0.04 mol, 2.0 eq.), AczO (3.78 mL, 0.04 mol, 2.0 eq.) and concentrated H2804 (0.1 mL, 1.8 mmol, cat.) were suspended in glacial acetic acid (60 mL) and stirred for 1 h at 50 °C. The solution was then slowly added to cold water (600 mL). The precipitate was filtered off, dissolved in EtOAc (200 mL), washed with water, dried, evaporated and crystallized from EtOAc and hexanes to yield 7.53 g desired product (74%). IH-NMR (300MHz, CDC13) 5 2.75 (dd, J = 15.9, 7.1 Hz, 1H), 2.97 (d, J = 15.9, 1H), 4.40 (m, 1H), 5.07 (s, 2H), 6.01 (d, J = 6.6 Hz, 1H), 7.0-7.4 (m, 20 H). Z-Asn(Trt)-OMe V-77 O NH(Trt) CszN 0M9 O 328 Methylation of V-76 in an identical fashion to the synthesis of V-66 was utilized to generate V-77 in 50% yield. lH-NMR (300MHz, CDCl3) 5 2.77 (dd, J = 15.4, 3.8 Hz, 1H), 3.04 (dd, J = 15.9, 4.4 Hz, 1H), 3.63 (s, 3H), 4.55 (m, 1H), 5.08 (s, 2H), 6.04 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 7.1-7.4 (m, 20 H). H-Asn(Trt)-0Me V-78 o NH(Trt) OMe O H2N Hydrogenation of compound V-77 catalyzed by Pd/C similar to the reaction procedure described for V-8 gave compound V-78 in 91% yield. lH-NMR (300MHz, CDC13) 5 1.80 (s, br, 2H), 2.55 (dd, J = 15.4, 8.2 Hz, 1H), 2.67 (dd, J: 15.4, 3.3 Hz, 1H), 3.69 (s, 3H), 3.81 (dd, J = 8.2, 3.3 Hz, 1H), 7.20 (m, 20H), 8.45 (s, 1H). H-Val-Asn(Trt)-0Me V-79 O O NH(Trt) H2N\/U\N 0M9 H o /\ DCC coupling of Z—Val-OH and compound V-78 followed by hydrogenation generated compound V-79 in 65 % yield over two steps. lH-NMR (300MHz, CDC13) 5 0.78 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 1.27 (s, br, 2H), 2.13 (m, 1H), 2.77 (dd, J = 16.5, 4.4 Hz, 1H), 3.07 (dd, J = 15.9, 4.9 Hz, 1H), 3.11 (d, J = 3.8 Hz, 1H), 3.62 (s, 3H), 4.73 (m, 1H), 6.76 (s, 1H), 7.15 (m, 6H), 7.23 (m,9H), 7.91 (d, J = 8.2 Hz, 1H). 329 DHQD-PYD-B-(D)-Pro-(L)-Val-(L)-Asn(Trt)-OMe V-80 H o N N\/U\o/ I O WNHUrt) O DCC coupling of compound V-37 and V-79 similar to the reaction procedure described for V-7 gave compound V-80 in 72% yield. lH-NMR (500MHz, CDCl3) 5 0.63 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H), 1.34 (m, 1H), 1.50 (m, 5H), 1.71 (s, 1H), 1.90 (m, 5H), 2.03 (m, 1H), 2.18 (dd, J = 13.7, 8.3 Hz, 1H), 2.49 (s, 1H), 2.71 (m, 1H), 2.73 (dd, J = 16.1, 4.4 Hz, 1H), 2.85 (m, 3H), 3.03 (dd, J = 16.1, 4.4 Hz, 1H), 3.22 (m, 1H), 3.28 (m, 1H), 3.47 (m, 1H), 3.62 (s, 3H), 3.92(s, 3H), 4.09 (dd, J = 7.8, 5.9 Hz, 1H), 4.22 (m,1H), 4.79 (m, 1H), 6.80-6.92 (m, 5H), 6.95 (d, J = 8.8 Hz, 1H), 7.14 (m, 5H), 7.20-7.28 (m, 11H), 7.30 (dd, J = 8.8, 2.4 Hz, 1H), 4.35 (d, J = 4.4 Hz, 1H), 7.47 (m, 1H), 7.94 (d, J = 8.8 Hz, 1H), 8.60 (d, J = 4.4 Hz, 1H). 13C- NMR (125MHz, CDC13) 5 12.0, 17.3, 19.0, 23.3, 25.3, 25.6, 26.1, 27.3, 31.0, 31.2, 37.4, 38.1, 40.9, 47.5, 48.6, 50.2, 50.9, 52.5, 55.7, 55.9, 58.2, 59.5, 70.9, 102.0, 118.0, 119.4, 121.6, 127.0, 127.1, 128.0, 128.4, 128.6, 128.7, 131.5, 144.2, 144.5, 147.3, 154.9, 157.5, 157.6, 169.5, 171.0, 171.1, 171.3. Z-(L)-Asn(Trt)-(L)-Val-0Me V-81 330 o NH(Trt) H 0 CszN N\i/ll\OMe O /\ DCC coupling of Z-Asn(Trt)—OH and H-Val-OMe similar to the reaction procedure described for V-7 gave compound V-81 in 81% yield. 1H-NMR (300MHz, CDCl3) 5 0.80 (dd, J = 15.4, 6.6 Hz, 6H), 2.07 (m, 1H), 2.66 (dd, J = 15.4, 6.0 Hz, 1H), 2.97 (dd, J = 15.4, 2.7 Hz, 1H), 3.67 (s, 3H), 4.37 (dd, J = 8.2, 4.9 Hz, 1H), 4.54 (m, 1H), 5.08 (d, J = 3.3 Hz, 2H), 6.58 (d, J = 7.7 Hz, 1H), 7.24 (m, 20 H). H-(L)-Asn(Trt)-(L)-Val-0Me V-82 NH(Trt) H O H2N NgkOMe O /\ Hydrogenation of compound V-81 catalyzed by Pd/C similar to the reaction procedure described for V-8 gave compound V-82 in 98% yield. lH—NMR (300MHz, CDC13) 5 0.85 (dd, J = 7.1, 3.8 Hz, 6H), 1.78 (s, 2H), 2.08 (m, 1H), 2.61 (dd, J = 14.8, 7.7 Hz, 1H), 2.68 (dd, J = 15.4, 4.4 Hz, 1H), 3.63 (dd, J = 7.7, 3.8 Hz, 1H), 3.69 (s, 3H), 4.39 (dd, J = 8.8, 4.9 Hz, 1H), 7.22 (m, 15H), 7.83 (d, J = 8.8 Hz, 1H). DHQD-PYD-B-(D)-Pro-(L)-Asn(Trt)-(L)-Val-0Me V-83 331 C)NH(Trt) YCOOMe =N DCC coupling of compound V-37 and V-82 similar to the reaction procedure described for V-7 gave compound V-83 in 69% yield. lH-NIVIR (500 MHz, CDC13) 5 _ 0.84 (dd, J = 6.8, 21.0 Hz, 6H), 0.90 (t, J = 7.3 Hz, 3H), 1.32 (m, 1H), 1.4-1.6 (m, 5H), 1.71 (s, 1H). 1.76 (m, 1H), 1.87 (m,3H), 2.02 (m. 1H), 2.10 (m, 1H), 2.25 (dd, J = 5.4, 14.6 Hz, 1H), 2.27 (dd, J = 7.8, 15.1 Hz, 1H), 2.51 (dd, J = 3.4, 14.6 Hz, 1H), 2.58 (dd, J = 5.4, 14.6 Hz, 1H), 2.72 (m, 1H), 2.86 (m, 3H), 3.14 (q, J = 7.8 Hz, 1H), 3.26 (m, 1H), 3.38 (m, 1H), 3.68 (s, 3H), 3.94 (s, 3H), 4.23 (m, 1H), 4.37 (dd, J = 4.9, 8.3 Hz, 1H), 4.60 (q, J = 5.4 Hz, 1H), 6.75 (d. J = 9.3 Hz, 1H), 6.77 (s, 1H), 6.81 (m, 1H), 6.90 (d, J = 9.3 Hz, 1H), 7.04 (m, 6H). 7.18 (m, 9H), 7.24 (d, J = 4.4 Hz, 1H), 7.28 (dd, J = 2.9, 9.3 Hz, 1H), 7.39 (d, J =§ 8.8 Hz, 1H), 7.46 (d, J :- 20 Hz, 1H), 7.91 (d, J = 9.3 Hz, 1H), 8.39 (m. 1H), 8.4] ((1,! = 4.4 Hz, 1H). 13c-NMR (125 MHz, CD05) [3 12.0, 17.7, 19.0, 23.4, 25.3, 26.2, 27.4, 30.7, 31.9, 37.2, 37.5, 41.3, 47.6, 50.3, 50.5, 51.1, 52.0, 55.5, 55.6, 57.6, 59.7, 70.7, 102.0, 118.4, 119.6. 121.7, 126.9, 127.8, 128.7, 131.5, 144.3, 144.5, 147.3, 154.9, 157.6, 158.1, 170.4, 171.0, 17.1.8, 172.]. Z'-(D)-Asn-(L)-Val-0Me V-84 z o HN NH o\ H2N O O DIC coupling of Z-(D)-Asn-OH and H—(L)-Val-OMe similar to the reaction procedure described for V-7 gave compound V-84 in 37% yield. 1H-NMR (300MHz, CDCl3) 5 0.88 (dd, J = 14.8, 6.6 Hz, 6H), 2.16 (m, 1H), 2.86 (t, J '= 4.4 Hz, 2H), 3.70 (s, 3H), 4.53 (dd, J = 8.2, 4.9 Hz, 1H),4.66 (q, J = 7.1 Hz, 1H), 5.12 (s, 2H), 5.97 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 7.32 (s, 5H). H-(D)-Asn-(L)-Val-0Me V-85 o H2N NH 0\ H2N o o Hydrogenation of compound V-84 catalyzed by I’d/C similar to the reaction procedure described for V-8 gave compound V—851n 98% yield. lH-NMR (300MHz, CDCI3) 5 0.90 (t, J = 7.1 Hz, 6H), 1.77 (s, 2H), 2.16 (m, 1H), 2.63 (dd, J = 17.0, 8.8 Hz, 1H), 3.03 (dd, J = 17.0, 4.4 Hz, 1H), 3.68 (dd, J = 8.8, 4.4 Hz, 1H), 3.71 (s, 3H), 4.44 (dd, J = 9.3, 4.9 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H). DHQD-PYD-B-(D)-Pro—(D)-Asn-(L)-Val-0Me V-86 333 DCC coupling of compound V-37 and V-85 similar to the reaction procedure described for V-7 gave compound V-86 in 65% yield. IH-NMR (500 MHz, CDC13) 5 0.83 (d, J = 6.8 Hz, 3H), 0.87 (m, 6H),1.34 (m, 1H), 1.51 (m, 5H), 1.72 (s, 1H), 1.97 (m, 6H), 2.30 (dd, J = 14.6, 7.2 Hz, 1H), 2.55 (m, 1H), 2.71 (m, 3H), 2.87 (m, 4H), 3.18 (m, 1H), 3.27 (m, 1H), 3.58 (s, 3H), 3.97 (s, 3H), 4.26 (m, 1H), 4.32 (dd, J = 8.8, 4.4 Hz, 1H), 4.66 (td, J = 8.8, 5.4 Hz, 1H), 6.77 (s, 1H), 6.80 (d, J = 9.3 Hz, 1H), 6.94 (d, J = 9.3 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 3.9 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 9.3 Hz, 1H), 8.61 (d, J = 4.4 Hz, 1H), 9.04 (d, J = 7.3 Hz, 1H). l3C-NMR (125 MHz, CDCl3) 5 12.0, 17.6, 18.9, 19.3, 22.3, 23.5, 25.3, 26.2, 27.3, 30.8, 32.2, 37.4, 40.9, 47.7, 49.5, 50.2, 51.0, 52.0, 55.7, 56.1, 57.3, 59.8, 102.1, 117.2, 118.3, 118.4, 120.1, 121.5, 126.9, 131.7, 144.5, 144.9, 147.4, 154.7, 157.6, 157.8, 165.5, 168.8, 171.7, 173.2. H-(L)-Asn-(D)-Val-0Me V-88 1‘1er 0 0 : H2N\./U\NH ‘ o\ ' T DCC coupling of Z-(L)-Asn-OH and H-(D)-Val-0Me, followed by hydrogenation gave compound V-88 in 37% yield. ’H-NMR (300MHz, CDClg) 8 0.91 (dd, J = 8.2, 6.6 334 Hz, 6H), 1.76 (s, 2H), 2.19 (m, 1H), 2.63 (dd, J = 17.0, 8.8 Hz, 1H), 3.00 (dd, J = 17.0, 4.4 Hz, 1H), 3.70 (dd, J = 8.8, 3.8 Hz, 1H), 3.72 (s, 3H), 4.45 (dd, J = 8.8, 4.9 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H). DHQD-PYD-B-(D)-Pro-(L)-Asn-(D)-Val-0Me V-89 DCC coupling of compound V-37 and V-88 similar to the reaction procedure described for v-7 gave compound V-89 in 65% yield. 'H—NMR (500 MHz, CDClg) 8 0.84 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H), 1.28 (m, 1H), 1.4-1.6 (m, 5H), 1.72 (s, 1H), 1.84-2.04 (m, 4H), 2.10 (m, 2H), 2.32 (dd, J = 14.6, 6.8 Hz, 1H), 2.38 (m, 2H), 2.64 (dd, J = 14.2, 2.9 Hz, 1H), 2.73 (m, 1H), 2.83 (m, 1H), 2.91 (d, J = 8.3 Hz, 1H), 3.14 (q, J = 7.3 Hz, 1H), 3.22 (m, 1H), 3.42 (td, J: 9.3, 2.9 Hz, 1H), 3.66 (s, 3H), 3.97 (s, 3H), 4.20 (m, 1H), 4.38 (dd, J = 8.3, 4.4 Hz, 1H), 4.49 (q, J = 6.8 Hz, 1H), 6.75 (s, 1H), 6.77 (d, J = 9.8 Hz, 1H), 6.96 (d, J = 9.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 4.4 Hz, 1H), 7.37 (dd, J = 9.3, 2.9 Hz, 1H), 7.40 (s, 1H), 8.00 (d, J = 9.3 Hz, 1H), 8.60 (d, J = 4.4 Hz, 1H), 9.49 (d, J = 4.9 Hz, 1H). 13C-NMR (125 MHz, CDC13) 5 12.0, 17.6, 18.5, 18.9, 21.8, 23.6, 25.3, 26.2, 27.3, 30.8, 33.1, 37.5, 40.9, 43.1, 47.6, 49.7, 50.5, 51.3, 52.0, 55.7, 56.6, 57.4, 59.6, 101.6, 116.8, 118.0, 118.2, 120.0, 121.7, 126.8, 131.7, 144.5, 144.7, 147.3, 154.5, 157.6, 157.8, 168.9, 171.8, 173.6. 335 DHQD-PYZ-(LHi-Pro-OH v.94 N lfi COOH / OMe E/ cafO-{NJ—NQ ."’ Compound - V-94 was synthesized from (L)-proline following the similar procedure described for the synthesis of compound V-36. 1H--NMR (500 MHz, CDC13) 5 0.79 (t, J = 7.3 Hz, 3H), 1.25 (m, 1H), 1.42 (m, 5H), 1.62 (s, 1H), 1.88 (m, 5H), 2.04 (dd, J = 14.6, 10.7 Hz, 1H), 2.40 (dd, J = 14.6, 2.9 Hz, 1H), 2.65 (m, 1H), 2.79 (m, 3H), 3.23 (m, 2H), 3.46 (t, J = 10.3 Hz, 1H), 3.84 (s, 3H), 4.10 (m, 1H), 6.77 (d, J = 9.8 Hz, 1H), 6.79 (d, J = 4.9 Hz, 1H), 6.84 (d, J = 9.8 Hz, 1H), 7.22 (dd, J = 8.8, 2.4 Hz, 1H), 7.29 (d, J = 4.4 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 9.3 Hz, 1H), 8.52 (d, J = 4.9 Hz, 1H), 10.7 (s, br, 1H). l3C—NMR (125 MHz, CDC13) 5 11.8, 22.2, 22.7, 25.1, 26.0, 27.0, 31.0, 37.2, 40.9, 47.0, 49.8, 50.5, 55.5, 56.1, 59.4, 75.9, 77.2, 102.1, 117.8, 118.5, 118.8, 121.3, 126.9, 131.3, 144.5, 144.7, 147.2, 154.8, 157.2, 157.3, 177.3. DHQD-PYZ-B-(L)-Pro-(L)-Trp-(L)-Val-0Me V-95 336 DCC coupling of compound V-94 and H-Trp-Val-OMe similar to the reaction procedure described for V-7 gave compound V-95 in 50% yield. 1H-NMR (500 MHz, CDC13) 5 0.27 (d, J = 6.8 Hz, 3H), 0.58 (d, J = 0.73 Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H), 1.20 (m, 1H), 1.55 (m, 5H), 1.79 (s, 1H), 2.00 (m, 5H), 2.25 (m, 2H), 2.81 (s, 1H), 2.86 (d, J = 12.7 Hz, 2H), 2.96 (m, 3H), 3.07 (m, 1H), 3.18 (m, 5H), 3.43 (m, 2H), 3.60 (s, 3H), 4.26 (dd, J = 8.3, 4.4 Hz, 1H), 4.32 (t, J = 8.8 Hz, 1H), 4.67 (s, 1H), 6.52 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 9.3 Hz, 1H), 7.05 (m, 3H), 7.18 (d, J = 7.3 Hz, 2H), 7.19 (m, 2H), 7.33 (m, 1H), 7.53 (d, J = 4.4 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.63 (s, 1H), 7.90 (d, J = 9.8 Hz, 1H), 8.68 (d, J = 4.4 Hz, 1H), 10.60 (s, 1H). l3C-NMR (125 MHz, CDC13) 5 11.9, 17.4, 17.9, 20.3, 23.6, 25.2, 25.9, 26.8, 31.0, 31.4, 37.1, 41.5, 47.3, 50.4, 50.8, 51.8, 53.6, 54.8, 67.0, 57.4, 59.3, 100.3, 109.6, 110.8, 117.9, 118.3, 118.9, 119.2, 119.6, 121.5, 122.3, 124.2, 126.3, 126.9, 127.5, 127.8, 128.5, 131.5, 136.5, 144.4, 147.2, 155.1, 157.4, 158.1, 170.9, 172.1, 172.2. DHQD-PYZ-B-(L)-Pro-(L)-Asn-(L)-Val-0Me V-96 DCC coupling of compound V-94 and H-Asn-Val-OMe similar to the reaction procedure described for V-7 gave compound V-96 in 50% yield. 1H—NMR (500 MHz, CDCl3) 5 0.82 (dd, J = 11.2, 6.8 Hz, 6H), 0.89 (t, J = 7.3 Hz, 3H), 1.30 (m, 1H), 1.47 (m, 337 6H), 1.71 (s, 1H), 2.00 (m, 7H), 2.24 (m, 3H), 2.63 (dd, J = 14.6, 3.9 Hz, 1H), 2.70 (m, 1H), 2.84 (m, 3H), 3.19 (m, 2H), 3.46 (m, 1H), 3.69 (s, 3H), 3.97 (s, 3H), 4.30 (m, 1H), 4.40 (dd, J = 8.8, 4.9 Hz, 1H), 4.43 (m, 1H), 6.76 (d, J = 4.4 Hz, 1H), 6.80 (d, J = 9.8 Hz, 1H), 6.98 (d, J = 9.3 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 7.37 (m, 2H), 7.43 (d, J = 2.4 Hz, 1H), 8.01 (d, J = 9.3 Hz, 1H), 8.65 (d, J = 4.9 Hz, 1H), 9.32 (d, J = 7.3 Hz, 111). 13C- vaIR (125 MHz, CDC13) 5 12.0, 17.5, 18.8, 18.9, 22.0, 23.6, 25.3, 25.6, 26.2, 27.3, 31.0, 32.8, 37.4, 43.0, 47.8, 49.6, 50.3, 51.1, 52.1, 55.7, 56.1, 57.3, 59.8, 101.7, 116.5, 118.2, 118.5, 120.4, 121.7, 126.8, 131.9, 144.5, 144.7, 147.6, 154.9, 157.8, 158.0, 168.7, 171.6, 172.9. H-(L)-Pro-DHQD V-98 N \ / OMe time I” Compound V-98 was obtained from compound V-97 following similar reaction procedure as the synthesis of compound V-44. 1H-NMR (300 MHz, CD3OH) 5 1.04 (t, J = 7.1 Hz, 3H), 1.74 (m, 3H), 1.98 (m, 2H), 2.22 (m, 4H), 2.40 (m, 1H), 2.63 (m, 2H), 3.40 (m, 3H), 3.53 (m,1H), 3.63 (m, 1H), 3.99 (t, J = 9.3 Hz, 1H), 4.19 (s, 3H), 4.97 (t, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.89 (dd, J = 9.3, 2.7 Hz, 1H), 8.02 (d, J = 2.2 Hz, 1H), 8.25 (d, J = 9.3 Hz, 1H), 8.32 (d, J: 5.5 Hz, 1H), 9.06 (d, J = 5.5 Hz, 1H). Z-(L)-Met-(L)-Pro-DHQD V-99 338 N \ ./ OMe 91%" EDIE?) 0Q DCC coupling of compound V-98 and Z-Met-OH similar to the reaction procedure described for V-7 gave compound V-99 in 72% yield. 1H-NMR (500 MHZ, CDCl3) 5 0.87 (t, J = 7.3 Hz, 3H), 1.31 (m, 1H), 1.45 (m, 5H), 1.69 (s, 1H), 1.77 (m, 2H), 1.90 (s, 3H), 1.95 (m, 3H), 2.18 (m, 1H), 2.41 (m, 2H), 2.52 (m, 1H), 2.64 (m, 2H), 2.78 (m, 1H), 2.87 (dd, J = 14.2, 9.8 Hz, 1H), 3.20 (q, J = 6.8 Hz, 1H), 3.62 (m, 1H), 3.72 (m, 1H), 3.88 (s, 3H), 4.63 (m, 2H), 5.02 (m, 2H), 5.67 (d, J = 8.3 Hz, 1H), 6.45 (d, J = 6.3 Hz, 1H), 7.28 (m, 71D, 7.42 (d, J = 4.9 Hz, 1H), 7.95 (d, J = 9.3 Hz, 1H), 8.72 (d, J = 4.4 Hz, 1H). l3C-NMR (125 MHz, CDC13) 5 11.9, 15.3, 22.6, 24.8, 25.3, 25.9, 27.0, 28.7, 29.6, 32.2, 37.2, 46.9, 49.9, 50.9, 51.1, 55.4, 58.6, 58.7, 66.8, 74.7, 101.0, 118.4, 121.6, 126.7, 127.9, 128.0, 128.4, 131.6, 136.1, 142.7, 144.4, 147.5, 156.0, 157.7, 170.3, 171.1. Z-(L)-Lys(Boc)-(L)-Pro-DHQD V-100 N \ ./ OMe $551k 51; “ll/0Q NH O °1< 339 DCC coupling of compound V-98 and Z-Lys(Boc)-OH similar to the reaction procedure described for V-7 gave compound V-100 in 75% yield. 1H-NMR (500 MHz, CDC13) 5 0.86 (t, J = 7.3 Hz, 3H), 1.22 (m, 3H), 1.35 (s, 9H), 1.45 (m, 6H), 1.61 (s, 1H), 1.68 (s, 1H), 1.77 (s, 1H), 1.95 (m, 2H), 2.17 (m, 1H), 2.57 (s, 1H), 2.64 (m, 2H), 2.76 (m, 1H), 2.88 (m, 2H), 3.19 (m, 1H), 3.53 (m, 1H), 3.66 (m, 1H), 3.87 (s, 3H), 4.37 (m, 1H), 4.62 (dd, J: 8.8, 3.9 Hz, 1H), 4.70 (m, 1H), 5.01 (dd, J = 17.1, 12.2 Hz, 2H), 5.63 (d, J = 8.3 Hz, 1H), 6.42 (d, J = 5.9 Hz, 1H), 7.28 (m, 7H), 7.43 (d, J = 4.4 Hz, 1H), 7.95 (d, J = 9.3 Hz, 1H), 8.70 (d, J = 4.9 Hz, 1H). 13C-NMR (125 MHz, CDC13) 5 11.9, 21.9, 22.5, 24.8, 25.3, 25.5, 25.9, 27.0, 28.2, 28.6, 29.3, 31.9, 33.8, 37.1, 39.8, 46.7, 49.9, 50.9, 51.9, 55.4, 58.7, 66.7, 74.8, 78.7, 101.0, 118.4, 121.5, 126.6, 127.8, 127.9, 128.3, 131.5, 136.1, 142.7, 144.3, 147.5, 155.8, 156.0, 157.7, 170.7, 171.3. Z-(L)-Lys-(L)-Pro-DHQD V-101 [9in?) N5 “Worm/Q NH2 Compound V-101 was obtained from compound V-100 following similar reaction procedure as the synthesis of compound v-44.‘H-NMR (300 MHz, CDClg) 8 0.88 (t, J = 6.6 Hz, 3H), 1.25 (m, 7H), 1.44 (m, 7H), 1.70 (m, 5H), 1.81 (m, 1H), 1.98 (m, 3H), 2.19 (m, 1H), 2.45 (m, 2H), 2.79 (m, 4H), 3.17 (m, 1H), 3.55 (m, 1H), 3.70 (m, 1H), 3.89 (s, 3H), 4.41 (m, 1H), 4.66 (dd, J = 8.2, 3.3 Hz, 1H), 5.03 (dd, J = 15.4, 12.1 Hz, 2H), 5.56 340 (d, J = 8.2 Hz, 1H), 6.43 (d, J = 5.5 Hz, 1H), 7.30 (m, 7H), 7.43 (d, J = 4.4 Hz, 1H), 7.97 (d, J= 8.8 Hz, 1H), 8.71 (d, J: 4.4 Hz, 1H). Fmoc-(L)-Phe-(L)-Pro-DHQD V-102 \ I / _ OMe O N 0'9 ”’6 NH‘Fmoc 0U ‘ ., Ph I’u DCC coupling of compound V-98 and Fmoc-Phe-OH similar to the reaction procedure described for V-7 gave compound V-102 in 75% yield. 1H-NMR (500 MHz, CDCl;;) 5 0.90 (t, J = 7.3 Hz, 3H), 1.30 (m, 3H), 1.49 (m, 6H), 1.72 (s, 1H), 1.87 (m, 1H), 1.94 (m, 2H), 2.20 (m, 1H), 2.73 (m, 2H), 2.84 (m, 2H), 2.93 (dd, J = 13.7, 9.8 Hz, 1H), 2.99 (dd, J = 13.7, 6.3 Hz, 1H), 3.23 (m, 1H), 3.30 (m, 1H), 3.63 (m, 1H), 3.94 (s, 3H), 4.14 (m, 1H), 4.20 (m, 1H), 4.32 (dd, J = 10.3, 7.3 Hz, 1H), 4.69 (m, 2H), 5.58 (d, J = 8.8 Hz, 1H), 6.51 (d, J = 5.4 Hz, 1H), 7.02 (m, 4H), 7.10 (t, J = 7.3 Hz, 1H), 7.27 (m, 4H), 7.37 (m, 3H), 7.51 (m, 3H), 7.72 (d, J = 7.8 Hz, 2H), 8.03 (d, J = 8.8 Hz, 1H), 8.75 (d, J = 4.9 Hz, 1H). H-(D)-Pro-DHQD V-104 N I \ / OMe CVNfO-ir. N'“ o L) ’1 ’/ 341 Compound V-104 was obtained from compound V-l03 following similar reaction procedure as the synthesis of compound V-44.1H-NMR (300 MHz, CD30D) 5 0.93(t, J = 7.1 Hz, 3H), 1.51 (m, 6H), 1.73 (m, 5H), 1.96 (m, 1H), 2.21 (m, 1H), 2.81 (m, 6H), 3.30 (m, 1H), 3.87 (dd, J = 8.2, 5.5 Hz, 1H), 3.97 (s, 3H), 6.58 (d, J = 5.5 Hz, 1H), 7.43 (dd, J = 9.3, 2.7 Hz, 1H), 7.48 (m, 2H), 7.93 (d, J: 9.3 Hz, 1H), 8.65 (d, J: 4.4 Hz, 1H). Z-(L)-Phe-(D)-Pro-DHQD V-105 N I \ :/ OMe : 6’0 NH 0 51,/Mr 0‘9"! N’ ‘c” 0 5 Ph DCC coupling of compound V-104 and Z-(L)-Phe-OH similar to the reaction procedure described for V-7 gave compound V-105 in 70% yield. 1H-NMR (500 MHz, CDC13) 5 0.92 (t, J = 7 .3 Hz, 3H),1.47 (m, 5H), 1.67 (m, 4H), 1.76 (m, 2H), 1.86 (m, 1H), 2.07 (m, 1H), 2.58 (m, 1H), 2.69 (m, 2H), 2.89 (dd, J = 13.7, 9.3 Hz, 1H), 2.97 (dd, J = 12.7, 9.8 Hz, 1H), 3.12 (dd, J = 12.7, 4.9 Hz, 1H), 3.29 (m, 1H), 3.44 (m, 1H), 3.95 (s, 3H), 4.40 (m, 1H), 4.69 (m, 1H), 5.10 (q, J = 15.6 Hz, 2H), 5.66 (d, J = 8.8 Hz, 1H), 6.47 (d, J = 6.8 Hz, 1H), 7.36 (m, 13H), 8.01 (d, J = 8.8 Hz, 1H), 8.72 (d, J = 4.9 Hz, 1H). l3c-NMR (125 MHz, CDC13) 8 12.0, 24.0, 24.2, 25.4, 26.0, 27.2, 28.5, 37.4, 40.3, 46.7, 49.8, 50.7, 54.0, 55.5, 58.6, 59.7, 66.8, 101.3, 121.8, 127.0, 127.2, 127.7, 128.0, 128.1, 128.4, 128.5, 129.0, 129.4, 131.7, 136.1, 136.3, 144.0, 144.6, 147.3, 155.4, 157.8, 169.8, 170.8. 342 Z-(L)-Trp-(D)-Pro-DHQD V-106 N I \ / OMe E ’0 H NfQ—g, N’d N-Cbz 'I H 5p o L) N l I ’I I DCC coupling of compound V-104 and Z-(L)-Trp-OH similar to the reaction procedure described for V-7 gave compound V-106 in 70% yield. 1H-NMR (500 MHz, CDCl3) 5 0.94 (t, J = 7.3 Hz, 3H), 1.47 (m, 111-I), 1.75 (m, 2H), 2.37 (m, 1H), 2.71 (m, 3H), 2.87 (dd, J = 14.2, 9.3 Hz, 1H), 3.17 (dd, J = 14.2, 10.3 Hz, 1H), 3.28 (m, 3H), 3.90 (s, 3H), 4.26 (dd, J = 8.3, 3.9 Hz, 1H), 4.73 (td, J = 9.3, 4.9 Hz, 1H), 5.14 (dd, J = 18.6, 12.7 Hz, 2H), 5.86 (d, J = 8.3 Hz, 1H), 6.47 (d, J = 7.3 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 7.10 (t, J = 7.3 Hz, 1H), 7.17 (t, J = 6.8 Hz, 1H), 7.37 (m, 9H), 7.59 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 9.8 Hz, 1H), 8.66 (s, 1H), 8.70 (d, J = 4.9 Hz, 1H). 343 (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) Reference Pasteur, M. L. C. R. Hebd. Seances Acad. Sci. 1858, 46, 615-618. Fischer, E. Ber. Dtsch. Chem. Ges. 1890, 23, 370—394. Marckwald, W.; McKenzie, A. Berichte Der Deutschen Chemischen Gesellschaft 1901, 34, 469-478. Marckwald, W.; McKenzie, A. Ber. Dtsch. Chem. Ges. 1899, 32, 2130-2136. Moss, G. P. Pure and Applied Chemistry 1996, 68, 2193-2222. Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. Journal of the American Chemical Society 1981, 103, 6237-6240. Kagan, H. B.; Fiaud, J. C. In Topics in Stereochemistry; Eliel, E. L., Wilen, S. H., Eds.; John Wiley & Sons: New York, 1988; Vol. 18. Finn, M. G.; Sharpless, K. B. In Asymmetric synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1985; Vol. 5. Pfenninger, A. Synthesis-Stuttgart 1986, 89-116. Vedejs, B.; J ure, M. Angewandte Chemie-Intemational Edition 2005, 44, 3974- 4001. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. Journal of the American Chemical Society 1987, 109, 5765-5780. Adam, W.; Humpf, H. U.; Roschmann, K. J .; Saha—Moller, C. R. Journal of Organic Chemistry 2001, 66, 5796-5800. Lattanzi, A.; Iannece, P.; Vicinanza, A.; Scettli, A. Chemical Communications 2003, 1440-1441. 344 (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) Lorenz, J. C.; Frohn, M.; Zhou, X. M.; Zhang, J. R.; Tang, Y.; Burke, C.; Shi, Y. Journal of Organic Chemistry 2005, 70, 2904-2911. Kramer, R.; Bruckner, R. Synlett 2006, 33—38. Sharpless, K. B.; Behrens, C. H.; Katsuki, T.; Lee, A. W. M.; Martin, V. S.; Takatani, M.; Viti, S. M.; Walker, F. J .; Woodard, S. S. Pure and Applied Chemistry 1983, 55, 589-604. Roush, W. R.; Brown, R. J. Journal of Organic Chemistry 1983, 48, 5093-5101. Roush, W. R.; Spada, A. P. Tetrahedron Letters 1983, 24, 3693-3696. Roush, W. R.; Spada, A. P. Tetrahedron Letters 1982, 23, 3773-3776. Hawkins, J. M.; Nambu, M.; Meyer, A. Journal of the American Chemical Society 1994, 116, 7642-7645. Yokomatsu, T.; Yamagishi, T.; Sada, T.; Suemune, K.; Shibuya, S. Tetrahedron 1998, 54, 781-790. Corey, E. J .; Noe, M. C.; Guzmanperez, A. Journal of the American Chemical Society 1995, 11 7, 10817-10824. Rios, R.; Jimeno, C.; Carroll, P. J .; Walsh, P. J. Journal of the American Chemical Society 2002, 124, 10272-10273. Vannieuwenhze, M. S.; Sharpless, K. B. Journal of the American Chemical Society 1993, 115, 7864-7865. Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angewandte Chemie- International Edition in English 1985, 24, 1-30. Lohray, B. B.; Bhushan, V. Tetrahedron Letters 1993, 34, 3911-3914. Licini, G.; Bonchio, M.; Broxterrnan, Q. B.; Kaptein, B.; Moretto, A.; Toniolo, C.; Scrimin, P. Biopolymers 2006, 84, 97-104. 345 (28) (29) (30) (31) (32) (33) (34) (35) (36) (37) (38) (39) (40) (41) Blank, J. T.; Miller, S. J. Biopolymers 2006, 84, 38—47. Christensen, C. A.; Meldal, M. Chemistry-a European Journal 2005, II, 4121- 4131. Tsogoeva, S. B. Letters in Organic Chemistry 2005, 2, 208-213. Murphy, K. E.; Hoveyda, A. H. Organic Letters 2005, 7, 1255-1258. Agarkov, A.; Greenfield, S. J .; Ohishi, T.; Collibee, S. B.; Gilbertson, S. R. Journal of Organic Chemistry 2004, 69, 8077-8085. Tang, Z.; Yang, Z. H.; Cun, L. F.; Gong, L. 2.; Mi, A. Q.; Jiang, Y. Z. Organic Letters 2004, 6, 2285-2287. Fonnaggio, F.; Barazza, A.; Bertocco, A.; Toniolo, C.; Broxterrnan, Q. B.; Kaptein, B.; Brasola, E.; Pengo, P.; Pasquato, L.; Scrimin, P. Journal of Organic Chemistry 2004, 69, 3849-3856. Kofoed, J .; Nielsen, J .; Reymond, J. L. Bioorganic & Medicinal Chemistry Letters 2003, 13, 2445-2447. de la Torre, M. C.; Sierra, M. A. Angewandte Chemie-Intemational Edition 2004, 43, 160-181. Berkessel, A. Current Opinion in Chemical Biology 2003, 7, 409-419. J arvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481-2495. List, B. Tetrahedron 2002, 58, 5573-5590. Movassaghi, M.; Jacobsen, E. N. Science 2002, 298, 1904-1905. Shimizu, K. D.; Snapper, M. L.; Hoveyda, A. H. Chemistry-a European Journal 1998, 4, 1885-1889. 346 (42) (43) (44) (45) (46) (47) (48) (49) (50) (51) (52) (53) (54) de Bruin, B.; Hauwert, P.; Reek, J. N. H. Angewandte Chemie-Intemational Edition 2006, 45, 2660-2663. Dolle, R. B. Journal of Combinatorial Chemistry 2005, 7, 739-798. Brooks, C. J.; Hagemeyer, A. G.; Yaccato, K.; Carhart, R.; Herrmann, M.; Lesik, A.; Strasser, P.; Volpe, A. P.; Turner, H. W.; Weinberg, H. Abstracts of Papers of the American Chemical Society 2005, 229, U600—U600. Bricker, M. L.; Sachtler, A.; Gillespie, R.; Holmgren, J. Abstracts of Papers of the American Chemical Society 2004, 228, U884-U884. Dahmen, S.; Brase, S. Synthesis-Stuttgart 2001, 143 1 - 1449. Chen, G. Y.; Chan, B. C.; Sun, Y. P.; Morris, N. D.; Mallouk, T. E.; Smotkin, E. S.; Sarangapani, S. Abstracts of Papers of the American Chemical Society 2001, 221, U700-U700. Bein, T. Angewandte Chemie-Intemational Edition 1999, 38, 323-326. Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827-10852. Kolk, H.-A. Highlights in Bioorganic Chemsitry, Weinheim, Germany, 2004; p 554-557. Albericio, F. Current Opinion in Chemical Biology 2004, 8, 211-221. Sabatino, G.; Chelli, M.; Brandi, A.; Papini, A. M. Current Organic Chemistry 2004, 8, 291-301. Sculimbrene, B. R.; Miller, S. J. Journal of the American Chemical Society 2001, 123, 10125-10126. Degrado, S. J .; Mizutani, H.; Hoveyda, A. H. Journal of the American Chemical Society 2001, 123, 755-756. 347 (55) (56) (57) (58) (59) (60) (61) (62) (63) (64) (65) (66) (67) Imbriglio, J. E.; Vasbinder, M. M.; Miller, S. J. Organic Letters 2003, 5, 3741- 3743. Jarvo, E. R.; Copeland, G. T.; Papaioannou, N.; Bonitatebus, P. J .; Miller, S. J. Journal of the American Chemical Society 1999, 121, 11638-11643. Krueger, C. A.; Kuntz, K. W.; Dzierba, C. D.; Wirschun, W. G.; Gleason, J. D.; Snapper, M. L.; Hoveyda, A. H. Journal of the American Chemical Society 1999, 121, 4284-4285. Porter, J. R.; Wirschun, W. G.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. Journal of the American Chemical Society 2000, 122, 2657-2658. Josephsohn, N. S.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. Journal of the American Chemical Society 2001, 123, 11594-11599. Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. Journal of the American Chemical Society 2001, 123, 984-985. Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. Journal of the American Chemical Society 2001, 123, 10409-10410. Deng, H. B.; Isler, M. R.; Snapper, M. L.; Hoveyda, A. H. Angewandte Chemie- Intemational Edition 2002, 41, 1009-+. J osephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. Journal of the American Chemical Society 2003, 125, 4018-4019. J osephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. Journal of the American Chemical Society 2004, 126, 3734-3735. Huang, J .; Corey, E. J. Organic Letters 2003, 5, 3455-3458. Christmann, U.; Vilar, R. Angewandte Chemie-International Edition 2005, 44, 366-374. Ali, M. H.; Buchwald, S. L. Journal of Organic Chemistry 2001, 66, 2560-2565. 348 (68) Ma, D. W.; Zhang, Y. D.; Yao, J. C.; Wu, S. H.; Tao, F. G. Journal of the American Chemical Society 1998, 120, 12459-12467. (69) Cardillo, G.; Gentilucci, L.; Qasem, A. R.; Sgarzi, F.; Spampinato, S. Journal of Medicinal Chemistry 2002, 45, 2571-2578. (70) Xu, D. Q.; Park, C. Y.; Sharpless, K. B. Tetrahedron Letters 1994, 35, 2495-2498. (71) Kon, K.; Isoe, S. Tetrahedron Letters 1980, 21, 3399-3402. (72) Smith, A. B.; Boschelli, D. Journal of Organic Chemistry 1983, 48, 1217-1226. (73) Rachele, J. R. Journal of Organic Chemistry 1963, 28, 2898-&. (74) Shin, M. S.; Kang, Y. J.; Chung, H. A.; Park, J. W.; Kweon, D. H.; Lee, W. 8.; Yoon, Y. J.; Kim, S. K. Journal of Heterocyclic Chemistry 1999, 36, 1135-1142. (75) Sieber, P.; Riniker, B. Tetrahedron Letters 1991, 32, 739-742. 349