Application of the Prins Cyclization to a Synthesis of the Tetrahydropyran Rings of Lasonolide A
APPLICATION OF THE PRINS CYCLIZATION TO A SYNTHESIS OF THE TETRAHYDROPYRAN RINGS OF LASONOLIDE A
DISSERTATION
Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University
By Ruth Figueroa, M. S. *****
The Ohio State University 2004
Dissertation Committee:
ABSTRACT
This thesis describes studies toward the synthesis of the tetrahydropyran- containing marine macrolide lasonolide A. A summary of studies done by Lee and coworkers, that led to a revision of the structure as well as its first total synthesis is presented. This is followed by a literature review of the partial and completed syntheses of lasonolide A reported by other groups. The studies presented are based on the use of a Prins cyclization as the key reaction. The cyclization uses vinylogous carbonates as the source to generate the oxocarbenium ion. Therefore, we first introduce the background that led to the development of this reaction. The Prins cyclizations were promoted using trifluoroacetic acid and the products were immediately hydrolyzed to afford in most of the cases the tetrahydropyran rings as the major product. The cyclization of alkyne derived vinylogous carbonates resulted in instability of the product to the reaction conditions. Also, formation of 5-membered ring was a competing pathway. Vinlogous carbonates derived from Z-alkenes gave the all cis-2,3,4,6-tetrahydropyran in 59-70% yield. The E-alkene derived enol ethers gave the C3 epimeric tetrahydrofuran. Inversion of the secondary alcohol in the tetrahydropyran ring was partially accomplished using a Mitsunobu reaction. This methodology led to the racemic and asymmetric syntheis of the B ring of lasonolide A. The racemic synthesis was accomplished in 8 steps from 3-buten- 1-ol. An asymmetric synthesis was also accomplished in 12 steps from (R)-malic acid. The quaternary stereogenic center of the A ring of lasonolide A was constructed via C-H insertion reaction using Doyle’s catalyst (Rh2(4R-MEOX)4).
ii
Dedicated to my family
iii ACKNOWLEDGMENTS
I wish to thank Dr. David J. Hart, my adviser, for his intellectual support, encouragement and enthusiasm for the work that made this thesis possible. Also, for his patience in correcting my scientific errors.
This gratitude is further extended to the members of the Hart group.
I am very grateful of my family. To my parents: William Figueroa and Eminelia Ares because only with their love and emotional support I have been able to go through a very significant step in this long process of achieving my academic goals. To my sisters: Arelis, Merari, Eminelia, Willnelia and Rose Mary, and to my brother Samuel for their unconditional love and encouragement.
Finally, I will like to thank the technician support staff at The Ohio State University.
iv VITA
August 22, 1976………………………….. Born-Humacao, Puerto Rico
2000………………………………………. M. S. Chemistry, The Ohio State University
1999-Present ………………………………Graduate Teaching and Reasearch Assistant The Ohio State University
PUBLICATIONS
Research Publications
1. M. Ortiz-Marciales, E. Gonzalez, M. De Jesus, S. Espinosa, J. Martinez, W. Correa, R. Figueroa, “Efficient Synthesis of B-Alkylated Oxazaborolidines Derived from Ephedrine and Norephedrine” Organic Lett. 5, 3447 (2003).
2. M. Ortiz-Marciales, L. M. Tirado, R. Colon, L. M. Ufret, R. Figueroa, M. Lebron, M. De Jesus; J. Martinez, T. Malave, "N-tert-Butyldimethylsilyl Imines as Intermediates for the Synthesis of Amines and Ketones." Synth. Comm. 28, 4067 (1998).
FIELDS OF STUDY
Major Field: Chemistry
v TABLE OF CONTENTS Page Abstract……………………………………………………………………………………ii Dedication………………………………………………………………………………...iii Acknowledgments………………………………………………………………………..iv Vita………………………………………………………………………………………..v List of Schemes…………………………………………………………………………viii List of Tables……………………………………………………………………………xiii List of Figures………………………………………………………………………….. xiv List of Abbreviations ...... xvi
Chapters:
1. Lasonolide A: Isolation, biological activity and structure...... 1
1.1 Introduction...... 1 1.2 Structure description ...... 2 1.3 Lasonolide A: Structure revision and first total synthesis ...... 4
2. Review of previous (-) and (+) lasonolide A syntheses...... 15
2.1 Lee’s synthesis of (-) and (+) lasonolide A...... 15 2.2 Kang’s synthesis of (+)-lasonolide A ...... 20 2.3 Hart-Patterson-Unch formal synthesis of (+)-lasonolide A...... 27 2.4 Partial syntheses of lasonolide A ...... 32
3. Background: The Prins cyclization reaction...... 35
vi 3.1 The Prins cyclization reaction...... 35 3.2 Enol ethers to generate the oxonium ion in the Prins cyclization...... 37 3.3 Bennett’s elaboration of the Fráter-Nussbaumer variation of the Prins cyclization...... 40
4. Studies toward the synthesis of the A and B rings of lasonolide A...... 52
4.1 Alkynes as the π-component in the Prins cyclization...... 52 4.2 Prins cyclization with alkenes as the π-component of the Prins cyclization ..57 4.3 Studies toward inversion of the C9 stereogenic center...... 66 4.4 Studies toward a substituent other than methyl at the C10 position...... 74 4.5 Studies toward elaboration of the C7 side chain of the A and B rings ...... 80 4.6 Studies toward correction of the C9 relative stereochemistry in tetrahydropyran 321...... 87 4.7 Studies toward C-H insertion to construct the C22 quaternary center...... 109 4.8 Preliminary studies in a new approach for the synthesis of the B ring...... 123 4.9 Conclusion ...... 129
5. Experimental Section...... 131
List of references...... 221
vii LIST OF SCHEMES
Scheme Page
1.1 Lee’s retrosynthesis analysis of structure 1 ...... 5
1.2 Lee’s synthesis of the A ring ...... 7
1.3 Lee’s synthesis of the B ring...... 8
1.4 Lee’s elaboration of B ring ...... 9
1.5 Lee’s final steps for the synthesis of lasonolide A (1)...... 10
1.6 Lee’s synthesis of the branched chain of lasonolide A...... 11
1.7 Some of the lasonolide A isomers synthesized by Lee and coworkers ...... 13
2.1 Lee’s preparation of A-ring carbon chains ...... 17
2.2 Lee’s final steps in the total synthesis of (-)-lasonolide A (58)...... 18
2.3 Lee’s elaboration of the branched chain of (-)-lasonolide A ...... 19
2.4 Kang’s retrosynthesis analysis of (+)-lasonolide A (ent-58)...... 21
2.5 Kang’s synthesis of the A-ring ...... 23
2.6 Kang’s elaboration of the side chain of the A-ring...... 24
2.7 Kang’s synthesis of the B-ring...... 25
2.8 Kang’s final steps for the synthesis of (+)-lasonolide A ...... 26
2.9 Key cyclization reaction for the construction of the A and B rings...... 27
2.10 Hart-Patterson synthesis of the A-ring...... 29
2.11 Hart-Unch synthesis of the B-ring ...... 31
viii 2.12 Gurjar’s cyclopropane sugar derivatives for the preparation of the A and B rings of lasonolide A (1)...... 32
2.13 Hoffman approach to the preparation of the A and B rings of lasonolide A (1) .. 33
2.14 Some of Shishido’s key intermediates for the preparation of the B-ring ...... 34
3.1 The Prins cyclization...... 36
3.2 Fráter’s synthesis of (±)-(cis-6-methyltetrahydropyran-2-yl)acetic acid (177) and (±)-cis-α-irone (181) via Prins cyclization...... 38
3.3 Kozmin’s variation of the Prins cyclization...... 39
3.4 Vinylogous carbonates as the source for the oxocarbenium ion in the Prins cyclization...... 40
3.5 Cyclization results of the enol ethers 199 and 203 ...... 44
3.6 Proposed mechanism for the formation of structures 201, 202 and 205 ...... 45
3.7 Cyclization of vinylogous carbonates 208 and 214 ...... 46
3.8 Proposed mechanism for formation of tetrahydropyrans 211 and 212...... 47
3.9 Prins cyclization of enol ether 224...... 49
3.10 Prins cyclization of enol ether 229……………………………………………….50
4.1 Proposed pathway to the B-ring from alkyne derived enol ethers...... 53
4.2 Synthesis of terminal alkyne derived vinylogous carbonate 247...... 54
4.3 Prins cyclization of terminal alkyne derived vinylogous carbonate 240 ...... 54
4.4 Proposed mechanism for the formation of 248 and 249...... 55
4.5 Synthesis of internal alkyne derived vinylogous carbonate 257...... 56
4.6 Prins cyclization results of terminal alkyne 257...... 57
4.7 General approach to the A and B rings of lasonolide A ...... 59
4.8 Mechanistic rationale for the stereochemistry expected from cis-vinylogous carbonate 266 ...... 60
ix 4.9 Mechanistic rationale for the stereochemistry expected from trans-vinylogous carbonate 279...... 60
4.10 Synthesis of cis-4-penten-2-ol derived enol ether 282 ...... 61
4.11 Prins cyclization of Z-4-hexen-2-ol derived vinylogous carbonate 282...... 62
4.12 Synthesis of E-4-hexen-2-ol derived enol ether 286...... 64
4.13 Prins cyclization of E-4-hexen-2-ol derived enol ether 286 ...... 65
4.14 Results of the Mitsunobu reaction of tetrahydropyran 190a ...... 66
4.15 Explanation of the results of the Mitsunobu reaction of alcohols 283 and 284...... 68
4.16 Mitsunobu reaction of tetrahydropyrans 283 and 284 using trichloroacetic acid...... 70
4.17 Reduction of t-butylcyclohexanone with L-selectride...... 71
4.18 Oxidation-reduction of tetrahydropyrans 283 and 284...... 72
4.19 Mechanistic rationale for reduction of ketones 293 and 299...... 73
4.20 General approach to the A and B rings of lasonolide A (58) from vinylogous carbonates of type 283 ...... 75
4.21 Synthesis of Z-6-benzyloxy-4-hexen-2-ol derived vinylogous carbonate 310...... 76
4.22 Prins Cyclization of of Z-6-benzyloxy-4-hexen-2-ol derived vinylogous carbonate 310 ...... 77
4.23 Initial approach to the synthesis of vinylogous carbonate 316...... 78
4.24 Synthesis of Z-6-phenelselenenyl-4-hexen-2-ol derived vinylogous carbonate 316a ...... 79
4.25 Prins cyclization of Z-6-phenylselenenyl-4-hexen-2-ol derived vinylogous carbonate 316a ...... 80
4.26 Synthesis of Z-1-benzyloxy-4-hexen-2-ol derived vinylogous carbonate 316b...... 81
x 4.27 Products isolated from the Prins cyclization of vinylogous carbonate 316b...... 82
4.28 Proposed mechanism for the formation of products 322-324...... 84
4.29 Synthesis of 1-benzyloxy-5-hepten-3-ol derived vinylogous carbonate 336 ...... 85
4.30 Prins cyclization of vinylogous carbonate 336 ...... 86
4.31 Results for the Mitsunobu reaction of tetrahydropyran 336 ...... 87
4.32 Revised pathway to the A and B rings using the Mitsunobu elimination product (339) as a potential intermediate ...... 89
4.33 Attempted hydroboration of olefin 339 ...... 90
4.34 A derivative of alkene 339...... 90
4.35 Hydroboration-oxidation of alkene 342...... 91
4.36 Rationale for the selectivity in the hydroboration of alkene 342...... 93
4.37 Synthesis of epoxide 335a via hydrobromination-substitution ...... 98
4.38 Dihydroxylation of olefin 339 ...... 101
4.39 Asymmetric hydroboration of methylcyclohexene with (-)-IpcBH2 ...... 103
4.40 Asymmetric hydroboration of olefin 342 with (-)-IpcBH2 ...... 105
4.41 Synthesis of Shi’s catalyst ...... 105
4.42 Asymmetric epoxidation of methylcyclohexene with Shi’s catalyst...... 106
4.43 Asymmetric epoxidation of olefin 342 with Shi’s catalyst...... 106
4.44 Attempted inversion of alcohol 337 by displacement of mesylate 374...... 108
4.45 Deprotection of the inversion product 338 to afford the B ring (376)...... 109
4.46 Doyle’s result for C-H insertion in diazoacetate 278a and 278b using Rh2(4R-MEOX)4 ...... 111
4.47 Preparation of diazoacetate 385 from tetrahydropyran 376...... 113
4.48 Results of C-H insertion of racemic diazoacetate 385 using
xi Rh2(4R-MEOX)4 ...... 115
4.49 Asymmetric synthesis of the A and B ring via kinetic resolution of diazoacetate 385 ...... 116
4.50 Asymmetric synthesis of epoxide 394 from (R)-malic acid ...... 117
4.51 Asymmetric synthesis of diazoacetate 385a...... 119
4.52 Results of the C-H insertion of the enantiomerically pure diazoacetate 385a...... 120
4.53 Mosher’s ester of racemic and enantioriched alcohols 337...... 122
4.54 New approach towards the synthesis of the B ring...... 123
4.55 Mechanistic rationale for setting the trans diaxial stereochemistry at C9 and C10 via novel approach ...... 125
4.56 Synthesis of enone 401 via a Hetero Diels Alder reaction ...... 127
4.57 Results of the Prins cyclization of enone 401 and alcohol 413 ...... 128
xii LIST OF TABLES
Table Page
3.1 Results of Prins cyclization of vinylogous carbonates of type 189 ...... 41
4.1 NOE results for the all cis tetrahydropyran 283 ...... 63
4.2 NOE results for tetrahydropyran 284...... 65
4.3 Results of the Mitsunobu reaction of the mixture of alcohols 283 and 284 ...... 67
4.4 NOE results for tetrahydropyran 336...... 87
4.5 NOE results for tetrahydropyrans 343 (B-ring) and 344 ...... 92
4.6 Results of epoxidation of olefins 339 and 342...... 95
4.7 NOESY results for diol 362...... 101
4.8 Product distribution for the dihydroxylation of olefin 342...... 102
4.9 NOE results for tetrahydropyran 338 (B ring)...... 110
xiii LIST OF FIGURES
Figure Page
1.1 Proposed structure for lasonolide A...... 2
1.2 Lasonolide A substructures...... 3
1.3 Lee’s 6-endo, 6-exo tandem radical cyclization ...... 6
2.1 Lee’s major bond disconnection of (-)-lasonolide A ...... 16
3.1 By-products in the cyclization of vinylogous carbonate 189a...... 42
3.2 By-products in the cyclization of vinylogous carbonate 189c...... 42
3.3 By-products in the cyclization of vinylogous carbonate 189g...... 43
3.4 Stereochemical outcome for enol ethers of type 233-235 ...... 51
4.1 Prins cyclization of vinylogous carbonates of type 259 and 262...... 58
4.2 NMR signals of H9 for tetrahydropyrans 283 and 284...... 63
4.3 Chair conformations of tetrahydropyrans 283 and 284 ...... 69
4.4 Boat-like conformations of 283 and 284 ...... 69
4.5 Oxidation-reduction pathway to inversion of the C9 stereogenic center in alcohol 283...... 71
4.6 Oxocarbenium ion from vinylogous carbonate 310...... 77
4.7 Comparison of tetrahydropyran 330 with the A and B rings of lasonolide A...... 84
4.8 Multiplicity observed for H9 in tetrahydropyran 343...... 92
4.9 Revised pathway to the B-ring via epoxidation or dihydroxylation
xiv of olefins 339 and 342...... 95
4.10 Synthesis of epoxides 350 via hydrobromination-substitution...... 97
4.11 Mechanistic rationale for formation of epoxide 350a and 351a...... 99
4.12 Formation of lactone 356 via neighboring group participation ...... 100
4.13 Proposed selectivity for the asymmetric hydroboration of racemic 342 ...... 104
4.14 Possible insertion positions in the B ring...... 112
4.15 Structure of Doyle’s catalyst Rh2(4R-MEOX)4 as its acetonitrile complex...... 112
4.16 Possible product from insertion at C8...... 115
4.17 Isomers of oxocarbenium ion 406...... 129
xv LIST OF ABBREVIATIONS
[α] specific rotation Ac acetyl AIBN 2,2’-azobisisobutyronitrile Ar aryl atm atmosphere (s) 9-BBN 9-borabicyclo[3.3.1]nonane Bn benzyl bp boiling point Bu butyl i-Bu iso-butyl t-Bu tert-butyl Bz benzoyl °C degrees Celsius calcd calculated cat catalytic cm centimeters COSY correlation spectroscopy CSA camphorsulfonic acid DCC N,N-dicyclohexylcarbodiimide DCM dichloromethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DEAD diethyl azodicarboxylate DEPT distortionless enhancement by polarization transfer DIAD diisopropyl azodicarboxylate
xvi DIBAL diisobutylaluminum hydride DIC diisopropylcarbodiimide DIPA diisopropylamine DIPEA diisopropylethylamine DMAP 4-dimethylaminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMM dimethoxymethane DMS dimethylsulfide DMSO dimethylsulfoxide EDTA ethylenediaminetetraacetic acid ee enantiomeric excess Et ethyl HMBC heteronuclear multiple bond correlation HMDS hexamethyldisilazane HMPA hexamethylphosphoric triamide HMQC heteronuclear multiple quantum coherence HOHAHA homonuclear hartmann hahn Hz hertz Ipc isopinocampheyl IR infrared J coupling constant (in NMR) L liter (s) LDA lithium diisopropylamide lit literature µ micro MCPBA meta-chloroperoxybenzoic acid Me methyl min minute (s) mp melting point
xvii Ms methanesulfonyl (mesyl) MS mass spectrometry or molecular sieves m/z mass to charge ratio (in mass spectrometry) NBS N-bromosuccinimide NMM N-methylmorpholine NMO N-methylmorpholine oxide NMR nuclear magnetic resonance NMP N-methyl-2-pyrrolidinone NOE nuclear Overhauser effect NOESY nuclear Overhauser effect spectroscopy Nu nucleophile Ph phenyl Piv pivaloyl PMB p-methoxybenzyl PMP p-methoxyphenyl PNBz p-nitrobenzoyl ppm parts per million (in NMR) PPTS pyridinium p-toluenesulfonate PTSA p-toluenesulfonic acid ROESY rotating frame NOE spectroscopy rt room temperature SEM 2-(trimethylsilyl)ethoxymethyl
SN2 bimolecular nucleophilic substitution TAO trimethylamine oxide TBAF tetrabutylammonium fluoride TBDMS tert-butyldimethylsilyl TBDPS tert-butyldiphenylsilyl TBS tert-butyldimethylsilyl TEA triethylamine TES triethylsilyl
xviii Tf trifluoromethanesulfonyl (triflyl) TFA trifluoroacetic acid THF tetrahydrofuran THP tetrahydropyran TIPS triisopropylsilyl TMEDA N,N,N,N-tetramethyl-1,2-ethylenediamine TMS trimethylsilyl Ts tosyl, p-toluenesulfonyl TS transition state
xix CHAPTER 1
LASONOLIDE A: ISOLATION, BIOLOGICAL ACTIVITY AND STRUCTURE ELUCIDATION
1.1 Introduction
The total synthesis of natural products and their analogs has received attention from synthetic chemists for many years. The interest in preparing such molecules is due in many cases to their biological activity and in other cases to structural issues such as resolution of stereochemical assignments. The challenges involved in the synthesis of natural products are numerous and have served as a motivation to discover new reactions and improve already well-known reactions.
The studies presented in this thesis are directed toward the synthesis of a macrolide marine natural product called lasonolide A. This project was undertaken for the reasons cited above: (1) potent biological activity (2) structural issues and (3) the challenge of developing the Prins cyclization as the key reaction for the synthesis of major portions of the natural product. The details behind these reasons will hopefully become clear to the reader as they proceed through this thesis.
The first chapter of this thesis will focus on a description of the isolation of lasonolide A, its biological properties and its structure elucidation. This will include a review of some synthetic work from other laboratories, because synthesis did ultimately
1 play a role in the structure determination of lasonolide A. The second chapter will review synthetic efforts toward lasonolide A, including some of the early work done in our group. The third chapter will focus on the Prins cyclization and background material that supports my thesis work. Chapters 4 and 5 will present an extensive discussion of my own studies towards this natural product target.
1.2 Structure Description
Lasonolide A was first isolated by McConnell and co-workers of the Cold Harbor Oceanographic Institute, from the Carribean marine sponge Forcepia sp. A total of 2.3 mg of the natural product were obtained from an initial harvest of 100 g of the frozen marine sponge. Lasonolide A showed a high biological activity as an antitumor agent. It was found to be a potent cytotoxin against the A-549 human lung (IC50 = 40 ng/mL)
carcinoma and P388 murine leukemia cells (IC50 = 2 ng/mL). Lasonolide A also presented cell adhesion in the EL-4.IL-2 cell line (IC50 = 19 ng/mL), but it also showed toxicity against these cells (> 25 ng/mL). The pharmacophore of lasonolide A remains unknown.1 Lasonolide A was described as an optically active orange oil with a specific
rotation (Na D-Line) of + 24.4 (c 0.045, CDCl3) and with a molecular formula of
C41H60O9. In 1994, the McConnell group proposed the structure for lasonolide A on the basis of NMR experiments as shown in Figure 1.1.1
OH 26 18 34 O O 17 31 28 25 A O 22 OH O O 1 12 O B 7 OH
Figure 1.1: Proposed structure for lasonolide A.1
2 13C and DEPT NMR experiments suggested that this molecule had two carbonyl carbons, 14 olefinic carbons, nine oxygenated sp3 carbons and four methyl groups. Based on 1H-1H COSY, 2-D HOHAHA and HMQC experiments five substructures (2-6) were elucidated as shown in Figure 1.2. The connection of the substructures was established by HMBC experiments which relies on the use of the 1H-13C long range correlations. The regiochemistry and relative stereochemistry were elucidated using ROESY and deuterium exchange experiments.1
H H H H OOOCH3 13 H 14 O 2 H H H CH3 O 21 2 3
H O CH3 30 22 28 O 34 CH3 23 CH O H O 3 H H
4 5 6
Figure 1.2: Lasonolide A substructures.1
The important features of this macrolide structure are two tetrahydropyran rings (A and B) with four stereogenic centers each one of them, an additional stereogenic center at C28, four trans double bonds, two cis double bond (C17-C18) and an additional olefin at C31. It is also important to mention that the tetrahydropyran rings contain 2,6- cis stereochemistry. In addition, the A ring is characterized by a quaternary center at C22. Even with the extensive work of McConnell and coworkers the stereochemistry at C28 was not elucidated relative to the eight other stereogenic centers. In addition, the
3 absolute stereochemistry of the natural product was not determined. Finally, the NMR data did not clearly relate relative stereochemistry between the two tetrahydropyran rings.
1.3 Lasonolide A: Structure Revision and First Total Synthesis
The proposed structure of lasonolide A immediately captured the attention of synthetic chemists and many groups started working on its synthesis. Ultimately the Lee group at Seoul National University of Korea reported the first total synthesis of the proposed structure of lasonolide A (1).2-4
Lee’s retrosynthesis analysis of structure 1 is as shown in Scheme 1.1.4 Lee first disconnected the branched chain between C25 and C26. The two major proposed disconnections of the macrolide (8) were at C3-C4 and C17-C18. Formation of the bond between C3 and C4 was to be accomplished using a Stille coupling reaction,5 and the cis double bond between C17 and C18 was to be set using a Wittig reaction.6 These two major disconnections led to two main fragments, 8 and 13. It was proposed to use intermediates like 11 and 15 to prepare the tetrahydropyran A and B rings (10 and 14) via key radical cyclization reactions.
4 HO O O OR' RO2C OR' RO2COR'
OR O O Br Si Si
12 11 10
O O O RO2C H RO2C OR'
R'O O R'O OH O 9 8 Z
18 O X RO C 17 2 A
OH O 1 (28S and 28R) O 12 Y 3 4 O O B OH OH 7 13
HO O O OR' RO2C OR' RO2C OR' X X OR' OR' OH 16 15 14
Scheme 1.1: Lee’s retrosynthesis analysis of structure 1.4
5 The synthesis of structures related to 8 and 13 was accomplished by first making the A and B rings in the form of aldehyde 27 and ester 33, respectively. Lee’s synthesis of 27 (A-ring) proceeded as shown in Scheme 1.2. The key step in the synthesis of the A-ring was a 6-endo, 6-exo tandem radical cyclization reaction of enol ether 22 to give
23 upon treatment with Bu3SnH and AIBN as an initiator. This reaction set two of the four THP stereogenic centers, including the quaternary center. The stereochemistry was proposed to be controlled by chair transition states as shown in Figure 1.3.2-4
Me Me Me Si Si Me Si Me H O Me H O H O BnO BnO BnO H 6-endo H 6-exo H O O O
CO Et CO2Et 2 CO2Et
Figure 1.3: Lee’s 6-endo, 6-exo tandem radical cyclization.4
6 OBn OBn HO CO Et 2 a-b HO c-d HO e-g (72%) (57%) (88%) EtO2C O EtO2C 17 18 19
OBn OBn OBn O HO O EtO C h-iEtO2C j 2 k PMBO (97%) (80%) O OH Br Si 20 21 22
PivO PivO CO2Et OBn OBn OBn O O O l-n o-s t-v
(76%) H O OH OH OTBS Si HO 23 24 25
PivO PivO OH O O O w H
(65%) OO OO
26 27 a) BH3·SMe2, NaBH4, THF; b) Bu2SnO, PhH; BnBr, TBAI; c) MeNH(OMe)·HCl, Me3Al, THF; d) H2C=C(Me)MgBr, THF; e) Et3B, NaBH4, THF-MeOH; f) (p- MeO)PhCH(OMe)2, CSA, DCM; g) DIBAL, DCM; h) HC≡CCO2Et, NMM, MeCN; i) DDQ, DCM-H2O; j) BrCH2SiMe2Cl, TEA, DMAP, PhH; k) n-Bu3SnH, AIBN, PhH; l) LiBH4, ether; m) PivCl, DMAP, pyridine, DCM; n) H2O2, KF, KHCO3, THF-MeOH; o) TBSOTf, 2,6-lutidine, DCM; p) CSA, MeOH; q) (o-NO2)PhSeCN, Bu3P, THF; H2O2; r) OsO4, NMO, acetone-water; NaIO4; s) NaBH4, EtOH; t) HCl, MeOH; u) Me2C(OMe)2, CSA, acetone; v) H2, Pd(OH)2/C, MeOH; w) SO3-pyridine, TEA, DMSO-DCM.
Scheme 1.2: Lee’s synthesis of the A-ring.2-4
7 The synthesis of tetrahydropyran 33 (B-ring) is shown in Scheme 1.3. The key step once again was a radical cyclization reaction of enol ether 32 to give tetrahydropyran 33 in 96% yield.
O O HO O OH OBn a-c d-f O N OBn (70%) (81%) Ph OBn 28 29 30 g-i (87%)
O HO O EtO C OBn EtO2COBnm 2 j-l OBn (96%) Br (92%) TBSO OBn OBn OBn
33 32 31
a) n-Bu2BOTf, TEA, DCM; BnOCH2CHO; b) MeNH(OMe)·HCl, Me3Al, THF; c) CH2=CHMgBr, THF; d) Et3B, NaBH4, THF-MeOH; e) PhCH(OMe)2, CSA, DCM; f) DIBAL, DCM; g) OsO4, NMO, acetone-H2O; NaIO4; h) NaBH4, EtOH; i) TBSCl, imidazole, DCM; j) HC≡CCO2Et, NMM, MeCN; k) HCl, MeOH; l) CBr4, Ph3P, pyridine DCM; m) n-Bu3SnH, AIBN, benzene.
Scheme 1.3: Lee’s synthesis of the B-ring.2-4
The macrolide was assembled by first elaborating the chains of the B-ring as shown in Scheme 1.4. Key steps involved selective deprotection of the diol 35, elaboration of the chain to the aldehyde oxidation state, followed by a Gennari-Still reaction to give aldehyde 37.7 The product of the Julia-Julia reaction of 34 with 36 was further elaborated to the phosphonium salt 39.8 This phosphonium salt was coupled to A- ring aldehyde 27 via a Wittig reaction, to provide 40 (Scheme 1.5).6 Elaboration of 40 to carboxylic acid 43 was followed by a Yamaguchi esterification to provide macrocylic lactone 44.9 This method of macrocycle formation marked an improvement over the
8 originally planned (and also executed) intramolecular Stille coupling. Adjustment of oxidation state in the C23 side chain then provided aldehyde 45 and set the stage for completion of the synthesis.
MeO2C O f-h a-e I OTBS O 33 I (56%) (78%) PivO OTBS OTBS
O2S 35 36 N S i-j 34 (93%)
PivO Ph3P O
I H O l-n O k O I I I (95%) (95%)
OTBS OTBS OTBS
39 38 37
a) H2, Pd/C, MeOH; b) TBSOTf, 2,6-lutidine, DCM; c) LiBH4, ether; d) SO3-pyridine, TEA, DMSO-DCM; e) CrCl2, CHI3, dioxane-THF; f) CSA, MeOH; g) SO3-pyridine, TEA, DMSO-DCM; h) MeO2C(Me)CHPO(OCH2CF3)2, KHMDS, 18-c-6, THF; i) DIBAL, DCM; j) MnO2, DCM; k) 35, LDA, THF; 37; l) DIBAL, DCM; m) Ph3P, I2, imidazole, THF; n) Ph3P, MeCN.
Scheme 1.4: Lee’s elaboration of B-ring.2-4
9 PivO O PivO O
a b (71%) TBSO OH 39 O O (92%) c (88%) O O I I
OTBS OTBS SnBu3 HO2C 42 40 41
PivO O PivO O
d e TBSO OH TBSO O (85%) (80%) O O HO2C O 44 43 OTBS OH
H 23 O h-i (1-28S) O (46%) f (68%) TBSO O
g (90%) O j-i O (1-28R) 45 (38%) OH a) KHMDS, THF; 27; b) CSA, MeOH, (HOCH2)2 (s.m. 20%); c)TBSCl, imidazole, DCM; d) 42, Pd2dba3, DIPEA, NMP; e) 2,4,6-Cl3PhCOCl, TEA, THF; DMAP, benzene; f) LiEt3BH, THF (s.m. 19%); THF; g) SO3-pyridine, TEA, DMSO-DCM; h) 50a, KHMDS, DME; 45; i) HF.pyridine, THF; j) 50b, KHMDS, DME; 45.
Scheme 1.5: Lee’s final steps for the synthesis of lasonolide A (1).2-4
10 The end game in Lee’s synthesis required preparation of enantiomeric sulfones 50a (28S) and 50b (28R). These were made from the corresponding enantiomers of malic acid, as shown in Scheme 1.6. Coupling of these compounds with aldehyde 45 gave the two diastereomers of structure 1 which differed only in the configuration at C28 (Scheme 1.5). Neither compound fit all data reported for lasonolide A!
OH a-c OTBS CO H d-f 2 O O HO2C OH (64%) O (55%) 46 OTBS O O 47 48
Ph g-h N N SH (81%) NN
49 PhN N N TBSO O2S N i-m OH O TBSO OTBS 28 (51%) 51 52 50a (28S) O 50b (28R) a) cyclohexanone, BF3·OEt2, ether; b) BH3·DMS, B(OMe)3, THF; c)TBSCl, imidazole, DCM; d) 52, NaHMDS, THF; e) TBSCl, imidazole, DMAP, DCM; f) HF·pyridine, pyridine, THF; g) 49, DIAD, Ph3P, THF; h) (NH4)6Mo7O24, H2O2, EtOH; i) O3, DCM; DMS; j) (CH3)2CHCH2CH2MgBr, THF; k) (COCl)2, DMSO, DIPA, DCM; l) Zn dust, CH2Br2, TiCl4, THF; m) HCl, MeOH.
Scheme 1.6: Lee’s synthesis of the branched chain of lasonolide A.2-4
In a quest for the synthesis of lasonolide A, Lee and coworkers used this approach to synthesize seven isomers of structure 1 (Scheme 1.7). Isomers 53 and 54 were prepared because the presence of the triene and diene groups insulate the tetrahydropyran rings from one another and make it difficult to differentiate between these isomers and the originally assigned structure. However, the NMR spectra of 53 and 54 did not match the natural product. The synthesis of 53 and 54 together with previous experience with
11 the synthesis of another natural product led to the observation of an important detail. The originally proposed isomers (1-28R and 1-28S) showed a chemical shift of H19 around 4.70 ppm, but the natural product chemical shift was at 4.30 ppm. Based on this observation, Lee decided to work on the geometry of the olefins. Isomers 55 and 56, which differ on the geometry of the double bond at C17-C18 were prepared. Even though the chemical shift for H19 in these trans-double bond isomers matched the natural product, discrepancies in this region persisted, so Lee’s next choice was to change the geometry at C25-C26 bond to a cis geometry. The combination of these two geometry changes led to a synthesis of the natural product. Both stereochemical isomers at C28 were synthesized (57 and 58), which led to the assignment of the absolute configuration at this center. Indeed the spectral data for 58 matched those reported for the natural product, establishing the structure of lasonolide A with the exception of absolute configuration. It is notable that in order to have a complete structural analysis, Lee and coworkers made isomer 59, which also did not match the natural product.4
The next difficulty was associated with the reported specific rotation. The optical
rotation that Lee measured was [α]D = -24.1 (c 0.055, CDCl3) which was opposite to the one reported for the natural product. To solve this problem the Lee group made the enantiomer of 58. Thus the rotation of ent-58 matched that reported for lasonolide A
[[α]D = +24.4 (c 0.045, CDCl3)]. However, when 58 and ent-58 were evaluated for biological activity (antitumor activity), the biological activity resided in isomer 58. Thus, Lee concluded that the optical rotation originally reported was wrong.4
12 OH 26 18 34 O O 17 31 28 25 A O 22 OH O O 53 (28S) 12 54 (28R) O B 7 OH
OH 18 26 34 O O 31 28 A O 25 22 17 HO O O 55 (28S) O 56 (28R) B OH OH 26 34 O 31 28 25 17 O O A 18 22 57 (28S) HO O 58 (28R) O O B OH OH 26 34 O 31 28 25 17 O O A 18 22 59 (28R) HO O O O B OH
Scheme 1.7: Some of the lasonolide A isomers synthesized by Lee and coworkers.4
13 In summary, Lee and coworkers established a revised structure for lasonolide A as 58. This differs from the original structure in the geometry of the double bonds at C17-C18 and C25-C26, has an R absolute configuration at C28 and a specific rotation of –24.1. As one can see, this work presents a strong case for synthesis as a tool for structure determination, even in an age where NMR spectroscopy is reported to be sophisticated enough to afford detailed structures of proteins.
14 CHAPTER 2
REVIEW OF PREVIOUS (-) AND (+)-LASONOLIDE A SYNTHESES
Several groups have reported work on the total synthesis of lasonolide A. Most of these efforts involved syntheses of lasonolide A substructures. At the moment of writing this thesis, two groups have completed a syntheses of this target: the group of Eun Lee at Seoul National University and the group of Sun Ho Kang at Korea Institute of Science and Technology. As indicated in Chapter 1, the Lee group completed syntheses of both enantiomers of lasonolide A. Kang’s group completed a synthesis of (+)-lasonolide A (ent-58).
In the previous chapter we discussed the synthesis of the originally proposed structure of lasonolide A (1) by Lee. In this chapter we will discuss how he modified his synthesis to accomplish a synthesis of the revised structure 58. Then, a discussion of Kang’s synthesis will be presented. To set the stage for my research, I will then review work previously done in my research group towards this molecule. Last, I will briefly mention partial syntheses reported by other groups.
2.1 Lee’s Synthesis of (-) and (+)-Lasonolide A.
Lee’s synthesis of (-)-lasonolide A (58) was achieved via modification of the previous sequence described in Schemes 1.4 and 1.5. The side chain was first disconnected at C25-C26 as before. The two major bond constructions came from the formation of the double bonds between C17-C18 and C14-C15. The macrocyclic ring
15 was formed using a Stille reaction to construct the C3-C4 bond. This plan is summarized in Figure 2.1.
Wittig Kocienski-Julia OH Reaction 26 34 O 31 28 25 18 O O A 17 22 HO O O 3 O (-)-Lasonolide A (58) B 4 OH
Stille Couping
Figure 2.1: Lee’s major bond disconnection of (-)-lasonolide A.2-4
In the forward direction, the A and B rings were introduced in the form of aldehydes 27 and 37, prepared as presented before in Schemes 1.2 and 1.4. These aldehydes were stitched together with 3-carbon fragment 59 via sequential Kocienski- Julia olefinations.10 Thus, reaction of the anion derived from sulfone 59 with 27, followed by removal of the TBS protecting group, gave homoallylic alcohol 60. Displacement of the alcohol with thiol 49, followed by oxidation at sulfur, provided sulfone 61 (Scheme 2.1). The anion of 61 was then coupled to with aldehyde 37 (Scheme 2.2) to provide skipped diene 62, with trans-geometry at the C14-C15 and C17-C18 double bonds. Vinyl iodide 62 was converted to 64 in several steps and then, the macrolide ring was formed via an intramolecular Stille coupling reaction. Adjustment of oxidation states then provided aldehyde 66.
16
PivO O Ph N SO2 OTBDPS a-b OH N (76%) OO N N 59 60 c-d (80%) PivO O O PivO O
Ph N SO2 N N N SH OO OO N N NN Ph 27 49 61 a) LiHMDS, DMF-HMPA (4:1), -35 °C; 27, -35 °C to rt; b) TBAF, THF; c) 49, DIAD, Ph3P, THF, 0 °C; d) (NH4)6Mo7O24, H2O2, EtOH, 0 °C to rt.
Scheme 2.1: Lee’s preparation of A-Ring carbon chains.2-4
17 PivO O PivO O a N SO2 N (86%) OO N N OO Ph O I 61 62 OTBS
b (69%) c (93%)
PivO O PivO O d
(64%) TBSO O TBSO OH I O O O I OTBS OTBS SnBu3 64 63
e (62%)
PivO O H O
O f (62%) TBSO O TBSO O g (87%) O O O O
OTBS OTBS 65 66 h-i (60%)
(-)-lasonolide A (58) a) LiHMDS, THF; 37; b) CSA, MeOH, (HOCH2)2, (s.m. 18%); c) TBSCl, imidazole, DCM; d) 42, DIC, DMAP, DCM; e) Pd2dba3, DIPEA, NMP; f) LiEt3BH, THF (s.m. 17%); g) SO3-pyridine, TEA, DMSO-DCM (1:1); h) HF·pyridine, pyridine, THF; i) 69, KHMDS, THF; 66.
Scheme 2.2: Lee’s final steps in the total synthesis of (-)-lasonolide A (58).2-4
18 The side chain was coupled to the macrolide via a Wittig reaction between aldehyde 66 and the phosphonium salt 69 to obtain the cis geometry at C25 and the final target (Scheme 2.2).6 The required phosphonium salt was prepared as described in Scheme 2.3. The synthesis of the side chain of (-)-lasonolide A (58) was also modified. The alcohol 50b was reacted with hydrofluoric acid-pyridine complex, followed by Mitsunobu11 conditions to afford the phosphonium salt 69.2-4
OH a-c O CO2H HO2C O OTBS 67 O 68
d-f
I TBSO PPh OTBS 3 g-h O O OH O O 69 50b a) cyclohexanone, BF3·OEt2, ether; b) BH3·DMS, B(OMe)3, THF; c) TBSCl, imidazole, DCM; d) 52, NaHMDS, THF; e) TBSCl, imidazole, DMAP, DCM; f) HF·pyridine, pyridine, THF; g) Ph3P, I2, THF; h) Ph3P, MeCN, reflux.
Scheme 2.3: Lee’s elaboration of the branched chain of (-)-lasonolide A.2-4
In summary, the synthesis of (-)-lasonolide A (58) was done in 36 steps (longest linear chain) from ethyl L-malate in 0.68% total yield. The A and B rings were efficiently constructed via stereocontrolled radical cyclization reactions. The macrolide was also assembled in an efficient manner by utilizing reactions such as the Wittig6 and Kocienski-Julia10 reactions, not only to couple the required pieces, but also to achieve
19 control of double bond geometry. Lee’s synthesis of (+)-lasonolide A (ent-58) was performed in the same way, but by using ethyl D-malate as the starting material.
2.2 Kang’s Synthesis of (+)-Lasonolide A.
The group of Sung Ho Kang and coworkers reported a total synthesis of (+)- lasonolide A (ent-58) in 2003.13 Their retrosynthetic analysis started with disconnection of the side chain at C25, followed by disconnecting at C2 to afford intermediate 70. In a forward manner, the plan was to form the double bonds at C25 and C2 in a stereoselective manner via a Wittig6 and intramolecular Hormer-Emmons12 reactions, respectively. Intermediate 70 was to come from a Kocienski-Julia10 reaction between sulfone 71 and aldehyde 72. Sulfone 71 was to come from an iodoetherification of δ- hydroxyalkene 75, leading to the formation of the A-ring. The quaternary center in this ring was to be obtained by thermodynamic differentiation of the two alkoxymethyl groups in allylic alcohol 76. Aldehyde 72, which contains the B-ring, was to be prepared by an intramolecular conjugate addition of alcohol 73. Alcohol 73 was to be prepared from alkene 74.13-15
20 O 28 O O 15 25 A 17 OH 22 14 HO O
(+)-lasonolide A O 3 ent-58 O 2 B 4 OH
TBSO O OH TBSO 2 O (EtO) OP 2 O OO O 3 OTBS 70 OTBS 76
TBSO O OH SO TBSO 2 OH SN OO
71 Ph 75
+
OHC EtOOC OBn OH O HO
OBn OTBS OTBS OTIPS 72 73 74
Scheme 2.4: Kang’s retrosynthesis analysis of (+)-lasonolide A (ent-58).13-15
21 Kang’s synthesis of the A-ring started with alcohol 77 as shown in Scheme 2.5. After oxidation of this alcohol to the aldehyde and asymmetric allylation, it was possible to obtain benzylidene acetal 79 via thermodynamic control. Partitioning between 79 and 80 in the acetal-forming reaction was 5:1. A second asymmetric allylation was used to obtain alcohol 75. Treatment of alcohol 75 with iodine effected Kang’s key cyclization reaction to afford the A–ring with a 2,6-cis stereochemistry. After displacement of the iodide with benzoate, ozonolysis, reduction and a series of protection and deprotection steps, aldehyde 87 was obtained.13-15
Aldehyde 87 was then reacted with sulfone 90 (prepared as shown in Scheme 2.6) to afford intermediate 91 with the trans geometry required at C17. A series of protection and deprotections completed the upper fragment of (+)-lasonolide A.13-15
Kang’s synthesis of the B-ring started with the known alcohol 74. The secondary hydroxyl group was protected and the alkene was then oxidized as shown in Scheme 2.7. The resulting aldehyde was reacted with Brown’s allylborane to afford alcohol 94. A series of transformations afforded the α,β-unsaturated ester 97. This ester was then used to perform the key intramolecular Michael addition for the formation of the B-ring in a stereoselective manner. After elaboration of the cyclization product 98 to the tetrahydropyran 104, with the required E-olefin at C4 and Z-olefin at C12, the ester 104 was reduced to afford aldehyde 72. This completed Kang’s synthesis of the lower fragment (72) of (+)-lasonolide A.13-15
The final steps of the synthesis proceeded as expected according to the retrosynthetic plan (Scheme 2.8). The coupling of sulfone 71 and aldehyde 72 was achieved via a Kocienski-Julia reaction.10 The macrolide was formed via the proposed intramolecular Hormer-Emmons reaction.12 The side chain was coupled via the Wittig reaction of the phosphonium salt 109 with aldehyde 106.6
22 In summary, Kang and coworkers synthesis of (+)-lasonolide A was achieved in 26 steps (longest linear sequence) and an overall yield of 7.2% from alcohol 74.
OH OH OH CO -i-Pr O a-b O c O 4 2 B O O OO O 5 CO2-i-Pr 77 76 Ph 79 78r :(4R, 5R) 78s :(4S, 5S) a-d
O O OBz I OH HO
f e OO OO OO OO Ph Ph Ph Ph 82 81 75 80
g-h
O P1O O TBSO O TBSO O OBz OH H kj
OP1 OP2 TBSO OTES TBSO OTES
83 86 87
1 2 i,j 84: P , P = H 1 2 85: P = TBS, P = TES a) (COCl)2, DMSO, CH2Cl2, Et3N; b) 78r, 4 Å MS, PhMe, 2N NaOH, 86% (for steps a, b); c) PhCHO, CF3CO2H, PhMe, 82% (after two cycles); d) 78s, 4 Å MS, PhMe, 2N NaOH, 77% (for steps a, d); e) I2, K2CO3, MeCN, 91%; f) NaOBz, NMP, 97%; g) O3, NaHCO3, MeOH; NaBH4, 96%; h) H2, 10% Pd/C, HOAc, MeOH, 89%; I) TBSCl, imidazole, DMF, 95%; j) TESOTf, 2,6-lutidine, CH2Cl2, 98%; k) K2CO3, MeOH, 91%; l) Dess-Martin periodinane, pyridine, CH2Cl2.
Scheme 2.5: Kang’s synthesis of the A-ring.13-15
23
Ph HO a-b N N N S S OH N N O2 S 88 90 d,e Ph N N O2 N SH O S N N S 49
P1OOP2 N 1 2 SH f 91: P = TBS, P = TES 1 2 S 92: P , P = H g 1 2 71: P = TBS, P = H 89
a) 49, DEAD, Ph3P, THF, 81%; b) (NH4)6Mo7O24·4H2O, H2O2, phosphate buffer (pH 7.6), THF, EtOH, 83%; c) 90, DEAD, Ph3P, THF, 90%; d) 87, KHMDS, DME, 95% (from 86), e) H2O2, phosphate buffer (pH 7.6), (NH4)6Mo7O24·4H2O, THF, EtOH, 94%; f) p-TsOH·H2O, MeOH, 98%; g) TBSCl, imidazole, DMF, 96%.
Scheme 2.6: Kang’s elaboration of the side chain of the A-ring.13-15
24 EtO2C OBn OH OP OP P1O OBn b-c OBn b-d g
OP2 94 a 74: P = H 93: P = PMB 1 2 e 95: P = PMB, P = H 96: P1 = PMB, P2 = TIPS f 73: P1 = H, P2 = TIPS 97: P1 = H, P2 = TBS
EtO2C OBn O O O h-i OBn j OBn m-n
EtO2C OTIPS OTIPS OP1 OTIPS
1 2 98 99k 100: P = H, P = Bn 101: P1 = H, P2 = H l 102: P1 = TBS, P2 = H
MeOOC 13 OHC q 5 O 12 TBSO O
4 OTBS OP OTBS
o-p 103: P = TIPS 72 104: P = TBS
a) NaH, PMBCl, n-Bu4NI, DMF, THF, 97%; b) OsO4, NaIO4, H2O, THF; c) (-)- Ipc2BCH2CH=CH2, Et2O, then 3 N NaOH, H2O2, 74% (for steps b, c); d) Ph3P=CHCO2Et, PhH, 87% (for b, d); e) TIPSOTf, 2,6-lutidine, CH2Cl2, 98%; f) DDQ, H2O, CH2Cl2, 87%; g) NaH, THF, 81%; h) DIBAL, CH2Cl2; i) EtOOCCH2PO(OEt)2, NaH, THF, 89%, (for steps h-i); j) DIBAL, CH2Cl2, 91%; k) Li, NH3 (liq.), THF, 87%; l) NaH, TBSCl, THF, 94%; m) (COCl)2, DMSO, CH2Cl2; Et3N; n) KHMDS, 18-crown-6, MeOOCCH(Me)PO(OCH2CF3)2, THF, 79% (for steps m-n); o) TBAF, THF, 99%; p) TBSOTf, 2,6-lutidine, CH2Cl2, 99%; q) DIBAL, CH2Cl2, 88%.
Scheme 2.7: Kang’s synthesis of the B-ring.13-15
25
O TBSO O O H c b-f 71 + 72 TBSO OH HO O O O TBSO O
OH 105OTBS 106
O O Br O OETS 107 g-i O j-k PPh3Br (+)-Lasonolide A (ent-58) + O
109 OH
108
a) LiHMDS, DME, 82%; b) HCOOCCH2PO(OEt)2, DCC, DMAP, CH2Cl2, 94%; c) PPTS, MeOH, 91%; d) MnO2, EtOAc; e) K2CO3, 18-crown-6, PhMe, 71% (for steps d, e); f) Dess-Martin periodinane, pyridine, CH2Cl2; g) p-TsOH·H2O, PhMe, 85%; h) TESOTf, 2,6-lutidine, CH2Cl2, 99%; i) PPh3, MeCN, 89%; j) KHMDS, THF, 86% (for steps f-j); k) HF·py, pyridine , THF, 87%.
Scheme 2.8: Kang’s final steps for the synthesis of (+)-lasonolide A.13-15
26 2.3 Hart-Patterson-Unch Formal Synthesis of (+)-Lasonolide A.
The Hart group started to work on the total synthesis of lasonolide A several years prior to Lee’s 2002 report. As stated earlier, the interest in the preparation of this molecule was due to its high biological activity, structure elucidation details and development of new chemistry for the formation of the A and B tetrahydropyran rings. During the course of these studies, Lee published the revised structure of lasonolide A as previously discussed. Thus, the structural impetus for performing a synthesis disappeared, but the goal of developing new methodology that could be applied to the synthesis of the tetrahydropyran units in lasonolide A and another natural products still remained.
In 2003, the Hart group reported the synthesis of the A and B rings fragments ent- 26 and ent-33, that correspond to the intermediates prepared by the Lee group in their synthesis of (-)-lasonolide A.16 The key reaction to construct the two tetrahydropyran rings is shown in Scheme 2.9. The tetrahydropyran rings were to be prepared by a cycloetherification reaction using an allylic alcohol of type 110 as the cyclization substrate. Based on previous studies in the group it was expected that stereochemistry would be transfer from the C6 and C4 stereogenic centers to two more centers (C2 and C3) via a cyclic chair like transition state. The electrophilic cyclization reaction would set the required 2,6-cis-stereochemistry in the tetrahydropyran ring.16-17
R 6 OH R' RR'6 O 2 electrophilic 3 4 4 X addition OH OH 110 111: X = SePh reduction 112:X=H
Scheme 2.9: Key cyclization reaction for the construction of the A and B rings.16
27 The Hart-Patterson synthesis of the A-ring fragment follows as shown in Scheme 2.10. The synthesis started with the oxidation of diacetone glucose to provide the known diacetonide 113, followed by its conversion to nitroalkene 114. After a Michael addition, oxidation, reduction and protection of the resulting alcohol with benzyl chloride, compound 118 was obtained. To elaborate the C23 side chain of the A-ring in lasonolide A, a sequence of reactions that involved selective deprotection of the exocyclic acetonide, vicinal didehydroxylation, and hydroboration-oxidation of the resulting terminal olefin, followed by protection of the alcohol as a benzyl ether gave tetrahydrofuran 121. This tetrahydrofuran was further elaborated to the required substrate for the cyclization reaction (122) and to introduce the furan functionality that was going to become the C19 side chain of the A-ring.16 This was accomplished by hydrolysis of the remaining acetonide, a Wittig reaction, and isomerization of the undesired minor Z-isomer to give the acyclic intermediate 122 with high E-selectivity. The cycloetherification reaction went as proposed (anti addition of the electrophile and hydroxyl group across the double bond) with high stereochemical control to give tetrahydropyran 123. Elaboration of the furan ring into the C19 side chain was then achieved by ozonolysis and reduction of the resulting carboxylic acid. After a series of protection and deprotection steps, tetrahydropyran ent-26 was obtained. This material matched spectra data provided by Lee for intermediate 26 in his synthesis of 58.16
28 O O O R O O cg-hO O O O O O O BnO X O X
113 X = O d 119 X = CH=CH a-b 115 X = CH2NO2 o 2 114 X = CHNO 120 X = CH CH OH 2 e 116 X = CO2H 2 2 p 121 X = CH CH OBn 117 X = CH2OH 2 2 f 118 X = CH2OBn
k-m
BnO BnO BnO OR O O OH q-r O n O
X BnO OPiv BnO OR BnO OH 123 X = SePh, R = H 122 126 R = H o s 124 X = R = H 127 R = TBDPS p 125 X = H, R = Piv
t
RO PivO PivO OTBDPS OTBDPS OR O v O w O
BnO OH HO OH OO
128 R = Bn 130 131 R = TBDPS u x 129 R = H ent-26 R = H a) CH3NO2, 0.2 N aq. NaOH, Bu4NI, benzene (95%); b) Ac2O, DMSO (90%); c) Me2CuLi, Et2O (50-80%); d) 0.5 M aq. NaH2PO4-1.0M aq NaOH (1:1); aq. ozone; 10 % aq HCl (85%); e) LiAlH4, THF (95%); f) Cl3CC(=NH)OBn, CH2Cl2-cyclohexane, CF3SO3H (90%); g) 60% aq. CH3CO2H (81%); h) Ph3P, I2, imidazole, toluene (80%); i) 9-BBN; 2.0 N aq NaOH-30% aq. H2O2 (89%); j) BnBr, Bu4NI, NaOH (86%); k) Dowex-50, 50% aq. dioxane (70%); l) Ph3PCH2(2- furyl)Br, dioxane, KO-t-Bu (86%, trans:cis = 3:1); m) n-Bu3SnH, AIBN (99%, trans:cis = 30:1); n) PhSeCl, CH2Cl2 (87%); o) n-Bu3SnH, AIBN, benzene (88%); (p) t-BuCOCl, pyridine (93%); q) O3, MeOH; r) BH3·THF (64% for 2 steps); s) t-BuPh2SiCl, DMF, imidazole (87%); t) i- Bu2AlH, toluene (72%); u) H2, 10% Pd/C (60%); v) t-BuCOCl, pyridine (74%); w) Me2C(OMe)2, PPTS (96%), x) n-Bu4NF, THF (87%).
Scheme 2.10: Hart-Patterson synthesis of the A-ring.16
29 Hart’s synthesis of the B-ring fragment (Scheme 2.11) started with an asymmetric aldol reaction between the known thiazolidinethione 132 and the appropriate alkylating agent to afford alcohol 133 with high diastereoselectivity. After removal of the chiral auxiliary and protection of the alcohol with triethylsilyl chloride, the resulting Weinreb amide was treated with benzyloxymethyllithium to afford ketone 136.18 Ketone 136 was treated with trifluoroacetic acid to obtain the deprotected alcohol 137. The next task involved diastereoselective reduction of the ketone. Although formation of β-elimination product was a minor problem in this reduction, the cyclization substrate 140 was eventually obtained, together with its C2 epimer, as a 4:1 mixture. The cyclization reaction of alcohol 140 itself proceeded with the expected selectivity. Thus, it is probable that the C3 methyl and C4 hydroxy groups were axially oriented in a chair like transition state, while the side chains at C2 and C6 were equatorial. This conformational arrangement gave tetrahydropyran 141 with the required 2,6-cis-stereochemistry.16
The rest of the synthesis focused on elaboration of tetrahydropyran 141 to match Lee’s intemediate 33. This was accomplished by first protecting the C4 hydroxyl group as a benzyl ether, bromohydrin formation, and reduction to afford tetrahydropyran 144 contaminated with its Cα-epimer. The mixture was submitted to sequential Dess-Martin, Baeyer Villager oxidation and finally transesterification to give ent-33.19-20
In summary, the Hart-Patterson-Unch synthesis of the A and B rings of lasonolide A were accomplished in 23 and 12 steps, respectively. The plan utilized the electrophilic addition of phenylselenyl chloride, via a chair like transition state, to effectively control the required 2,6-cis-stereochemistry relative to other stereogenic centers.
30 PMP S S PMP S S OMe abON ONMe ON
OH OR 132 133 134 R = H c 135 R = TES
d
PMP PMP PMP OBn OBn O g HO f OR'
PhSe OR OR OR
141 R = H 140 136 R = TES, R' = CH OBn h e 2 142 R = Bn 137 R = H ' 138 R = TES, R = NHCH3 i 139 R = TES, R' = CH2NHOCH3
PMP OH PMP O EtO O OBn OBn OBn O k O l O Z
X OR OBn OBn
143 X = SePh, Z = Br, R = Bn 147 ent-33 e 144 X = Z = H, R = Bn 145 X = Z = SePh, R = H 146 X = Z = R = H
a) Sn(OTf)2, N-ethylpiperidine, CH2Cl2; (E,E)-PMPCH=CHCH=CHCHO (79%); b) CH2Cl2, Me2AlN(OMe)Me (93%); c) Et3SiCl, imidazole, DMF (94%); d) n- Bu3SnCH2OCH2Ph, n-BuLi (55-65%); e) CF3CO2H, THF-H2O (5:1); f) Zn(BH4), toluene, Et2O, (45%-55% for 2 steps); g) PhSeCl, CH2Cl2 (55-65%); h) PhCH2Br, n- Bu4NI, NaOH, sonication (64%); i) NBS, acetone-H2O (2:1), 0 °C to rt. (86%); j) n- Bu3SnH, Et3B, O2, PhH (95%); k) Dess-Martin peridionane, CH2Cl2; l) MCPBA, p-TsOH (cat); EtOH, H2SO4 (cat) (65%).
Scheme 2.11: Hart-Unch synthesis of the B-ring.16
31 2.4 Partial Syntheses of Lasonolide A.
Several other groups have reported syntheses of the A and/or B ring fragments of lasonolide A. This work is briefly summarized below.
In 1996, Gurjar and coworkers, at the Indian Institute of Chemical Technology reported the synthesis of the C18-C23 segment 150 (A-ring fragment).21 In 1997, the same group described a synthesis of the C7-C16 segment 153 (B-ring fragment), working with the unrevised structure of lasonolide A (1).22 Their syntheses were based on the use of cyclopropanated sugar derivatives in the elaboration of the two rings (Scheme 2.12).
TBSO Me O O O O 4 steps O 14 steps O O BnO BnO OH HO OMe OMe OMe HO OH 148 149 150 A-Ring Segment
CO2Et
OR HO AcO AcO O 3 stepsHO 15 steps O OMe AcO O AcO BnO Me OMe OMe 151 152 153 B-Ring Segment
Scheme 2.12: Gurjar’s cyclopropane sugar derivatives for the preparation of the A and B rings of lasonolide A (1).21-22
32 The group of Hoffman in Germany has utilized bicyclic compounds such as 154 and 156 to construct the A and B ring substructures of lasonolide A (Scheme 2.13).23-24
O O OH 6 steps O
O O OTBDMS HO 154 A-Ring segment 155
OSEM
O MeO2C
20 steps O O OBn
racemic chiral B-Ring 156 segment 157
Scheme 2.13: Hoffman approach to the preparation of the A and B rings of lasonolide A (1).23-24
Last, the Shishido group at the University of Tokushima in Japan recently reported a synthesis of the C1-C16 segment of (+)-lasonolide A (ent-58) which includes the B-ring. Their chemistry involved the use of key reactions such as an Oppolzer asymmetric aldol reaction and a reduction of an oxonium salt to set the 2,6-cis- stereochemistry of the tetrahydropyran ring (Scheme 2.14).25-26
33 5 steps OO 4 steps OOHOH OH BnO OH OHC HO 158 159 160
2 steps
OTBS OTBS OTBS 9 steps 4 steps
O H O OTBDPS O O OTBDPS O
163 162 161 OPiv CO2Et
Scheme 2.14: Some of Shishido’s key intermediates for the preparation of the B-ring.25
In summary, in this chapter has presented a small review of the two different total syntheses of either enantiomer of lasonolide A (Lee and Kang), a formal synthesis of the (+)-isomer (Hart-Patterson-Unch), and work in progress of other groups toward this target (Gurjar, Hoffman and Shishido).
34 CHAPTER 3
BACKGROUND: THE PRINS CYCLIZATION AND ITS MODIFICATION
In this chapter, we will first present a brief review of the Prins cyclization reaction and the background that led us chose this reaction as a key step for the synthesis of the A and B-rings of (-)-lasonolide A (58). We will then discuss the early work done in the Hart group toward development of the methodology needed to synthesize the two tetrahydropyran structures of 58.
3.1 The Prins Cyclization Reaction
The Prins cyclization reaction has been shown to be a very useful reaction for the construction of oxygen-containing heterocyclic units that appear in many natural products.27 This reaction typically involves the reaction between an aldehyde (164) and a homoallylic alcohol (165) promoted by acid as shown in Scheme 3.1. This reaction is believed to proceed via an oxocarbenium ion intermediate (168a) that largely adopts E- geometry as the most stable geometrical isomer.28 Mechanistically, it can be affected by the competing cationic oxa-Cope rearrangement. This 3,3-sigmatropic rearrangement has been shown to be of great relevance in the distribution of products. The equilibrium is affected by substituents on the double bonds and at the allylic position. The stability of the two isomers 168a and 168b relate to product ratios. The Prins cyclization reaction itself proceeds largely through a chair-like transition state that allows for control of stereoisomers in the course of the reaction. This organization of the reaction, in principle,
35 should allow one to set four relative stereogenic centers in one step. In additon capture of the positive cationic intermediate 170 can introduce a fifth stereogenic center. It is notable that this reaction can also provide tetrahydrofurans. The product ring size usually depends on olefin substituents in intermediates 168a and 168b, that is, which carbon can best stabilize the resulting positive charge. 28-29
R O R O HO R4 R O R 1 4 acid 1 4 + and/or R1 H R2 R3 R2 R3 R2 R3 Nu 164 165 171 172
-H Nucleophile R1 O R4 acid
R2 R3
170
R1 O -H2O R1 O R4 [3,3] R1 O R4 OH R3 R2 R3 R2 R3 R 2 167 168a 169b
Scheme 3.1: The Prins cyclization.28-29
36 The relevance of this reaction as a carbon-carbon bond forming reaction has led to the study and application of many variations. Some of these variations are:
a) the use of Lewis acids to promote the reaction (such as BF3·Et2O, SnCl4, TiCl4, 29-30 TiBr4, FeCl3, InCl3). b) the use of acetals, mixed acetals and α-acetoxy ethers to generate the oxonium ion.29-31 c) the use of alkynes, allylsilanes, alkenes, and enolsilanes as the π-component.29-31 d) termination of the cyclization with a variety of nucleophiles (Cl, Br, F, allylsilanes)29-31
This reaction is definitely a very important tool for the preparation of oxygen- containing heterocycles, especially the 2,6-cis-tetrahydropyran unit that is present in many natural products including lasonolide A. This is one of the reasons why we decided to study a variation of the Prins cyclization as a key reaction to prepare the A and B-rings of lasonolide A (58).
3.2 Enol Ethers to Generate the Oxonium Ion in the Prins Cyclization.
One variation of the Prins cyclization that has been reported is the use of enol ethers as the source of the oxocarbenium ion. The first two examples of this modification were published by Fráter and Nussbaumer.32-33 They utilized this methodology for the synthesis of the natural products (±)-(cis-6-methyltetrahydropyran-2-yl)acetic acid (177) and (±)-cis-α-irone (181) as shown in Scheme 3.2. Enol ethers (vinylogous carbonates) 174 and 179 were prepared by reacting the homoallylic alcohols 173 and 178 with methyl propiolate in presence of N-methylmorpholine to afford the targets with E-geometry and in high yield. In both cases, the cyclization reaction was efficient. The cyclization was promoted by using trifluoroacetic acid in one case and methanesulfonic acid in the other.
37 It was observed by Fráter and Nussbaumer that the resulting tetrahydropyran rings had a 2,6-cis stereochemistry. The stereochemical outcome of the cyclization of 174 was explained by chair like transition state in which the ester functionality and methyl group occupied quasi-equatorial positions and the addition of electrophile (oxocarbenium ion) and nucleophile (trifluoroacetate) occurred largely in an anti fashion. The cyclization of 179 illustrates termination of a Prins cyclization by loss of a proton rather than capture by a nucleophile. In both cases, the cyclization had a high yield and diastereoselectivity.
OR 11:1 a b CO CH OH (85%) 2 3 O (87%) O O CO2CH3 CO2H 173 174 175 R = COCF3 177 176 R = H
CH3O2C OH O O a c O (88%) (94%) H3CO2C
178 179 180 181
a) methyl propiolate, N-methylmorpholine; b) trifluoroacetic acid, CH2Cl2, 0 °C; K2CO3; c) methanesulfonic acid, CH2Cl2, -10 °C.
Scheme 3.2: Fráter’s synthesis of (±)-(cis-6-methyltetrahydropyran-2-yl)acetic acid (177) and (±)-cis-α-irone (181) via Prins cyclization.32-33
Another example of using an enol ether as the source of the oxocarbenium ion intermediate was recently reported by Kozmin.34 The application of this methodology was toward the synthesis of the natural product leucascandroline A (182). In this case, Kozmin used 4-methoxy-3-buten-2-one as the reagent to generate the enol ether
38 (vinylogous ester) 184 as shown in Scheme 3.3. The cyclization was promoted using trifluoroacetic acid. The resulting trifluoroacetate was hydrolyzed using LiOH to afford the all cis tetrahydropyran 185 in high yield. The observed stereochemistry in the product was consistent with Fráter’s explanation. The reaction proved to be efficient in the construction of the three stereogenic centers and only one isomer was observed.
H H O
OOOMe O
N O O
leucascandroline A NHCO2Me 182
OH a b O O (92%) (77%) HO O O
183 184 185
a) 4-methoxy-3-buten-2-one, PPTS, toluene; b) TFA, 5 °C; LiOH, THF-H2O.
Scheme 3.3: Kozmin’s variation of the Prins cyclization.34
In summary, these three examples are the only ones that have been reported where an enol ether is the starting material for the Prins cyclization. Due to the versatility of this methodology and the efficiency with which the enol ethers can be prepared, it was decided to further study this variation of the Prins cyclization. In addition, an important factor in the decision to further study this reaction was that it promised to provide
39 tetrahydropyrans with substitution patterns and stereochemistry that might prove useful in an approach to lasonolide A (vide infra). In fact, this work was initiated prior to 2002 report on the structure of lasonolide A, and at a time when it was becoming clear that the Hart-Patterson-Unch synthesis would be unacceptably long. Thus, the initial purpose of our work was to study the scope and limitations of the Fráter-Nussbaumer variation of the Prins cyclization.
3.3 Bennett’s Elaboration of the Fráter-Nussbaumer Variation of the Prins Cyclization
The early studies done in our research group by Bennett were directed toward developing the Fráter-Nussbaumer variation of the Prins cyclization, in other words, developing vinylogous carbonates of type 186 as the source of the oxocarbeniums ion 187 and tetrahydropyrans 188 as described in Scheme 3.4. The potential of this reaction to provide the two tetrahydropyran rings of lasonolide A with the appropriate substitution pattern was the main reason to further study this reaction (as mentioned before). Since the two tetrahydropyran rings share similar substitution patterns it was hoped that this methodology could be applied to the construction of both tetrahydropyran rings.35
CO2R 2 RO O R6 acid OR6 O 6 R6 RO2C Nu 3 5 O 4 R3 R5 R3 R5 R3 R5 Nu 186 187 188
Scheme 3.4. Vinylogous carbonates as the source for the oxocarbenium ion in the Prins cyclization.
40 The development of this methodology included determining the effect of substituents at the C5 and C6 position. The studies directed toward the C6 position are summarized in Table 3.1. The reactions were promoted, in most of the cases, by the use of 10 equivalents of trifluoroacetic acid in a 0.1 M solution of dichloromethane solution. The resulting trifluoroacetate was hydrolyzed using potassium carbonate in ethanol. Some of the reactions gave similar results to the ones obtained by Fráter and Nussbaumer.35
CO2Et CO2Et OR6 O 6 R EtO C 1. Acid 6 O 6 R6 2 + 5 5 2. K CO 4 4 2 3 R5 R EtOH 5 189 OH OH 190 191
Entry Substrate R Acid Time Yield Ratio (h) 190 + 191 % 190:191
1 189a n-C6H13 TFA 0.75 85 91:9 2 189b Ph TFA 2.0 77 95:5
3 189c CH2OBn TFA 5.25 58 50:50
4 189d CH2OTBDPS TFA 3.5 66 57:43
5 189e CH2CH2Bn TFA 1.75 78 91:9
6 189f CH=CH2 TFA 1.0 72 91:9 7 189g TFA 5.0 42 80:20 TMS
Table 3.1: Results of Prins cyclization of vinylogous carbonates of type 189.35
41 Initial studies evaluated substituent effects at the C6 position. When the substituent was an alkyl or aryl group the cyclization proceeded as expected with a 10:1 selectivity (at C4) favoring the all cis tetrahydropyran (entries 1-2). The reactions also produced a mixture of dihydropyrans 192 as minor products that came from elimination of an α-proton (Figure 3.1).
CO2Et OC6H13
(10-12%) 192
Figure 3.1: By-products in the cyclization of vinylogous carbonate 189a.35
The study of a benzyloxymethyl group at C6 was relevant from the point of view of lasonolide A (entry 3). This substituent contains a functional group that could be utilized in the elaboration of the macrolide. However, the selectivity at C4 was only 1:1 and many other products were isolated including bicyclic ether 196, which has a 2,6- trans stereochemistry (Figure 3.2).
CO Et O 6 CO2Et OBn OBn 2 EtO2C O HO HO 2 O (10-13%) (11%) (trace) (12%) 193 194 195 196
Figure 3.2: By-products in the cyclization of vinylogous carbonate 189c.35
42 The use of a tert-butyldiphenylsilyl group instead of a benzyl was examined with the purpose of eliminating the formation of the bicyclic ether 196 (entry 4). This strategy succeeded, however, the stereoselectivity at C4 was not improved and elimination products (dihydropyrans) were also observed in 13% yield. To prove that the oxygen in the C6 side chain was the cause of the stereochemical erosion at C4, vinylogous carbonate 189e was examined (entry 5). In fact, the cyclization of this substrate proceeded smoothly in 78% yield with 91:9 diastereoselectivity at C4.35
Studies were then directed toward the effect of hybridization in the C6 side chain. Double bond functionality, in principle, provides another way to elaborate the side chains in the two tetrahydropyran rings of lasonolide A. Therefore vinylogous carbonate 189f, with an sp2-hybridize side chain, was prepared and reacted under the standard conditions to afford the all cis tetrahydropyran 191f as the major product (entry 6). Studies using an sp-hybridized side chain, vinylogous carbonate 189g, showed a significant distribution of products in which the 2,6-cis-stereoselectivity was reduced (entry 7). In fact, in addition to the product shown in Table 3.1, 2,6-trans products were observed in a 30% yield (Figure 3.3). This result was explained by reduction of the steric demands provided by the alkynyl group in the quasi-axial position in the chair-like transition state, presumably leading to trans products.35
CO2Et TMS CO Et TMS CO Et 2 2 O O HO
OH
(4%) (27%) (cis:trans, 2:1; 9%) 195 197 198
Figure 3.3: By-products in the cyclization of vinylogous carbonate 189g.35
43 The effect of substituents at the C5 position is also very relevant for the construction of the A and B rings of lasonolide A (Scheme 3.4). Therefore, Bennett studied the effect of a methyl group at this position. Vinylogous carbonates 199 and 203 were reacted under the standard conditions to provide an interesting distribution of products as shown in Scheme 3.5. It was notable that tetrahydropyrans were now the minor reaction products. In the case of 199, bicyclic ethers were the major products. In the case of 203, a new bicyclic compound (205) became the major product.35
R1 OBn CO2Et OBn EtO C O 6 2 R2 O 1. TFA, CH Cl O EtO C 2 2 2 + 2 5 2. K2CO3, EtOH 4 CH3 CH3 O 199 OH 200 201 R1=Me, R2=H (50%) (7%) 202 R1=H, R2=Me (16%)
OBn CO Et OBn 2 H O 1. TFA, CH2Cl2 O EtO2C O EtO2C + 5 O 2. K2CO3, EtOH 4 CH3 CH 3 H 203 OH CH3 204 205 (11%) (41%)
R1 EtO C O 6 CO2Et OBn 2 R2 O + 2 4 O CH3 OH 200 201 R1=Me, R2=H (6%) 202 R =H, R =Me (4%) (4%) 1 2
Scheme 3.5: Cyclization results of the enol ethers 199 and 203.35
44 The mechanism proposed for the formation of compounds 201, 202 and 205 is shown in Scheme 3.6. Protonation of enol ethers 199 and 203 presumably affords oxocarbenium ions 206a and 206b, respectively. Sigmatropic rearrangement of 206a and 206b results in the formation of oxocarbenium ions 207a and 207b. Isomerization of 207 by addition-elimination of nucleophiles in the reaction mixture affords oxocarbenium ion 209 with a Z-geometry of the oxocarbenium ion. Cyclization with participation of the oxygen of the benzyl group as a nucleophile, followed by elimination of benzyl carbocation affords structures 201 and 202. Cyclization of 207 via a competing 5-endo cyclization affords secondary carbocations 208a and 208b. Cyclization of 208b, via participation of the benzyl group, affords structure 205. The selectivity for isomer 205 in the reaction of 203, as opposed to 201 in the reaction of 199, was explained by an unfavorable steric interaction that would appear in a 5-endo cyclization of 207a (endo methyl group). The formation of structures 201 and 202 was not surprising since similar results were previously observed in the reaction of enol ether 189c.35
R1 R1 R1 OBn OBn EtO C 6 2 O 6 OBn EtO2C O 6 [3,3] EtO2C O R2 R2 R 4 2 4 4 206 207 208
a R1=Me, R2=H b R1=H, R2=Me
R1 R1 H 6 H EtO2C O EtO2C O 6 R EtO C O 2 2 R O 2 35 2 3 4 H CH3 O OBn 201 R1=Me, R2=H (50%) 205 202 R1=H, R2=Me (16%) 209
Scheme 3.6: Proposed mechanism for the formation of structures 201, 202 and 205.35
45
CO2Et CO2Et O 1. TFA, CH2Cl2 O O EtO2C + 5 2. K2CO3, EtOH 4 4 CH3 CH3 CH3 210 OH OH (anti:syn, 20:1) 211 (45-46%) 212 55:45
OH OH CO2Et CO2Et OH O O + + CO2Et 4 4 CH3 CH3 OH OH 213 214 215 (5-11%) (10-11%) (9%) Z:E = 3:1 2 isomers
OH CO2Et CO2Et O 1. TFA, CH2Cl2 O O EtO2C + 5 2. K2CO3, EtOH 4 4 CH3 CH3 CH3 216 OH OH (syn:anti, 20:1) 217 218 (47-50%) (8-13%) + impurities + 10% impurities
OH
CO2Et
213 (5-11%) Z:E =10-7:1
Scheme 3.7: Cyclization of vinylogous carbonates 210 and 216.35
46 The formation of 205 was a surprise! To avoid the formation of these by- products, the C6 side chain was changed to a vinyl group. Vinylogous carbonates 210 and 216 were prepared and treated with trifluoroacetic acid. After hydrolysis, many products were observed as shown in Scheme 3.7. Most notable was the erosion of stereochemistry at C5 relative to C6 in the cyclization of 210. Enol ether 216 cyclized without suffering such stereochemical erosion.35
Me Me Me 6 6 O EtO2C O 5 EtO2C O 5 EtO2C 4 4 221 219 220
Me Me H Me O 6 O 5 EtO2C O 6 5 EtO2C OH 4 4 EtO2C 222 210 211
6 5 EtO C O EtO C O 6 2 5 Me 2 Me OH 4 4 223 212
Scheme 3.8. Proposed mechanism for formation of tetrahydropyrans 211 and 212.35
47 The formation of tetrahydropyrans 211 and 212 in an almost 1:1 ratio was explained by a series of isomerizations of the presumed oxocarbenium ion 219 (derived from protonation of 210) as shown in Scheme 3.8. Tetrahydropyran 211 was proposed to come from the cyclization of oxocarbenium ion 220 in the normal manner. The stereochemical erosion at C5 was explained by invoking a 3,3-sigmatropic rearrangement of 219 via a boat conformation,29 which led to a trans geometry in the resulting double bond and an equatorial position of the methyl group in the more stable chair conformation 223 (219 → 221 → 222 → 223). Cyclization of 223 led to tetrahydropyran 212 with “inverted” C5 stereochemistry.
Vinylogous carbonates 199 and 210 gave severe stereochemical erosion at C5 in the Prins cyclization. To determine whether this stereochemistry problem was due to the anti relationship between C5 and C6, or effects unique to the C6 benzyloxymethyl (199) and vinyl (210) substituents, enol ethers 224 and 231 were prepared. The cyclization of 224 (the anti-isomer) once again proceeded with erosion of C5-C6 on the stereochemistry. The 6:1 ratio of the product (tetrahydropyrans 225 and 226) did not reflect the initial 19:1 anti:syn ratio of the starting enol ether as shown in Scheme 3.9. In addition many minor products were observed.
The cyclization of enol ether 231 (the syn-isomer) afforded tetrahydropyrans 225 and 226 in a 1:11 ratio. Although this result does not represent any erosion in C5-C6 stereochemistry, some stereochemical scrambling was observed in the sigmatropic rearrangement-hydrolysis product, alkene 213. As with 224, many minor products were also observed in the cyclization of enol ether 229 (Scheme 3.10).
48
CO Et CO Et 1. TFA, 2 2 CO2Et OMe O Me O Me O Me EtO2C CH2Cl2 5 + + 4 4 4 Me 2. K2CO3, Me Me Me EtOH OH OH OH 224 225 (72-76%) 226 227 (anti:syn, 19:1) 6:1 (trace)
EtO2C EtO2C CO2Et O Me O Me O Me + + 4 (4%) Me Me Me HO HO OH
228a 228b 229 (major) (minor) (minor)
(diastereoisomers)
EtO2C O Me OH
+ CO2Et Me HO
230 213 (major) (4%) E:Z = 1:6
Scheme 3.9: Prins cyclization of enol ether 224.35
49 CO Et 1. TFA, 2 CO2Et CO2Et OMe O Me O Me O Me EtO2C CH2Cl2 5 + + 4 4 4 Me 2. K2CO3, Me Me Me EtOH 231 OH OH OH (syn:anti, 10:1) 225 (76-78%) 226 227 1:10-11 (1%)
EtO2C EtO2C CO2Et EtO2C O Me O Me O Me O Me + + + 4 Me Me Me Me (4-5%) HO HO OH HO
228a 228b 229 232 (major) (minor) (major) (minor)
(diastereoisomers)
OH 213 + CO2Et (4-5%) E:Z = 5:1
Scheme 3.10: Prins cyclization of enol ether 231.35
The studies presented above led to the conclusion that vinylogous carbonates of type 233 and 235 undergo Prins cyclization with a high degree of stereoselectivity (Figure 3.4). On the other hand, vinylogous carbonates of type 234, with a syn relationship between substituents at C5 and C6, provide tetrahydropyrans with considerably erosion of stereochemistry across C5 and C6. The degree to which stereochemistry is lost is a function of the C6 substituent, but loss of stereochemistry was observed in all cases examined (199, 210, 224). These results suggested that application of the Prins cyclization to the synthesis of the A and B rings of lasonolide A might be problematic. Our plans for these substructures required cyclizations that gave access to tetrahydropyrans of type 237 (vide infra). Nonetheless, it was felt that variations of the Prins cyclization that had not yet been examined might still provide access to lasonolide
50 A substructures. Evaluation of these variations, which constitute the studies I conducted for this thesis, will be presented in the next chapter.
OR6 OR6 6 OR6 6 EtO2C EtO2C EtO2C
5 R5 5 R5 233 234 235
EtO2C EtO2C EtO2C
OR6 OR6 OR6
5 R5 R5 OH OH OH
236 237 238
Good Poor Good Stereoselectivity Stereoselectivity Stereoselectivity at C5
Figure 3.4: Stereochemical outcome for enol ethers of type 233-235.35
51 CHAPTER 4
STUDIES TOWARD THE SYNTHESIS OF THE A AND B RINGS OF LASONOLIDE A
This chapter will present an extensive discussion of my research work toward the synthesis of the A and B rings of lasonolide A (58). As mentioned before, our goal was to develop the Fráter-Nussbaumer variation of the Prins cyclization for this purpose. The studies of Bennett developed this methodology to a degree. However, achievement of cyclizations that gave the required all cis 2,3,4,6-tetrasubstituted tetrahydropyran in a very efficient manner still remained as a goal. As we will show, my goal was not just to use this methodology efficiently to construct two tetrahydropyran rings, but to use the same intermediates in the synthesis of both the A and B rings. The execution of this plan led us to focus first on the synthesis of the B ring.
4.1 Alkynes as the π-Component in the Prins Cyclization
Our initial studies were directed toward the use of alkynes as the π-component for the Prins cyclization, with a vinylogous carbonate the source of the oxocarbenium ion. The studies by Bennett utilized olefins as the π-component. However, alkynes were not tested in this variation of the reaction. It was proposed that this functionality could be very useful in constructing the substitution pattern required for the two tetrahydropyran
52 rings of lasonolide A, in other words, a cis relationship between the substituents at C7, C19 and C11 (lasonolide A numbering system) and a trans relationship of the C9- hydroxyl group with respect to the other groups. This substitution pattern sets the methyl and the hydroxyl groups in axial positions in the most stable chair conformation. The retrosynthetic analysis that illustrates this proposed pathway for the synthesis of the B ring is shown in Scheme 4.1. It was hoped that cyclization of enol ethers of type 239 would afford the trifluoracetate 240, which upon hydrolysis would afford ketone 241. Formation of the thermodynamically more stable triflate 242, followed by Pd-mediated reduction, would provide alkene 243. Hydroboration-oxidation of 243 would complete a synthesis of B ring tetrahydropyran 244. A shorter variation of this plan would involve direct conversion of 239 to vinyl triflate 242 using triflic acid. As the reader might notice, until now we have use the IUPAC numeration for the substituents of the tetrahydropyran rings. However from now on we will use the numeration assigned to the rings of lasonolide A to directly correlate our work with the target.
CO2Et CO2Et OR O R O R EtO2C
H3C OCOCF3 O 239 240 241
CO Et CO2Et 2 CO2Et 11 O 7 R O R O R
10 9
OH OTf B Ring 243 242 244
Scheme 4.1: Proposed pathway to the B-ring from alkyne derived enol ethers.
53 We first decided to study a model system that lacked of the C10-methyl group and had a methyl group at C7. The commercially available alcohol 245 was reacted with ethyl propiolate (246) in presence of triethylamine to afford the corresponding vinylogous carbonate 247 in 74% yield (Scheme 4.2).
O HO CH3 Et3N OCH3 EtO2C OEt + Et2O, rt H (74%) H 245 246 247
Scheme 4.2: Synthesis of terminal alkyne derived vinylogous carbonate 247.
Vinylogous carbonate 247 was treated with trifluoroacetic acid, followed by ethanolysis to afford a complex mixture of products. Only esters 248 and 249 were identified as products (Scheme 4.3).
OCH3 o OO OO EtO2C 1. TFA, 0 C + OEt OEt 2. K2CO3, EtOH, rt 249 H 248 247 and other materials
Scheme 4.3: Prins cyclization of terminal alkyne derived vinylogous carbonate 240.
The formation of these two esters was explained by the mechanism shown in Scheme 4.4. The Prins cyclization may have proceeded as expected to afford ketone 250, but instability of this product under the reaction conditions allowed for the formation of the two esters (248 and 249). We propose that conversion of 250 to the observed
54 products started with protonation to afford intermediate 251, followed by retroaldol to give oxocarbenium ion 252. Hydrolysis of the oxocarbenium ion 252 afforded alcohol 253, which dehydrated in both ways in the strongly acidic conditions of the reaction to give the α,β-unsaturated ketone 248 and α,β-unsaturated ester 249.
CO Et CO Et OCH3 2 2 EtO2C O O TFA H (Prins Rxn) H O O H 247 250 251
OO
OEt CO2Et CO2Et 248 Dehydration OH O -CH3CHO + OO O OEt OH 249 253 252
Scheme 4.4: Proposed mechanism for the formation of 248 and 249.
Even with the finding that pyrones of type 250 might be quite sensitive to the reaction conditions, we decided to modify the model system and add the methyl group at C10, which is present in the B-ring of lasonolide A. This would also allow us to study the difference in reactivity between terminal and internal alkynes in this variation of the Prins cyclization. The required vinylogous carbonate 257 was prepared as shown in Scheme 4.5. Alcohol 245 was protected as the tetrahydropyranyl ether 255 in 61%
55 yield.36 Alkylation of the protected alcohol 255 was accomplished by deprotonation of 255 with n-BuLi and then addition of methyl iodide to afford alcohol 256 after hydrolysis of the THP protecting group.37 Derivatization of alcohol 256 with ethyl propiolate gave vinylogous carbonate 257 in good yield.
HO CH3 O PTSA, CH2Cl2 THPO CH3 + 0 oC rt H (61%) 245 254H 255
1. n-BuLi 2. MeI 3. MeOH, HCl (73%)
O
OEt OCH3 HO CH3 EtO2C Et3N, Et2O
rt, 43 h H C H C 3 (86%) 3 257 256
Scheme 4.5: Synthesis of internal alkyne derived vinylogous carbonate 257.
Cyclization of internal alkyne 257 using a solution of trifluoroacetic acid in dichloromethane also gave a complex mixture of products. Only, tetrahydrofuran 258 was isolated from the mixture in 13% yield (Scheme 4.6). It is possible that ketone 258 comes from the competitive 5-endo cyclization,29d followed by hydrolysis and tautomerization of the resulting enol. The relative 2,5-cis-stereochemistry was established via NOE studies. The stereochemistry at C3 was not elucidated even though this ketone appeared to be a single isomer by NMR spectroscopy.
56 OCH EtO C EtO C 3 2 2 1. TFA, CH2Cl2 2 O 5
3 2. K2CO3, EtOH H C O 3 (13%) 257 258
Scheme 4.6: Prins cyclization results of terminal alkyne 257.
In summary, the Prins cyclization of alkyne derived vinylogous carbonates did not proceed as hoped. The reaction conditions appear to be harsh for survival of the product in the case of the terminal alkyne derived enol ether 247. The reaction of the internal alkyne derived vinylogous carbonate 257, a substrate that is more relevant in the construction of the tetrahydropyran rings of lasonolide A, was not any better than the previous substrate. The isolation of ketone 258 only gave indications of a competing pathway for this reaction. Due to these unfavorable results we decided to return our studies to the use of alkenes as the π-component of the reaction.
4.2 Prins Cyclization with Alkenes as the π-Component of the Reaction
Our approach next returned to the use of olefins as the π-component in the Prins cyclization. The studies of Bennett (Chapter 3) had shown that substrates of type 259 provide tetrahydropyrans of type 261, but only with considerably erosion of the stereochemistry across C5 and C6 (Figure 4.1). This loss of stereochemistry was presumably caused by a number of events including intervening 3,3-sigmatropic rearragements via boat conformations. It was noticed that substrates of type 262 might also provide tetrahydropyrans, such as 264, with substitution patterns amenable to the synthesis of the lasonolide A and B ring. This approach provides different C2 and C6 substituents (than the Bennett system), and also has “planning consequences” when one considers issues of absolute stereochemistry, but appeared to be an attractive variation to
57 evaluate. The general strategy for applying this conjecture to the tetrahydropyrans of lasonolide A is shown in Scheme 4.7.
EtO C stereochemical 2 2 6 OR6 R6 erosion OR6 EtO2C O 4 EtO2C 5 OH 259 260 261
EtO2C OR2 EtO2C R2 6 OR2 2 O ? 4 EtO2C 5 OH 262 263 264
Figure 4.1: Prins cyclization of vinylogous carbonates of type 259 and 262.
Vinylogous carbonates of the type of 266, with a cis-geometry at the double bond, would be prepared from the corresponding cis-alcohol 265. Treatment of enol ether 266 with trifluoroacetic acid was to afford the all cis-tetrahydropyran 267 with three of the four stereogenic centers set with the appropriate relative stereochemistry (C7, C10, C11). Inversion of the C9 alcohol was then expected to afford the B-ring (269). The main difference between the A and B rings of lasonolide A is the presence of a quaternary center. Part of our plan was to further modify the B-ring (269) via a C-H insertion reaction to obtain lactone 268, which could then be degradated to afford the A ring. Even though in an asymmetric synthesis we would need the enantiomer of the B ring to obtain the needed absolute stereochemistry of the A ring, it was felt that it would be an advantage to use the same sequence of intermediates for the preparation of both tetrahydropyran rings.
58 CO2Et HO R EtO OR 11OR 7 HCCCO2Et Prins Cyclization 8 O 9 OH 10 10 265 266 267
Inversion
CO2Et CO2Et CO2Et 23 OR19 Degradation OR C-H Insertion OR 22 9 HO 21 OH O OH A-Ring O B - Ring 269 268 238
Scheme 4.7: General approach to the A and B rings of lasonolide A.
Our plan required a cis-geometry in the olefin that plays the role of the π- component in the cyclization. The mechanistic rationale that supports this statement is shown in Scheme 4.8. In the most stable chair-like conformation of vinylogous carbonate 266, the groups at C7 and C11 occupy an equatorial position and the C10 methyl group an axial position. Isomerization of the oxocarbenium ion 270 via 3,3- sigmatropic rearrangement should preserve the axial orientation of the methyl group, as much as the cyclization itself, to finally provide us with the all cis-tetrahydropyran 267.
59 R R R O 7 TFA O [3,3] O
11 10 CO2Et CO2Et CO2Et
cis-isomer 270 271 266
CO2Et 11 OR7 R R O Nu O Nu 10 CO Et CO2Et OH 2 267 273 272
Scheme 4.8: Mechanistic rationale for the stereochemistry expected from cis-vinylogous carbonate 266.
R R R O 7 TFA O [3,3] O 1110 CO Et CO2Et CO2Et 2 trans-isomer 275 276 274
CO2Et OR R R 10 O O 9 Nu Nu OH CO2Et CO2Et 279 278 277
Scheme 4.9: Mechanistic rationale for the stereochemistry expected from trans-vinylogous carbonate 274.
60 The opposite should be true for the trans-isomer 274 as shown in Scheme 4.9. In this case, the methyl group should occupy an equatorial position in the chair like conformation. Preservation of the methyl group as an equatorial substituent should now be reflected in the stereochemistry at C10 of epimeric tetrahydropyran 279. Tetrahydropyran 279 has only two stereogenic centers (C7 and C11) with the stereochemistry required by lasonolide A. This analysis leads to the conclusion that cis vinylogous carbonate 266 is best suited to set the stereogenic centers in lasonolide A and should be the most useful substrate for our studies.
O
HO CH3 THPO CH3 THPO CH3 PTSA, CH2Cl2 1. n-BuLi
0 oC rt 2. MeI (100%) H (75%) H H3C 245 255 280
1. H2, Pd/BaSO4 quinoline 2. MeOH, HCl (55%)
HO CH3 OCH3 O EtO2C Et3N OEt + Et2O, rt
(73%) CH3 CH3
Z/E = 5:1 246 Z/E = 5:1 282 281
Scheme 4.10: Synthesis of cis-4-hexen-2-ol derived enol ether 282.
61 Once again we decided to simplify our system and use a model system having a methyl group at the C7 position. Preparation of the required cis-vinylogous carbonate 282 proceeded as shown in Scheme 4.10. 4-Pentyn-2-ol (245) was protected as the tetrahydropyranyl ether, using dihydropyran and p-toluenesulfonic acid as a catalyst, to afford alkyne 255 in 75% yield. Alkylation of the protected alcohol 255 with methyl iodide as the alkylating agent gave the homologated alkyne 280 in quantitatively.37 Hydrogenation of alkyne 280 using a modified Lindlar’s catalyst, followed by deprotection of the resulting cis alkene, gave alcohol 281 with a Z/E ratio of 5:1, in 55% yield over the two steps. Even though it was clear that this geometry ratio needed to be improved, the isomeric mixture of 281 was used in the next reaction to prepare vinylogous carbonate 282 in 73% yield with preservation of the olefin geometry ratio.
Vinylogous carbonate 282 was then submitted to the standard cyclization conditions to afford a mixture of tetrahydropyrans 283 and 284 in a 5:1 ratio and 59% yield (Scheme 4.11).
CO2Et CO Et OCH7 3 2 EtO2C o 7 1. TFA, CH2Cl2, 0 C O O 7 + 2. K CO , EtOH, rt 2 3 10 10 CH3 (59%) OH OH 282 2835:1 284 Z/E = 5:1
Scheme 4.11: Prins cyclization of Z-4-hexen-2-ol derived vinylogous carbonate 282.
The cyclization of this mixture proceeded with apparent stereocontrol at C10 as a 5:1 mixture of tetrahydropyrans 283 and 284 was obtained. The relative stereochemistry of the major isomer in the mixture (283) was established via NOE studies. For example irradiation of H7 gave a 1.68% and 0.88% enhancement at H11 and H9, respectively. Also, irradiation of H7 did not show enhancement at the C10 methyl group. Irradiation
62 of other key signals, such as H7 and the methyl group at C10, confirmed the proposed stereochemistry for isomer 283 as shown in Table 4.1. The multiplicity of H9 also supported the stereochemical assignment. For example, this proton appeared as a doublet of triplets (J = 11.7, 4.8, 4.8 Hz) suggesting a gauche relationship between H9 and H10.
CH3 CO2Et O H10 HO CH3
H11 H9 H7 283
Key signals Enhancement (%)
H11 1.38 (H9), 2.05 (H7)
H10 1.39 (H11), 1.58 (H9), 0.97 (C10-CH3)
H9 1.38 (H11), 1.01 (H7)
H7 1.68 (H11), 0.87 (H9), 1.33 (C7-CH3)
C10-CH3 no significant enhancements
at H11, H9 or H7
Table 4.1: NOE results for the all cis tetrahydropyran 283.
Figure 4.2: NMR signals of H9 for tetrahydropyrans 283 and 284.
63 Tetrahydropyran 283 was believed to come from the Z-isomer of the mixture of alkenes 282, and tetrahydropyran 284 presumably came from the E-isomer as initially proposed in Schemes 4.8 and 4.9. This stereochemical outcome reinforced the proposed plan of placing the required methyl group at the C3 position to control the stereochemical erosion previously observed when it was at the C5 position. To further support these arguments, the E-isomer (enol ether 286) was prepared with clean double bond geometry as shown in Scheme 4.12. Therefore, alkyne 280 was submitted to Birch reduction conditions to afford 4-hexen-2-ol (285) as a single stereoisomer.38 Derivatization of 285 in the usual manner gave the cyclization substrate 286.
O
OEt THPO CH 3 1. Na, NH , THF HO CH3 OCH3 3 Et3N, Et2O EtO2C 2. MeOH, HCl H3C rt, 43 h H3C H C (20%) (59%) 3 280 285 286
Scheme 4.12: Synthesis of E-4-hexen-2-ol derived enol ether 286.
Cyclization of vinylogous carbonate 286 using trifluoroacetic acid, followed by ethanolysis, afforded tetrahydropyran 284 in 69% yield (Scheme 4.13). The relative stereochemistry was once again established via NOE studies (Table 4.2) and the multiplicity of key signals in the 1H-NMR spectra. For example, irradiation of H2 and H6 confirmed the 2,6-cis relative stereochemistry. Irradiation of the methyl group at C10 helped establish the proposed anti relationship between this methyl group and the hydroxyl group at C9. The lack of enhancement at H10 when H7 and H11 were irradiated was also consistent with the assigned stereochemistry. In terms of multiplicity, H9 appeared as a triplet of doublets (J = 10.4, 10.4, 4.7 Hz) at 2.97 ppm, an indication that this proton was anti to H10.
64
CO2Et o O OCH3 1. TFA, CH2Cl2, 0 C EtO2C 10 9 2. K2CO3, EtOH, rt H3C (69%) OH 286 284
Scheme 4.13: Prins cyclization of E-4-hexen-2-ol derived enol ether 286.
H10 CO2Et O H3C HO CH3
H11 H9 H7 284
Key signals Enhancement (%)
H11 1.70 (H7), 1.32 (H9), 0.98 (CH3)
H9 1.33 (H11), 0.89 (H7), 1.02 (CH3)
H7 1.26 (H11), 0.70 (H9), 1.02 (CH3)
C10-CH3 1.38 (H11), 1.58 (H9)
Table 4.2: NOE results for tetrahydropyran 284.
The cyclization of enol ether 286 proceeded with apparent complete stereocontrol at C10 since tetrahydropyran 283 was not observed (the C10 epimer). Also, comparison of the NMR data from this experiment with spectra of the mixture obtained from enol ether 282, allowed us to confirm the presence of 284 as the minor isomer in the cyclization of 282.
65 In summary, the Prins cyclization of vinylogous carbonates of the type of 282 and 286 was successful from the point of generating clean stereochemistry at C10 (Schemes 4.11 and 4.13). From the point of view of the synthesis of the A and B ring of lasonolide A, the desired all cis tetrahydropyran was obtained in good yield and with excellent diastereoselectivity. This result suggested that if vinylogous carbonates of type 266 could be prepare with good Z-selectivity, this could translate in good selectivity in the cyclization reaction. Improvement of the E:Z selectivity was definitely one of the issues to solve, but we decided to first focus on the inversion of the stereochemistry of the C9 position.
4.3 Studies Toward Inversion of the C9 Stereogenic Center.
The A and B rings of lasonolide A require a trans relationship between the C9 hydroxyl and the C10 methyl groups. To establish this relationship, inversion of the C9 stereogenic center was required. The plan was to use the Mitsunobu reaction for the inversion of the previously prepared mixture of secondary alcohols 283 and 284.11 The hope for success in this reaction was high, because Bennett had already shown that alcohol 190a reacted smoothly under Mitsunobu conditions to provide inverted p- nitrobenzoate 287.
CO2H CO2Et CO2Et OCH OCH 6 13 O2N 6 13
9 9 Ph3P, DEAD OH PhH OPNBz (90%) 190a 287
Scheme 4.14: Results of the Mitsunobu reaction of tetrahydropyran 190a.
66 In the event, the 5:1 mixture of 283 and 284 was reacted with p-nitrobenzoic acid, triphenylphosphine and diethyl azodicarboxylate as shown in entry “a” of Table 4.3. The reaction afforded a 1:1 mixture of the inversion products, tetrahydropyrans 288a and 289a, in 31% yield. However, the major product was alkene 290 which came from elimination across the C9-C10 bond. The formation of alkene 290 was a disappointment! It was decided to try other reaction conditions with the purpose of decreasing the yield of the elimination product 290. Therefore, the tetrahydropyran mixture of 283 and 284 was submitted to the same reaction conditions, but benzoic acid was used as the source of the nucleophile. Unfortunately, the distribution of products was about the same as before (entry “b”, Table 4.3).
CO2H
CO2Et CO2Et CO2Et CO2Et CO2Et O O R O O O
10 + 10 + + 9 9 Ph3P, DEAD PhH OH OH OAr OAr 283 284 288 289 290 (5:1)
Entry R Ratio % Yield % Yield 288:289 288 + 289 290
a NO2 50:50 31 43 b H 43:57 30 46
Table 4.3: Results of the Mitsunobu reaction of the mixture of alcohols 283 and 284.
Our explanation for the observed results in the Mitsunobu reaction is shown in Scheme 4.15. Tetrahydropyran 289 was obtained in about 16% yield based on the observed NMR ratio. The fact that tetrahydropyran 284 (the minor alcohol) was also present to the extent of about 16% in the starting mixture led us to conclude that
67 inversion at C9 in this isomer proceeded quantitatively. We also concluded that the elimination product 290 came mostly from the all cis tetrahydropyran 283 (the major alcohol).
CO2H CO2Et CO2Et CO2Et O O O O2N + Ph3P, DEAD OH PhH OPNBz 283 288 290 (26% inversion) (74% elimination)
CO2H CO Et CO Et 2 2 O O O N 2 (quantitative)
Ph3P, DEAD OPNBz OH PhH 284 289
Scheme 4.15: Explanation of the results of the Mitsunobu reaction of alcohols 283 and 284.
The difference between tetrahydropyrans 283 and 284 is the configuration at C10. In the most stable chair conformation of 283, the C11 methyl group occupies an axial position, and in tetrahydropyran 284 the C11 methyl group occupies an equatorial position (Figure 4.3). The C10 hydroxyl group occupies an equatorial position in both 283 and 284. Thus, neither isomer is truly set to undergo a facile elimination reaction.
The stereoelectronic requirements for an SN2 reaction (backside attack) also suggested that neither alcohol (283 and 284) is really set to undergo a facile substitution reaction. We suggested that all reactions of 283 and 284 take place via a boat like or twist boat like conformation (Figure 4.4). Whereas neither boat conformation looks particularly good for a displacement reaction, only 283 is disposed such that elimination to give a C9-C10
68 double bond is possible. Thus 283 give both elimination and substitution where as 284, by default, gives only the substitution product. It is notable that both 283 and 284 (Figure 4.3) have a C8 proton anti to the hydroxyl group. Therefore one might have expected to see elimination to give a C8-C9 double bond in both cases, but this was not observed. This also might have been expected in Bennett’s sample (Scheme 4.14), with tetrahydropyran 199a, but once again it was not observed. Thus the formation of a trisubstituted olefin (283→290) must accelerate elimination relative to reactions that would afford disubstituted olefins (284, 283 and 199a eliminating toward C8).
CH3 H10 CO2Et CO2Et O O H10 H3C HO CH3 HO CH3
11H 11H H9 H7 H9 H7 283 284
Figure 4.3: Chair conformations of tetrahydropyrans 283 and 284.
OH OH OH H 9 H 9 H O O O 9 H3C H H3C H C H H 8 8 6 13 8
H CH3 H H H H H 10 10 10 H H H H H
H CH3 H EtO2C EtO2C EtO2C 283 (boat) 284 (boat) 199a (boat)
Figure 4.4: Boat-like conformations of 283 and 284.
69 Before finishing our studies using Mitsunobu conditions as the tool to invert the C9 stereogenic center, the tetrahydropyran mixture 283 and 284 was treated with trichloroacetic acid (Scheme 4.16).39 Since the conjugate base of trichloroacetic acid is weak relative to benzoate or p-nitrobenzoate, it was hoped to reduce the presence of potential bases in the reaction system and reduce the elimination pathway. However, acylation of tetrahydropyrans 283 and 284 was observed, along with reduction of one C- Cl bond, to afford tetrahydropyrans 291 and 292 in 5:1 ratio and only 32% yield. Although formation of the elimination product 290 was reduced (7%), the inversion products were not observed.
CO Et CO Et CO2Et 2 CO2Et 2 CO2Et O O O Cl3CCO2H O O
+ Ph3P, DEAD + +
PhH OH OH O CHCl2 O CHCl2 283 284 O O (5:1) 291 292 290 (5:1, 32%) (7%)
Scheme 4.16: Mitsunobu reaction of tetrahydropyrans 283 and 284 using trichloroacetic acid.
At this point it was clear that inversion of the C9 stereogenic center was not going to be accomplished via a Mitsunobu reaction. We also examined other inversion procedures but these also failed (vide infra). Thus, we decided to next examine the possibility of inversion of alcohol 283 via oxidation, followed by selective reduction of ketone 293 to afford the desired alcohol 294 as shown in Figure 4.5. This plan requires equatorial delivery of the hydride to obtain alcohol 294 with the trans relationship between the C9 hydroxyl group and the C10 methyl group required by both the A and B rings of lasonolide A.
70
O O O Oxidation Reduction OH 10 10 10 9 9 O CO2Et CO2Et CO2Et OH 283 293 294
Figure 4.5: Oxidation-reduction pathway to inversion of the C9 stereogenic center in alcohol 283.
Swern oxidation of the 5:1 mixture of tetrahydropyrans 283 and 284 gave ketone 293 as expected.40 However, ketone 293 turned out to be unstable and epimerized at C10 during the purification. To avoid epimerization, crude ketone 293 was used immediately use in the next reaction without any purification. The reduction was done using L- selectride as the reducing agent since it is known to have a preference for equatorial delivery of hydride.41 For example, reduction of t-butylcyclohexanone (295) affords alcohol 297 with 96.5% selectivity towards the equatorial delivery of the hydride (Scheme 4.17).42
t-Bu t-Bu L-selectride O 295 297 OH (96.5%) R H t-Bu B R
O R 296
Scheme 4.17: Reduction of t-butylcyclohexanone with L-selectride.42
71 The oxidation of the 5:1 mixture of tetrahydropyrans 283 and 284, followed by the immediate reduction of the resuling ketones 293 and 299 (vide infra), afforded tetrahydropyrans 283, 294 and 298 in a ratio of 68:9:23, respectively (Scheme 4.18). Surprisingly the major product was alcohol 283, which represents no inversion at the C9 stereogenic center.
CO2Et CO Et CO2Et CO Et CO2Et 2 1. COCl2, DMSO 2 O O O 11 O 11 O Et3N, CH2Cl2 10 + 10 + 10+ 10 9 9 2. L-selectride, THF 9 8 9 8 OH OH (64%) OH OH OH 283 284 283 294 298 (5:1) (68:9:23)
Scheme 4.18: Oxidation-reduction of tetrahydropyrans 283 and 284.
Structure elucidation of the mixture was performed by NMR spectroscopy of the individually synthesized isomers and multiplicity of the new isomers. Alcohol 283 was unmistakeable as it served as the major starting material for the reaction sequence. The absence of alcohol 284 was also easily confirmed via comparison of the NMR spectra with those of previously prepared samples. The other two possible isomers were alcohols 294 and 298. One tetrahydropyran showed a ddd at 4.37 ppm with coupling constants of 8.4, 5.7 (with the adjacent methylene) and 2.4 (with H10). This is consistent with alcohol 294, and inconsistent with alcohol 298, which is expected to have a big coupling constant corresponding to a trans relationship between H10 and H11. This argument was used to assign structures 294 and 298. We note that the axial orientation of the C9 hydroxyl group in both 294 and 298 was assigned by the absence of the usual pattern (a 1:3:3:1 quartet with J = 12 due to the presence of three big couplings - two 1,3-diaxial and one geminal) of the C8 axial hydrogen when this hydroxyl group is equatorial. This analysis led us to conclude that the minor isomer in the mixture was tetrahydropyran 294 and the other one must be tetrahydropyran 298.
72 CO2Et O equatorial O hydride delivered EtO2C disfavored 294 O OH OH 9 EtO2C 10 O axial O CO Et 293 OH 2 hydride delivered EtO2C O favored 283 (89:11) OH
CO2Et O equatorial O hydride delivered EtO2C quantitative OH O 298 OH 9 EtO2C 10 O axial O CO2Et OH 299 hydride delivered EtO2C O not observed 284 OH
Scheme 4.19: Mechanistic rationale for reduction of ketones 293 and 299.
The next concern related to this reaction was to explain the correlation between the product distribution and the starting mixture of tetrahydropyrans 283 and 284. The proposed mechanistic rationale for this result is shown in Scheme 4.19. Oxidation of tetrahydropyrans 283 and 284 afforded ketones 293 and 399, respectively. Reduction of ketone 293 via equatorial hydride delivery would afford the desired tetrahydropyran 294, while the axial delivery would afford the starting tetrahydropyran 283. The ratio of tetrahydropyrans 283 and 294 demonstrated that the predicted equatorial delivery of the hydride was disfavored. In the case of the minor ketone 299, the absence of tetrahydropyran 284 demonstrates that the hydride was delivered equatorial as usually observed in cyclohexanone reductions with L-selectride. Comparison of the results from
73 each ketone led us to conclude that the axially disposed methyl group at C10 in ketone 293 hinders equatorial delivery of the hydride.
Unfortunately, inversion of the C9 stereogenic center was more difficult than expected. It was evident that setting the trans diaxial relationship required between the C9 hydroxyl and the C10 methyl group present in the A and B rings of lasonolide A was going to be a challenge. The presence of an axially disposed methyl group at C10 caused problems in both plans. In the Mitsunobu reaction, the elimination pathway was favored. In the case of the oxidation-reduction plan, even when the problem of epimerization of ketone 293 was overcome, the methyl group hindered the desired selectivity in the reaction.
4.4 Studies Toward a Substituent Other than Methyl at the C10 Position
The difficulties confronted in our studies toward the inversion of the C9 stereogenic center in tetrahydropyran 283, led us to think about the evaluation of other groups at this position. This idea led to a modification of the originally proposed route for the synthesis of the A and B rings of lasonolide A as shown in Scheme 4.20. The modified approach would utilize groups that could be further modified into the methyl group. For example, Prins cyclization of a vinylogous carbonate of type 300 would be expected to afford the all cis tetrahydropyran 301. Elimination across the C10-C36 bond would afford the allylic alcohol 302. Inversion of the secondary alcohol 302 via Mitsunobu reaction should now give tetrahydropyran 303, since the steric effects of the axially disposed group at C10 would be eliminated. Directed hydrogenation of alkene 303 should then afford the B ring (238) which could be elaborated into the A ring as previously proposed in Scheme 4.7.
74 CO2Et CO2Et EtO OR7 OR OR Prins Elimination O 10 10 Cyclization 9 36 10 X OH OH 300 X 301 302
Inversion
CO2Et CO2Et CO2Et OR7 OR OR Directed 10 9 Hydrogenation 9 HO OH OH OH
269 238 303 A-Ring B-Ring
Scheme 4.20: General approach to the A and B rings of lasonolide A (58) from vinylogous carbonates of type 283.
Our initial studies in this area were directed to the use of a benzyloxymethyl group at the C10 position. In order to study one variation at a time, the system was simplified to a methyl group at the C7 position as before. The synthesis of the required vinylogous carbonate (310) was achieved as presented in Scheme 4.21. Propargyl alcohol (304) was protected using benzyl bromide following the literature procedure to afford the benzyl ether 305 in 85% yield.43 Deprotonation of the terminal alkyne 305,
followed by addition of BF3·Et2O and opening of propene oxide (306), by SN2 displacement at the less hindered side, afford secondary alcohol 307 in 44% yield.44 Protection of alcohol 307 as a tetrahydropyranyl ether 308 was accomplished using standard reaction conditions. Hydroboration of the protected alcohol 308 using in situ generated cyclohexylborane, followed by protonolysis with acetic acid90 and deprotection via acetal exchange afforded the cis alcohol 309 as a single stereoisomer in 48% yield over the three steps. This sequence provided an improvement in selectivity for the Z-
75 isomer compared with the previous hydrogenation using a modification of the Lindlar’s catalyst (280→281). Vinylogous carbonate 310 was prepared by reaction of alcohol 309 with ethyl propiolate in presence of triethylamine in 84% yield.
NaOH, H2O OH nBu4NBr, BnBr 1. nBuLi, THF H H BnO OH o OBn . o toluene, 50 C 2. BF3 OEt2, -78 C 304 305 307 (85%) O (44%) 306 O
. pTSA H2O
CH2Cl2, rt (79%)
O
o OEt 1. Cy2BH, THF, 0 C OCH3 EtO C o 2 Et N OH 2. CH CO H, 110 C 3 3 2 OTHP BnO Et O, rt 3. pTSA.H O, OBn 2 2 (84%) BnO CH3OH, rt 310 309 308 (48%)
Scheme 4.21: Synthesis of Z-6-benzyloxy-4-hexen-2-ol derived vinylogous carbonate 310.
Reaction of the vinylogous carbonate 310 with 10 equivalent of trifluoroacetic acid in dichloromethane, followed by hydrolysis using potassium carbonate in ethanol, afforded a complex mixture of materials (Scheme 4.22).
76 OCH EtO C 3 2 1. TFA, CH2Cl2 complex mixture 2. K2CO3, EtOH, rt 310 OBn
Scheme 4.19: Prins cyclization of of Z-6-benzyloxy-4-hexen-2-ol derived vinylogous carbonate 310.
The failure of the cyclization of the vinylogous carbonate 310 was attributed to electronic effects. It was proposed that the presence of a benzyloxy group at C36, an electron withdrawing group, might destabilize the oxocarbenium ion (311) that results from the protonation of 310 (Figure 4.6). Therefore, we decided to use a less electron withdrawing group at the C36 position, a phenylselenyl substituent.
OBn H OBn H C 36 H3C 36 3 O O EtO C 10 EtO2C 10 2 310 311
Figure 4.6: Oxocarbenium ion from vinylogous carbonate 310.
The synthesis of the cyclization substrate 316 was initially pursued as shown in Scheme 4.23. Phenyl propargyl selenide (313) was prepared from propargyl chloride (312) in 84% yield using Bieber’s conditions.45 Deprotonation of alkyne 313, followed 44 by addition of BF3·OEt2 and epoxide 306 gave the secondary alcohol 314 in 48% yield. Reduction of the triple bond via hydrogenation was unsuccessful under a variety of conditions. The starting alkyne 314 was always recovered. The lack of reactivity of alkyne 314 was apparently due to poisoning of the Pd catalyst by the selenium.
77 Hydrogenation using diimide was also problematic due to overreduction. It was clear that a different approach to vinylogous carbonate 316 was necessary.
1. Ph2Se2 1. nBuLi, THF OH PhSe Cl PhSe . o Zn, K2HPO4, H2O 2. BF3 OEt2, -78 C 312 313 314 2. HCl O (48%) (84%) 306
O
OEt OH OCH3 H , Pd/BaSO EtO2C 2 4 Et3N
pyridine Et2O, rt PhSe SePh
315 316
Scheme 4.23: Initial approach to the synthesis of vinylogous carbonate 316.
To overcome the problem of poisoning of the catalyst during the hydrogenation, a substrate without the selenium was required. However, the substrate needed to have an appropiate functional group for introduction of the phenylselenyl substiutent at C36. Having this in mind, a new synthesis for the vinylogous carbonate 316 was developed as shown in Scheme 4.23. Propargyl alcohol (317a) was protected as the tetrahydropyranyl ether in 92% yield using standard conditions.46 Deprotonation of alkyne 318, followed by the now usual opening of epoxide 306a gave secondary alcohol 319a in 45% yield.47 Hydrogenation of alkyne 319 was successful using a modified of the Lindlar’s catalyst in 92% yield. The Z/E ratio was about 14:1. This large improvement in the Z-selectivity was achieved by conducting the reaction at one atmosphere, as it was established that a higher pressure, such as that used with 280, led to a much lower Z/E ratio. After accomplishing the reduction of the triple bond, the next goal was to elaborate the
78 tetrahydropyranyl ether into the phenylselenyl substituent required at C36. Protection of the secondary alcohol with an acetyl group, followed by deprotection of the primary alcohol via acetal exchange, afforded alcohol 321a in 66% yield over two steps.48 The primary alcohol was converted into a good leaving group using mesyl chloride. Displacement of the mesylate with phenylselenide afforded allylic selenide 321b in 76% yield.49 The acetyl group was efficiently removed via ethanolysis to afford the desired alcohol 315.50 Derivatization of alcohol 315 in the usual manner gave vinylogous carbonate 316a in 78% yield.
O 1. nBuLi, THF OH . o THPO HO PTSA, CH2Cl2 THPO 2. BF3 OEt2, -78 C H H 317a 0 oC rt 318 O 319a (92%) (45%) 306a
1. Ac O, CH Cl OH 2 2 2 OAc 1. MsCl, Et3N H2, Pd/BaSO4 Et3N, 4-DMAP CH2Cl2, rt pyridine 2. pTsOH.H O 2. Ph Se , NaBH THPO 2 2 2 4 1 atm HO o 320a MeOH, rt 321a EtOH, 0 C (92%) (66%) (76%)
O
OEt OAc OH OCH3 K CO EtO2C 2 3 Et3N
MeOH, rt Et2O, rt PhSe PhSe SePh 321b (93%) 315 (78%) 316a 36
Scheme 4.24: Synthesis of Z-6-phenelselenenyl-4-hexen-2-ol derived vinylogous carbonate 316a.
79 Unfortunately, the cyclization reaction of enol ether 316a under the standard conditions gave a complex mixture of materials (Scheme 4.25), and the intent to cyclize this substrate in a clean manner was abandoned. The synthesis of the vinylogous carbonate 316a was probably too long, involving a lot of protecting and deprotecting steps, and also, the initial cyclization results were not promising.
OCH EtO C 3 2 1. TFA, CH2Cl2 complex mixture 2. K2CO3, EtOH, rt 316a SePh 36
Scheme 4.25: Prins cyclization of Z-6-phenylselenenyl-4-hexen-2-ol derived vinylogous carbonate 316a.
In summary, the presence of a benzyloxy or phenylselenenyl group at C36 was not tolerated by the Prins cyclization conditions. Regardless of whether the lack of success was due to stereoelectronic effects or not, we decided to return to the use of a methyl group at this position. It was evident that this approach was going to require a large survey of substrates to be able to understand the effects of substituents other than a methyl at this position. Given that we were interested in proceeding toward lasonolide A, no other substituents were examined.
4.5 Studies Toward Elaboration of the C7 Side Chain of the A and B rings
The results in the previous section led us to reconsider the initial plan presented in Scheme 4.7, and maintain a methyl group at the C10 position. We also decided to replace the C7 methyl group (model systems) with actual side chains that could be used to elaborate the A and B rings of lasonolide A.
80 Vinylogous carbonate 316b was chosen as the next cyclization substrate. This compound would provide 2-carbon and 1-carbon 2,6-substituents in the expected tetrahydropyran, suitable for elaboration of the C11 and C23 side chains of the A ring, and after some manipulations, the C7 and C11 side chains of the B ring of lasonolide A.
1. nBuLi, THF OH H3CH OBn 2. BF .OEt , -78 oC 317b 3 2 319b O OBn 306b
(89%) H2, Pd/BaSO4 quinoline 1 atm (73%)
O OBn OEt O OH EtO2C Et3N OBn
Et2O, rt (75%) 316b 320b (Z/E = 10:1) (Z/E = 10:1)
Scheme 4.26: Synthesis of Z-1-benzyloxy-4-hexen-2-ol derived vinylogous carbonate 316b.
Preparation of the cyclization substrate 316b is shown in Scheme 4.26.
Deprotonation of propyne (317b) using n-BuLi, followed by addition of BF3·OEt2 and
SN2 displacement at the least hindered side of the commercially available epoxide 306b, afforded secondary alcohol 319b in 89% yield. Hydrogenation under the already established conditions gave alkene 320b with a Z/E selectivity of 10:1. Derivatization of
81 alcohol 320b using ethyl propiolate in presence of triethylamine gave the cyclization substrate 316b in 75% yield with preservation of the double bond geometry as a 10:1 mixture of Z and E isomers, respectively.
OBn CO2Et OBn O O CO2Et EtO2C 1. TFA, CH2Cl2 O + 2. K2CO3, EtOH O 316b OH 322 323 (34%) (34%)
HO H OBn O O OBn + O H
320b 324 (15%) (4.5%)
Scheme 4.27: Products isolated from the Prins cyclization of vinylogous carbonate 316b.
Reaction of vinylogous carbonate 316b with 10 equivalents of trifluoroacetic acid, followed by ethanolysis, afforded four products (Scheme 4.27). The two major products, formed in equal ratio, were the expected all cis tetrahydropyran 322 and bicyclic ether 322, which has a 2,6 trans relationship. The other two products were alcohol 320b and lactone 324 isolated in 15% and 4.5% yields, respectively. The isolation of alcohol 320b was explained by hydrolysis of the starting enol ether 316b. The isolation of the other three products was explained via the mechanistic rationale presented in Scheme 4.28. We imagine that protonation of enol ether 316b gave oxocarbenium ion 325, which can rearrange to oxocarbenium ion 326. Cyclization from either of the two oxocarbenium ions (325 and 326) affords carbocation 327. Trapping of
82 carbocation 327 with trifluoroacetate, followed by hydrolysis affords tetrahydropyran 322. If C9 of the olefin behaves as a nucleophile instead of C10, the 5-membered carbocation 328 would be obtained. Participation of the ester as a nucleophile and loss of the ethyl group would afford lactone 324. Isomerization of the oxocarbenium ion 326 by addition-elimination of nucleophiles present in the reaction mixture, would give oxocarbenium ion 329. Cyclization of oxocarbenium ion 329, followed by participation of the oxygen of the benzyloxy group and loss of benzyl carbocation, would afford bicyclic ether 323.
OBn OBn OBn
O 7 TFA O 7 [3,3] O 7 10 EtO C EtO C 10 EtO C 10 2 9 2 9 2 9 316b 325 326
isomerization
O OBn EtO O EtO C O 2 O O EtO2C BnO 327 328 329 Ph
-CH2CH3 -CH2Ph
CO2Et OBn O H O O O OBn EtO2C O OH H O 322 324 323
Scheme 4.25: Proposed mechanism for the formation of products 322-324.35
83 The isolation of bicyclic ether 323 and the lactone 324 was not a surprise. Bennett’s studies with vinylogous carbonate 189c (Table 3.1) with a benzyloxymethyl group at the C7, gave the same type of product resulting from neighboring group participation (Figure 3.2). The cyclization leading to tetrahydrofuran 324 is also a known phenomenon in Prins cyclizations.28-29
The distribution of products obtained in the cyclization of 316b made it unuseful for the synthesis of the tetrahydropyran rings of lasonolide A. Instead it was felt that the formation of bicyclic ether 323 had to be reduced. We knew from Bennett’s work that changing to another protecting or using a vinyl group was probably not the solution to the problem. Therefore, we decided to homologate the C7 side chain and use a benzyloxyl ethyl group at this position instead of a benzyloxymethyl substituent. Homologating the side chain would require a more elaborate pathway to set the aldehyde oxidation state required in the A ring at C18. However, the use of a substrate such as 330 for the construction of the A and B rings of lasonolide A was still very attractive (Figure 4.7).
OBn CO2Et 6 or 18 O 18 O 6 7 O
OH HO OH OH 330 A-ring B-ring
Figure 4.7: Comparison of tetrahydropyran 330 with the A and B rings of lasonolide A.
84 The synthesis of the required cyclization substrate 336, in racemic form, was accomplished following the same sequence of reactions used previously to prepare enol ether 316b (Scheme 4.29). The necessary epoxide 333 was prepared following the literature procedure of Lygo.52 Thus 3-butenol (331) was protected as the benzyl ether in good yield. The resulting alkene 332 was epoxidized using m-chloroperoxybenzoic acid in presence of sodium bicarbonate to afford epoxide 333 in 57% yield. Opening of 333 with the anion derived from propyne, followed by hydrogenation of the resulting alkyne 334 at one atmosphere, gave cis alcohol 335. Derivatization of 335 in the usual manner afforded vinylogous carbonate 336 in 65% yield.
1. NaH, THF MCPBA O OH OBn OBn 2. BnBr NaHCO3
331(78%) 332 CH2Cl2 333 (57%)
H3C Li . BF3 OEt2 (86%)
O OBn OBn OBn OEt O HO HO EtO2C Et N 3 H2, Pd/BaSO4
Et2O, rt pyridine, 1 atm (65%) (90-97%) 336 335 334
Scheme 4.29: Synthesis of 1-benzyloxy-5-hepten-3-ol derived vinylogous carbonate 336.
85 Cyclization of vinylogous carbonate 336 under standard conditions afforded the all cis tetrahydropyran 337, contaminated with very small amounts of what we suspect is the C10 epimer, in 70% yield (Scheme 4.30). The success of this cyclization provided us with a potential substrate, tetrahydropyran 337, for the synthesis of the A and B rings of lasonolide A (58)! The relative stereochemistry was established by NOE studies. The same enhancements previously observed for the all cis tetrahydropyran 283 was observed once again (Table 4.4). The multiplicity of the H9 was also the same as for tetrahydropyran 283, in other words, a doublet of triplets (J = 11.6, 4.6, 4.6 Hz) at 3.96 ppm indicating the gauche relationship between H9 and H10.
OBn OBn CO2Et O O 7 EtO2C 1. TFA, CH2Cl2 10 9 2. K2CO3, EtOH (70%) OH 336 337
Scheme 4.30: Prins cyclization of vinylogous carbonate 336.
86 CH3 CO2Et O H10 HO OBn
H11 H9 H7 336
Key signals Enhancement (%)
H11 1.27 (H9), 2.91 (H10)
H10 1.39 (H11), 1.58 (H9), 0.97 (C10-CH3)
H9 1.82 (H11), 2.53 (H7)
C10-CH3 no significant enhancements
at H11, H9 or H7
Table 4.4: NOE results for tetrahydropyran 336.
Tetrahydropyran 336 only requires inversion of the C9 stereogenic center to become the B ring substructure of lasonolide A, and elaboration of the C11 and C7 side chains for preparation of the macrolide. Our next studies were directed toward establishing the correct relative stereochemistry at C9 in this substrate.
4.6 Studies Toward Correction of the C9 Relative Stereochemistry in Tetrahydropyran 321.
In section 4.3 of this chapter, we presented a study of the Mitsunobu reaction in an attempt to invert the C9 stereogenic center in a model system. Although the results were disappointing, we decided to try this reaction in the actual system (tetrahydropyran 337). Tetrahydropyran 337 was reacted with p-nitrobenzoic acid in presence of diethyl
87 azodicarboxylate and triphenylphosphine to afford the inversion product 338 in 12% yield (Scheme 4.31).53 It was no surprise to find that the major product of the reaction was the elimination product 339 obtained in 61% yield. The elimination/inversion ratio observed for this system was actually worse than in the model system (tetrahydropyran 283). Our explanation for this result would be the same as the one previously given in the discussion of the model system (Figure 4.4).
OBn OBn OBn CO2Et CO2Et CO2Et O p-NO2BzOH O O + DEAD, PPh3 9 THF OH O Ar (12%) (61%) 337 338 O 339
Scheme 4.31: Results for the Mitsunobu reaction of tetrahydropyran 336.
Although the inversion of the C9 stereogenic center via the Mitsunobu reaction did not work efficiently, we decided that the resulting alkene 339 might still be a potential intermediate in the synthesis of the A and B rings of lasonolide A (58). Therefore, our approach to the synthesis of the two tetrahydropyran rings was revised as shown in Scheme 4.32. In other words, it was anticipated that hydroboration-oxidation of alkene 339 from the less hindered side would afford tetrahydropyran 340 (B ring). The reader should note that this strategy actually represents a return to the plan introduced in the section on alkyne-oxocarbenium ions cyclization (Scheme 4.1).
88 OBn OBn OBn CO2Et HO EtO O O HC CCO2Et Prins O Cyclization
OH 335 336 337
Elimination
OBn OBn OBn CO Et CO Et CO2Et 2 2 ? O O ? O
HO OH OH 339 A-ring B-ring 341 340
Scheme 4.32: Revised pathway to the A and B rings using the Mitsunobu elimination product (339) as a potential intermediate.
We initially hoped that the hydroboration of alkene 339 could be accomplished using 9-BBN as the reagent. The reason to use this reagent was to increase steric hindrence between the reagent and the substituents at C7 and C11 and favor hydroboration from the opposite side. Unfortunately, no reaction was observed using 9- BBN.54 The reaction using borane-tetrahydrofuran complex (a less hindered reagent) resulted in a complex mixture of materials (Scheme 4.33).54, 87
89 1. 9-BBN, THF no reaction
2. TAO·2H2O OBn CO2Et 11O 7
1. BH3·THF 339 complex mixture 2. TAO·2H2O
Scheme 4.33: Attempted hydroboration of olefin 339.
The unexpected result from both reactions led us to reconsider the substrate. It was thought that the ester functionality at C11 was probably one of the reasons why the reaction with borane was complex. Alkene 339 was modified to a possible intermediate for elaboration of the C11 side chain as shown in Scheme 4.30. Alkene 339 was treated with phenyl magnesium bromide in tetrahydrofuran to afford the tertiary alcohol 342 as a crystalline solid in 81% yield.55
Ph OBn OBn CO2Et Ph OH PhMgBr 11 O O THF (81%) 339 342
Scheme 4.34: A derivative of alkene 339.
Hydroboration of alkene 342 proceeded in an unexpected manner (Scheme 4.35).54 The predicted tetrahydropyran 343 (B ring) was the minor product of the reaction! The undesired isomer, tetrahydropyran 344, was the major product of the reaction. The relative stereochemistry of both isomers was established by NOE studies.
90 Each isomer was isolated and characterized. Tetrahydropyran 343 showed the trans axial relationship required between the methyl group at C10 and the hydroxyl group at C9 (Table 4.5). Irradiation of H9 showed a 4.09% enhancement to the C10 methyl group and no enhancement of H11 or H7. The trans axial relationship between these two groups was confirmed by the multiplicity of H9 in the 1H-NMR spectra. H9 appeared as a doublet of a doublet of doublets with three small coupling constants (J = 3.0, 3.0, 3.0 Hz) that showed the gauche relationship between this proton and both H8 and H10 (Figure 4.8). The 2,6-cis relationship was demonstrated by irradiation of H7 and H11. Tetrahydropyran 344, the major product, showed the typical NOE pattern that we have previously discussed for tetrahydropyrans with a trans diequatorial relationship between the C10 methyl group and the C9 hydroxyl group, as well as typical multiplicity pattern of H9 (Table 4.5).
Ph Ph Ph OH OBn Ph OH OBn Ph OH OBn Ph O 1. BH3·THF O O + 2. H2O2, NaOH
342 OH OH (19%) (48%) 343 344
Scheme 4.35: Hydroboration-oxidation of alkene 342.
91 Ph Ph CH H 3 OH 10 OH O O H10 H3C H9 OBn HO OBn H Ph Ph 11 H11 HO H7 H9 H7 343 344
Key signals Enhancements for 343 (%) Enhancements for 344 (%)
H11 5.13 (H7), 4.32 (H10) 4.26 (H7), 0.98 (H9), 2.05 (CH3)
H9 2.93 (CH3) 2.19 (H7), 1.45 (H11), 2.39 (CH3)
H7 5.00 (H11) 1.51 (H9), 3.87 (H11)
C10-CH3 4.09 (H9) 3.19 (H9), 2.55 (H11)
Table 4.5: NOE results for tetrahydropyrans 343 (B-ring) and 344.
H11 H9 H7
3.95 3.90 3.85 3.80 3.75 3.70 3.65 3.63.600
Figure 4.8: Multiplicity observed for H9 in tetrahydropyran 343.
92
O 11 9 8 Ph2(HO)C 10 OBn H 7 342 H Bottom Face Top Face Addition HBH2 Addition
HBH O 2
Ph2(HO)C OBn O H Ph (HO)C H 2 OBn H HBH2 H
OBn Ph (HO)C OBn Ph2(HO)C 2 H H3C O H O H
BH2 H3C H H H HH H H H2B H 345a 345b
C(OH)Ph C(OH)Ph2 H 2 CH3 O H O H3C H OBn HO OBn H H OH H H H 343 344
Scheme 4.36: Rationale for the selectivity in the hydroboration of alkene 342.
93 Although the synthesis of the B-ring tetrahydropyran 343 was accomplished, it was not in an efficient manner. The hydroboration-oxidation of alkene 342 was not controlled by the proposed steric effects. Our explanation of his result is presented in Scheme 4.36. The hydroboration of alkene 342 can occur from either the top or bottom face of the most stable half chair conformation of 342. If the hydroboration occurs from the “bottom” face (opposite the C7 and C11 substituents) a torsional strain is developed in the transition state between the C10 methyl group and the methylene in the C11 side chain. Also, the product of the “bottom” face hydroboration (345a) may be born in a higher energy boat conformation due to the eclipsed interaction between C10 methyl group and C11 substituents. On the other hand, if the hydroboration occurs from the top face of the alkene, then this torsional strain is not observed and the hydroboration product (345b) is born in a more stable chair conformation. This mechanistic rationale may explain why hydroboration from the top face of alkene 342 is more favorable. As a consequence, the undesired tetrahydropyran 344 was the major product of the reaction.
The results observed in the hydroboration-oxidation of alkene 342 were not very promising. However, we decided to study other reactions that might provide useful substrates, such as dihydroxylation and epoxidation of both olefins (339 and 342). Epoxides of the type of 346 could potentially be converted to allylic alcohols of type 348 via a syn elimination (Figure 4.10).89 Diols of type of 347 could be converted to the same alcohol via dehydration. In fact, we had already proposed to prepare of this type of allylic alcohol (348) when we studied the effect of substituents other than methyl at the C10 position (Scheme 4.20, Section 4.4). These reactions represented another opportunity to evaluate the preparation of the B ring via directed hydrogenation of alcohols of type 348. Also, it was of interest to see if the same type of selectivity observed in the hydroboration-oxidation of alkene 342 would remain, or if that problem could be overcome.
94 OBn R O Syn Elimination
O OBn OBn 346 R R O O Hydrogenation
OH OH OBn R 348 B-Ring O Dehydration 349
HO OH 347
Figure 4.9: Revised pathway to the B-ring via epoxidation or dihydroxylation of olefins 339 and 342.
The epoxidation route was most attractive. Therefore, we started this modified approach by reacting olefins 339 and 342 with m-chloroperoxybenzoic acid in dichloromethane (Table 4.6).52 The reaction of olefin 339 gave epoxide 351a in 42% yield. The complexity of the reaction mixture did not let us isolate the desired isomer 350a. The isolation of epoxide 351a showed that addition to the double bond was, once again, favored from the “top” face of the olefin, as in the hydroboration experiment. Epoxidation of alkene 339 was consistent in the face selectivity as the undesired epoxide 351b was isolated in 61% yield. The desired isomer 350a was isolated in only 13% yield and its characterization was difficult due to its instability. This product distribution is probably due to the same phenomena presented for the hydroboration experiment (Scheme 4.36).
95 OBn OBn OBn R R R O MCPBA O O + CH2Cl2 O O 350 351
Entry Olefin (R) 350 Yield (%) 351 Yield (%)
a 339 (CO2Et) --- 42
b 342 (C(OH)Ph2) 13 61
Table 4.6: Results of epoxidation of olefins 339 and 342.
The results obtained in the hydroboration-oxidation and epoxidation reactions suggested that addition from the “top” face of both olefins was the favored reaction pathway. This led us to consider the preparation of the required epoxide via hydrobromination, followed by SN2 displacement. The plan was that formation of bromonium ion 338 should take from the “top” face, followed by nucleophilic attack of water at the more electrophilic C10 by the “bottom” face (Figure 4.10). This sequence of events would give bromohydrin 354, which now would give the desired epoxide 350 upon treatment with base. In the event, olefin 339 was treated with N-bromosuccinimide, sulfuric acid and water to afford a mixture of bromohydrins in 57% yield and lactone 356 in 28% yield. The mixture of bromohydrins was then treated with potassium carbonate in ethanol to give epoxide 351a and 350a in a 3:1 ratio, favoring the isomer with the undesired relative stereochemistry as shown in Scheme 4.37.56
96
OBn O CO2Et 11 R O 7 OBn H H Br 352 353
H2O
OBn OBn CO2Et CO2Et O O
O HO Br 350 354
Figure 4.10: Synthesis of epoxides 350 via hydrobromination-substitution.
97 OBn OBn OBn CO2Et CO2Et 11O 7 NBS O O + O H SO , H O 2 4 2 O acetone X 339 Y Br 355a X=OH, Y=Br 356 355b X=Br, Y=OH (28%) (57%)
K2CO3 EtOH -EtOH
OBn OBn OBn CO Et CO2Et CO2Et 2 O O O + HO O O Br 350a 351a 357 1:3 (91%)
Scheme 4.37: Synthesis of epoxide 335a via hydrobromination-substitution.
The formation of 351a was not expected. Also, whether 351a came from bromohydrin 355a and/or bromohydrin 355b was not determined. However to be able to explain the formation of 351a, we refer to the Furst-Plattner rule.57 In other words, if opening of the two possible bromonium ions 358 and 359 occurred to develop an anti relationship between the nucleophile and the bromide, which also results in a diaxial relationship, then formation of bromohydrins 360 and 343 should be favor and not 355a and 355b. In the other hand, formation of 360 is disfavored from the standpoint of electronic effects (C10 should have more positive charge than C9). Therefore, if bromohydrin 343 is the precursor of 351a, then the stereochemistry of bromonium ion formation parallels that of epoxide formation. Formation of 350a as the minor product would then be explained by bromohydrin 360 as the minor product (Figure 4.11).
98 δ Br CO2Et O Br H C CO2Et 3 OBn O H H C 3 OBn H H O 358 2 δ
OBn CO2Et Br O CO2Et H3C O H OBn O OH 350a 360
δ H2O CH3 CO Et CO2Et 2 O H3C O H OBn H OBn
Br Br δ 359
OBn CO2Et OH O CO2Et H3C O H OBn O Br 351a 343
Figure 4.11: Mechanistic rationale for formation of epoxide 350a and 351a.57
99 Lactone 356 could come from bromohydrin 343 or by neighboring group participation of the ester in bromonium ion 359 derived from “bottom” face attack of bromine as in Figure 4.12.
Et O OBn CH3 O CO2Et O O H3C O O H OBn H OBn O Br Br Br 359 361 356
Figure 4.12: Formation of lactone 356 via neighboring group participation.
Given the inconsistency of the previous results, we decided to start study dihydroxylation of olefins 339 and 342. The dihydroxylation of alkene 339 was done using standard conditions (Scheme 4.38).91 Thus, alkene 339 was reacted with osmium tetroxide and trimethylamine oxide to afford diol 362 in 48% yield and lactone 363 in 10% yield. Isolation of diol 362 as the major product was unexpected based on the selectivity observed in previous reactions (hydroboration, epoxidation). The relative stereochemistry of diol 362 was established by NOESY studies (Table 4.7). Irradiation at H11 showed a 23.5% enhancement at H7, which demonstrated the 2,6-cis relationship in the tetrahydropyran. The trans diaxial relationship between the C10 methyl group and the C9 hydroxyl group was established by irradiation of the methyl group and H9, since mutual enhancement was observed. A lack of enhancement at the C10 methyl group when H11 and H7 were irradiated indicated that the methyl group was cis to the substituents at C11 and C7. Up to this moment we can not offer an explanation regarding why the addition to the double bond is preferred from the “bottom” face in this dihydroxylation. Lactone 363 must come from diol 364, which comes from dihydroxylation on the “top” face of the double bond.
100 OBn OBn OBn OBn CO2Et CO Et CO Et 2 H 2 O OsO4, Me3NO O O O + O H2O-Acetone O t-BuOH HO OH HO 339 OH OH 362 363 364 (48%) (10%)
Scheme 4.38: Dihydroxylation of olefin 339.
CH3 CO2Et
HO O H9 OBn
11H HO H7 362
Key signals Enhancement (%)
H11 23.46 (H7)
H9 8.86 (C10-CH3)
H7 12.74 (H11)
C10-CH3 11.05 (H9)
Table 4.7: NOESY results for diol 362.
101 The dihydroxylation of olefin 342 was accomplished using two different conditions as shown in Table 4.8.58,91 The selectivity in both reactions, however, was the same. Triols 365 and 366 were obtained in a 1:1 ratio, indicating that there was no facial selectivity in this syn addition to the double bond.
Ph Ph Ph OH OBn Ph OH OBn Ph OH OBn Ph O O O +
HO HO OH OH 342 365 366
Conditions 365 Yield (%) 366 Yield (%)
OsO4, Me3NO 30 28 H2O-acetone-t-BuOH OsO4, NMO 36 37 H2O-acetone
Table 4.8: Product distribution for the dihydroxylation of olefin 342.
In general, we can say that it is difficult to predict the face selectivity in any addition reaction to the two olefins (339 and 342). The hydroboration-oxidation experiment seems to point out a torsional strain problem between the C10 methyl group and the C11 substituent. The epoxidation reaction via peroxide addition to the double bond is consistent with this observation, but not via the hydrobromination-elimination pathway. The dihydroxylation of olefin 339 gives better selectivity, relative to what is required by lasonolide A. However, no face selectivity was observed in the dihydroxylation of olefin 342. We can only conclude that setting the C9 stereochemistry in an efficient manner is still an unsolved problem.
102 It was evident that in order to use olefins 339 and 342 as possible intermediates in the synthesis of the A and B rings of lasonolide A, the face selectivity problem in the addition reactions needed to be solved. One proposed solution to this problem was to take advantage of the facial selectivity provided by chiral reagents. Our main interest was in the asymmetric hydroboration and epoxidation of these two olefins (393 and 342), since the products of these reactions were most attractive for use in the synthesis of the A and B rings.
The asymmetric hydroboration of alkene 342 was examined using (-)- monoisopinocampheyl borane (367).59-60 This reagent was chosen based on the reported face selectivity and yield for reactions with methylcyclohexene as shown in Scheme 4.39.61 In other words, our literature search was based on methylcyclohexene (368) as a model system. This model does not take into consideration that the B ring has two side chains at C11 and C7. It was our hope that 367 would react with 342 to afford the desired alcohol 344a and the unwanted alcohol 344b, in reactions whose stereochemistry would be reagent control. Isomer 344a represents an advanced intermediate related to the B ring of lasonolide A. It was our plan that if this hydroboration proceeded with the proposed selectivity, then upon preparation of the enantiomerically pure olefin 342 we would have a good synthesis of the B ring (344a) as shown in Figure 4.13.
OBn BH2 CO2Et O 1. 367 , THF
2. H O , NaOH S S 2 2 OH H3COH B-ring 368 369 (85%, 72% ee)
61 Scheme 4.39: Asymmetric hydroboration of methylcyclohexene with (-)-IpcBH2.
103 Ph Ph Ph OH OBn Ph OH OBn O O
OH 342a BH2 344a 1. 367 , THF + +
2. H2O2, NaOH Ph Ph Ph OH OBn Ph OH OBn O O
OH 342b 344b
Figure 4.13: Proposed selectivity for the asymmetric hydroboration of racemic 342.
Borane 367 was generated from the commercially available TMEDA complex from α-(+)-pinene (R-Alpine boramine), following Brown’s procedure.59-60 The hydroboration-oxidation of racemic alkene 342 using this reagent gave tetrahydropyran 344 in 24%.61 Thus the reaction stereochemistry was dominated by the substrate. The isolation of 344 was another disappointment, since this was the wrong isomer from the point of view of lasonolide A. The complexity of the reaction, its low yield and the wrong selectivity were enough reasons to abandon this study. Alkene 339 was not evaluated because its reaction with borane-tetrahydrofuran complex was also complex, and our expectations for success were low (Scheme 4.33).
104 BH2 Ph Ph OH OBn OH OBn Ph 1. 367 , THF Ph O O 2. H2O2, NaOH (24%) OH 342 344
Scheme 4.40: Asymmetric hydroboration of olefin 342 with (-)-IpcBH2.
The asymmetric epoxidation was studied using the Shi catalyst.62-64 The catalyst was prepared from D-fructose (352) following Shi’s procedure as shown in Scheme 4.41.62 Ketone 372 was chosen as the catalyst, using once again methylcyclohexene (368) as our model system (Scheme 4.42). This catalyst showed one of the highest enantioselectivities reported for alkene 368.64
MeO OMe OH O O O O O o O O OH PCC, 3A MS HO OH Me2CO, HClO4 O OH CH2Cl2 O O OH (46%) O (74%) O 370 371 372
Scheme 4.41: Synthesis of Shi’s catalyst.62
105 372, Ozone
CH3CN-DMM S R . NA2B4O7 10H2O O 368 Na2EDTA, K2CO3 373 (77%, 81%ee)
Scheme 4.42: Asymmetric epoxidation of methylcyclohexene with Shi’s catalyst.64
The asymmetric epoxidation of olefin 342 was first examined under the conditions Shi used for methylcyclohexene (368).64 Our substrate, however, was insoluble under these reaction conditions. Shi had already reported a solution to this problem.65 The epoxidation of olefin 342 was therefore carried using ketone 372 as the catalyst and hydrogen peroxide as the reoxidant under buffered conditions (Scheme 4.43). However, the reaction required a full equivalent of the “catalyst” and gave only a 14% yield of epoxide 351b. The relative stereochemistry of epoxide 351b was established by comparison of the NMR spectra with a previously prepared sample. Even though epoxide 351b show some optical activity, the very low yield and high catalyst loading required to afford product led us to not further study this reaction.
Ph Ph Ph OH OBn Ph OH OBn 372, H O O 2 2 O
CH3CN-EtOH-CH2Cl2 K2CO3-EDTA O 342 (14%) 351b racemic optically active
Scheme 4.43: Asymmetric epoxidation of olefin 342 with Shi’s catalyst.
106 The results observed in the asymmetric hydroboration and epoxidation of olefin 342 were neither useful, nor predictable. Thus, hydroboration and epoxidation were abandoned in our attempts to establish trans diaxial relationship between the C9 hydroxyl group and the C10 methyl group.
Before giving up on solving this problem, we decided to try one more classical approach. The plan was to convert the C9 hydroxyl group into a good leaving group and
invert via SN2 displacement. This approach is equivalent to the Mitsunobu reaction approach, but it allows for more flexibility in the selection of the nucleophile (base). Alcohol 337 was treated with mesyl chloride in presence of triethylamine to afford tetrahydropyran 374 in 79% yield as a single isomer (Scheme 4.44). Purification by flash chromatography allowed for the separation of the very small amount of the C10 epimer that contaminated the starting alcohol 337. Reaction of tetrahydropyran 374 with cesium 66 acetate did not afford the SN2 product (tetrahydropyran 375). The elimination product, alkene 339, was isolated from the complex mixture in low yield. This result was not a surprise, since up to this point we were not clear about the factors controlling substitution versus elimination. For an explanation of the results, we refer the reader to the same arguments that were used to explain the distribution of products in the Mitsunobu reaction.
107 OBn OBn CO2Et CO2Et O O MsCl, Et3N
CH2Cl2 OH (79%) OMs 337 374
CsOAc 4-DMAP toluene (19%)
OBn OBn CO2Et CO2Et O O
OAc 375 339
Scheme 4.44: Attempted inversion of alcohol 337 by displacement of mesylate 374.
In conclusion, the approaches tested to establish the trans diaxial relationship between the C9 hydroxyl group and the C10 methyl group largely met with failure. The problem was more complex than we had thought. The factors possibly controlling the failure of each plan became clear as we proceeded, but they were subtle and obviously not anticipated. Nonetheless, the synthesis of 337 was good enough that we were able to obtain gram quantities of 338. Therefore, at this point of our research, we decided to move on to studies toward the A ring using the current route to 338.
108 4.7 Studies toward C-H Insertion to Construct the C22 Quaternary Center
One of my goals was to elaborate the B ring into the A ring. The plan, as presented in Scheme 4.7, was to use a C-H insertion as the key reaction to construct the C22 quaternary center present in the A ring. Even though at this point of my research we did not have a very efficient synthesis of the B ring it was time to evaluate whether our plan for the construction of the A ring was going to work. Since the synthesis of the all cis tetrahydropyran 337 is quite efficient, I was able to prepare 18 g of this intermediate, which upon inversion via the previously studied Mitsunobu reaction (Scheme 4.31), and deprotection using ethanolysis,67 gave us the B ring (359) as a single isomer (Scheme 4.45).
OBn OBn CO2Et CO2Et O EtOH O
NO2 K2CO3 O (84%) OH
O 338 376 B ring
Scheme 4.45: Deprotection of the inversion product 338 to afford the B ring (376).
The relative stereochemistry of tetrahydropyran 376 was established via NOE studies and the multiplicity of H9 in the 1H-NMR spectra. Irradiation of H11 showed 4.26 and 2.67% enhancements to H7 and H10. This demonstrated the cis relationship between substituents at the C7, C10 and C11 position (Table 4.9). The trans diaxial relationship between the C10 methyl group and the C9 hydroxyl group was shown by irradiation of the C10 methyl group, which showed a 3.0% enhancement at H9. Also, H9 showed a doublet of doublet of doublets at 3.88 ppm with three small coupling constants (J = 2.6, 2.6, 2.6 Hz) due to its gauche relationship with H10 and the two H8 protons. 109 CH3 CO2Et O H10 H9 OBn 8 H11 HO H7 338
Key signals Enhancement (%)
H11 4.26 (H7), 2.67 (H10)
C10-CH3 3.00 (H9)
Table 4.9: NOE results for tetrahydropyran 338 (B ring).
With the B ring in our hands, the next step was to find a reliable catalyst to do the insertion chemistry. Our literature search was based on using trans-2- methylcyclohexanol as a model system. We found that Doyle and coworkers had done an extensive study with this system, both racemic and enantiopure substrate.68 To decide which catalyst we should use, we examined Doyle’s studies with (1R, 2R)-trans-2- methylcyclohexyl diazoacetate (378a), the stereochemistry required for the A ring. The
Doyle group showed that Rh2(4R)-MEOX4 showed a high selectivity towards insertion at C2, 84% relative yield as shown in Scheme 4.46. This result was very important for us because there are at least six possible insertion positions in diazoacetate 378a (C1, C2, C3, C5, C6 and methyl group) as well as in the B ring (C7, C8, C9, C10, C11 and C36) as shown in Figure 4.14. The fact that Doyle observed very high selectivity toward the C2 position, which is also the insertion position required for our purposes, encouraged us to examine this catalyst.68
110 3 5 2 Rh (4R-MEOX) 2 1 6 2 4 Me + 6 Me Me CH Cl O 2 2 O O N2 reflux O 378a O O 379a 380a (84%) (3%)
6 1 Me + Me Me O O OH O O 377a 381a 382a (4%) (9%)
3 5 2 Rh (4R-MEOX) 2 1 6 2 4 Me + 6 Me Me CH Cl O 2 2 O O N2 reflux O 378b O O 379b 380b (2%) (9%)
6 1 Me + Me Me O O OH O O 377b 381b 382b (87%) (2%)
Scheme 4.46: Doyle’s result for C-H insertion in diazoacetate 278a and 278b 68 using Rh2(4R-MEOX)4.
111 OBn CO2Et 11O 7
10 9 8 36 OH
376 B ring
Figure 4.14: Possible insertion positions in the B ring.
Therefore, Rh2(4R-MEOX)4 (383) was the catalyst of choice for our studies. This catalyst (Figure 4.15) was prepared as its acetonitrile complex following Doyle’s procedure (see experimental section).69
O
O MeO2C NO O N CO2Me H3CCN Rh Rh NCCH3 N O MeO2C O N CO2Me O O
383
Figure 4.15: Structure of Doyle’s catalyst Rh2(4R-MEOX)4 as its acetonitrile complex.69
112 Our next task was to prepare the diazoacetate derived from the B ring (alcohol 376). After trying some different conditions, we settled on Corey’s modified conditions of House’s procedure to prepare diazoacetates.70-71 Therefore, tetrahydropyran 376 was reacted with acyl chloride 384 (House’s reagent) in presence of N,N-dimethylaniline (Corey’s modification), and then triethylamine, to afford diazoacetate 385 in 87% yield (Scheme 4.47).
TsNH N OBn Cl OBn CO2Et H CO2Et O 384 O O
PhN(CH3)2
OH Et3N, CH2Cl2 O N2 (87%) 376 O B ring 385
Scheme 4.47: Preparation of diazoacetate 385 from tetrahydropyran 376.
The insertion experiment was then done as shown in Scheme 4.48. Diazoacetate 385 was added to a refluxing solution of Doyle’s catalyst 383 to afford three different products: lactone 386 in 23% yield, β-lactone 387 in 9.4% yield, and ether 388 in 21% yield. The relative stereochemistry of both lactones (386 and 387) was established on the basis of NMR experiments. Lactones 386 and 387 showed optical activity. Based on Doyle’s syudies, we proposed that the absolute configuration of the major enantioner of 386 would be as shown in Scheme 4.48. According to Doyle’s studies, enantiomer 385a should be more reactive than 385b with this catalyst toward insertion at C10 of the B ring. This means that lactone 386 (C10 insertion product) should be derived from enantiomer 385a. We suggest that 386 does not come from enantiomer 385b. Based on Doyle’s results with (1S, 2S)-trans-2-methylcyclohexanol (377b), shown in Scheme 4.45, we would predict that enantiomer 385b might give lactone 389 derived from insertion
113 into the equatorial CH bond at C8 (Figure 4.16). We note that lactone 386 was contaminated with a very small amount of another isomer (appearance of a small doublet at 0.55 ppm), which might be the C8 insertion product. The formation of β-lactone 387a was not a surprise. We knew from Doyle’s studies that this lactone could be formed as a minor product from either 385a or 385b. In fact, β-lactone 387a was observed in only 9.4% yield. Although 387a was optically active, it was not possible to predict the configuration of the major enantiomer and the structure shown in Scheme 4.48 is based on results that will be reported later in this chapter. The last product isolated was a racemic mixture of ether 388.
Let us examine this product distribution in more detail. The desired insertion product, lactone 386, was isolated in only 23%. However, if we consider the fact that we started the reaction with a racemic mixture, and that according to Doyle’s work only one enantiomer should be the source of this product, then in theory only 50% of the starting mixture would provide the desired product. If this is true, then our result was quite promising. If we were to prepare enantiomer 385a via an asymmetric synthesis, lactone 386 should be the major product. The results in Scheme 4.48 also confirmed that construction of the C22 quaternary center of the A ring via C-H insertion was viable to some extent.
114 OBn OBn OBn CO2Et CO2Et CO2Et O O O
10 9 8 10 + 9 O O O N 2 O 385a O O 386 387a major enantiomer major enantiomer (23%) (9.4%) Rh2(4R-MEOX)4 + Optically active CH2Cl2 reflux
OBn OBn OBn CO2Et CO2Et CO2Et O O O
10 98 + O O O N ) O ) O 2 2 388 2 385b O O O Racemic mixture (21%)
Scheme 4.48: Results of C-H insertion of racemic diazoacetate 385
using Rh2(4R-MEOX)4.
OBn CO2Et O
8
O O
389
Figure 4.16: Possible product from insertion at C8.
115 Finally, we note that the fact that lactone 386 showed optical activity was an indication of a possible kinetic resolution. If we could further develop this result, then we could propose an asymmetric synthesis of the A and B rings from a racemic starting material as shown in Scheme 4.49. In other words, with the use of a more selective catalyst, enantiomer 385a would react to give the desire lactone 386, which would be elaborated into the A ring. Recovery of enantioner 385b, followed by hydrolysis, would afford the B ring enantiomerically pure.
OBn OBn CO2Et OBn CO2Et CO Et O 2 O O 22 catalyst 22 Degradation 10 9 8 OH O OH O O N2 385a O 386 ent-341 A ring
+
OBn OBn OBn CO2Et CO2Et CO2Et O O O Hydrolysis recovered 9 10 98 O OH O N2 N 2 385b O 376 385b O B ring
Scheme 4.49: Asymmetric synthesis of the A and B ring via kinetic resolution of diazoacetate 385.
116 Even though the plan shown in Scheme 4.49 was very attractive, we decided to first focus on an asymmetric synthesis of the B ring from an optically active starting material. We hoped to follow the same sequence of steps as previously used for the preparation of the racemic B ring (376 in Schemes 4.29, 4.30 and 4.44). The asymmetric synthesis started with the preparation of chiral epoxide 394 following literature procedures as shown in Scheme 4.50. Reduction of (R)-malic acid (390), using borane dimethylsulfide complex in presence of trimethylborate, followed by methanol addition and distillation afforded triol 391 in 86% yield.72 Protection of the vicinal diol as the acetal to using 3-pentanone and p-toluenesulfonic acid as catalyst gave 391 in 75% yield.73, 88 The primary alcohol was then protected as the benzyl ether, followed by removal of the acetal to give diol 393 in 51% yield over three steps.74 Selective
conversion of the primary alcohol to the tosylate, followed by an intramolecular SN2 displacement, afforded epoxide 394 in only 15% yield.75
O O . HO HO 1. BH3 SMe2 HO OH OH O O O OH B(OMe)3, THF OH PTSA, THF 2. MeOH 390 391 (75%) 392 (86%)
BnO BnO 1. NaH, THF OH 1. TsCl, CH2Cl2 O OH 2. BnBr, nBu4NI pyridine 3. MeOH, HCl 393 2. MeOH, K2CO3 394 (51%) (15%)
Scheme 4.50: Asymmetric synthesis of epoxide 394 from (R)-malic acid.73-75
117 Even though the synthesis of the chiral epoxide 394 was accomplished, the yield of the last step of the sequence was very low. This last reaction was also very poor when it was conducted on large scale. From the selectivity point of view, we needed to exclusively form the primary tosylate. Formation of a tosylate from the secondary alcohol would give us the epoxide with the wrong absolute stereochemistry and, as a consequence, would lead to a decrease in enantiomeric purity in a synthesis of the B ring. Therefore, we decided to consider the use of a cyclic sulfate derivative as an equivalent of the epoxide. The synthesis was modified at the stage of diol 393, and instead of preparing the epoxide we made cyclic sulfate 377 (Scheme 4.51). Reaction of diol 393 with with thionyl chloride, followed by oxidation of the resulting sulfite with ruthenium trichloride monohydrate as catalyst and sodium periodate gave the cyclic sulfate 395 in 81% yield.76 The cyclic sulfate 395 was used in the next reaction without further purification due to instability. Selective opening of sulfate 395 with the anion derived from propyne, followed by hydrolysis with concentrated sulfuric acid, gave chiral alcohol (R)-334 in 52% yield.77 This sequence represented an improvement compared with the preparation of epoxide 394. Also, preparation of cyclic sulfate 395, as well as its opening was well behaved on small or big scale. The rest of the synthesis was done in the same manner as the racemic synthesis, as outlined in Scheme 4.50 without comment.
118
BnO 1. SOCl2, CCl4 BnO 1. H3C Li BnO OH . O . 2. RuCl3 H2O O BF3 OEt2 OH OH S O NaIO4, CH3CN O 2. H2SO4 393 395 (R)-334 H2O (52%) (81%)
OBn O O EtO C OEt 2 H2, Pd/BaSO4 BnO
pyridine, 1 atm OH Et3N, Et2O, rt (100%) (R)-335 (59%) (R)-336
OBn OBn CO Et CO2Et 2 O 1. TFA, CH2Cl2 O p-NO2BzOH
2. K2CO3, EtOH DEAD, PPh3 THF O Ar (60%) OH (14%) 337a 338a O
TsNH N OBn OBn CO Et Cl CO Et 2 H 2 O O EtOH 367 O 10 9 8 K2CO3 PhN(CH3)2 O (84%) OH Et3N, CH2Cl2 N2 376a (85%) 385a O
Scheme 4.51: Asymmetric synthesis of diazoacetate 385a.
119 The synthesis of the enantiomerically pure diazoacetate 385a allowed us to evaluate the key C-H insertion to the C10 position.70-71 Our goal was to obtain the insertion product in higher yield than from the racemic substrate (and in higher enantiomeric purity). Treatment of diazoacetate 385a with Rh2(4R-MEOX)4 under the same reaction conditions as before afforded the same three products: lactone 386 (28%), β-lactone 386 (9%) and ether 388a (24%) as shown in Scheme 4.52. Lactone 386 was isolated as a single isomer in almost the same yield as before, but with higher optical activity. Lactone 386 from the racemic mixture (385a + 385b) had an specific rotation of +23.6 where as lactone 386 from 385a had an specific rotation of +42.0. The optical activity was higher but the meaning of this fact was not completely clear. An interesting result was the fact that β-lactone 387b showed an opposite rotation to that observed in the sample from the racemic mixture. This result led us to the conclusion that β-lactone 387a from the racemic mixture should have the opposite configuration, as shown in Scheme 4.48. The reisolation of ether 388 in almost the same yield as before was a disappointment!
OBn OBn OBn OBn CO Et CO2Et CO2Et CO Et 2 2 O O O O Rh2(4R-MEOX)4 10 + 9 + 10 9 8 CH2Cl2 O O O ) O reflux O O 2 N2 O O O 386 387b 388 385a (28%) (8.9%) (24%) 22 22 [α] = +42 [α] = −15.8 α] 22 = +1.8 D D [ D
Scheme 4.52: Results of the C-H insertion of the enantiomerically pure diazoacetate 385a.
120 These studies with the racemic and enantiopure samples of diazoacetate 385 lead us to make some conclusions. First, the use of a C-H insertion reaction as the key step for the construction of the C22 quaternary center of the A ring is promising. Second, a better understanding of the formation of ether 388 is necessary to be able to inhibit this major competition pathway. Finally, a survey of other catalysts might be necessary to optimize the reaction. Once these problems are solved, then the synthesis of the A ring might be accomplished by degradation of lactone 386.
Until now we have indicated that 385a was enantiomerically pure without presenting any evidence. Indeed we know it is reasonably pure because we evaluated the enantiomeric purity of the all cis tetrahydropyran 337a from the asymmetric Prins cyclization (Scheme 4.51). The method of analysis was the use of Mosher derivatives. The Mosher ester from the racemic mixture 337 was prepared as shown in Scheme 4.53. Racemic tetrahydropyran 337 was reacted with (R)-Mosher acid (396) in presence of dicyclohexyldiimide and 4-dimethylaminopyridine to afford the corresponding esters 397a and 397b in a 1:1 ratio. The presence of both diastereoisomers in a 1:1 ratio was 1 19 1 very clear by both H and F-NMR. The H-NMR (C6D6) showed a doublet for the C10 methyl group at 0.78 ppm for one isomer and at 0.66 ppm for the other isomer. 19F-NMR
(C6D6) signals were observed at –71.30 and –71.37 ppm for the trifluoromethyl groups. The preparation of the racemic Mosher ester allowed us to establish that kinetic resolution was not going to be a problem in the evaluation of the enantiomeric excess of the enantioriched sample. Preparation of the Mosher ester of the enantioriched sample 337a was done following the same procedure used for the racemic material. The 1H- NMR showed a major doublet at 0.78 ppm and a minor doublet at 0.66 ppm in a ratio of 17:1. This result showed an enantiomeric excess of 88% for the all cis tetrahydropyran 337a. The 19F-NMR was consistent with the presence of mostly one enantiomer. This enantioselectivity was more than a good result. It showed that the Prins cyclization could be done in good yield and with good transfer of stereochemistry from the C7 chiral center to the other three stereogenic centers generated in the cyclization reaction.
121 OBn OBn OBn OBn CO2Et CO2Et CO2Et CO2Et DCC O O O O 4-DMAP 10 10 10 + 10 9 + 9 9 9 CH Cl 2 2 Ph CF3 Ph CF3 OH OH 396 O O OCH OCH3 (42%) 3 337a 337b O O racemic mixture 397a (1:1) 397b
OBn OBn CO2Et CO Et DCC 2 O Ph CF O 3 4-DMAP 10 HO 9 + 10 OCH3 9 CH2Cl2 O Ph CF3 OH (74%) O OCH3 337a 396 O 397a (88% ee)
Scheme 4.53: Mosher’s ester of racemic and enantioenriched alcohols 337.
Our progress toward the A and B rings of lasonolide A is summarized below. We have developed a route to the B-ring of lasonolide A (alcohol 376) that proceeds in 12 steps from malic acid. A racemic synthesis from 3-buten-1-ol, that requires 8 steps, has also been developed. Both of these syntheses suffer from one low yield step, the conversion of alcohol to 337 to inverted p-nitrobenzoate 338. We have also developed a 2-step procedure for converting the B-ring (376) into a potential A-ring precursor 386 with the C22 quaternary center intact. Although the key step of this sequence (C-H insertion) proceeds in low yield, only one catalyst has been examined and thus, there is still hope for improvement.
122 It is clear that the B ring C9-C10 stereochemistry problem remains to be solved. Our current plan for addressing that problem, without abandoning the Prins cyclization, will be the topic of the final section of this chapter.
4.8 Preliminary Studies in a New Approach for the Synthesis of the B Ring
The synthesis of the B ring, as shown before, is quite efficient except for the inversion reaction. The inversion of the C9 stereogenic center via traditional methods was clearly not favorable. Due to the efficiency of the Prins cyclization, we were able to prepare large quantities of tetrahydropyran 337 in both racemic and chiral form. However, the need for a better way to establish the trans diaxial relationship between the C9 hydroxyl and the C10 methyl groups remains. Our new plan directed toward the solution of this stereochemical problem is as shown in Scheme 4.54.
OTBS O 7 CHO OTBS + Diels Alder 11 O 10 Me2N O 36 NMe2 398 399 400 401
OAc RR'11 O 7 H Prins 10 O H 36 O H Cyclization OH OH B Ring 404 403 402
Scheme 4.54: New approach towards the synthesis of the B ring.
123 This plan involves a different approach to the generation of the oxocarbenium ion in the Prins cyclization. Our knowledge of the reaction leads us to be confident in this new proposal. The mechanistic rationale follows as shown in Scheme 4.55. Prins cyclization of a substrate such as 402 should occur via a chair conformation of the oxocarbenium ion 406. This conformation places the C10 methyl group in a equatorial position due to the trans geometry of the double bond and the nature of the substrate. Cyclization followed by trapping of the resulting carbocation 407 via an equatorial approach of the nucleophile would set the trans relationship between the C9 hydroxyl and the C10 methyl group in the resulting bicyclic ether 408. Hydrolysis of 408, followed by cleavage of the double bond in 403 would afford the B ring (404) with the required trans stereochemistry at all four stereogenic centers. This result relies on the C7 and C11 substituents being axially disposed in the Prins cyclization. Our plan for the preparation of the cyclization substrate 402 was as shown in Scheme 4.53. The hetero Diels Alder reaction between the β,γ-unsaturated aldehyde 398 and Rawal’s diene 399, following Rawal new methodology, was expected to generate in situ cycloadduct 400.78- 79 Deprotection of the resulting enol ether, followed by elimination, would afford enone 401. Selective 1,2-hydride reduction of enone 401 followed by protection of the alcohol would give the Prins cyclization substrate 403.
124
H OAc OAc
H
O TFA O O
402 405 406
OCOCF3 10 O O O -OCOCF3 7 11
408 407 406
hydrolysis
OH OH 9 11 OH O CH3 10 R' 7 11 7 O O cleavage 11 R 7 10 9 R R' 403 404a 404b
Scheme 4.55: Mechanistic rationale for setting the trans diaxial stereochemistry at C9 and C10 via novel approach.
125 Our progress in the laboratory is summarized in Schemes 4.56 and 4.57. Aldehyde 380 was prepared following a procedure reported by Oppolzer and 80 coworkers. SN2 displacement of trans-1,4-dichlorobutene (409) with the propyne derived Grignard reagent afforded diyne 410 in 42% yield. Dihydroxylation of diyne 410 under standard conditions gave diol 411. Reduction of the triple bonds to trans double bonds was done using lithium aluminium hydride. Cleavage of diol 412 with sodium periodate afforded aldehyde 398 in 41% yield. Aldehyde 398 was very labile and volatile and was used in the next reaction without any purification. The “alcohol-promoted” Diels Alder reaction between aldehyde 398 and Rawal’s diene 399,78 followed by acetylation of the resulting cycloadduct with acetyl chloride and elimination, gave enone 401 in only 38% yield.79
This sequence of reactions presented a series of problems. First, aldehyde 398 easily isomerized to the more favored α,β-unsaturated isomer. The synthesis of this aldehyde was inefficient in almost every step and could not be scaled up in our hands. The lithium aluminium hydride reduction of alcohol 412 in large scale was somewhat dangerous due to the high temperature required for the reaction to proceed. As a consequence of the aldehyde 398 instability, the hetero Diels Alder reaction was never performed with a pure sample.
126 Cl EtMgCl, THF OsO4, NMO Cl H t-BuOH-water 409 410 NaI, CuCl acetone (42%) (48%)
OH OH LiAlH4 NaIO4
diglyme H O-Et O OH OH 2 2 (59%) (41%) 411 412
TBSO O O 1. 2-butanol + H 2. CH3COCl N CH2Cl2 O (38%) 398 399 401
Scheme 4.56: Synthesis of enone 401 via a Hetero Diels Alder reaction.
At this point of my research, we decided to move forward and evaluate the Prins cyclization of enone 401 (Scheme 4.56). Therefore, enone 401 was treated with 10 equivalents of trifluoroacetic acid, the now usual conditions for us. Unfortunately, this enone did not react! The stability of ketone 401 to such strong acidic conditions was definitely a surprise! This unexpected result led us to reduce enone 401 with sodium borohydride and cesium trichloride to afford alcohol 413.81 It was proposed that the allylic alcohol 413 should be a more reactive substrate for the Prins cyclization than 401. Treatment of allylic alcohol 413 with 10 equivalents of trifluoroacetic acid followed by ethanolysis, however, gave a complex mixture of materials.
127 O 1. TFA, CH2Cl2 No reaction!
2. K2CO3, EtOH O 401
NaBH4
CeCl3
EtOH-H2O (53%)
O 1. TFA, CH Cl 2 2 complex mixture 2. K2CO3, EtOH OH 413
Scheme 4.57: Results of the Prins cyclization of enone 401 and alcohol 413.
The stability of ketone 401 toward the Prins cyclization conditions was difficult to explain, but the high reactivity of the allylic alcohol 413 under acidic conditions was expected. One of the possible difficulties that we could anticipate about this substrate is at the stage of the oxocarbenium ion cycliation. Two of the possible resonance structures for oxocarbenium ion 406 are shown in Figure 4.17. Cyclization at C11 would afford the desired product, but cyclization at C5 is also possible. This is just one of the possible problems related to alcohol 413. Therefore, the observed result suggested that milder conditions are required in the cyclization of this substrate (alcohol 413).
128 O O 11 5
406a 406b
Figure 4.17: Isomers of oxocarbenium ion 406.
Due to the inefficient nature of our current synthesis of 401 and 413, my studies ended at this point. Nonetheless, an improved synthesis of 413, and a careful study of its behavior under a variety of Prins cyclization condition, should be worthwhile.
4.9 Conclusions.
The studies presented in this thesis led us to conclude:
1. The Prins cyclization with vinylogous carbonates as the oxocarbenium ion precursor, proved to be efficient for the synthesis of 2,3,4,6-tetrasubstituted tetrahydropyrans when the methyl group resides as the C3 position.
2. The synthesis of a potential intermediate for the B ring of lasonolide A was accomplished in 12 steps for the asymmetric route, and in 8 steps for the racemic route.
3. A potential precursor to the A ring was developed using the B ring as a synthetic intermediate. Therefore, the proposed plan of using the same intermediates for the synthesis of the A and B rings of lasonolide A is very promising.
129 This means that some of my goals were accomplished and others were limited by the development of unexpected problems.
130 CHAPTER 5
EXPERIMENTAL
All melting points were taken with a Thomas-Hoover capillary point apparatus and are uncorrected as are all boiling points. Proton nuclear magnetic resonance spectra were recorded on a Bruker AM-250, Bruker DPX-400 or Bruker AM-500 spectrometers and recorded in parts per million from internal chloroform or dimethyl sulfoxide on the δ scale. The 1H NMR spectra are reported as follows: chemical shift [multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants in hertz, integration, interpretation]. 13C NMR data were obtained with Bruker DPX-400 and Bruker DRX-500 spectrometers. Multiplicities were determined using DEPT experiments. Infrared spectra were taken with Perkin-Elmer 1600 and 2000 instruments. Mass spectra were obtained on Kratos MS-25 at an ionization energy of 70 eV and a 3- Tesla Finnigan FTMS-2000. Compounds for which an exact mass is reported exhibited no significant peaks at m/z greater than that of the parent. Combustion analyses were performed by Atlantic MicroLaboratories, Inc., Norcross, Georgia. Solvents and reagents were dried and purified prior to use as necessary: diethyl ether and tetrahydrofuran were dried over sodium/benzophenone ketyl; triethylamine, acetonitrile, chlorobenzene, 2-butanol and dichloromethane were dried over calcium hydride. Reactions requiring an inert atmosphere were run under argon or nitrogen. Analytical thin-layer chromatography was conducted using EM Laboratories 0.25 mm thick precoated silica gel 60F-254 plates. Column chromatography was performed over EM laboraties, ICN, and Whatman silica gel (70-250 or 230-400 mesh). Organolithium
131 reagents were titrated prior to use with menthol using 1,10-phenanthroline as an indicator.92 Grignard reagents were titrated prior to use by the addition of excess standard HCl, followed by back titration with standard NaOH using 1,10-phenolphthalein as an indicator.93 The order of the selected experimental procedures follow the order of appearance in the text:
132 OCH3 EtO2C
H 247
(±)-3-(1-Methylbut-3-ynyloxy)acrylic acid ethyl ester (247). A 100-mL three-necked round-bottomed flask under argon atmosphere was charged with 1.8 mL (1.75 g, 17.85 mmol) of ethyl propiolate (246), 18 mL of dry diethyl ether and 2.5 mL (1.81 g, 17.85 mmol) of triethylamine. To the resulting yellow mixture was added a solution of 1.00 g (11.9 mmol) of 4-pentyn-2-ol (245) in 14 mL of dry diethyl ether. The brown solution was stirred for 43 h. The mixture was diluted with 100 mL of diethyl ether and washed
with 50 mL of 1M aqueous KHSO4, 50 mL of saturated aqueous NaHCO3 and 50 mL of
brine. The organic phase was separated, dried (Na2SO4) and concentrated in vacuo to afford 2.33 g of a brown oil. The oil was chromatographed over 120 g of silica gel (230– 400 mesh, eluted with 20% diethyl ether/80% hexanes) to give 1.61 g (74%) of the enol ether 247 as a colorless oil: IR (Neat) 3297, 2122, 1708, 1644 cm-1; 1H-NMR (400 MHz,
CDCl3) δ 1.24 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.36 (d, J = 6.2 Hz, 3H, CH3), 2.04 (t, J =
2.7 Hz, 1H, HC≡C), 2.41 (ddd, J = 16.8, 6.7, 2.7 Hz, 1H, CH2C≡C), 2.52 (ddd, J = 16.8,
5.5, 2.7 Hz, 1H, CH2C≡C), 4.13 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.20 (m, 1H, OCH), 5.25 13 (d, J = 17.0 Hz, 1H, HC=CHCO2Et), 7.52 (d, J = 17.0 Hz, 1H, HC=CHCO2Et); C-
NMR (100 MHz, CDCl3) δ 14.28 (q), 19.28 (q), 25.92 (t), 59.67 (t), 71.00 (s), 76.94 (d),
79.19 (s), 97.87 (d), 160.99 (d), 167.72 (s); exact mass calcd for C10H14O3 (M + Na) m/z 205.0835, found m/z 205.0844. NMR spectra show small signals that might correspond to the cis isomer of the enol ether.
133 OO OO OEt OEt 248 249
Ethyl trans-5-oxohex-3-enoate (248) and ethyl trans-5-oxohex-2-enoate (249). A 10- mL two-necked round-bottomed flask under argon atmosphere was charged with 200 mg (1.10 mmol) of the enol ether 247. The system was cooled to 0 °C (ice-water) and 4.4 mL of trifluoroacetic acid was added slowly down the walls of the flask via syringe. The mixture was stirred for 30 min and then diluted with 80 mL of dichloromethane. The solution was diluted with 80 mL of saturated aqueous sodium bicarbonate. The organic phase was separated. The aqueous phase was extracted with two 50-mL portions of dichloromethane. The combined organic phases were dried (Na2SO4) and concentrated in vacuo to afford 225 mg of a yellow oil. The oil was dissolved in 11 mL of ethanol and 15 mg (0.11 mmol) of anhydrous potassium carbonate was added. The mixture was stirred for 18 h at room temperature. The resulting solution was concentrated in vacuo and diluted in 30 mL of dichloromethane. The solution was washed with 30 mL of water. The organic layer was separated. The aqueous layer was extracted with two 30-mL portions of dichloromethane. The combined organic layers were dried (MgSO4) and concentrated in vacuo to afford 150 mg of a yellow oil. The oil was chromatographed over 13 g of silica gel (230–400 mesh, eluted with 30% diethyl ether/70% hexanes) to give 61 mg of a mixture of the α,β-unsaturated ketone 248 and α,β-unsaturated ester 249 1 in a 1:1.7 ratio, respectively. Isomer 249: H-NMR (400 MHz, CDCl3) δ 1.15-1.25 (m,
3H, OCH2CH3), 2.24 (s, 3H, CH3CO), 3.22 (d, J = 7.0 Hz, 2H, CH2CO), 4.10-4.17 (m,
2H, OCH2CH3), 5.99 (dd, J = 16.1, 1.3 Hz, 1H, CH=CHCO2Et), 6.82 (dt, J = 16.1, 7.1 1 Hz, 1H, CH=CHCO2Et). Isomer 248: H-NMR (400 MHz, CDCl3) δ 1.15-1.25 (m, 3H,
OCH2CH3), 2.27 (s, 3H, CH3CO), 3.30 (d, J = 7.3 Hz, 2H, CH2CO2Et), 4.10-4.17 (m, 2H,
OCH2CH3), 5.86 (dd, J = 15.8, 1.4 Hz, 1H, CH=CHCO), 6.82 (dt, J = 16.1, 7.1 Hz, 1H, CH=CHCO). Other impurities were detected by both 1H and 13C-NMR.
134 THPO CH3
H 255
Tetrahydropyranyl Ether of (±)-4-Pentyn-2-ol (255).36 A 250-mL three-necked round- bottomed flask under a nitrogen atmosphere was charged with 2.5 g (29.7 mmol) of 4- pentyn-2-ol (245) and 75 mL of dry dichloromethane. The solution was cooled to 0 °C (ice-water) and 3.0 mL (2.75 g, 32.7 mmol) of dihydropyran (254) was added via syringe, followed by 56 mg (0.298 mmol) of p-toluenesulfonic acid monohydrate. The ice bath was removed and the mixture was stirred for 6.0 h. To the reaction was added 20 mL of saturated aqueous sodium bicarbonate. The aqueous phase was separated. The organic phase was dried (MgSO4) and concentrated in vacuo to afford 5.15 g of a yellow oil. The oil was chromatographed over 150 g of silica gel (230-400 mesh, eluted with 20% diethyl ether/80% hexanes) to give 3.07 g (61%) of a 1:1 mixture of isomer ethers 255 as a 1 colorless oil: H-NMR (400 MHz, CDCl3) δ 1.25 and 1.32 (two d’s, J = 6.1 and 6.3 Hz,
3H, CH3), 1.45–1.65 (m, 4H, CH2 of THP ring), 1.65-1.75 (m, 1H, CH2 of THP ring),
1.75–1.90 (m, 1H, CH2 of THP ring), 1.97 and 1.99 (two t’s, J = 2.7 Hz, 1H, HC≡C),
2.31-2.60 (m, 2H, CH2C≡C), 3.47–3.52 (m, 1H, OCH2), 3.87-4.00 (m, 2H, OCH2 and OCH), 4.72 and 4.75 (two t’s, J = 3.6 and 2.8 Hz, 1H, OCHO).
135 HO CH3
H3C 256
(±)-4-Pentyn-2-ol (256).37 A 250-mL three-necked round-bottomed flask under argon atmosphere was charged with 3.07 g (18.24 mmol) of the protected alcohol 255 and 90 mL of dry THF. The solution was cooled to –78 °C (CO2/Acetone) and 12.5 mL (20.1 mmol) of 1.6 M n-BuLi in hexanes was added via syringe. The resulting yellow solution was stirred for 30 min and then, 1.7 mL (3.88 g, 27.4 mmol) of iodomethane was added dropwise via syringe. The mixture was stirred for 2 h. The ice bath was removed and the mixture was allowed to reach room temperature. After stirring for another 2 h, 30 mL of 10% aqueous NaCl was added. The mixture was extracted with three 50-mL portions of
ether. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford 3.13 g of a 1:1 mixture of isomers of the alkylated protected alcohol 280 as a 1 yellow oil: H-NMR (400 MHz, CDCl3) δ 1.21 and 1.29 (two dd’s, J = 6.3, 1.3 Hz, 3H,
CH3), 1.45–1.60 (m, 4H, CH2 of THP ring), 1.60-1.90 (m, 2H, CH2 of THP ring), 1.85
(sharp m, 3H, CH3C≡C), 2.15-2.55 (m, 2H, CH2C≡C), 3.47–3.50 (m, 1H, OCH2), 3.85-
4.00 (m, 2H, CH2O and OCH), 4.69 and 4.73 (two sharp m’s, 1H, OCHO). The alkylated protected alcohol 280 was dissolved in 12 mL of methanol and 0.6 mL of concentrated HCl was added. The reaction mixture was stirred for 2 h and then concentrated in vacuo to afford 3.3 g of a yellow oil. The oil was chromatographed over 150 g of silica gel (230-400 mesh, eluted with diethyl ether-hexanes, 3:7 and 1:1) to give 1 1.30 g (73%) of alcohol 256 as a colorless oil: H-NMR (400 MHz, CDCl3) δ 1.22 (d, J =
6.2 Hz, 3H, CH3), 1.81 (d, J = 2.5 Hz, 3H, CH3C≡C), 1.92 (broad s, 1H, OH), 2.20-2.30
(m, 1H, CH2C≡C), 2.30-2.40 (m, 1H, CH2C≡C), 3.89 (sextet, J = 6.3 Hz, 1H, CH).
136 OCH3 EtO2C
H3C 257
(±)-Ethyl 3-(1-Methylhex-3-ynyloxy)acrylate (257). A 100-mL three-necked round- bottomed flask under argon atmosphere was charged with 2.0 mL (1.92 g, 19.6 mmol) of ethyl propiolate (246), 20 mL of dry diethyl ether and 2.7 mL (1.98 g, 19.6 mmol) of triethylamine. To the resulting yellow mixture was added a solution of 1.28 g (13.0 mmol) of alcohol 256 in 15 mL of dry diethyl ether. The brown solution was stirred for 48 h. The mixture was diluted with 100 mL of diethyl ether and washed sequentially with 55 mL of 1 M aqueous KHSO4, two portions of 55-mL of saturated aqueous
NaHCO3 and 55 mL of brine. The organic phase was separated, dried (Na2SO4) and concentrated in vacuo to afford 2.69 g of a brown oil. The oil was chromatographed over 150 g of silica gel (230–400 mesh, eluted with ethyl acetate-hexanes, 1:9) to give 2.20 g (86%) of the enol ether 257 as a pale yellow oil: IR (Neat) 3088, 2234, 1709, 1643 cm-1; 1 H-NMR (400 MHz, CDCl3) δ 1.23 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.33 (d, J = 6.2 Hz,
3H, CH3), 1.78 (t, J = 2.5 Hz, 3H, CH3C≡C), 2.25-2.55 (m, 2H, CH2C≡C), 4.05-4.15 (m,
3H, OCH2CH3 and OCHCH3), 5.23 (d, J = 12.5 Hz, 1H, HC=CHCO2Et), 7.51 (d, J = 13 12.5 Hz, 1H, HC=CHCO2Et); C-NMR (100 MHz, CDCl3) δ 3.34 (q), 14.29 (q), 19.37 (q), 26.31 (t), 59.60 (t), 74.00 (s), 77.75 (s), 78.44 (d), 97.52 (d), 161.34 (d), 167.87 (s);
exact mass calcd for C11H16O3 (M + Na) m/z 219.0992, found m/z 219.0993. NMR spectra showed small signals that might correspond to the cis isomer of the enol ether.
137 EtO2C O
O
258
2-Carbethoxymethyl-3-acetyl-5-methyltetrahydrofuran (258). A 25-mL three-necked round-bottomed flask under argon atmosphere was charged with 150 mg (0.764 mmol) of the enol ether 257 and 7 mL of dry dichloromethane. The solution was cooled to 0 °C (ice-water) and 0.6 mL (871 mg, 7.64 mmol) of trifluoroacetic acid was added slowly via syringe. The mixture was stirred for 2 h at 0 °C and at room temperature for 3 h. The reaction mixture was diluted with 50 mL of dichloromethane. To the solution was added 50 mL of saturated aqueous sodium bicarbonate. The organic phase was separated. The aqueous phase was extracted with two 40-mL portions of dichloromethane. The
combined organic phases were dried (Na2SO4) and concentrated in vacuo to afford 164 mg of a yellow oil. The oil was dissolved in 8 ml of ethanol and 15 mg (0.11 mmol) of anhydrous potassium carbonate was added. The mixture was stirred for 2 h at room temperature. The resulting solution was concentrated in vacuo and diluted with 50 mL of dichloromethane. The residual solid was removed by filtration. The filtrate was concentrated in vacuo to afford 124 mg of a yellow oil. The oil was chromatographed over 10 g of silica gel (230–400 mesh, eluted with ethyl acetate-hexanes, 1:9) to give 20.4 mg (13%) of tetrahydrofuran 258 as a colorless oil: IR (Neat) 1732, 1713 cm-1; 1H-
NMR (500 MHz, CDCl3) δ 1.28 (d, J = 6.1 Hz, 3H, CH3), 1.30 (t, J = 7.1 Hz, 3H,
OCH2CH3), 1.76-1.83 (m, 1H, CH2CHCH3), 2.17-2.22 (m, 1H, CH2CHCH3), 2.25 (s, 3H,
CH3CO), 2.61 (dd, J = 15.4, 6.8 Hz, 1H, CH2CO2Et), 2.73 (dd, J = 15.4, 6.0 Hz, 1H,
CH2CO2Et), 3.07-3.11 (m, 1H, CHCOCH3), 4.08-4.12 (m, 1H, OCHCH3), 4.18 (q, J = 13 7.1 Hz, 2H, OCH2CH3), 4.44 (ddd, J = 6.4 Hz, 1H, OCHCH3); C-NMR (125 MHz,
CDCl3) δ 14.59 (q), 21.23 (q), 30.01 (q), 37.42 (t), 40.73 (t), 57.01 (d), 61.06 (t), 75.50
(d), 77.19 (d), 171.15 (s), 208.547 (s); exact mass calcd for C11H18O4 (M + Na) m/z 237.1097, found m/z 237.1098. The relative cis stereochemistry between C-2 and C-5
138 was well established by NOE studies. Although this material appeared to be a single isomer, the stereochemistry at C-3 was unclear.
HO CH3
CH3 281
(±)-(Z)-4-Hexen-2-ol (281).37 A 250-ml three-necked round-bottomed flask under nitrogen atmosphere was charged with 3.0 g (16.46 mmol) of alkyne 280, 90 mL of methanol, 549 mg of 5% Pd/BaSO4, and 260 µL of quinoline. A hydrogen balloon was
attached and the flask was evacuated and filled with H2 through a needle. The reaction mixture was stirred under hydrogen for 4 h. The mixture was filtered through a Celite pad. The filtrate was concentrated in vacuo to afford 2.84 g of a yellow oil. The oil was dissolved in 10 mL of methanol and 0.6 mL of concentrated HCl was added. The mixture was saturated with NaCl and then, extracted with four 30-mL portions of dichloromethane. The combined organic layers were concentrated by distillation at one atmosphere. The residue was distilled to give 2.00 g of a mixture of alcohol 281 (55%) 1 and 2-methoxytetrahydropyran: bp 75 °C at 40 mmHg; H-NMR (400 MHz, CDCl3) δ
1.23 (d, J = 6.2 Hz, 3H, CH3), 1.66 (dt, J = 6.8, 0.8 Hz, 3H, CH3C=C), 2.19 (s, 1H, OH),
2.20-2.30 (m, 2H, CH2C=C), 3.80-3.90 (m, 1H, CHOH), 5.45 (dtq, J = 10.9, 7.1, 1.8 Hz,
1H, CH3CH=CH), 5.64 (dqt, J = 10.9, 6.8, 1.4 Hz, 1H, CH3CH=CH). The Z/E ratio was 5:1 based on the integration of the signals at 5.56 (E) and 5.64 (Z) ppm. The ratio of 281:2-methoxytetrahydropyran was 1:1 based on 1H-NMR. The small signals in the spectra are due to the E-isomer. The yield of this reaction was calculated based on the integrals in the 1H-NMR. This mixture was used in the next reaction without any further purification.
139 OCH3 EtO2C
CH3 282
(±)-(Z)-Ethyl 3-(1-Methylpent-3-enyloxy)acrylate (282). A 100-mL three-necked round-bottomed flask under argon atmosphere was charged with 1.4 mL (1.32 g, 13.5 mmol) of ethyl propiolate (246), 14 mL of dry diethyl ether and 1.9 mL (1.36 g, 13.5 mmol) of triethylamine. To the resulting yellow mixture was added a solution of 900 mg (9.00 mmol) of alcohol 281 (containing 2-methoxytetrahydropyran as described in the preceding experiment) in 10 mL of dry diethyl ether. The orange solution was stirred for 72 h. The mixture was diluted with 100 mL of diethyl ether and washed with 50 mL of
1M aqueous KHSO4, 50 mL of saturated aqueous NaHCO3 and 50 mL of brine. The
organic phase was separated, dried (Na2SO4) and concentrated in vacuo to afford 2.87 g of a brown oil. The oil was chromatographed over 150 g of silica gel (230–400 mesh, eluted with 15% diethyl ether/85% hexanes) to give 1.30 g (73%) of the enol ether 282 as -1 1 a pale yellow oil: IR (Neat) 3020, 1710, 1642 cm ; H-NMR (400 MHz, CDCl3) δ 1.24
(t, J = 7.1 Hz, 3H, OCH2CH3), 1.25 (d, J = 6.5 Hz, 3H, CH3CH), 1.60 (dd, J = 6.8, 0.8
Hz, 3H, CH3C=C), 2.20-2.30 (m, 1H, CH2C=C), 2.30-2.40 (m, 1H, CH2C=C), 4.11 (q, J
= 7.1 Hz, 2H, OCH2CH3), 4.06 (sextet, J = 6.2 Hz, 1H, CHOH), 5.21 (d, J = 12.4 Hz, 1H,
CH=CHCO2Et), 5.25-5.40 (m, 1H, CH3CH=CH), 5.55-5.65 (m, 1H, CH3CH=CH), 7.50 13 (d, J = 12.4 Hz, 1H, CH=CHCO2Et); C-NMR (100 MHz, CDCl3) δ 12.91 (q), 14.32 (q), 19.94 (q), 33.55 (t), 59.56 (t), 79.28 (d), 97.11 (d), 124.44 (d), 127.21 (d), 161.74 (d),
168.08 (s); exact mass calcd for C11H18O3 (M + Na) m/z 221.114813, found m/z 221.1136. This material was contained small amount of the E-isomer and 2- methoxytetrahydropyran by 1H and 13C NMR. Nonetheless it was used directly in the next reaction.
140 CO2Et CO2Et O O
OH OH 283 284
rel-(2R, 3S, 4R, 6S)-2-Carbethoxymethyl-4-hydroxy-3,6-dimethyltetrahydropyran (283) and rel-(2R, 3R, 4R, 6S)-2-Carbethoxymethyl-4-hydroxy-3,6-dimethyltetra hydropyran (284). A 100-mL three-necked round-bottomed flask under argon atmosphere was charged with 1.10 g (5.55 mmol) of enol ether 282 (from the preceding experiment) and 51 mL of dry dichloromethane. The solution was cooled to 0 °C (ice- water) and 4.3 mL (6.33 g, 55.5 mmol) of trifluoroacetic acid was added slowly via syringe. The mixture was stirred for 2 h. To the solution was added 50 mL of saturated aqueous sodium bicarbonate. The organic phase was separated. The aqueous phase was extracted with three 40-mL portions of dichloromethane. The combined organic phases were dried (Na2SO4) and concentrated in vacuo to afford a yellow oil. The oil was dissolved in 8 ml of ethanol and 384 mg (2.78 mmol) of anhydrous potassium carbonate was added. The mixture was stirred for 2 h at room temperature. The resulting solution was concentrated in vacuo and diluted with 50 mL of ethyl acetate. The solution was washed with 20 mL of water. The aqueous layer was separated and extracted with two
30-mL portions of ethyl acetate. The combined organic layers were dried (MgSO4), and concentrated in vacuo to afford 986 mg of a yellow oil. The oil was chromatographed over 60 g of silica gel (230–400 mesh, eluted with 40% ethyl acetate/60% hexanes) to give 786 mg (66%) of tetrahydropyrans 283 and 284 as a colorless oil in a 5:1 ratio, -1 1 respectively: IR (Neat) 3446, 1738 cm . Isomer 283: H-NMR (400 MHz, CDCl3) δ
0.90 (d, J = 7.0 Hz, 3H, CH3), 1.20 (d, J = 6.2 Hz, 3H, OCHCH3), 1.26 (t, J = 7.1 Hz, 3H,
OCH2CH3), 1.35 (ddd, J = 12.5, 11.7 Hz, 1H, CH2CHOH), 1.55 (broad s, 1H, OH), 1.65
(dddd, J = 12.5, 4.8, 2.3, 0.9 Hz, 1H, CH2CHOH), 1.86–1.93 (m, 1H, CHCH3), 2.38 (dd,
J = 15.3, 5.4 Hz, 1H, CH2CO2Et), 2.62 (dd, J = 15.3, 8.4 Hz, 1H, CH2CO2Et), 3.46-3.56
(m, 1H, OCHCH3), 3.84 (ddd, J = 8.3, 5.4, 2.1 Hz, 1H, CHCH2CO2Et), 3.94 (ddd, J =
141 13 11.7, 4.8, 4.8 Hz, 1H, CHOH), 4.10-4.20 (m, 2H, OCH2CH3); C-NMR (100 MHz,
CDCl3) δ 4.86 (q), 14.08 (q), 21.43 (q), 36.53 (t), 37.48 (d), 38.21 (t), 60.42 (t), 70.56 (d), 1 72.27 (d), 74.90 (d), 171.45 (s). Isomer 284: H-NMR (400 MHz, CDCl3) δ 0.99 (d, J =
6.6 Hz, 3H, CH3), 1.18 (d, J = 6.7 Hz, 3H, OCHCH3), 1.26 (t, J = 7.1 Hz, 3H,
OCH2CH3), 1.35 (dd, J = 12.5, 11.7 Hz, 1H, CH2CHOH), 1.55 (broad s, 1H, OH), 1.86–
1.93 (m, 1H, CHCH3), 1.95 (ddd, J = 11.7, 4.7, 1.9 Hz, 1H, CH2CHOH), 2.41 (dd, J =
15.1, 9.1 Hz, 1H, CH2CO2Et), 2.61 (dd, J = 15.1, 5.6 Hz, 1H, CH2CO2Et), 3.35 (ddd, J =
11.0, 9.8, 4.7 Hz, 1H, CHOH), 3.46-3.56 (m, 2H, OCHCH3 and CHCH2CO2Et), 4.10- 13 4.20 (m, 2H, OCH2CH3); C-NMR (100 MHz, CDCl3) δ 4.86 (q), 12.69 (q), 21.48 (q), 39.12 (t), 42.68 (t), 43.42 (d), 60.35 (t), 71.52 (d), 73.07 (d), 77.73 (d), 171.77 (s). Exact
mass calcd for C11H20O4 (M + Na) m/z 239.1254, found m/z 239.1250. The ratio was based on the integration of the signals at 0.90 and 0.99 ppm. The relative stereochemistry for isomer 283 was established by NOE studies and for isomer 284 by the multiplicity of the 1H-NMR signals.
HO CH3
H3C 285
(±)-(E)-4-Hexen-2-ol (285).38 A 250-mL three-necked round-bottomed flask under nitrogen atmosphere and equipped with a condenser, was charged with 77 mL of ammonia and 2.00 g (87.0 mmol) of sodium. To the resulting blue solution was added a solution of 3.0 g (16.46 mmol) of alkyne 280 in 4.0 mL of dry THF. The mixture was
stirred for 2 h and 5.5 g of NH4Cl was added very slowly, followed by 20 mL of THF. The mixture was stirred overnight to allow the ammonia to evaporate. Then, 50 mL of water was added very slowly. The solution was diluted with 50 mL of dichloromethane.
The organic phase was dried (MgSO4) and concentrated in vacuo to afford 2.56 g of a yellow oil. The oil was dissolved in 8 mL of methanol and 0.5 mL of concentrated HCl was added. The mixture was stirred for 2 h and the minimum amount of saturated
142 aqueous sodium bicarbonate was added. The mixture was extracted with four 40-mL
portions of dichloromethane. The combined organic extracts were dried (MgSO4) and concentrated by atmospheric distillation of the solvents. The residue was chromatographed over 120 g of silica gel (70-230 mesh, eluted with 30% diethyl ether/70% pentane) to give 600 mg (20%) of alcohol 285 as a colorless liquid: 1H-NMR
(400 MHz, CDCl3) δ 1.19 (d, J = 6.2 Hz, 3H, CH3CHOH), 1.43 (s, 1H, OH), 1.70 (dd, J
= 6.3, 1.0 Hz, 3H, CH3C=C), 2.00-2.12 (m, 1H, CH2C=C), 2.15-2.20 (m, 1H, CH2C=C),
3.75-3.82 (m, 1H, CHOH), 5.44 (dtq, J = 15.2, 7.1, 1.5 Hz, 1H, CH3CH=CH), 5.56 (dqt,
J = 15.2, 6.3, 1.0 Hz, 1H, CH3CH=CH).
OCH3 EtO2C
H3C 286
(±)-(E)-Ethyl 3-(1-Methylpent-3-enyloxy)acrylate (286). A 50-mL three-necked round-bottomed flask under argon atmosphere was charged with 0.9 mL (882 mg, 8.99 mmol) of ethyl propiolate (246), 9 mL of dry diethyl ether and 1.3 mL (910 mg, 8.99 mmol) of triethylamine. To the resulting yellow mixture was added a solution of 600 mg (5.99 mmol) of alcohol 285 in 7 mL of dry diethyl ether. The brown solution was stirred for 48 h. The mixture was concentrated in vacuo to afford 1.37 g of a brown oil. The oil was chromatographed over 100 g of silica gel (230–400 mesh, eluted with 15% diethyl ether/85% hexanes) to give 707 mg (59%) of the enol ether 286 as a colorless oil: IR –1 1 (Neat) 1709, 1642, 1622 cm ; H-NMR (400 MHz, CDCl3) δ 1.23 (d, J = 6.2 Hz, 3H,
CH3CHOH), 1.24 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.70 (dd, J = 6.3, 1.0 Hz, 3H,
CH3C=C), 2.17-2.22 (m, 1H, CH2C=C), 2.27-2.33 (m, 1H, CH2C=C), 4.02 (sextet, J =
6.2 Hz, 1H, CH3CHO), 4.13 (q, J = 7.1 Hz, 2H, OCH2CH3), 5.20 (d, J = 12.4 Hz, 1H,
CH=CHCO2Et), 5.34 (dtq, J = 15.2, 7.0, 1.6 Hz, 1H, CH3CH=CH), 5.56 (dqt, J = 15.2, 13 6.3, 1.2 Hz, 1H, CH3CH=CH), 7.45 (d, J = 12.4 Hz, 1H, CH=CHCO2Et); C-NMR (100
MHz, CDCl3) δ 14.22 (q), 17.89 (q), 19.43 (q), 39.22 (t), 59.52 (t), 79.22 (d), 97.05 (d),
143 125.39 (d), 128.85 (d), 161.75 (d), 168.06 (s); exact mass calcd for C11H18O3 (M + Na) m/z 221.1148, found m/z 221.1145. This enol ether was contaminated with traces of diethyl 2-hexen-4-ynedioate.
CO2Et O
OH 284
rel-(2R, 3R, 4R, 6S)-2-Carbethoxymethyl-4-hydroxy-3,6-dimethyltetrahydropyran (284). A 25-mL two-necked round-bottomed flask under argon atmosphere was charged with 150 mg (0.757 mmol) of the enol ether 286 and 7 mL of dry dichloromethane. The solution was cooled to 0 °C (ice-water) and 0.6 mL (863 mg, 7.57 mmol) of trifluoroacetic acid was added slowly via syringe. The mixture was stirred for 2 h. To the solution was added 25 mL of saturated aqueous sodium bicarbonate, followed by dilution with 30 mL of dichloromethane. The organic phase was separated. The aqueous phase was extracted with three 30-mL portions of dichloromethane. The combined
organic phases were dried (Na2SO4) and concentrated in vacuo to afford 224 mg of a colorless oil. The oil was dissolved in 7 mL of ethanol and 52 mg (0.379 mmol) of anhydrous potassium carbonate was added. The mixture was stirred for 2 h at room temperature. The resulting solution was concentrated in vacuo and diluted with 20 mL of ethyl acetate. The solution was washed with 10 mL of water. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to afford 218 mg of a yellow oil. The oil was chromatographed over 13 g of silica gel (230–400 mesh, eluted with 40% ethyl acetate/60% hexanes, 60% ethyl acetate/40% hexanes) to give 113 mg (69%) of tetrahydropyran 284 as a colorless oil: IR (Neat) 3449, 1737 cm –1; 1H-NMR (400 MHz,
C6D6) δ 0.81 (d, J = 6.5 Hz, 3H, CH3), 0.96 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.05 (d, J =
6.1 Hz, 3H, OCHCH3), 1.07-1.17 (m, 2H, CH2CHOH), 1.28 (broad s, 1H, OH), 1.55
144 (ddd, J = 12.3, 4.7, 1.9 Hz, 1H, CHCH3), 2.37-2.46 (m, 2H, CH2CO2Et), 2.97 (ddd, J =
10.4, 10.4, 4.7 Hz, 1H, CHOH), 3.24 (ddd, J = 13.3, 6.5, 1.9 Hz, 1H, OCHCH3), 3.48 13 (ddd, J = 9.2, 9.2, 3.8 Hz, 1H, CHCH2CO2Et), 3.94-4.04 (m, 2H, OCH2CH3); C-NMR
(100 MHz, CDCl3) δ 12.69 (q), 14.10 (q), 21.48 (q), 39.12 (t), 42.70 (t), 43.42 (d), 60.33
(t), 71.51 (d), 73.07 (d), 77.73 (d), 171.75 (s); exact mass calcd for C11H20O4 (M + Na) m/z 239.1254, found m/z 239.1256. NMR spectra showed small signals that might correspond to the C-3 epimer. The relative stereochemistry was established base on NOE studies.
CO2Et CO2Et O O
NO NO 2 2 CO2Et O O O O O 288a 289a 290
rel-(2R, 3S, 4S, 6S)-2-Carbethoxymethyl-3,6-dimethyl-4-(4-nitrobenzoyl)tetrahydro pyran (288a), rel-(2R, 3R, 4S, 6S)-2-Carbethoxymethyl-3,6-dimethyl-4-(4- nitrobenzoyl)tetrahydropyran (289a), and rel-(2R, 6S)-2-Carbethoxymethyl-3,6-dimethyl- 5,6-dihydro-2H-tetrahydropyran (290).39 A 50-mL three-necked round-bottomed flask under argon atmosphere was charged with 79 mg (0.365 mmol) of the mixture of alcohol 283 and 284 (5:1), 7.4 mL of dry benzene, 671 mg (2.56 mmol) of triphenylphosphine and 433 mg (2.56 mmol) of p-nitrobenzoic acid. To the mixture was added 0.40 mL (446 mg, 2.56 mmol) of diethyl azodicarboxylate dropwise via syringe and at a rate to maintain control of the reflux. The mixture was stirred for 3.2 h. The solution was concentrated in vacuo to afford 2.38 g of a yellow oil. The oil was dissolved in 20 mL of dichloromethane and silica gel (230-400 mesh) was added. The mixture was concentrated in vacuo to afford a thin powder. This powder was chromatographed over
145 150 g of silica gel (230-400 mesh, eluted with 15% ethyl acetate/85% hexanes and 30% ethyl acetate/70% hexanes) to give 31 mg (43%) of olefin 290 as a colorless oil and 41 mg (31%) of tetrahydropyrans 289a and 288a in a 1:1 ratio as a yellow oil. Olefin 290: -1 1 IR (Neat) 1738, 1608 cm ; H-NMR (400 MHz, CDCl3) δ 0.97 (d, J = 6.9 Hz, 3H, CH3),
1.27 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.62 (s, 3H, CH3C=C), 1.85-2.00 (m, 2H, CH2C=C),
2.42 (dd, J = 14.7, 8.6 Hz, 1H, CH2CO2Et), 2.63 (dd, J = 14.7, 4.2 Hz, 1H, CH2CO2Et),
3.60-3.70 (m, 1H, OCHCH3), 4.20 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.40-4.50 (m, 1H, 13 CHCH2CO2Et), 5.52-5.57 (sharp m, 1H, HC=C); C-NMR (100 MHz, CDCl3) δ 14.18 (q), 18.73 (q), 21.34 (q), 32.91 (t), 39.15 (t), 60.35 (t), 69.81 (d), 74.79 (d), 121.30 (d),
134.08 (s), 171.69 (s); exact mass calcd for C11H18O3 (M + Na) m/z 221.1148, found m/z 221.1160. Tetrahydropyrans 289a and 288a: IR (Neat) 1725 cm-1. Isomer 289a: 1H-
NMR (500 MHz, CDCl3) δ 0.96 (d, J = 7.0 Hz, 3H, CH3), 1.19 (d, J = 6.2 Hz, 3H,
OCHCH3), 1.32 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.68 (ddd, J = 14.4, 11.7, 2.7 Hz, 1H,
CH2CHOAr), 1.80–1.90 (m, 1H, CHCH3), 2.00 (ddd, J = 14.4, 2.5, 2.5 Hz, 1H,
CH2CHOAr), 2.46 (dd, J = 14.9, 8.9 Hz, 1H, CH2CO2Et), 2.65 (dd, J = 14.9, 3.8 Hz, 1H,
CH2CO2Et), 3.91 (dqd, J = 11.7, 6.2, 1.8 Hz, 1H, OCHCH3), 4.10 (ddd, J = 9.6, 9.6, 3.7
Hz, 1H, CHCH2CO2Et), 4.23 (qd, J = 7.1, 1.4 Hz, 2H, OCH2CH3), 5.40-5.45 (sharp m, 1H, CHOAr), 8.27 (d, J = 8.7 Hz, 2H, ArH), 8.34 (d, J = 8.7 Hz, 2H, ArH). Isomer 288a: 1 H-NMR (500 MHz, CDCl3) δ 1.10 (d, J = 7.2 Hz, 3H, CH3), 1.24 (d, J = 6.2 Hz, 3H,
OCHCH3), 1.28 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.70-1.80 (m, 2H, CH2CHOAr), 1.95-
2.00 (m, 1H, CHCH3), 2.37 (dd, J = 15.4, 5.1 Hz, 1H, CH2CO2Et), 2.63 (dd, J = 15.4, 8.8
Hz, 1H, CH2CO2Et), 3.97 (dqd, J = 15.0, 5.1, 2.0 Hz, 1H, OCHCH3), 4.19 (q, J = 7.1 Hz,
2H, OCH2CH3), 4.43 (ddd, J = 8.3, 5.4, 2.5 Hz, 1H, CHCH2CO2Et), 5.15-5.25 (sharp m, 1H, CHOAr), 8.34 (d, J = 6.8 Hz, 2H, ArH), 8.35 (d, J = 6.8 Hz, 2H, ArH); 13C-NMR
(100 MHz, CDCl3, 288a + 289a) δ 10.65 (q), 13.41 (q), 14.15 (q), 14.22 (q), 21.38 (q), 21.63 (q), 32.68 (t), 34.91 (d), 38.13 (t), 38.16 (t), 38.25 (d), 39.30 (t), 60.52 (t), 68.48 (d), 69.55 (d), 71.68 (d), 73.88 (d), 74.77 (d), 74.94 (d), 123.58 (d), 123.64 (d), 130.67 (d), 130.70 (d), 135.65 (s), 135.80 (s), 150.63 (s), 163.74 (s), 164.05 (s), 171.30 (s),
171.61 (s); exact mass calcd for C18H23NO7 (M + Na) m/z 388.1367, found m/z 388.1371.
146 CO2Et CO2Et O O
CO2Et O O O O O 290 289b 288b
rel-(2R, 6S)-2-Carbethoxymethyl-3,6-dimethyl-5,6-dihydro-2H-tetrahydropyran (290), rel-(2R, 3R, 4S, 6S)-4-Benzoyl-2-carbethoxymethyl-3,6-dimethyltetrahydro pyran (289b) and rel-(2R, 3R, 4S, 6S)-4-Benzoyl-2-carbethoxymethyl-3,6- dimethyltetrahydropyran (288b). A 25-mL three-necked round-bottomed flask under argon atmosphere was charged with 100 mg (0.462 mmol) of the mixture of alcohol 283 and 284 (5:1), 6 mL of dry THF, 365 mg (1.39 mmol) of triphenylphosphine and 85 mg (0.693 mmol) of benzoic acid. To the colorless solution was added 0.22 mL (242 mg, 1.39 mmol) of diethyl azodicarboxylate dropwise via syringe and at a rate to maintain control of the reflux. The mixture was stirred for 18 h at room temperature. The orange solution was diluted with 40 mL of diethyl ether and washed with 20 mL of 5% aqueous
K2CO3. The aqueous layer was separated and extracted with 40 mL of diethyl ether. The
combined organic layers were dried (MgSO4) and concentrated in vacuo to afford 0.77 g of a brown oil. The oil was chromatographed over 40 g of silica gel (230-400 mesh, eluted with 5% ethyl acetate/95% hexanes) to give42 mg (46%) of the olefin 290 as a yellow oil and 44 mg (30%) of tetrahydropyrans 289b and 288b in a 1.3:1 ratio, respectively. Tetrahydropyrans 289b and 288b: IR (Neat) 1738, 1719 cm-1. Isomer 1 289b: H-NMR (400 MHz, CDCl3) δ 0.92 (d, J = 6.9 Hz, 3H, CH3), 1.15 (d, J = 6.2 Hz,
3H, OCHCH3), 1.29 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.60 (ddd, J = 14.3, 11.3, 2.7 Hz, 1H,
CH2CHOPh), 1.78 (dqd, J = 10.2, 7.0, 2.9 Hz, 1H, CHCH3), 1.95 (ddd, J = 14.4, 2.9, 2.2
Hz, 1H, CH2CHOPh), 2.42 (dd, J = 14.5, 9.0 Hz, 1H, CH2CO2Et), 2.62 (dd, J = 14.5, 3.7
Hz, 1H, CH2CO2Et), 3.91 (dqd, J = 11.3, 6.2, 1.8 Hz, 1H, OCHCH3), 4.15 (ddd, J = 9.6,
9.6, 3.7 Hz, 1H, CHCH2CO2Et), 4.22 (qd, J = 7.1, 0.9 Hz, 2H, OCH2CH3), 5.30-5.35 (sharp m, 1H, CHOPh), 7.40-7.50 (m, 3H, PhH), 8.08 (d, J = 8.3 Hz, 2H, PhH); Isomer 147 1 288b: H-NMR (400 MHz, CDCl3) δ 1.05 (d, J = 7.2 Hz, 3H, CH3), 1.19 (d, J = 6.2 Hz,
3H, OCHCH3), 1.24 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.65-1.75 (m, 2H, CH2CHOPh),
1.88-1.95 (m, 1H, CHCH3), 2.38 (dd, J = 15.3, 5.0 Hz, 1H, CH2CO2Et), 2.59 (dd, J =
15.4, 8.8 Hz, 1H, CH2CO2Et), 3.94-4.00 (m, 1H, OCHCH3), 4.15 (q, J = 7.1 Hz, 2H,
OCH2CH3), 4.43 (ddd, J = 8.7, 5.0, 2.5 Hz, 1H, CHCH2CO2Et), 5.15-5.17 (sharp m, 1H, CHOAr), 7.55-8.0 (m, 3H, PhH), 8.08 (d, J = 8.3 Hz, 2H, PhH); 13C-NMR (100 MHz,
CDCl3, 289b + 288b) δ 10.67 (q), 13.40 (q), 14.13 (q), 14.21 (q), 21.40 (q), 21.65 (q), 32.70 (t), 35.00 (d), 38.27 (t), 38.29 (t), 38.38 (d), 39.39 (t), 60.43 (t), 68.51 (d), 69.58 (d), 71.73 (d), 72.44 (d), 73.60 (d), 74.84 (d), 128.38 (d), 128.44 (d), 129.55 (d), 129.57 (d), 130.33 (d), 130.46 (d), 132.99 (s), 133.03 (s), 165.58 (s), 165.88 (s), 171.37 (s),
171.74 (s); exact mass calcd for C18H24O5 (M + Na) m/z 343.1516, found m/z 343.1515. The 1H-NMR data for olefin 290 matched previously reported data. However, the olefin was contaminated with small amounts of other impurities.
CO2Et CO2Et O O
CO2Et O O CHCl2 O CHCl2 O O 290 291 292
rel-(2R, 6S)-2-Carbethoxymethyl-3,6-dimethyl-5,6-dihydro-2H-tetrahydropyran (290), rel-(2R, 3R, 4R, 6S)-2-Carbethoxymethyl-4-(2’,2’-dichloroacetyl)-3,6- dimethyl-tetrahydropyran (291) and rel-(2R, 3S, 4R, 6S)-2-carbethoxymethyl-4- (2’,2’-dichloroacetyl)-3,6-dimethyltetrahydropyran (292). A 25-mL three-necked round-bottomed flask under argon atmosphere was charged with 100 mg (0.462 mmol) of a mixture of alcohol 283 and 284 (5:1), 6 mL of dry THF, 365 mg (1.39 mmol) of triphenylphosphine and 113 mg (0.693 mmol) of trichloroacetic acid. To the colorless solution was added 0.22 mL (242 mg, 1.39 mmol) of diethyl azodicarboxylate dropwise
148 via syringe at a rate to maintain control of the reflux. The mixture was stirred for 18 h at room temperature. The orange solution was diluted with 40 mL of diethyl ether and washed with 20 mL of 5% aqueous K2CO3. The aqueous layer was separated and
extracted with 40 mL of diethyl ether. The combined organic layers were dried (MgSO4) and concentrated in vacuo to afford 778 mg of a mixture of a yellow oil and a solid residue. The mixture was chromatographed over 40 g of silica gel (230-400 mesh, eluted with 10% ethyl acetate/90% hexanes) to give 5 mg (7%) of the olefin 290 as a yellow oil and 54 mg (32%) of a mixture of tetrahydropyrans 291 and 292 as a colorless oil in a 5:1 ratio, respectively. Tetrahydropyrans 291 and 292: IR (Neat) 1738 cm-1. Isomer 291: 1H-
NMR (400 MHz, CDCl3) δ 0.96 (d, J = 6.9 Hz, 3H, CH3), 1.24 (d, J = 6.2 Hz, 3H,
OCHCH3), 1.26 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.56 (ddd, J = 14.3, 11.9 Hz, 1H,
CH2CHO), 1.75-1.85 (m, 1H, CH2CHO), 2.10-2.20 (m, 1H, CHCH3), 2.36 (dd, J = 15.5,
5.2 Hz, 1H, CH2CO2Et), 2.61 (dd, J = 15.5, 8.4 Hz, 1H, CH2CO2Et), 3.50-3.60 (m, 1H,
OCHCH3), 3.91 (ddd, J = 7.2, 5.3, 2.0 Hz, 1H, CHCH2CO2Et), 4.16 (qd, J = 7.1, 0.9 Hz, 13 2H, OCH2CH3), 5.10 (ddd, J = 12.0, 4.9, 4.9 Hz, 1H, CHOCO), 5.93 (s, 1H, CHCl2); C-
NMR (100 MHz, CDCl3) δ 5.70 (q), 14.16 (q), 21.37 (q), 32.67 (t), 34.55 (d), 38.03 (t), 60.54 (t), 64.40 (d), 72.11 (d), 74.53 (d), 76.67 (d), 163.69 (s), 170.90 (s). Isomer 292: 1 H- NMR (400 MHz, CDCl3) δ 0.92 (d, J = 6.9 Hz, 3H, CH3), 1.22 (d, J = 6.2 Hz, 3H,
OCHCH3), 1.26 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.56 (ddd, J = 14.3, 11.9 Hz, 1H,
CH2CHO), 1.95-2.00 (m, 1H, CH2CHO), 2.05-2.10 (m, 1H, CHCH3), 2.45 (dd, J = 14.4,
9.6 Hz, 1H, CH2CO2Et), 2.66 (dd, J = 14.4, 2.4 Hz, 1H, CH2CO2Et), 3.50-3.60 (m, 2H,
OCHCH3 and CHCH2CO2Et), 4.16 (qd, J = 7.1, 0.9 Hz, 2H, OCH2CH3), 4.71 (ddd, J = 13 13.3, 11.9, 3.0 Hz, 1H, CHOCO), 5.94 (s, 1H, CHCl2); C-NMR (100 MHz, CDCl3) δ 5.70 (q), 12.63 (q), 21.37 (q), 38.31 (t), 38.98 (t), 40.17 (t), 60.39 (t), 71.20 (d), 73.45
(d), 77.55 (d), 79.37 (d), 163.69 (s), 170.90 (s). Exact mass calcd for C13H20Cl2O5 (M + Na) m/z 349.0580, found m/z 349.0579. The ratio was calculated based on the signals at 4.71 and 5.10 ppm in the 1H-NMR spectra. The 1H-NMR data for olefin 290 matched previously reported data.
149 CO2Et CO2Et O O
O O 293 299
CO2Et CO2Et CO2Et O O O
OH OH OH 283 294 298
rel-(2R, 3S, 6S)-2-Carbethoxymethyl-3,6-dimethyl-4-oxotetrahydropyran (293), rel- (2R, 3S, 6S)-2-Carbethoxymethyl-3,6-dimethyl-4-oxotetrahydropyran (299), rel-(2R, 3S, 4R, 6S)-2-Carbethoxymethyl-4-hydroxy-3,6-dimethyltetrahydropyran (283) rel- (2R, 3S, 4S, 6S)-2-Carbethoxymethyl-4-hydroxy-3,6-dimethyltetrahydropyran (294), and rel-(2R, 3R, 4S, 6S)-2-Carbethoxymethyl-4-hydroxy-3,6-dimethyltetrahydro pyran (298).40-41 A 25-mL two-necked round-bottomed flask under argon atmosphere
was charged with 4 mL of dry CH2Cl2 and 100 µL (147 mg, 1.16 mmol) of oxalyl
chloride. The solution was cooled to –78 °C (CO2/acetone) and 170 µL (187 mg, 2.39 mmol) of dimethylsulfoxide was added dropwise. A solution of 100 mg (0.462 mmol) of
the alcohols 283 and 284 (5:1) in 5 mL of dry CH2Cl2 was added dropwise and stirred for 30 min. Triethylamine (0.4 mL, 280 mg; 2.77 mmol) was then added dropwise. The mixture was stirred for 20 min. The dry ice/acetone bath was removed and replaced with an ice-water bath. The mixture was stirred for 40 min. The solvent was removed in vacuo and the residue was diluted with 20 mL of diethyl ether. The solution was washed with 10 mL of 1.0 M aqueous KHSO4 and 10 mL of saturated aqueous NaHCO3. The organic phase was dried (MgSO4) and concentrated in vacuo to afford 99.1 mg of a
150 mixture of ketones 293 and 299 as a yellow oil in a 5:1 ratio, respectively. Ketone 293: 1 H-NMR (400 MHz, C6D6) δ 0.79 (d, J = 7.2 Hz, 3H, CH3), 0.90 (d, J = 7.7 Hz, 3H,
OCHCH3), 0.92 (t, J = 6.5 Hz, 3H, OCH2CH3), 1.85-1.95 (m, 2H, CH2CO), 1.94 (dd, J =
15.4, 4.6 Hz, 1H, CH2CO2Et), 2.23 (qd, J = 7.2, 2.7 Hz, 1H, CHCH3), 2.48 (dd, J = 15.4,
8.6 Hz, 1H, CH2CO2Et), 3.20-3.30 (m, 1H, OCHCH3), 3.85-4.00 (m, 2H, OCH2CH3), 1 4.00-4.10 (m, 1H, CHCH2CO2Et). Ketone 299: H-NMR (400 MHz, C6D6) δ 0.83 (d, J =
6.7 Hz, 3H, CH3), 0.90 (d, J = 6.1 Hz, 3H, OCHCH3), 0.92 (t, J = 7.1 Hz, 3H,
OCH2CH3), 1.82 (dd, J = 13.9, 11.6 Hz, 1H, CH2CO), 1.85-1.93 (m, 1H, CHCH3), 2.06
(dd, J = 13.9, 2.4 Hz, 1H, CH2CO), 2.27-2.40 (m, 2H, CH2CO2Et), 3.27 (dqd, J = 11.6,
6.1, 2.4 Hz, 1H, OCHCH3), 3.58 (ddd, J = 10.6, 7.3, 4.2 Hz, 1H CHCH2CO2Et), 3.85-
4.04 (m, 2H, OCH2CH3). The ratio was 5:1 based on the signals at 2.23 and 3.58 ppm. This material was used in the next reaction without any further purification. A 50-mL three-necked round-bottomed flask under argon atmosphere was charged with 99.1 mg of the mixture of ketone 293 and 299, and 5 mL of dry THF. The solution was cooled to –78 °C and 0.46 mL (0.46 mmol) of 1.0 M L-selectride in tetrahydrofuran was added. The mixture was stirred for 45 min and 1.1 mL of ethanol was added. The mixture was stirred for 20 min at room temperature and 0.2 mL of 30%
aqueous H2O2 was added. After the exothermic reaction subsided, 15 mL of water was added. The mixture was extracted with three 20-mL portions of diethyl ether. The
combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford 80 mg of a colorless oil. The oil was chromatographed over 10 g of silica gel (230-400 mesh, eluted with 40% ethyl acetate/60% hexanes) to give 50.1 mg (50%) of tetrahydropyran 283 and 13.6 mg (14%) of a mixture of tetrahydropyran 294 and 298 as colorless oil in a 1:2.5 ratio, respectively. Tetrahydropyrans 294 and 298: IR (Neat) –1 1 3460, 1737 cm . Isomer 294: H-NMR (400 MHz, CDCl3) δ 0.94 (d, J = 7.1 Hz, 3H,
CH3), 1.16 (d, J = 7.3 Hz, 3H, OCHCH3), 1.26 (t, J = 7.2 Hz, 3H, OCH2CH3), 1.45-1.65
(m and broad s, 4H, CH2CHOH, CHCH3 and OH), 2.31 (dd, J = 13.8, 5.6 Hz, 1H,
CH2CO2Et), 2.56 (dd, J = 13.8, 8.6 Hz, 1H, CH2CO2Et), 3.85-4.00 (m, 2H, OCHCH3 and
CHOH), 4.10-4.23 (m, 2H, OCH2CH3), 4.37 (ddd, J = 8.4, 5.7, 2.4 Hz, 1H, 13 CHCH2CO2Et); C-NMR (100 MHz, CDCl3) δ 10.92 (q), 14.22 (q), 21.71 (q), 35.48 (t),
151 37.92 (d), 38.35 (t), 60.39 (t), 68.66 (d), 70.71 (d), 73.69 (d), 171.55 (s). Isomer 298: 1H-
NMR (400 MHz, CDCl3) δ 0.93 (d, J = 7.0 Hz, 3H, CH3), 1.13 (d, J = 6.2 Hz, 3H,
OCHCH3), 1.26 (t, J = 7.2 Hz, 3H, OCH2CH3), 1.45-1.60 (m, 2H, CH2CHOH and
CHCH3), 1.64 (broad s, 1H, OH), 1.75 (ddd, J = 13.9, 3.0, 2.3 Hz, 1H, CH2CHOH), 2.34
(dd, J = 14.7, 9.0 Hz, 1H, CH2CO2Et), 2.54 (dd, J = 14.7, 3.8 Hz, 1H, CH2CO2Et), 3.85- 13 4.00 (m, 3H, OCHCH3, CHCH2CO2Et and CHOH), 4.10-4.23 (m, 2H, OCH2CH3); C-
NMR (100 MHz, CDCl3) δ 13.56 (q), 14.20 (q), 21.52 (q), 39.37 (d), 39.51 (t), 41.27 (t),
60.32 (t), 67.54 (d), 69.39 (d), 73.69 (d), 171.88 (s). Exact mass calcd for C11H20O4 (M + Na) m/z 239.1254, found m/z 239.1253. The spectral data for 283 matched those previously reported.
H BnO
305
Prop-2-ynyloxymethylbenzene (305).43 A 100-mL three-necked round-bottomed flask was charged with 4.4 mL (4.22 g, 75.2 mmol) of propargyl alcohol (304), 35 mL of
toluene, 7.5 mL of 10.0 M aqueous NaOH and 2.42 g (7.52 mmol) of Bu4NBr. The resulting mixture was heated at 50 °C and 8.1 mL (11.7 g, 68.4 mmol) of benzyl bromide was added dropwise via syringe. The biphasic solution was stirred for 16 h at 50 °C. The mixture was allowed to cool to room temperature. The two layers were separated.
The organic layer was washed with two 30-mL portions of brine, dried (MgSO4) and concentrated in vacuo to afford a pale yellow oil. The oil was distilled to give 8.53 g (85%) of the protected alcohol 305 as a colorless oil: bp 115 °C, 13 mmHg [lit bp 100- 1 102 °C, 20 mmHg]; H-NMR (400 MHz, CDCl3) δ 2.48 (t, J = 2.4 Hz, 1H, ≡CH), 4.20
(d, J = 2.4 Hz, 2H, CH2C≡), 4.63 (s, 2H, OCH2Ph), 7.28-7.37 (m, 5H, ArH).
152 OH BnO
307
(±)-6-Benzyloxy-4-hexyn-2-ol (307).44,82 A 250-mL three-necked round-bottomed flask under argon atmosphere was charged with 2.0 g (13.7 mmol) of protected alcohol 305
and 30 mL of dry THF. The solution was cooled to -78 °C (acetone/CO2) and 5.8 mL of 2.4 M n-BuLi in hexanes was added dropwise via syringe. The resulting yellow solution
was stirred for 20 min and 2.6 mL (20.5 mmol) of BF3·Et2O was added. The mixture was stirred for another 5 min and a solution of 1.2 mL (0.993 g, 17.1 mmol) of propylene oxide in 45 mL of dry THF at -78 °C was added via cannula. The reaction was stirred for
2 h at -78 °C and 25 mL of saturated aqueous NaHCO3 was added. The mixture was pour into 25 mL of water and extracted with three 60-mL portions of diethyl ether. The combined organic extracts were washed with 50 mL of brine, dried (MgSO4) and concentrated in vacuo to afford a yellow oil. The oil was chromatographed over 120 g of silica gel (230-400 mesh, eluted with 30% EtOAc/70% hexanes) to give 1.24 g (44%) of 1 alcohol 307 as a colorless oil: H-NMR (400 MHz, CDCl3) δ 1.28 (d, J = 6.2 Hz, 3H,
CH3), 1.88 (broad s, 1H, OH), 2.40 (m, 2H, CH2C≡C) 3.93-4.00 (m, 1H, CHOH), 4.20 (t,
J = 2.1 Hz, 2H, BnOCH2), 4.60 (s, 2H, OCH2Ph), 7.27-7.37 (m, 5H, ArH).
OTHP BnO
308
Tetrahydropyranyl Ether of (±)-6-Benzyloxy-4-hexyn-2-ol (308). A 50-mL three- necked round-bottomed flask under argon atmosphere was charged with 1.20 g (5.87
mmol) of alcohol 307 and 15 mL of dry CH2Cl2. The solution was cooled to 0 °C (ice-
153 water). To the cold solution was added 0.8 mL (8.81 mmol) of dihydropyran and 6 mg (0.029 mmol) of p-toluenesulfonic acid monohydrate. The ice bath was removed. The mixture was stirred for 2 h at room temperature. To the reaction was added with 5 mL of
saturated aqueous NaHCO3. The organic phase was separated, dried (MgSO4) and concentrated in vacuo to afford 1.69 g of a yellow oil. The oil was chromatographed over 40 g of silica gel (230–400 mesh, eluted with 30% diethyl ether/70% hexanes) to give 1.34 g (79%) of the protected alcohol 308 (1:1 mixture of diastereoisomers) as a colorless -1 1 oil: IR (Neat) 3063, 3029, 2221, 1605 cm ; H-NMR (400 MHz, CDCl3) δ 1.27 and 1.34
(two d, J = 6.2 Hz, 3H, CH3), 1.40-2.00 (m, 6H, CH2 manifold), 2.34-2.50 and 2.61-2.66
(two m, 2H, CH2CHOTHP), 3.48-3.60 (broad m, 1H, CHOTHP), 3.80-4.00 (m, 2H,
OCH2CH2), 4.16-4.18 (sharp m, 2H, BnOCH2), 4.59 and 4.60 (two s, 2H, OCH2Ph), 4.72-4.74 and 4.76-4.78 (two m, 1H, OCHO), 7.25-7.40 (m, 5H, ArH); exact mass calcd for C18H24O3 (M + Na) m/z 311.1618, found m/z 311.1610.
OH
BnO 309
(±)-(Z)-6-Benzyloxy-3-hexen-2-ol (309). A 25-mL three-necked round-bottomed flask under argon atmosphere was charged with 3.1 mL of dry THF and 4.55 mL (4.55 mmol) of 1.0 M borane-tetrahydropyran complex. The solution was cooled to 0 °C (ice-water) and 0.98 mL (793 mg, 9.65 mmol) of cyclohexene was added slowly. The resulting white suspension was stirred for 1 h. The ice bath was replaced by an ice-salt bath and 1.30 g (4.51 mmol) of the acetylene 308 was added (0.5 mL of dry THF was used to help with the addition). The mixture was stirred for 20 min. The ice bath was removed and the solution was stirred for 1 h. The solvent was removed in vacuo to give a slightly cloudy oil. The oil was cooled in an ice bath and dissolved in 3.2 mL of glacial acetic acid. The mixture was stirred for 5 min. The ice bath was removed and the mixture was
154 heated to reflux for 1.5 h. The reaction mixture was carefully poured into 50 mL of ice- water. This was followed by the cautious addition of 6.5 mL of 3 N aqueous NaOH and
6.5 mL of 30% H2O2. The resulting cloudy solution was stirred for 1 h and 6.5 mL of
brine was added. The mixture was diluted in 65 mL of CH2Cl2. The layers were
separated. The aqueous layer was extracted with two 65-mL portions of CH2Cl2. The combined organic layers were washed with 50 mL of brine, dried (MgSO4) and concentrated in vacuo to afford 2.12 g of a yellow oil. The crude oil was dissolved in 30 mL of methanol and 30 mg of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred for 2 h. The solution was partitioned between 16 mL of saturated aqueous NaHCO3 and 100 mL of diethyl ether, filtered and washed with two 30-mL
portions of brine. The organic layer was dried (MgSO4) and concentrated in vacuo to afford 1.40 g of a yellow oil. The oil was chromatographed using MPLC (63–200 µm silica gel and 460-520 m2/g, eluted with 15% acetone in dichloromethane) to give 445 mg (48%) of the alkene 309 as a colorless oil: IR (Neat) 3396 cm-1; 1H-NMR (400 MHz,
CDCl3) δ 1.18 (d, J = 6.1 Hz, 3H, CH3), 2.00 (broad s, 1H, OH), 2.20-2.30 (m, 2H,
CH2CHOH), 3.83 (sextet, J = 6.1 Hz, 1H, CHOH), 4.00-4.10 (m, 2H, OCH2CH=CH),
4.54 (s, 2H, OCH2Ph), 5.65-5.72 (m, 1H, OCH2CH=CH), 5.78-5.83 (m, 1H, 13 OCH2CH=CH), 7.28-7.37 (m, 5H, ArH); C-NMR (100 MHz, CDCl3) δ 22.94 (q), 37.35 (t), 65.44 (t), 67.14 (d), 72.40 (t), 127.66 (d), 127.84 (d), 128.37 (d), 128.91 (d), 129.82
(d), 138.08 (s); exact mass calcd for C13H18O2 (M + Na) m/z 229.1199, found m/z 229.1204.
155 OCH3 EtO2C
OBn 310
(±)-Ethyl 3-(5-Benzyloxy-1-methylpent-3-enyloxy)acrylate (310). A 10-mL three- necked round-bottomed flask under argon atmosphere was charge with 0.3 mL (288 mg, 2.94 mmol) of ethyl propiolate (246) and 3 mL of dry diethyl ether. To the colorless solution was added 0.40 mL (297 mg, 2.94 mmol) of triethylamine. To the resulting yellow mixture was added a solution of 405 mg (1.96 mmol) of the alcohol 309 in 2.2 mL of dry ether. The brown solution was stirred for 48 h. The mixture was diluted in 30 mL
of diethyl ether and washed with 10 mL of 1 M aqueous KHSO4, two 10-mL portions of
saturated aqueous NaHCO3 and 10 mL of brine. The organic phase was separated, dried
(MgSO4) and concentrated in vacuo to afford 617 mg of a brown oil. The oil was chromatographed over 40 g of silica gel (230–400 mesh, eluted with 15% EtOAc in hexanes) to give 503 mg (84%) of the enol ether 310 as a pale yellow oil: IR (Neat) 3063, -1 1 3029, 1708, 1641, 1622, 1454 cm ; H-NMR (400 MHz, CDCl3) δ 1.272 (d, J = 6.2 Hz,
3H, OCHCH3), 1.274 (t, J = 7.1 Hz, 3H, CH2CH3), 2.30-2.35 (m, 1H, CHHCH(O)CH3),
2.38-2.41 (m, 1H, CHHCH(O)CH3), 4.05-4.10 (m, 3H, OCHCH3 and CH=CHCH2OBn),
4.16 (q, J = 7.1 Hz, 2H, CH2CH3), 4.52 (s, 2H, OCH2Ph), 5.24 (d, J = 12.4 Hz, 1H,
CH=CHCO2Et) 5.53-5.62 (m, 1H, CH=CHCH2OBn), 5.72-5.81 (m, 1H,
CH=CHCH2OBn), 7.28-7.37 (m, 5H, ArH), 7.51 (d, J = 12.4 Hz, 1H, CH=CHCO2Et) ; 13 C-NMR (100 MHz, CDCl3) δ 14.31 (q), 19.61 (q), 34.24 (t), 59.61 (t), 65.61 (t), 72.24 (t), 78.79 (d), 97.35 (d), 127.32 (d), 127.59 (d), 127.70 (d), 128.33 (d), 129.42 (d), 138.11
(s), 161.49 (s), 167.94 (d); exact mass calcd for C18H24O4 (M + Na) m/z 327.1567, m/z found 327.1570.
156 THPO H 318
Tetrahydropyranyl Ether of 2-Propynol (318).46 A 500-mL three-necked round- bottomed flask under argon atmosphere was charged with 8.0 g (143 mmol) of 2- propynol (317a) and 300 mL of dry dichloromethane. The solution was cooled to 0 °C (ice-water) and 20 mL (18.0 g, 214 mmol) of dihydropyran was added via syringe, followed by 136 mg (0.714 mmol) of p-toluenesulfonic acid. The ice bath was removed and the mixture was stirred for 20 min. To the resulting purple solution was added 150 mL of saturated aqueous sodium bicarbonate. The organic layer was separated, dried
(MgSO4) and concentrated in vacuo to afford a yellow oil. The oil was distilled to give 18.3 g (92%) of the protected alcohol 318 as a colorless oil: bp 101-105 °C at 28 mmHg 1 [lit bp 63-65 °C at 9 mmHg]; H-NMR (500 MHz, C6D6) δ 1.10-1.20 (m, 2H, CH2 of
THP ring), 1.20-1.30 (m, 1H, CH2 of THP ring), 1.50-1.60 (m, 2H, CH2 of THP ring),
1.60-1.70 (m, 1H, CH2 of THP ring), 2.00 (dd, J = 3.9, 2.3 Hz, 1H, C≡CH), 3.28-3.31 (m,
1H, CH2O), 3.63 (ddd, J = 11.9, 9.2, 2.9 Hz, 1H, CH2O), 4.08-4.16 (m, 2H, OCH2C≡C), 4.79 (t, J = 3.3 Hz, 1H, OCHO).
OH THPO
319a
(±)-6-(Tetrahydropyran-2-yloxy)-4-hexyn-2-ol (319a). A 250-mL three-necked round- bottomed flask equipped with a low temperature thermometer and under argon atmosphere, was charged with 5.0 g (35.7 mmol) of alkyne 318 and 95 mL of dry THF.
The light yellow solution was cooled to –75 °C (CO2/acetone), and 14.6 mL (40.0 mmol) of 2.74 M n-BuLi in hexanes was added via syringe at a rate to maintain the internal temperature below –65 °C. The mixture was stirred for 30 min. To the resulting brown
157 solution was added 5.1 mL (5.68 g, 40.0 mmol) of BF3·Et2O via syringe at a rate that the internal temperature did not exceed –65 °C. The mixture was stirred for 45 min. A solution of 2.8 mL (2.32 g, 40.0 mmol) of propylene oxide in 36 mL of dry THF was added via cannula. The mixture was stirred for another 3 h and 125 mL of saturated aqueous sodium bicarbonate was added. The bath was removed and the mixture was allowed to reach room temperature. The organic phase was separated. The aqueous phase was extracted with three 100-mL portions of ethyl acetate. The combined organic
phases were washed with 100 mL of brine, dried (MgSO4) and concentrated in vacuo to afford a yellow oil. The oil was chromatographed over 250 g of silica gel (70-230 mesh, eluted with 30% EtOAc/70% hexanes) to give 3.20 g (45%) of alcohol 319a as a -1 1 colorless oil: IR (Neat) 3396, 2238, 1716 cm ; H-NMR (400 MHz, C6D6) δ 1.11 (d, J =
6.2 Hz, 3H, CH3), 1.17–1.30 (m, 2H, CH2 of THP ring), 1.30–1.40 (m, 1H, CH2 of THP ring), 1.43–1.60 (m, 2H, CH2 of THP ring), 1.60–1.75 (m, 1H, CH2 of THP ring), 2.10-
2.13 (m, 2H, CH2CH(OH)CH3), 2.51 (broad s, 1H, OH), 3.32–3.36 (m, 1H, CHOH),
3.67–3.77 (m, 2H, CH2OCHO), 4.24 (two overlapping ddt, J = 15.4, 6.5, 2.1 Hz, 2H, 13 OCH2C≡C), 5.55 (t, J = 3.25 Hz, 1H, OCHO); C-NMR (100 MHz, C6D6) δ 19.19 (t), 22.45 (q), 25.69 (t), 29.63 (t), 30.58 (t), 54.65 (t), 61.54 (t), 66.38 (d), 78.94 (s), 83.40 (s),
96.69 (d); exact mass calcd for C11H18O3 (M + Na) m/z 221.1148, found m/z 221.1138.
OH
THPO 320a
(±)-(Z)-6-(Tetrahydropyran-2-yloxy)-4-hexen-2-ol (320a). A 100-mL three-necked round-bottomed flask under argon atmosphere was charged with 18 mL of pyridine and 1.07 g of 5% palladium on barium sulfate. The mixture was prehydrogenated at 1 atmosphere until the catalyst turned black. Then a solution of 2.5 g (12.6 mmol) of alkyne 319a in 7 mL of pyridine was added via syringe. The mixture was hydrogenated
158 for 40 min (∼ 300 mL of hydrogen uptake). The mixture was filtered through a pad of Celite and the filtered cake was rinse with 100 mL of chloroform. The filtrate was washed with three 100-mL portions of 1 N aqueous HCl. The organic phase was then concentrated in vacuo to afford 6.0 g of a brown oil. The oil was chromatographed over 150 g of silica gel (230-400 mesh, eluted with 10% acetone/90% hexanes) to give 2.32 g (92%) of alkene 320a (1:1 mixture of diastereoisomers) as a colorless oil: IR (Neat) -1 1 3410, 3024, 1722 cm ; H-NMR (400 MHz, C6D6) δ 1.03 (d, J = 6.2 Hz, 3H, CH3),
1.15–1.40 (m, 3H, CH2 of THP ring), 1.45–1.65 (m, 2H, CH2 of THP ring), 1.65–1.80
(m, 1H, CH2 of THP ring), 1.94-2.10 (m, 1H, CH=CHCHH), 2.10-2.20 (m, 1H, CH=CHCHH), 2.40 (broad s, 1H, OH), 3.36 (dd, J = 10.1, 4.2 Hz, 1H, CHHOCHO), 3.60–3.70 (m, 1H, CHOH), 3.78 (qd, J = 10.1, 2.8, 1H, CHHOCHO), 4.05 (dt, J = 12.3,
7.0, Hz, 1H, THPOCH2CH=CH), 4.25-4.35 (m, 1H, THPOCH2CH=CH), 4.62–4.65 (m,
1H, OCHO), 5.52–5.60 (m, 1H, THPOCH2CH=CH), 5.73–5.80 (m, 1H, 13 THPOCH2CH=CH); C-NMR (100 MHz, C6D6) δ 19.38 (t), 19.40 (t), 23.11 (q), 23.26 (q), 25.82 (t), 30.82 (t), 30.87 (t), 37.67 (t), 37.71 (t), 61.53 (t), 61.58 (t), 62.68 (t), 62.87 (t), 67.54 (d), 97.51 (d), 97.79 (d), 128.79 (d), 129.00 (d), 129.90 (d), 130.04 (d); exact
mass calcd for C11H20O3 (M + Na) m/z 223.1305, found m/z 223.1314. NMR spectra showed small signals that might correspond to the E-isomer.
OAc
HO 321a
(±)-(Z)-5-Acetoxy-2-hexen-1-ol (321a).48 A 50-mL three-necked round-bottomed flask under argon atmosphere was charged with 1.0 g (4.99 mmol) of the alcohol 320a and 13 mL of dry dichloromethane. To the colorless solution was sequentially added 1.4 mL (1.01 g, 9.98 mmol) of triethylamine, 0.6 mL (649 mg, 6.36 mmol) of acetic anhydride and 61 mg (0.499 mmol) of 4-dimethylaminopyridine. The mixture was stirred for 2 h
159 and diluted with 40 mL of dichloromethane. The solution was washed with 20 mL of
saturated aqueous ammoniun chloride, dried (Na2SO4) and concentrated in vacuo to afford 1.29 g of the expected acetate as a colorless oil. The crude ester was dissolved in 10 mL of anhydrous methanol and 95 mg (0.499 mmol) of p-toluenesulfonic acid monohydrate was added. The mixture was stirred for 2 h and then concentrated in vacuo to afford a cloudy oily residue. The residue was dissolved in 50 mL of diethyl ether and washed with 20 mL of saturated aqueous sodium
bicarbonate. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to afford 738 mg of a pale yellow oil. The oil was chromatographed over 50 g of silica gel (230–400 mesh, eluted with 30% EtOAc/70% hexanes) to give 517 mg (66%) of alcohol 321a as a colorless liquid: IR (Neat) 3422, 3023, 1736 cm-1; 1H-NMR (400
MHz, CDCl3) δ 1.23 (d, J = 6.3 Hz, 3H, CH3), 1.57 (broad s, 1H, OH), 2.02 (s, 3H, CH3), 2.25–2.33 (m, 1H, CH=CH-CHH), 2.36–2.44 (m, 1H, CH=CH-CHH), 4.19 (dd, J = 6.7,
0.6 Hz, 2H, HOCH2), 4.93 (sextet, J = 6.3 Hz, 1H, CHOAc), 5.50–5.57 (m, 1H, 13 HOCH2CH=CH), 5.72–5.78 (m, 1H, HOCH2CH=CH); C-NMR (100 MHz, CDCl3) δ 19.44 (q), 21.18 (q), 33.65 (t), 58.21 (t), 70.27 (d), 126.93 (d), 131.44 (d), 170.67 (s); exact mass calcd for C8H14O3 (M + Na) m/z 181.0835, found m/z 181.0829. NMR spectra show small signal that might correspond to the E-isomer.
O
O
PhSe 321b
(±)-(Z)-2-Acetoxy-5-phenylselenyl-3-pentene (321b). A 25-mL three-necked round- bottomed flask under argon atmosphere was charged with 250 mg (1.58 mmol) of alcohol 321a and 7 mL of dry dichloromethane. To the colorless solution was added 330 µL (240 mg, 2.37 mmol) of triethylamine via syringe, followed by 184 µL (271 mg, 2.37
160 mmol) of methanesulfonyl chloride dropwise via syringe. The reaction was stirred for 3 h and another 1.5 equivalents of both triethylamine and methanesulfonyl chloride were added. The same procedure was repeated after the 5 h. After stirring for another 15 h, the mixture was diluted with 40 mL of dichloromethane. The solution was washed with 30 mL of water and 30 mL of saturated aqueous ammonium chloride. The combined aqueous washes were extracted with three 30-mL portions of dichloromethane. The
combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford 499 mg of the crude mesylate. A 25-mL three-necked round-bottomed flask under argon atmosphere was charged with 493 mg (1.58 mmol) of diphenyl diselenide and 10 mL of absolute ethanol.
The yellow solution was cooled to 0 °C (ice-water) and 180 mg (4.5 mmol) of NaBH4 was added in small portions until the solution turned colorless and the solid went into solution (about 40 min). To this solution was added a solution of the mesylate in 5 mL of absolute ethanol. The solution turned yellow immediately and a precipitate was observed. The mixture was stirred for 3 h at 0 °C and then concentrated in vacuo. The residue was diluted with 25 mL of ethyl acetate and washed with two 10-mL portions of saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4) and concentrated in vacuo to give 663 mg of a yellow oil. The oil was chromatographed over 40 g of silica gel (230–400 mesh, eluted with 4% EtOAc/96 % hexanes) to give 357 mg 1 (76%) of selenide 321b as a pale yellow oil: H-NMR (400 MHz, CDCl3) δ 1.16 (d, J =
6.3 Hz, 3H, CH3), 2.02 (s, 3H, OCOCH3), 2.04–2.15 (m, 1H, CH2CHOAc), 2.19–2.25
(m, 1H, CH2CHOAc), 3.50–3.62 (m, 2H, PhSeCH2), 4.03 (sextet, J = 6.3 Hz, 1H,
CHOAc), 5.41 (ddd, J = 10.7, 7.5 Hz, 1H, PhSeCH2CH=CH), 5.75 (dtt, J = 10.7, 8.3, 1.6 13 Hz, 1H, PhSeCH2CH=CH), 7.25–7.28 (m, 3H, ArH), 7.53–7.55 (m, 2H, ArH); C-NMR
(100 MHz, CDCl3) δ 19.51 (q), 21.25 (q), 24.59 (t), 33.19 (t), 70.16 (d), 127.11 (d), 127.26 (d), 127.99 (d), 128.94 (d), 129.95 (s), 133.72 (d), 170.53 (s); exact mass calcd for
C14H18O2Se (M + Na) m/z 321.0364, found m/z 321.0347. NMR spectra showed small signals that might correspond to the E-isomer.
161 OH
PhSe 315
(±)-(Z)-6-Phenylselenyl-4-hexen-2-ol (315). A 50-mL round-bottomed flask was charged with 341 mg (1.15 mmol) of protected alcohol 322 and 12 mL of methanol. To the colorless solution was added 159 mg (1.15 mmol) of K2CO3. The colorless solution was stirred for 4.3 h. The mixture was concentrated in vacuo to afford a residue composed of a cloudy oil and a solid. The residue was diluted with 50 mL of dichloromethane. The solution was washed with 20 mL of water and 20 mL of brine,
dried (MgSO4) and concentrated in vacuo to afford 274 mg (93%) of alcohol 315 as -1 1 colorless oil: IR (Neat) 3383, 3071, 3018, 1578 cm ; H-NMR (400 MHz, CDCl3) δ 1.15
(d, J = 6.2 Hz, 3H, CH3), 1.40 (broad s, 1H, OH), 2.00–2.16 (m, 2H, HC=CHCH2), 3.50–
3.62 (m, 2H, PhSeCH2), 3.71 (sextet, J = 6.2 Hz, 1H, CHOH), 5.44–5.51 (m, 1H,
PhSeCH2CH=CH), 5.74–5.82 (m, 1H, PhSeCH2CH=CH), 7.25–7.27 (m, 3H, ArH), 7.53– 13 7.55 (m, 2H, ArH); C-NMR (100 MHz, CDCl3) δ 22.88 (q), 24.65 (t), 36.59 (t), 67.45 (d), 127.29 (d), 128.19 (d), 128.22 (d), 128.92 (d), 129.81 (s), 133.82 (d); exact mass
calcd for C12H16OSe (M + Na) m/z 279.0259, found m/z 279.0264. NMR spectra showed small signals that might correspond to the E-isomer.
OCH3 EtO2C
SePh 316
(±)-(Z)-Ethyl 3-(1-Methyl-5-phenylselenyl-3-pentenyloxy)acrylate (316a). A 25-mL three-necked round-bottomed flask under argon atmosphere was charged with 165 µL (158 mg, 1.61 mmol) of ethyl propiolate (246) and 1.6 mL of dry diethyl ether. To the
162 colorless solution was added 230 µL (163 mg, 1.61 mmol) of triethylamine. To the resulting yellow solution was added a solution of 272 mg (1.1 mmol) of alcohol 315 in 2.0 mL of diethyl ether via syringe. The resulting brown solution was stirred for 41 h. The mixture was diluted with 20 mL of diethyl ether and was washed with 15 mL of 1 M aqueous KHSO4, 15 mL of saturated aqueous NaHCO3 and 15 mL of brine, dried
(MgSO4) and concentrated in vacuo to afford 444 mg of a brown oil. The oil was chromatographed over 40 g of silica gel (230–400 mesh, eluted with 5% EtOAc/95% hexanes) to give 296 mg (78%) of enol ether 316a as pale yellow oil: IR (Neat) 1707, -1 1 1641, 1621 cm ; H-NMR (400 MHz, CDCl3) δ 1.18 (d, J = 6.2 Hz, 3H, CH3), 1.27 (t, J
= 7.1 Hz, 3H, OCH2CH3), 2.08–2.14 (m, 1H, HC=CHCH2), 2.17–2.25 (m, 1H,
HC=CHCH2), 3.47–3.57 (m, 2H, PhSeCH2), 3.81 (sextet, J = 6.2 Hz, 1H, OCHCH3),
4.13 (q, J = 7.1 Hz, 2H, OCH2CH3), 5.19 (d, J = 12.4 Hz, 1H, CH=CHCO2Et), 5.35–5.41
(m, 1H, PhSeCH2CH=CH), 5.71–5.76 (m, 1H, PhSeCH2CH=CH), 7.23–7.28 (m, 3H, 13 ArH), 7.44 (d, J = 12.4 Hz, 1H, CH=CHCO2Et), 7.52–7.54 (m, 2H, ArH); C-NMR (100
MHz, CDCl3) δ 14.36 (q), 19.67 (q), 24.70 (t), 33.39 (t), 59.64 (t), 78.84 (d), 97.34 (d), 126.38 (d), 127.44 (d), 128.45 (d), 128.97 (d), 129.68 (s), 134.13 (d), 161.58 (d), 168.00
(s); exact mass calcd for C17H22O3Se (M + Na) m/z 377.0626, found m/z 377.0620. NMR spectra showed small signals that might correspond to the E-isomer.
OH OBn 319b
(±)-1-Benzyloxy-4-hexyn-2-ol (319b).83 A 25-mL graduated cylinder under argon
atmosphere was cooled to -78 °C (acetone/CO2) and 3.0 mL of propyne (317b) was condensed, therein. A 100 mL three-necked round-bottomed flask, equipped with a low temperature thermometer under argon atmosphere was charged with 31 mL of dry THF and cooled to -78 °C. Then, 2.5 mL (1.75 g, 43.7 mmol) of the previously condensed
163 propyne was added to the THF via cannula. To the solution was added 5.5 mL (12.8 mmol) of 2.2 M n-BuLi in hexanes at a rate to maintain the internal temperature below – 70 °C. The resulting solution was stirred for 30 min and 1.6 mL (1.82 g, 12.8 mmol) of
BF3·Et2O was added at a rate to maintain the internal temperature below –70 °C. The mixture was stirred for 1 h and a solution of 1.0 g (6.09 mmol) of 2- (benzyloxymethyl)oxirane (306b) in 6 mL of dry THF at -78 °C was added via cannula.
The reaction was stirred for 1.5 h at -78 °C and 20 mL of saturated aqueous NaHCO3 was added. The mixture was allowed to reach room temperature and was then extracted with two 30-mL portions of diethyl ether. The combined organic extracts were washed with
20 mL of brine, dried (MgSO4) and concentrated in vacuo to afford 1.31 g of a yellow oil. The oil was chromatographed over 65 g of silica gel (230-400 mesh, eluted with 30% EtOAc/70% hexanes) to give 1.10 g (89%) of the alcohol 319b as a colorless oil: 1H-
NMR (400 MHz, CDCl3) δ 1.77 (t, J = 2.6 Hz, 3H, CH3), 2.15 (broad s, 1H, OH), 2.35-
2.42 (m, 2H, CH2C≡C), 3.50 (dd, J = 9.5, 4.0 Hz, 1H, CH2OBn), 3.60 (dd, J = 9.5, 6.7
Hz, 1H, CH2OBn), 3.91 (dddd, J = 6.4, 6.4, 6.4, 4.0 Hz, 1H, CHOH), 4.59 (s, 2H,
CH2Ph), 7.30-7.40 (m, 5H, ArH).
OH OBn
320b
(±)-(Z)-1-Benzyloxy-4-hexen-2-ol (320b). A 25-mL two-necked round-bottomed flask under argon atmosphere was charged with 5.0 mL of methanol and 150 mg (0.734 mmol) of alkyne 319b. To the solution was added 39 mg of 5% palladium on barium sulfate and 7 µL (8 mg, 0.062 mmol) of quinoline. A hydrogen balloon was attached and the flask was evacuated and filled with H2 through a needle. The reaction mixture was stirred for 4 h and the mixture was filtered through a Celite pad. The filtrate was concentrated in
164 vacuo to afford 160 mg of a yellow oil. The oil was chromatographed over 15 g of silica gel (230-400 mesh, eluted with 10% acetone/90% hexanes) to give 108 mg of the alkene 320b contaminated with traces of quinoline. The alkene was diluted with 20 mL of dichloromethane and washed with two 10-mL portions of 10% aqueous HCl. The
organic phase was dried (MgSO4) and concentrated in vacuo to give 90 mg (60%) of the alkene 320b as a colorless oil: IR (Neat) 3450, 3026, 1454 cm-1; 1H-NMR (400 MHz,
CDCl3) δ 1.63 (dt, J = 6.7, 0.7 Hz, 3H, CH3), 2.22 (broad s, 1H, OH), 2.25-2.35 (m, 2H,
CH2C=C), 3.40 (dd, J = 9.5, 7.4 Hz, 1H, CH2OBn), 3.54 (dd, J = 9.5, 3.3 Hz, 1H,
CH2OBn), 3.87 (dddd, J = 6.7, 6.7, 6.7, 3.3 Hz, 1H, CHOH), 4.57 (s, 2H, CH2Ph), 5.44
(dtq, J = 11.5, 7.4, 1.7 Hz, 1H, CH3CH=CH), 5.62 (dqt, J = 11.5, 6.7, 1.5 Hz, 1H, 13 CH3CH=CH), 7.30-7.40 (m, 5H, ArH); C-NMR (100 MHz, CDCl3) δ 12.92 (q), 30.94 (t), 70.29 (d), 73.38 (t), 73.95 (t), 125.46 (d), 126.82 (d), 127.71 (d), 127.74 (d), 128.43
(d), 138.00 (s); exact mass calcd for C13H18O2 (M + Na) m/z 229.1199, found m/z 229.1198. The Z/E ratio was 10:1 based on the integration of signals at 1.63 and 1.66 ppm.
OBn O EtO2C
316b
(±)-(Z)-Ethyl 3-(1-Benzyloxymethyl-3-pentenyloxy)acrylate (316b). A 10-mL two- necked round-bottomed flask under nitrogen atmosphere was charged with 66 µL (64 mg, 0.654 mmol) of ethyl propiolate (246), 0.7 mL of dry diethyl ether and 90 µL (66 mg, 0.654 mmol) of triethylamine. To the resulting yellow mixture was added a solution of 90 mg (0.436 mmol) of alcohol 320b in 0.5 mL of dry diethyl ether via syringe. The brown solution was stirred for 48 h. The mixture was diluted with 20 mL of diethyl ether 165 and washed with two 3-mL portions of 1M aqueous KHSO4, two 3-mL portions of
saturated aqueous NaHCO3 and 3 mL of brine. The organic phase was separated, dried
(MgSO4) and concentrated in vacuo to afford 126 mg of a brown oil. The oil was chromatographed over 12 g of silica gel (230–400 mesh, eluted with 10% diethyl ether/90% hexanes) to give 100 mg (75%) of the enol ether 316b as a colorless oil: IR -1 1 (Neat) 1708, 1641, 1620 cm ; H-NMR (400 MHz, CDCl3) δ 1.27 (t, J = 7.1 Hz, 3H,
OCH2CH3), 1.64 (dt, J = 6.8, 0.7 Hz, 3H, CH3), 2.41 (t, J = 6.8 Hz, 2H, CH2C=C), 3.54
(dd, J = 10.6, 6.3 Hz, 1H, CH2OBn), 3.58 (dd, J = 10.6, 3.8 Hz, 1H, CH2OBn), 4.10
(dddd, J = 6.3, 6.3, 6.3, 3.8 Hz, 1H, CHOH), 4.17 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.55 (s,
2H, CH2Ph), 5.30 (d, J = 12.3 Hz, 1H, CH=CHCO2Et), 5.36 (dtq, J = 11.5, 7.4, 1.8 Hz,
1H, CH3CH=CH), 5.60 (dqt, J = 11.5, 6.8, 1.4 Hz, 1H, CH3CH=CH), 7.27-7.37 (m, 5H, 13 ArH), 7.63 (d, J = 12.3 Hz, 1H, CH=CHCO2Et); C-NMR (100 MHz, CDCl3) δ 12.91 (q), 14.35 (q), 28.82 (t), 59.60 (t), 71.33 (t), 73.43 (t), 82.59 (d), 97.44 (d), 123.91 (d), 127.57 (d), 127.63 (d), 127.70 (d), 128.37 (d), 137.76 (s), 162.59 (d), 167.99 (s); exact mass calcd for C18H24O4 (M + Na) m/z 327.1567, found m/z 327.1569. NMR spectra showed small signals that correspond to the E-isomer.
CO2Et OBn O CO2Et O
OH O 322 323
H HO O O OBn OBn O H 324 320b
166 rel-(2R, 3R, 4R, 6S)-6-Benzyloxymethyl-2-carbethoxymethyl-4-hydroxy-3-methyl tetrahydropyran (322), rel-(1S, 3R, 4R, 5R)-Ethyl 1-(4-methyl-2,6-dioxabicyclo- [3.2.1]oct-3-yl)acetate (323) and rel-(2R, 4S, 5R, 9R)-2-Benzyloxymethyl-4-methyl hexahydro-furo[3,2-c]pyran-6-one (324) and (±)-(Z)-1-Benzyloxy-4-hexen-2-ol (320b). A 25-mL three-necked round-bottomed flask under argon atmosphere was charged with 98 mg (0.322 mmol) of enol ether 321 (from the preceding experiment) and 3.2 mL of dry dichloromethane. The solution was cooled to 0 °C (ice-water) and 0.25 mL (367 mg, 3.22 mmol) of trifluoroacetic acid was added slowly via syringe. The ice bath was removed and the mixture was stirred for 5.3 h. To the solution was added 13 mL of saturated aqueous sodium bicarbonate. The mixture was extracted with three 20-
mL portions of dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to afford 123 mg of a yellow oil. The oil was dissolved in 3.2 mL of ethanol and 22 mg (0.161 mmol) of anhydrous potassium carbonate was added. The mixture was stirred for 12 h at room temperature. The resulting solution was concentrated in vacuo and diluted with 25 mL of ethyl acetate. The solution was washed with 10 mL of water. The aqueous layer was separated and extracted with two 15-mL portions of ethyl acetate. The combined organic layers were dried (MgSO4), and concentrated in vacuo to afford 95 mg of a yellow oil. The oil was chromatographed over 15 g of silica gel (230–400 mesh, eluted with 20% ethyl acetate/80% hexanes and 40% ethyl acetate/60% hexanes) to give 35 mg (34%) of tetrahydropyran 322 as a yellow oil, 24 mg (34%) of bicyclic ether 323 as a yellow oil, 4 mg (4.5%) of lactone 324 as a colorless oil and 10 mg (15%) of alcohol 320b as a colorless oil. Tetrahydropyran 322: -1 1 IR (Neat) 3446, 1735 cm ; H-NMR (400 MHz, CDCl3) δ 0.90 (d, J = 6.9 Hz, 3H, CH3),
1.24 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.46 (ddd, J = 12.0, 12.0, 12.0 Hz, 1H, CH2CHOH),
1.67 (dddd, J = 12.0, 2.1, 2.1, 2.1 Hz, 1H, CH2CHOH), 1.88 (broad s, 1H, OH), 1.90-1.99
(m, 1H, CHCH3), 2.40 (dd, J = 15.3, 5.7 Hz, 1H, CH2CO2Et), 2.65 (dd, J = 15.3, 5.7 Hz,
1H, CH2CO2Et), 3.40-3.50 (m, 1H, CH2OBn), 3.50-3.60 (m, 1H, CH2OBn), 3.61-3.63
(m, 1H, OCHCH2OBn), 3.88 (ddd, J = 6.9, 6.9, 2.1 Hz, 1H, CHCH2CO2Et), 3.95 (ddd, J
= 11.7, 4.8, 4.8 Hz, 1H, CHOH), 4.10-4.20 (m, 2H, OCH2CH3), 4.52-4.62 (sharp m, 2H, 13 OCH2Ph), 7.28-7.39 (m, 5H, ArH); C-NMR (100 MHz, CDCl3) δ 4.86 (q), 14.14 (q),
167 31.44 (t), 37.68 (d), 38.15 (t), 60.48 (t), 70.53 (d), 72.79 (t), 73.25 (t), 75.19 (d), 75.66 (d), 127.50 (d), 127.59 (d), 128.28 (d), 138.29 (s), 171.26 (s); exact mass calcd for
C18H26O5 (M + Na) m/z 345.1672, found m/z 345.1660. NMR spectra showed small signals that might correspond to the C-3 epimer. Bicyclic ether 323: IR (Neat) 1736 cm- 1 1 ; H-NMR (500 MHz, CDCl3) δ 0.85 (d, J = 7.1 Hz, 3H, CH3), 1.25 (t, J = 7.1 Hz, 3H,
OCH2CH3), 1.50 (ddd, J = 11.8, 6.0, 2.4 Hz, 1H, OCHCH2CHO), 1.85-1.90 (m, 1H,
CHCH3), 2.12 (d, J = 11.9 Hz, 1H, OCHCH2CHO), 2.30 (dd, J = 15.1, 5.0 Hz, 1H,
CH2CO2Et), 2.46 (dd, J = 15.1, 9.0 Hz, 1H, CH2CO2Et), 3.76 (dd, J = 9.9, 2.9 Hz, 1H,
OCH2), 4.10-4.20 (m, 2H, OCH2CH3), 4.24 (d, J = 9.9 Hz, 1H, OCH2), 4.34 (dd, J = 5.4,
5.4 Hz, 1H, OCHCHCH3), 4.40 (broad s, 1H, OCH2CHO), 4.47 (ddd, J = 11.2, 4.6, 4.6 13 Hz, 1H, CHCH2CO2Et); C-NMR (100 MHz, CDCl3) δ 10.61 (q), 14.15 (q), 31.69 (t), 37.35 (t), 37.69 (d), 60.49 (t), 69.09 (d), 70.58 (t), 75.05 (d), 79.42 (d), 171.29 (s); exact
mass calcd for C11H18O4 (M + Na) m/z 237.1097, found m/z 237.1097. Lactone 324: IR -1 1 (CH2Cl2) 1748 cm ; H-NMR (500 MHz, CDCl3) δ 1.34 (d, J = 6.4 Hz, 3H, CH3), 1.63
(ddd, J = 12.6, 11.4, 11.1 Hz, 1H, CH2CHCH2OBn), 1.98 (ddd, J = 12.6, 8.5, 4.6 Hz, 1H,
CH2CHCH2OBn), 2.53 (dd, J = 15.8, 4.6 Hz, 1H, CH2CO2), 2.65 (dddd, J = 9.3, 9.3, 9.3,
2.8 Hz, 1H, CH3CHCH), 2.85 (dd, J = 15.8, 1.4 Hz, 1H, CH2CO2), 3.55 (d, J = 5.2 Hz,
2H, CH2OBn), 3.90-4.00 (m, 1H, OCHCH2OBn), 4.35-4.45 (m, 1H, CHCH3), 4.45-4.50
(m, 1H, CHCH2CO2), 4.52 (AB d, J = 12.1 Hz, 1H, OCH2Ph), 4.62 (AB d, J = 12.0 Hz, 13 1H, OCH2Ph), 7.27-7.38 (m, 5H, ArH); C-NMR (100 MHz, CDCl3) δ 18.28 (q), 28.71 (t), 35.64 (t), 42.28 (d), 72.30 (t), 73.82 (d), 74.03 (t), 75.15 (d), 78.44 (d), 128.09 (d), 128.29 (d), 128.81 (d), 138.45 (s), 171.35 (s). The relative stereochemistry for tetrahydropyran 322, byciclic ether 323 and lactone 324 was established by NOESY studies. The 1H-NMR data for alcohol 320b matched previously reported data.
168 OBn
332
4-Benzyloxybutene (332).52, 84 A 250-mL three-necked round-bottomed flask under argon atmosphere was charged with 90 mL of dry THF and 1.1 g (45.8 mmol) of sodium hydride. The suspension was cooled to 0 °C (ice-water) and 3.0 g (41.6 mmol) of 3- buten-1-ol (331) was added dropwise via syringe. The ice bath was removed and the reaction was stirred for 1 h at room temperature. Then, 5.4 mL (7.83 g, 45.8 mmol) of benzyl bromide was added dropwise via syringe. The mixture was stirred for 18 h and 45 mL of brine was added. The organic phase was separated. The aqueous layer was extracted with three 75-mL portions of diethyl ether. The combined organic layers were
dried (MgSO4) and concentrated under vacuo to afford 8.34 g of a yellow oil. The oil was distilled to give 6.74 g (78%) of the protected alcohol 332 as colorless oil: bp 120- 84 1 125 °C at 16 torr [lit bp 108-110 °C at 19 torr]; H-NMR (250 MHz, CDCl3) δ 2.41 (qt,
J = 6.7, 1.3 Hz, 2H, CH2=CHCH2), 3.56 (t, J = 6.8 Hz, 2H, CH2OBn), 4.55 (s, 2H,
CH2Ph), 5.04-5.18 (m, 2H, CH2=CHCH2), 5.86 (ddt, J = 17.1, 10.3, 6.8 Hz, 1H,
CH2=CHCH2), 7.26-7.41 (m, 5H, ArH).
O OBn
333
(±)-1-Benzyloxy-3-butene oxide (333).52 A 100-mL three-necked round-bottomed flask under argon atmosphere was charged with 2.20 g (13.57 mmol) of the benzyl ether 332 and 20 mL of dry dichloromethane. The solution was cooled to 0 °C (ice-water). To the
169 cooled solution was added 1.48 g (17.64 mmol) of sodium bicarbonate, followed by 5.2 g (21.03 mmol) of m-chloroperoxybenzoic acid in small portions. The white suspension was stirred for 1 h. The ice bath was removed and 5 mL of dry dichloromethane was added (to help the stirring). The mixture was stirred for 15 h and 1.0 g of sodium thiosulphate was added. The mixture was stirred for another 20 min and diluted with 40 mL of dichloromethane. The white solid was filtered and the filtrate was concentrated in vacuo to afford a white suspension. The suspension was partitioned between 40 mL of water and 40 mL of diethyl ether. The mixture was extracted with three 50-mL portions
of diethyl ether. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford 2.48 g of a yellow oil. The oil was chromatographed over 150 g of silica gel (230-400 mesh eluted with 20% diethyl ether/80% low boiling petroleum ether) to 1 give 1.38 g (57%) of epoxide 333 as a colorless oil: H-NMR (400 MHz, CDCl3) δ 1.81
(dddd, J = 14.4, 6.0, 6.0, 6.0 Hz, 1H, CH2CH2OBn), 1.89-1.97 (m, 1H, CH2CH2OBn),
2.54 (dd, J = 5.0, 2.7 Hz, 1H, CH2OCH), 2.80 (dd, J = 4.9, 4.2 Hz, 1H, CH2OCH), 3.07-
3.10 (m, 1H, CH2OCH), 3.60-3.70 (m, 2H, CH2OBn), 4.58 (s, 2H, CH2Ph), 7.27-7.40 (m, 5H, ArH).
OH
OBn
334
(±)-1-Benzyloxy-5-heptyn-3-ol (334). A 25-mL graduate cylinder under argon
atmosphere was cooled to -78 °C (acetone/CO2) and 25 mL of propyne was condensed therein. A 100-mL three-necked round-bottomed flask, equipped with a low temperature thermometer and under argon atmosphere, was charged with 330 mL of dry THF and
170 cooled to -75 °C. Then, 22 mL (15.7 g, 391 mmol) of the previously condensed propyne was added to the THF via cannula. To the solution was added 65 mL (130 mmol) of 2.0 M n-BuLi in hexanes at a rate to maintain the internal temperature below –70 °C. The resulting cloudy solution was stirred for 30 min and 17.3 mL (19.4 g, 137 mmol) of
BF3·Et2O was added at a rate to maintain the internal temperature below –70 °C. The mixture was stirred for 1 h and a solution of 11.6 g (65.1 mmol) of epoxide 333 in 66 mL of dry THF at -78 °C was added via cannula. The reaction was stirred for 2 h at -78 °C
and 225 mL of saturated aqueous NaHCO3 was added. The mixture was allowed to reach room temperature. The organic layer was separated. The aqueous layer was extracted with three 150-mL portions of ethyl acetate. The combined organic layers were washed
with 100 mL of brine, dried (MgSO4) and concentrated in vacuo to afford 14.40 g of a yellow oil containing a white precipitate. The mixture was chromatographed over 400 g of silica gel (230-400 mesh, eluted with 30% EtOAc/70% hexanes) to give 12.25 g (86%) -1 1 of alcohol 334 as a colorless oil: IR (Neat) 3452 cm ; H-NMR (400 MHz, CDCl3) δ
1.79 (t, J = 2.5 Hz, 3H, CH3), 1.83-1.89 (m, 2H, CH2CH2OBn), 2.35 (dq, J = 6.0, 2.5 Hz,
2H, CH2C≡C), 3.20 (broad s, 1H, OH), 3.66 (ddd, J = 9.4, 7.6, 4.8 Hz, 1H, CH2OBn),
3.73 (ddd, J = 9.4, 6.1, 5.0 Hz, 1H, CH2OBn), 3.93 (m, 1H, CHOH), 4.50 (s, 2H, CH2Ph), 13 7.15-7.36 (m, 5H, ArH); C-NMR (100 MHz, CDCl3) δ 3.40 (q), 27.38 (t), 35.36 (t), 68.47 (t), 69.55 (d), 73.17 (s), 75.33 (t), 77.82 (s), 127.56 (d), 127.61 (d), 128.33 (d),
137.86 (s); exact mass calcd for C14H18O2 (M + Na) m/z 241.1199, found m/z 241.1207.
171 OH
OBn
335
(±)-(Z)-1-Benzyloxy-5-hepten-3-ol (335). A 250-mL of three-necked round-bottomed flask was charged with 40 mL of pyridine and 2.34 g of 5% Pd/BaSO4. The brown mixture was evacuated and prehydrogenated. To the resulting black mixture was added a solution of 6.0 g (27.5 mmol) of alkyne 334 in 16 mL of pyridine. The mixture was hydrogenated for 2 h at one atmosphere. The mixture was flushed with argon and filtered through a Celite pad. The pad was washed with chloroform up to a filtrate volume of 200 mL. The filtrate was washed with three 100-mL portions of 10% aqueous HCl. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to afford 6.05 g (99%) of the alkene 335 as a yellow oil: IR (Neat) 3434 cm-1; 1H-NMR (400 MHz,
CDCl3) δ 1.65 (dd, J = 6.8, 0.8 Hz, 3H, CH3), 1.75-1.90 (m, 2H, CH2CH2OBn), 2.15-3.15
(m, 2H, CH2CH=CH), 2.55 (broad s, 1H, OH), 3.64-3.69 (m, 1H, CH2OBn), 3.70-3.74
(m, 1H, CH2OBn), 3.76-3.82 (m, 1H, CHOH), 4.55 (s, 2H, CH2OBn), 5.37 (dqt, J = 10.9,
7.4, 1.7 Hz, 1H, CH=CHCH3), 5.53 (dqt, J = 10.9, 7.3, 2.0 Hz, 1H, CH=CHCH3), 7.28- 13 7.38 (m, 5H, ArH); C-NMR (100 MHz, CDCl3) δ 12.97 (q), 34.89 (t), 35.88 (t), 69.03 (t), 70.98 (d), 73.30 (t), 126.14 (d), 126.63 (d), 127.65 (d), 127.70 (d), 128.42 (d), 137.98
(s); exact mass calcd for C14H20O2 (M + Na) m/z 243.1355, found m/z 243.1360.
172 OBn
O EtO2C
336
(±)-(Z)-Ethyl 3-[(1-Benzyloxyethyl)pent-3-enyloxy]acrylate (336). A 1000-mL three- necked round-bottomed flask under argon atmosphere was charged with 18 mL (17.4 g, 177 mmol) of ethyl propiolate (246), 177 mL of dry diethyl ether and 25 mL (17.9 g, 177 mmol) of triethylamine. To the resulting yellow mixture was added a solution of 26 g (118 mmol) of alcohol 335 in 170 mL of dry diethyl ether via cannula. The brown solution was stirred for 72 h. The mixture was diluted with 300 mL of diethyl ether and
washed with two 200-mL portions of 1M aqueous KHSO4, two 200-mL portions of
saturated aqueous NaHCO3 and 200 mL of brine. The organic phase was separated, dried
(MgSO4) and concentrated in vacuo to afford 42 g of a brown oil. The oil was chromatographed over about 800 g of silica gel (230–400 mesh, eluted with 10% diethyl ether/90% hexanes) to give 24.2 g (64%) of the enol ether 336 as a pale yellow oil: IR -1 1 (Neat) 1708, 1639, 1622 cm ; H-NMR (400 MHz, CDCl3) δ 1.29 (t, J = 7.1 Hz, 3H,
OCH2CH3), 1.62 (ddd, J = 6.8, 0.8, 0.8 Hz, 3H, CH3), 1.80-2.00 (m, 2H, CH2CH2OBn),
2.30-2.45 (m, 2H, CH2CH=CH), 3.50-3.60 (m, 2H, CH2OBn), 4.18 (q, J = 7.1 Hz, 2H,
OCH2CH3), 4.16-4.22 (m, 1H, CHO), (ABq, J = 11.9 Hz, 2H, OCH2Ph), 5.29 (d, J = 12.7
Hz, 1H, CH=CHCO2Et), 5.40 (dtq, J = 11.1, 7.4, 1.7 Hz, 1H, CH=CHCH3), 5.62 (dqt, J =
10.9, 6.8, 1.4 Hz, 1H, CH=CHCH3), 7.27-7.39 (m, 5H, ArH), 7.56 (d, J = 12.4 Hz, 1H, 13 CH=CHCO2Et); C-NMR (100 MHz, CDCl3) δ 12.92 (q), 14.35 (q), 32.04 (t), 34.38 (t), 59.56 (t), 65.84 (t), 73.12 (t), 80.71 (d), 96.98 (d), 124.23 (d), 127.36 (d), 127.63 (d),
127.73 (d), 128.35 (d), 138.08 (s), 162.67 (d), 168.08 (s); exact mass calcd for C19H26O4 (M + Na) m/z 341.1723, found m/z 341.1728. The Z/E ratio was 13:1 based on the signals at 1.62 and 1.68 ppm.
173 OBn CO2Et O
OH 337
rel-(2R, 3R, 4R, 6S)-6-Benzyloxyethyl-2-carbethoxymethyl-4-hydroxy-3-methyl tetrahydropyran (337). A 2000-mL three-necked round-bottomed flask under argon atmosphere was charged with 24.2 g (76 mmol) of enol ether 336 (from the preceding experiment) and 700 mL of dry dichloromethane. The solution was cooled to 0 °C (ice- water) and 59 mL (86.7 g, 760 mmol) of trifluoroacetic acid was added slowly via syringe. The ice bath was removed and the mixture was stirred for 2 h. The solution was cooled to 0 °C and 300 mL of saturated aqueous sodium bicarbonate was added very slowly. The organic phase was separated. The aqueous phase was extracted with three
200-mL portions of dichloromethane. The combined organic phases were dried (Na2SO4) and concentrated in vacuo to afford 26 g a yellow oil. The oil was dissolved in 700 mL of absolute ethanol and 5.25 g (38.0 mmol) of anhydrous potassium carbonate was added. The mixture was stirred for 16 h at room temperature. The resulting solution was concentrated in vacuo and diluted with 500 mL of ethyl acetate. The solution was washed with 200 mL of water. The aqueous layer was separated and extracted with two
200-mL portions of ethyl acetate. The combined organic layers were dried (MgSO4), and concentrated in vacuo to afford 26 g of a yellow oil. The oil was chromatographed over 800 g of silica gel (230–400 mesh, eluted with 40% ethyl acetate/60% hexanes) to give 17.9 g (70%) of tetrahydropyran 337 as a colorless oil: IR (Neat) 3450, 1735 cm-1; 1H-
NMR (400 MHz, CDCl3) δ 0.90 (d, J = 7.1 Hz, 3H, CH3), 1.27 (t, J = 7.1 Hz, 3H,
OCH2CH3), 1.39 (ddd, J = 12.1, 12.1, 12.1 Hz, 1H, CH2CHOH), 1.59 (broad s, 1H, OH),
1.65 (ddd, J = 12.4, 4.6, 2.5 Hz, 1H, CH2CHOH), 1.70-1.88 (m, 2H, CH2CH2OBn), 1.89-
1.96 (m, 1H, CHCH3), 2.37 (dd, J = 15.2, 5.1 Hz, 1H, CH2CO2Et), 2.59 (dd, J = 15.2, 8.6
Hz, 1H, CH2CO2Et), 3.50-3.60 (m, 3H, CHCH2CH2OBn and CH2OBn), 3.85 (ddd, J =
7.9, 5.0, 2.0 Hz, 1H, CHCH2CO2Et), 3.96 (ddd, J = 11.6, 4.6, 4.6 Hz, 1H, CHOH), 4.15
174 13 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.67 (s, 2H, OCH2Ph), 7.27-7.41 (m, 5H, ArH); C-
NMR (100 MHz, CDCl3) δ 4.92 (q), 14.18 (q), 34.93 (t), 35.95 (t), 37.74 (d), 38.25 (t), 60.42 (t), 66.69 (t), 70.65 (d), 73.02 (t), 73.21 (d), 75.05 (d), 127.48 (d), 127.61 (d),
128.30 (d), 138.44 (s), 171.36 (s); exact mass calcd for C19H28O5 (M + Na) m/z 359.1829, found m/z 359.1807. NMR spectra showed small signals that might correspond to the C- 3 epimer. The relative stereochemistry for tertrahydropyran 337 was established by NOE studies.
OBn CO2Et O
NO OBn 2 CO2Et O O
O 338 339
rel-(2R, 3R, 4S, 6S)-6-Benzyloxyethyl-2-carbethoxymethyl-3-methyl-4-(4’-nitro benzoyl)tetrahydropyran (338) and rel-(2R, 6R)-6-Benzyloxy-2-carbethoxymethyl- 5,6-dihydro-2H-tetrahydropyran (339).53 A 50-mL three-necked round-bottomed flask under argon atmosphere was charged with 300 mg (0.892 mmol) of alcohol 337, 12 mL of dry THF, 703 mg (2.68 mmol) of triphenylphosphine and 224 mg (1.34 mmol) of 4- nitrobenzoic acid. To the colorless solution was added 0.42 mL (467 mg, 2.68 mmol) of diethyl azodicarboxylate dropwise via syringe at a rate to maintain control of the reflux. The mixture was stirred for 8 h at room temperature. The orange solution was diluted
with 80 mL of diethyl ether and washed with 40 mL of 5% aqueous K2CO3. The aqueous layer was separated and extracted with 80 mL of diethyl ether. The combined organic
layers were dried (MgSO4) and concentrated in vacuo to afford a yellow oil. The oil was chromatographed over 50 g of silica gel (230-400 mesh, eluted with 10% ethyl acetate/90% hexanes) to give 51 mg (12%) of the tetrahydropyran 338 as a colorless oil
175 and 173 mg (61%) of alkene 339 as a colorless oil. Tetrahydropyran 338: IR (Neat) -1 1 1724, 1608 cm ; H-NMR (400 MHz, CDCl3) δ 1.06 (d, J = 7.2 Hz, 3H, CH3), 1.24 (t, J
= 7.1 Hz, 3H, OCH2CH3), 1.70-1.85 (m, 4H, CH2CHOAr and CH2CH2OBn), 1.95 (qdd, J
= 7.2, 2.5, 2.5 Hz, 1H, CHCH3), 2.32 (dd, J = 15.2, 5.0 Hz, 1H, CH2CO2Et), 2.57 (dd, J =
15.2, 8.9 Hz, 1H, CH2CO2Et), 3.50-3.60 (m, 2H, CH2OBn), 3.94-4.00 (m, 1H,
CHCH2CH2OBn), 4.13 (qd, J = 7.1, 1.7 Hz, 2H, OCH2CH3), 4.37 (ddd, J = 8.8, 5.0, 2.5
Hz, 1H, CHCH2CO2Et), 4.48 (ABq, J = 11.9 Hz, 2H, CH2Ph), 5.20 (ddd, J = 2.7, 2.7,2.7 Hz, 1H, CHOAr), 7.25-7.31 (m, 5H, ArH), 8.22 (d, J = 8.9 Hz, 2H, ArH), 8.28 (d, J = 8.9 13 Hz, 2H, ArH); C-NMR (100 MHz, CDCl3) δ 10.65 (q), 14.20 (q), 31.12 (t), 35.12 (d), 36.06 (t), 38.11 (t), 60.49 (t), 66.43 (t), 70.52 (d), 71.81 (d), 73.10 (t), 74.79 (d), 123.56 (d), 127.54 (d), 127.60 (d), 128.31 (d), 130.71 (d), 135.74 (s), 138.42 (s), 150.56 (s),
163.73 (s), 171.20 (s); exact mass calcd for C26H31NO8 (M + Na) m/z 508.1942, found m/z 508.1951. The relative stereochemistry for tertrahydropyran 338 was established by -1 1 NOE studies. Alkene 339: IR (Neat) 1737 cm ; H-NMR (400 MHz, CDCl3) δ 1.25 (t, J
= 7.1 Hz, 3H, OCH2CH3), 1.60 (d, J = 1.0 Hz, 3H, CH3), 1.73-1.86 (m, 2H,
CH2CH2OBn), 1.86-2.04 (m, 2H, CH2CH=CCH3), 2.38 (ddd, J = 14.5, 9.2 Hz, 1H,
CH2CO2Et), 2.64 (ddd, J = 14.5, 4.0 Hz, 1H, CH2CO2Et), 3.53-3.61 (m, 2H, CH2OBn),
3.62-3.70 (m, 1H, CHCH2CH2OBn), 4.14 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.40-4.50 (m,
1H, CHCH2CO2Et), 4.49 (ABq, J = 11.6 Hz, 2H, CH2Ph), 5.52-5.55 (sharp m, 1H, 13 CH=CCH3), 7.25-7.36 (m, 5H, ArH); C-NMR (100 MHz, CDCl3) δ 14.22 (q), 18.66 (q), 31.31 (t), 35.87 (t), 39.19 (t), 60.32 (t), 66.87 (t), 70.79 (d), 72.97 (t), 74.84 (d), 121.19 (d), 127.40 (d), 127.53 (d), 128.28 (d), 134.21 (s), 138.59 (s), 171.59 (s); exact mass calcd for C19H26O4 (M + Na) m/z 341.1723, found m/z 341.1744.
176 Ph Ph OH OBn O
342
rel-(2R, 6R)-6-Benzyloxy-2-(1’,1’-diphenyl-1’-hydroxyethyl)-5,6-dihydro-2H-tetra hydropyran (342). A 50-mL of three-necked round-bottomed flask, equipped with a pressure equalizer addition funnel and under argon atmosphere, was charged with 500 mg (1.57 mmol) of the ester 339 and 30 mL of dry THF. The pale yellow solution was cooled to 0 °C (ice-water) and 7.9 mL (7.9 mmol) of 1M phenylmagnesium bromide in tetrahydropyran was added over a 20 min period. The brown mixture was stirred for 2 h at 0 °C and 2 h at room temperature. The reaction was cooled to 0 °C and 30 mL of saturated aqueous ammonium chloride. The mixture was extracted with three 30-mL portions of ethyl acetate. The combined organic extracts were washed with 30 mL of
brine, dried (MgSO4) and concentrated in vacuo to afford 790 mg of a red to orange oil. The oil was chromatographed over 50 g of silica gel (230-400 mesh, eluted with 15% diethyl ether/85% hexanes) to give 548 mg (81%) of the alcohol 342 as a pink solid. The solid was recrystallized (to obtain an analytical sample) from hexanes to afford 956 mg
(74%) of alcohol 342 as a white crystalline solid: mp 83-85 °C; IR (CH2Cl2) 3442, 3030, -1 1 1595 cm ; H-NMR (500 MHz, CDCl3) δ 1.62 (s, 3H, CH3), 1.77-1.91 (two m, 3H,
CH2CH2OBn and CH2C=C), 2.00-2.10 (m, 1H, CH2C=C), 2.28 (dd, J = 14.5, 11.3 Hz,
1H, CH2C(OH)Ph2), 2.85 (dd, J = 14.5, 1.9 Hz, 1H, CH2C(OH)Ph2), 3.50-3.63 (m, 3H,
CHCH2CH2OBn and CHCH2CH2OBn) 4.15 (broad d, J = 10.9 Hz, 1H,
CHCH2C(OH)Ph2), 4.49 (s, 2H, CH2Ph), 5.52 (broad d, J = 5.9 Hz, 1H,
CHCH2C(OH)Ph2), 5.70 (s, 1H, OH), 7.21-7.38 (m, 11H, ArH), 7.45 (d, J = 8.6 Hz, 2H, 13 ArH), 7.56 (d, J = 8.2 Hz, 2H, ArH); C-NMR (100 MHz, CDCl3) δ 18.90 (q), 31.09 (t), 35.81 (t), 43.35 (t), 66.81 (t), 71.16 (d), 73.23 (t), 76.72 (d), 78.33 (s), 120.50 (d), 125.80 (d), 126.36 (d), 126.42 (d), 126.71 (d), 127.55 (d), 127.73 (d), 128.02 (d), 128.06 (d),
128.34 (d), 134.61 (s), 138.35 (s), 146.17 (s), 147.98 (s); exact mass calcd for C29H32O3 (M + Na) m/z 451.2244, found m/z 451.2254. 177 Anal. calcd. for C29H32O3: C, 81.27; H, 7.53. Found: C, 81.35; H, 7.61.
Ph Ph Ph OH OBn Ph OH OBn O O
OH OH 343 344
rel-(2R, 3R, 4S, 6S)-6-Benzyloxyethyl-4-hydroxy-3-methyl-2-(1’,1’-diphenyl-1’- hydroxyethyl)-tetrahydropyran (343) and rel-(2R, 3S, 4R, 6S)-6-Benzyloxyethyl-4- hydroxy-3-methyl-2-(1’,1’-diphenyl-1’-hydroxyethyl)-tetrahydropyran (344). A 25- mL round-bottomed flask under argon atmosphere was charged with 100 mg (0.233 mmol) of olefin 342 and 0.5 mL of dry THF. The colorless solution was cooled to 0 °C
(ice-water) and 470 µL (0.47 mmol) of 1.0 M BH3·THF was added via syringe. The colorless solution was stirred for 1 h. The ice bath was removed and the mixture was stirred at room temperature for 1 h. To the solution was added very slowly 0.1 mL of water, followed by cooling to 0 °C. To the cold solution was added dropwise 80 µL of 3M aqueous NaOH and 60 µL of 30% aqueous hydrogen peroxide. The ice bath was removed and the mixture was heated for 1h at an oil bath temperature of 45 °C. The mixture was dissolved with 30 mL of diethyl ether. The aqueous layer was saturated by
the addition of solid sodium chloride. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to afford 100 mg of a colorless oil. The oil was chromatographed over 15 g of silica gel (230-400 mesh, eluted with 30% ethyl acetate/70% hexanes) to give 20 mg (19%) of the tetrahydropyran 343 and 49 mg (48%) of tetrahydropyran 344 as colorless oils. Tetrahydropyran 343: IR (Neat) 3423, 3060, -1 1 3030, 1599 cm ; H-NMR (400 MHz, CDCl3) δ 0.91 (d, J = 7.1 Hz, 3H, CH3), 1.32
(broad d, J = 14.1 Hz, 1H, CH2CHOH), 1.32-1.50 (m, 2H, CHCH3 and OH), 1.56 (ddd, J
= 14.1, 12.1, 2.5 Hz, 1H, CH2CHOH), 1.56-1.65 (m, 1H, CH2CH2OBn), 1.65-1.80 (m, 178 1H, CH2CH2OBn), 2.20 (dd, J = 14.7, 1.5 Hz, 1H, CH2C(OH)Ph2), 2.39 (dd, J = 14.7,
11.1 Hz, 1H, CH2C(OH)Ph2), 3.51 (dd, J = 7.0, 5.6 Hz, 2H, CH2OBn), 3.66 (dddd, J =
9.1, 6.6, 3.0, 2.5 Hz, 1H, CHCH2CH2OBn), 3.74 (dd, J = 5.6, 3.0 Hz, 1H, CHOH), 3.95
(ddd, J = 11.1, 1.8 Hz, 1H, CHCH2C(OH)Ph2), 4.47 (ABq, J = 11.8 Hz, 2H, CH2OBn), 5.40 (broad s, 1H, OH), 7.00-7.10 (m, 2H, ArH), 7.10-7.30 (m, 9H, ArH), 7.30-7.40 (m, 13 4H, ArH); C-NMR (100 MHz, CDCl3) δ 11.30 (q), 34.04 (t), 36.03 (t), 39.14 (d), 43.03 (t), 66.87 (t), 69.95 (d), 70.23 (d), 72.58 (d), 73.21 (t), 78.22 (s), 125.68 (d), 126.19 (d), 126.41 (d), 126.61 (d), 127.54 (d), 127.84 (d), 128.01 (d), 129.08 (d), 128.35 (d), 138.38
(s), 146.63 (s), 148.23 (s); exact mass calcd for C29H34O4 (M + Na) m/z 469.2349, found -1 1 m/z 469.2335. Tetrahydropyran 344: IR (CHCl3) 3422, 3060, 3009, 1599 cm ; H-NMR
(500 MHz, CDCl3) δ 1.00 (d, J = 6.5 Hz, 3H, CH3), 1.34 (ddd, J = 11.3 Hz, 1H,
CH2CHOH), 1.35-1.40 (m, 1H, CHCH3), 1.68 (broad s, 1H, OH), 1.75-1.80 (m, 1H,
CH2CH2OBn), 1.85-1.92 (m, 2H, CH2CHOH and CH2CH2OBn), 2.33 (dd, J = 14.7, 10.6
Hz, 1H, CH2C(OH)Ph2), 2.82 (dd, J = 14.7, 1.7 Hz, 1H, CH2C(OH)Ph2), 3.13 (ddd, J =
10.2, 10.2, 1.6 Hz, 1H, CHCH2C(OH)Ph2), 3.22 (ddd, J = 10.4, 10.4, 4.7 Hz,1H, CHOH),
3.40-3.34 (m, 1H, CHCH2CH2OBn), 3.62 (dd, J = 7.0, 7.0 Hz, 2H, CH2OBn), 4.60 (ABq, 13 J = 12.1 Hz, 2H, CH2Ph), 5.65 (broad s, 1H, OH), 7.13-7.52 (m, 15H, ArH); C-NMR
(100 MHz, CDCl3) δ 12.83 (q), 35.94 (t), 40.84 (t), 43.16 (t), 43.88 (d), 66.61 (t), 72.54 (d), 72.90 (d), 73.17 (t), 78.27 (s), 79.76 (d), 125.76 (d), 126.22 (d), 126.42 (d), 126.73 (d), 127.57 (d), 127.77 (d), 128.02 (d), 128.03 (d), 128.33 (d), 138.24 (s), 146.34 (s),
147.88 (s); exact mass calcd for C29H34O4 (M + Na) m/z 469.2349, found m/z 469.2348. The relative stereochemistry for tertrahydropyrans 343 and 344 was established by NOE studies.
179 OBn CO2Et O
O 351a
rel-(2R, 3R, 4R, 6S)-6-Benzyloxyethyl-2-carbethoxymethyl-3,4-epoxy-3-methyl tetrahydropyran (351a). A 10-mL two-necked round-bottomed flask under argon atmosphere was charged with 100 mg (0.314 mmol) of olefin 339 and 0.6 mL of dry dichloromethane. The solution was cooled to 0 °C (ice-water) and 39.6 mg (0.471 mmol) of solid NaHCO3 was added, followed by 106 mg (0.471 mmol) of 77% 3- chloroperoxybenzoic acid. The mixture was stirred for 1 h and 0.3 mL of dry dichloromethane was added to help the stirring of the resulting white suspension. The mixture was stirred for another hour. The ice bath was removed and the suspension was stirred for 0.5 h at room temperature. The white suspension was diluted with 30 mL of dichloromethane. The white solid was removed by filtration. The filtrate was dried
(MgSO4) and concentrated in vacuo to afford 115 mg of a mixture of solid and oil. The mixture was chromatographed over 12 g of silica gel (230-400 mesh eluted with 30% diethyl ether/70% hexanes) to give 44.1 mg (42%) of the epoxide 351a as a colorless oil: -1 1 IR (Neat) 1737 cm ; H-NMR (500 MHz, C6D6) δ 0.88 (s, 3H, CH3), 0.96 (t, J = 7.1 Hz,
3H, OCH2CH3), 1.33 (ddd, J = 14.9, 5.8, 3.9 Hz, 1H, CH2 of tetrahydropyran ring), 1.49-
1.62 (m, 3H, CH2 of tetrahydropyran ring and CH2CH2OBn), 2.52 (dd, J = 15.3, 3.4 Hz,
1H, CH2CO2Et), 2.60 (d, J = 5.8 Hz, 1H, CHOCCH3), 2.69 (dd, J = 15.3, 9.4 Hz, 1H,
CH2CO2Et), 3.23 (dddd, J = 11.4, 8.0, 3.8, 3.8 Hz, 1H, CHCH2CH2OBn), 3.34
(ddd, J = 9.2, 5.6 Hz, 1H, CH2OBn), 3.47 (ddd, J = 8.7, 8.7, 5.3 Hz, 1H, CH2OBn), 3.92-
4.02 (m, 2H, OCH2CH3), 4.07 (dd, J = 9.4, 3.4 Hz, 1H, CHCH2CO2Et), 4.33 (ABq, J =
12.0 Hz, 2H, CH2Ph), 7.09 (t, J = 7.3 Hz, 1H, ArH), 7.19 (t, J =7.6 Hz, 2H, ArH), 7.30 13 (d, J = 7.6 Hz, 2H, ArH); C-NMR (100 MHz, CDCl3) δ 14.16 (q), 18.32 (q), 29.95 (t), 35.55 (t), 36.53 (t), 55.42 (s), 58.59 (d), 60.49 (t), 66.32 (t), 70.44 (d), 73.00 (t), 74.04 (d), 127.44 (d), 127.54 (d), 128.27 (d), 138.43 (s), 171.29 (s); exact mass calcd for
180 C19H26O5 (M + Na) m/z 357.1672, found m/z 357.1666. The relative stereochemistry for epoxide 351a was established by NOE studies.
Ph Ph Ph OH OBn Ph OH OBn O O
O O
350b 351b
rel-(2R, 3S, 4S, 6S)-6-Benzyloxyethyl-3,4-epoxy-3-methyl-2-(1’,1’-diphenyl-1’- hydroxy)tetrahydropyran (350b) and rel-(2R, 3R, 4R, 6S)-6-Benzyloxyethyl-3,4- epoxy-3-methyl-2-(1’,1’-diphenyl-1’-hydroxy)tetrahydropyran (351b). A 25-mL three-necked round-bottomed flask under argon atmosphere was charged with 100 mg (0.233 mmol) of olefin 342 and 1.0 mL of dry dichloromethane. The solution was cooled
to 0 °C (ice-water) and 29.4 mg (0.350 mmol) of solid NaHCO3 was added, followed by 78.4 mg (0.350 mmol) of 77% 3-chloroperoxybenzoic acid. The mixture was stirred for 1 h. The ice bath was removed and the suspension was stirred for 4 h at room temperature. The resulting white slurry was diluted with 15 mL of dichloromethane. The white solid was removed by filtration. The filtrate was concentrated in vacuo to afford 112 mg of an oil. The oil was chromatographed over 20 g of silica gel (230-400 mesh eluted with 30% diethyl ether/70% hexanes) to give 7.4 mg (13%) of epoxide 350b and 63.2 mg (61%) of epoxide 351b as colorless oils: Epoxide 350b: 1H-NMR (400 MHz,
CDCl3) δ 1.26 (s, 3H, CH3), 1.60-1.70 (m, 3H, CH2CH2OBn and CH2 of tetrahydropyran ring), 1.90 (broad d, J = 14.5 Hz, 1H, CH2 of tetrahydropyran ring), 2.39 (dd, J = 14.4,
12.0 Hz, 1H, CH2C(OH)Ph2), 2.64 (dd, J = 14.4, 2.1 Hz, 1H, CH2C(OH)Ph2), 3.01 (s,
1H, CH3COCH), 3.30-3.40 (m, 2H, CH2OBn), 3.40-3.50 (m, 1H, CHCH2CH2OBn), 3.85
181 (dd, J = 11.9, 1.7 Hz, 1H, CHCH2C(OH)Ph2), 4.36 (s, 2H, OCH2Ph), 5.33 (s, 1H, OH), 7.12-7.26 (m, 11H, ArH), 7.36 (d, J = 7.9 Hz, 2H, ArH), 7.42 (d, J = 7.8 Hz, 2H, ArH). This epoxide was not fully characterized due to its instability. The relative stereochemistry for epoxide 350b was established by the multiplicity of the signals in the 1 -1 1 H-NMR. Epoxide 351b: IR (Neat) 3458, 1598 cm ; H-NMR (500 MHz, CDCl3) δ 1.17
(s, 3H, CH3), 1.55-1.70 (m, 2H, CH2CH2OBn), 1.70-1.80 (m, 2H, CH2 of tetrahydropyran
ring), 2.47 (dd, J = 14.7, 10.8 Hz, 1H, CH2C(OH)Ph2), 2.70 (dd, J = 14.7, 1.2 Hz, 1H,
CH2C(OH)Ph2), 2.97 (d, J = 5.3 Hz, 1H, CH3COCH), 3.15-3.25 (m, 1H,
CHCH2CH2OBn), 3.30-3.45 (m, 2H, CH2OBn), 3.66 (dd, J = 10.7, 1.6 Hz, 1H,
CHCH2C(OH)Ph2), 4.36 (ABq, J = 11.8 Hz, 2H, OCH2Ph), 5.30 (s, 1H, OH), 7.10-7.30 (m, 11H, ArH), 7.36 (d, J = 7.6 Hz, 2H, ArH), 7.47 (d, J = 7.5 Hz, 2H, ArH); 13C-NMR
(100 MHz, CDCl3) δ 18.30 (q), 29.92 (t), 35.41 (t), 40.66 (t), 55.65 (s), 57.90 (d), 66.27 (t), 70.73 (d), 73.12 (t), 75.83 (d), 78.06 (s), 125.85 (d), 126.28 (d), 126.57 (d), 126.76 (d), 127.55 (d), 127.68 (d), 127.97 (d), 128.11 (d), 128.30 (d), 138.18 (s), 146.12 (s),
147.63 (s); exact mass calcd for C29H32O4 (M + Na) m/z 467.2193, found m/z 467.2194. The relative stereochemistry for epoxide 57 was established by NOE studies.
OBn OBn CO Et H 2 O O O O HO Br Br 356 355a
rel-(3R, 5S, 7R, 8R)-5-(2’-Benzyloxyethyl)-7-bromo-8-methylhexahydrofuro[3.2.0] pyran-2-one (356) and 6-Benzyloxyethyl-4-bromo-2-carbethoxymethyl-3-hydroxy-3- methyltetrahydropyran (355a). A 25-mL round-bottomed flask was charged with 200 mg (0.628 mmol) of alkene 339, 2.2 mL of acetone, 4.4 mL of water, 224 mg (1.26 mmol) of N-bromosuccinimide and 11 µL of concentrated sulfuric acid. The mixture was
182 stirred for 3 h and diluted with 30 mL of diethyl ether. To the solution was added 15 mL
of saturated aqueous NaHSO3. The aqueous layer was separated and extracted with three
30-mL portions of diethyl ether. The combined organic layers were dried (MgSO4) and concentrated in vacuo to afford 294 mg of a yellow oil. The oil was chromatographed over 40 g of silica gel (230-400 mesh, eluted with 25% ethyl acetate/75% hexanes) to give 64 mg (28%) of lactone 356 and 148.3 mg (57%) of bromohydrin 355 as a mixture of isomers both as colorless oil. Lactone 356: IR (Neat) 1792 cm-1; 1H-NMR (400 MHz,
CDCl3) δ 1.53 (s, 3H, CH3), 1.68-1.84 (m, 2H, CH2CH2OBn), 1.97 (ddd, J = 14.7, 3.8,
2.3 Hz, 1H, CH2CHBr), 2.16 (ddd, J = 14.7, 10.0, 3.5 Hz, 1H, CH2CHBr), 2.45 (d, J =
17.5 Hz, 1H, CH2CO2), 2.81 (dd, J = 17.5, 4.1 Hz, 1H, CH2CO2), 3.50-3.61 (two m, 2H,
CH2OBn), 4.08-4.14 (m, 1H, CHCH2CH2OBn), 4.23 (d, J = 4.0 Hz, 1H, CHCH2CO2),
4.46 (t, J = 3.5 Hz, 1H, CHBr), 4.49 (ABq, J = 12.1 Hz, 2H, OCH2CH3), 7.26-7.37 (m, 13 5H, ArH); C-NMR (100 MHz, CDCl3) δ 24.71 (q), 35.21 (t), 35.45 (t), 38.24 (t), 50.86 (d), 65.94 (t), 67.36 (d), 72.88 (t), 74.69 (d), 82.75 (s), 127.50 (d), 127.57 (d), 128.29 (d),
138.34 (s), 174.56 (s); exact mass calcd for C17H21O4Br (M + Na) m/z 391.0515, found m/z 391.0506. The relative stereochemistry for lactone 356 was established by NOE studies. The 1H and 13C-NMR of bromohydrins 355 were complex.
OBn OBn CO2Et CO2Et O O
O O 351a 350a
rel-(2R, 3R, 4R, 6S)-6-Benzyloxyethyl-2-carbethoxymethyl-3,4-epoxy-3-methyl tetrahydropyran (351a) and rel-(2R, 3S, 4S, 6S)-6-Benzyloxyethyl-2-carbethoxy methyl-3,4-epoxy-3-methyltetrahydropyran (350a). A round-bottomed flask under argon atmosphere was charged with 157 mg (0.378 mmol) of the bromohydrins 355
183 (from the preceding experiment) and 0.6 mL of absolute ethanol. To the solution was
added 65 mg (0.470 mmol) of K2CO3. The mixture was stirred at room temperature for 1 h. The mixture was diluted with 30 mL of diethyl ether and washed with 10 mL of brine.
The organic phase was dried (MgSO4) and concentrated in vacuo to afford 114.5 mg (91%) of a mixture of epoxide 351a and 35a as a colorless oil in a ratio of 3:1. The 1H- NMR data for epoxide 351a matched previously reported data. The mixture was not further characterized.
OBn OBn CO Et H 2 O O O O HO OH OH
363 362
rel-(2R, 3R, 4R, 6S)-5-(2-Benzyloxyethyl)-7-hydroxy-7a-methyl-hexahydrofuro[3,2- b]pyran-2-one (363) and rel-(2R, 3S, 4S, 6S)-6-Benzyloxyethyl-2-carbethoxymethyl- 3,4-dihydroxy-3-methyltetrahydropyran (362). A 5-mL conical, vial equipped with a condenser, was charged with 150 mg (0.471 mmol) of olefin 339, 0.14 mL of acetone, 70
µL of t-butanol, 66 µL of 1% OsO4 in water and 78.6 mg (0.707 mmol) of trimethylamine N-oxide dihydrate. The black mixture was heated to 70 °C (oil bath temperature) and stirred for 4 h. The mixture was allowed to cool to room temperature and diluted with 30 mL of dichloromethane. The solution was dried (MgSO4) and concentrated in vacuo to afford 400 mg of a brown oil. The oil was chromatographed over 30 g of silica gel (230-400 mesh, eluted with ethyl acetate-hexanes, 1:1) to give 15 mg (15%) of the lactone 363 and 80 mg (48%) of diol 362, both as colorless oils. -1 1 Lactone 363: IR (Neat) 3438, 1778 cm ; H-NMR (400 MHz, CDCl3) δ 1.50 (s, 3H,
CH3), 1.62 (ddd, J = 12.3 Hz, 1H, CH2CHOH), 1.71-1.84 (m, 3H, CH2CH2OBn and OH),
184 1.89 (ddd, J = 12.7, 5.2 Hz, 1H, CH2CHOH), 2.49 (d, J = 17.5 Hz, 1H, CH2CO2), 2.86
(dd, J = 17.5, 4.1 Hz, 1H, CH2CO2), 3.48-3.61 (two m, 3H, CH2OBn and
CHCH2CH2OBn), 3.62 (dd, J = 11.9, 5.2 Hz, 1H, CHOH), 4.01 (d, J = 4.0 Hz, 1H, 13 CHCH2CO2), 4.48 (ABq, J = 12.0 Hz, 2H, OCH2Ph), 7.12-7.37 (m, 5H, ArH); C-NMR
(100 MHz, CDCl3) δ 21.04 (q), 35.57 (t), 35.86 (t), 37.88 (t), 65.89 (t), 71.09 (d), 71.70 (d), 72.98 (t), 77.40 (d), 84.39 (s), 127.64 (d), 127.66 (d), 128.37 (d), 138.32 (s), 174.79
(s); exact mass calcd for C17H22O5 (M + Na) m/z 329.1359, found m/z 329.1346. Diol -1 1 362: IR (Neat) 3440, 1736 cm ; H-NMR (400 MHz, CDCl3) δ 1.14 (s, 3H, CH3), 1.25
(t, J = 7.1 Hz, 3H, OCH2CH3), 1.62-1.76 (m, 4H, CH2CHOH and CH2CH2OBn), 2.38
(dd, J = 15.3, 9.2 Hz, 1H, CH2CO2Et), 2.66 (dd, J = 15.3, 4.0 Hz, 1H, CH2CO2Et), 2.96
(broad s, 2H, two OH), 3.54 (t, J = 6.7 Hz, 2H, CH2OBn), 3.67 (sharp m, 1H, CHOH),
3.90-3.97 (m, 1H, CHCH2CH2OBn), 4.04 (dd, J = 9.2, 4.0 Hz, 1H, CHCH2CO2Et), 4.11
(q, J = 7.1 Hz, 2H, OCH2CH3), 4.46 (ABq, J = 11.9 Hz, 2H, OCH2Ph), 7.24-7.37 (m, 5H, 13 ArH); C-NMR (100 MHz, CDCl3) δ 14.17 (q), 18.72 (q), 35.21 (t), 35.57 (t), 38.90 (t), 60.65 (t), 66.98 (t), 69.28 (d), 70.41 (s), 72.72 (d), 73.05 (t), 74.48 (d), 127.50 (d), 127.86
(d), 128.31 (d), 138.38 (s), 172.79 (s); exact mass calcd for C19H28O6 (M + Na) m/z 375.1778, found m/z 375.1777. The relative stereochemistry for lactone 363 and diol 362 was established by NOESY studies.
185 Ph Ph Ph OH OBn Ph OH OBn O O
HO HO OH OH
365 366
rel-(2R, 3S, 4S, 6S)-6-Benzyloxyethyl-3,4-dihydroxy-2-(1’,1’-diphenyl-1’-hydroxy ethyl)-3-methyltetrahydropyran (365) and rel-(2R, 3R, 4R, 6S)-6-Benzyloxyethyl-3,4- dihydroxy-2-(1’,1’-diphenyl-1’-hydroxyethyl)-3-methyltetrahydropyran (366).58 A 5-mL conical vial, equipped with a condenser, was charged with 100 mg (0.233 mmol) of olefin 342, 0.28 mL of acetone, 77 µL of t-butanol, 33 µL of 1% OsO4 in water and 39 mg (0.35 mmol) of trimethylamine N-oxide. The black mixture was heated to 70 °C (oil bath temperature) and stirred for 20 h. The mixture was allowed to cool to room temperature and diluted with 20 mL of dichloromethane. The solution was dried
(MgSO4) and concentrated in vacuo to afford 110 mg of a brown oil. The oil was chromatographed over 25 g of silica gel (230-400 mesh, eluted with 40% ethyl acetate/60% hexanes and 50% ethyl acetate/50% hexanes) to give 32 mg (30%) of the triol 365 as a colorless oil and 30 mg (28%) of the triol 366 as a white solid. Triol 365: -1 1 IR (Neat) 3435 cm ; H-NMR (400 MHz, C6D6) δ 0.99 (s, 3H, CH3), 1.15-1.25 (broad
m, 2H, CH2CHOH), 1.35-1.55 (two m, 2H, CH2CH2OBn), 2.04 (broad s, 1H, OH), 2.36
(broad dd, J = 14.5, 10.3 Hz, 2H, CH2C(OH)Ph2 and OH), 2.98 (d, J = 14.6 Hz, 1H,
CH2C(OH)Ph2), 3.16 (broad s, 1H, CHOH), 3.30-3.37 (m, 1H, CH2OBn), 3.40-3.45 (m,
1H, CH2OBn), 3.65-3.75 (m, 1H, CHCH2CH2OBn), 3.92 (d, J = 10.0 Hz, 1H,
CHCH2C(OH)Ph2), 4.40 (ABq, J = 11.9 Hz, 2H, OCH2Ph), 5.50 (s, 1H, OH), 6.99-7.04 (m, 2H, ArH), 7.10-7.33 (m, 7H, ArH), 7.32 (d, J = 7.7 Hz, 2H, ArH), 7.70 (d, J = 8.2 13 Hz, 2H, ArH), 7.75 (d, J = 8.1 Hz, 2H, ArH); C-NMR (125 MHz, C6D6) δ 19.02 (q), 35.87 (t), 37.07 (t), 39.77 (t), 67.18 (t), 69.77 (d), 70.31 (s), 72.70 (d), 73.42 (t), 76.49 (d), 78.66 (s), 126.29 (d), 126.75 (d), 126.79 (d), 127.02 (d), 127.79 (d), 128.18 (d), 128.35 (d), 128.45 (d), 128.63 (d), 139.11 (s), 147.83 (s), 149.36 (s); exact mass calcd for
186 C29H34O5 (M + Na) m/z 485.2298, found m/z 485.2289. Triol 366: mp 116-117 °C; IR -1 1 (CHCl3) 3440 cm ; H-NMR (500 MHz, CDCl3) δ 1.20 (s, 3H, CH3), 1.43 (ddd, J = 11.4
Hz, 1H, CH2CHOH), 1.75-1.81 (m, 1H, CH2CH2OBn), 1.82-1.90 (m, 2H, CH2CHOH
and CH2CH2OBn), 2.15 (broad s, 2H, two OH), 2.61 (dd, J = 15.0, 10.6 Hz, 1H,
CH2C(OH)Ph2), 2.72 (dd, J = 15.0, 1.7 Hz, 1H, CH2C(OH)Ph2), 3.24 (dd, J = 10.6, 1.7
Hz, 1H, CHCH2C(OH)Ph2), 3.29 (dd, J = 11.4, 5.1 Hz, 1H, CHOH), 3.39-3.44 (m, 1H,
CHCH2CH2OBn), 3.59-3.62 (m, 2H, CH2OBn), 4.60 (ABq, J = 10.9 Hz, 2H, OCH2Ph), 5.10 (broad s, 1H, OH), 7.20-7.40 (m, 11H, ArH), 7.42 (d, J = 8.2 Hz, 2H, ArH), 7.46 (d, 13 J = 8.1 Hz, 2H, ArH); C-NMR (100 MHz, CDCl3) δ 19.67 (q), 35.68 (t), 36.85 (t), 38.44 (t), 66.41 (t), 71.75 (s), 71.87 (d), 73.15 (t), 73.63 (d), 77.85 (s), 80.92 (d), 125.83 (d), 126.07 (d), 126.59 (d), 126.84 (d), 127.63 (d), 127.78 (d), 128.04 (d), 128.16 (d),
128.35 (d), 138.13 (s), 146.21 (s), 147.58 (s); exact mass calcd for C29H34O5 (M + Na) m/z 485.2298, found m/z 485.2301. The relative stereochemistry for triols 365 and 366 was established by NOE studies.
Ph Ph Ph OH OBn Ph OH OBn O O
HO HO OH OH
365 366
rel-(2R, 3S, 4S, 6S)-6-Benzyloxyethyl-3,4-dihydroxy-2-(1’,1’-diphenyl-1’-hydroxy ethyl)-3-methyltetrahydropyran (365) and rel-(2R, 3R, 4R, 6S)-6-Benzyloxyethyl-3,4- dihydroxy-2-(1’,1’-diphenyl-1’-hydroxyethyl)-3-methyltetrahydropyran (366).61 A 5-mL round bottom flask was charged with 100 mg (0.233 mmol) of olefin 342 and 7 mL of a mixture of 1:1 of acetone-water. To the partially dissolve olefin was added 54.6 mg
187 (0.466 mmol) of trimethylamine N-oxide and a crystal of OsO4 (∼1 mg). The black mixture was stirred for 3 h and diluted with 20 mL of dichloromethane. The solution was
dried (MgSO4) and concentrated in vacuo to afford 120 mg of a black oil. The oil was chromatographed over 20 g of silica gel (230-400 mesh, eluted with 50% ethyl acetate/50% hexanes) to give 39 mg (36%) of triol 365 and 40.3 mg (37%) of triol 366 as colorless oils. The 1H-NMR data for triols 365 and 366 matched the data reported in the preceding experiment.
Ph Ph OH OBn O
OH
344
rel-(2R, 3S, 4R, 6S)-6-Benzyloxyethyl-4-hydroxy-3-methyl-2-(1’,1’-diphenyl-1’- hydroxyethyl)-tetrahydropyran (344). A 25-mL two-necked round-bottomed flask under argon atmosphere was charged with 123.2 mg (0.296 mmol) of (+)-
(Ipc2BH2)2TMEDA complex and 0.8 mL of THF. To the solution was added 75 µL (84.0 . mg, 0.592 mmol) of BF3 OEt2 via syringe and dropwise. The mixture was stirred for 2 h. A precipitate was observed after the first 30 min. The resulting slurry was cooled to –30 °C and a solution of 127 mg (0.296 mmol) of the olefin 342 in 200 µL of dry THF was added dropwise via syringe. The mixture was stirred at –25 °C for 24 h and 24 µL of methanol was added very slowly. Then, 100 µL of 3 M aqueous NaOH was added,
followed by 100 µL of 30% aqueous H2O2. The mixture was heated at 55 °C for 1 h. The mixture was partitioned between 10 mL of water and 10 mL of diethyl ether. The
organic phase was dried (MgSO4) and concentrated in vacuo to afford 142 mg of a
188 mixture of an oil and a solid. The mixture was chromatographed over 20 g of silica gel (eluted with 30% ethyl acetate/70 % hexanes) to give 30 mg (24%) of diol 344 as a colorless oil. The 1H-NMR data for diol 344 matched previously reported data.
O O O
O OH O
371
1,2:4,5-Di-O-isopropylidene-β-D-fructopyranose (371).62 A 500-mL three-necked round bottomed flask under argon atmosphere was charged with 175 mL of acetone, 9.0 g (50.0 mmol) of D-fructose (370) and 3.7 mL (3.12 g, 30.0 mmol) of 2,2- dimethoxypropane. The flask was cooled to in an ice-water for 15 min and 2.2 mL of perchloric acid was added in one portion. The solution was stirred for 6 h, but it did not become homogeneous solution until 1 h after onset of stirring. To the solution was added 2.4 mL of concentrated ammonium hydroxide. The solution was concentrated in vacuo at room temperature to afford a white solid. The solid was dissolved in 100 mL of dichloromethane and washed with two 25-mL portions of brine, dried (Na2SO4) and concentrated in vacuo to a volume of about 20 mL to afford a mixture of a solid and a liquid. To the mixture was added 50 mL of boiling hexanes and allowed to cool to room temperature. The solution was cooled to –25 °C for 4 h. The solid was collected and washed with three 15-mL portions of hexanes at –25 °C. The solid was dried overnight in vacuo to afford 5.58 g (46%) of the alcohol 371 as fine white needles: mp 115-116 °C
189 23 25 [lit. 118.5-119.5 °C]; [α]D = -144.1 (CHCl3, c 1.0), [lit. [α]D = -144.2 (CHCl3, c 1.0)]; 1 H-NMR (400 MHz, CDCl3) δ 1.37 (s, 3H, CH3), 1.44 (s, 3H, CH3), 1.51 (s, 3H, CH3),
1.53 (s, 3H, CH3), 1.96 (broad s, 1H, OH), 3.66 (d, J = 6.7 Hz, 1H, CHOH), 3.98 (d, J =
8.8 Hz, 1H, OCHCH2O), 4.00 (d, J = 13.1 Hz, 1H, CH2O), 4.12 (d, J = 13.3, 2.5 Hz, 1H,
CH2O), 4.13 (dd, J = 6.9, 5.8 Hz, 1H, OCHCHCHOH), 4.18 (d, J = 8.8 Hz, 1H,
OCHCH2O), 4.21 (ddd, J = 5.8, 2.5, 0.7 Hz, 1H, OCHCHOH).
O O O
O O O
372
1,2:4,5-Di-O-isopropylidene-D-erythro-2,3-hexodiulo-2,6-pyranose (372).62 A 250- mL three-necked round-bottomed flask was charged with 38 mL of dry dichloromethane, 3.0 g (11.53 mmol) of alcohol 371 and 4.32 g of freshly powder 3 Å molecular sieves. To the mixture was added 6.21 g (28.83 mmol) of pyridinium chlorochromate in small portions over a 10 min period. The brown mixture was stirred for 18 h and 58 mL of diethyl ether was added slowly with vigorous stirring. The mixture was filtered through a 10 g pad of Celite. The filtrate was concentrated in vacuo to afford a brown solid. To the solid was added 8 mL of 1:1 diethyl ether-hexanes mixture followed by transfer to a 60 g silica gel column (230-400 mesh). This process was repeated until all the solid was transferred to the silica pad. The pad was eluted with diethyl ether-hexanes, 1:2 to give 2.21 g of the crude ketone 372 as a white solid. The solid was dissolved with 10 mL of
190 boiling hexanes. The flask was cooled to –25 °C for 2 h. The solid was collected, washed with three 7-mL portions of cold (–25 °C) hexanes and dried to give 2.00 g 23 (67%) of the ketone 372 as a white solid: mp 103-104 °C [lit. 101-103 °C]; [α]D = - 25 1 120.0 (CHCl3, c 1.0), [lit. [α]D = -125.4 (CHCl3, c 1.0)]; H-NMR (400 MHz, CDCl3) δ
1.40 (s, 6H, CH3), 1.47 (s, 3H, CH3), 1.56 (s, 3H, CH3), 4.00 (d, J = 9.5 Hz, 1H,
OCHCH2O), 4.12 (d, J = 13.5 Hz, 1H, CH2O), 4.39 (d, J = 13.5, 2.2 Hz, 1H, CH2O), 4.55
(d, J = 5.5, 1.7 Hz, 1H, OCHCHCHOH), 4.61 (d, J = 9.5 Hz, 1H, OCHCH2O), 4.73 (d, J = 5.6 Hz, 1H, CHC=O).
Ph Ph OH OBn O
O
351b
rel-(2R, 3R, 4R, 6S)-6-Benzyloxyethyl-3,4-epoxy-3-methyl-2-(1’,1’-diphenyl-1’- hydroxy)tetrahydropyran (351b).65 A 5-mL round bottomed flask was charged with 100 mg (0.233 mmol) of olefin 342 and 6.0 mg (0.0233 mmol) of the ketone 372. The
mixture was cooled to 0 °C (ice-water) and 470 µL of a CH3CN-EtOH-CH2Cl2 (1:1:2 v/v) solution was added. Once the solid dissolved, 0.35 mL of an aqueous solution 2.0 M -4 in K2CO3 and 4 x 10 M in EDTA was added, followed by the addition of 100 µL of 30% aqueous hydrogen peroxide. The mixture was stirred for 1 h and 12.0 mg of ketone 372 was added. The mixture was stirred at 0 °C for 5 h and at room temperature for 30 h. Then, 12.0 mg of the ketone 372 was added. The mixture was stirred for 24 h and 30 mg of the ketone 372 was added, followed by 100 µL of 30% aqueous hydrogen peroxide.
191 The mixture was extracted with three 15-mL portions of hexanes. The combined organic
extracts were washed with 15 mL of 1 M aqueous Na2S2O3 and 15 mL of brine, dried
(Na2SO4), filtered and concentrated in vacuo to afford 97 mg of a colorless oil. The oil was chromatographed over 20 g of silica gel (230-400 mesh, packed with 1% triethylamine in hexanes, eluted with 30% diethyl ether/70 % hexanes) to give 14.9 mg 23 1 (14%) of epoxide 351b as a colorless oil: [α]D = -5.1 (CHCl3, c 0.7). The H-NMR data for epoxide 351b matched previously reported data.
OBn CO2Et O
OMs
374
rel-(2R, 3R, 4R, 6S)-6-Benzyloxyethyl-2-carbethoxymethyl-3-methyltetrahydropyran
-4-yl methanesulfonate (374). A 25-mL three-necked round-bottomed flask under argon atmosphere was charged with 500 mg (1.49 mmol) of alcohol 337 and 7 mL of dry dichloromethane. To the colorless solution was added 0.31 mL (227 mg, 2.24 mmol) of triethylamine, followed by 0.18 mL (257 mg, 2.24 mmol) of methanesulfonyl chloride dropwise via syringe at a rate to maintain control of the reaction. The mixture was stirred for 1 h and 50 mL of water was added. The mixture was diluted with 50 mL of dichloromethane. The aqueous phase was separated and extracted with two 30-mL portions of dichloromethane. The combined organic phases were dried (MgSO4) and concentrated in vacuo to afford 630 mg of a pale yellow oil. The oil was chromatographed over 40 g of silica gel (230-400 mesh, eluted with 2% acetone/98% hexanes) to give 487 mg (79%) of mesylate 374 as a colorless oil: IR (Neat) 1736 cm-1;
192 1 H-NMR (400 MHz, CDCl3) δ 0.95 (d, J = 6.9 Hz, 3H, CH3), 1.24 (t, J = 7.1 Hz, 3H,
OCH2CH3), 1.66 (ddd, J = 12.0 Hz, 1H, CH2CHOMs), 1.70-1.85 (m, 3H, CH2CH2OBn and CH2CHOMs), 2.19 (qd, J = 6.4, 6.4 Hz, 1H, CHCH3), 2.33 (dd, J = 15.3, 5.1 Hz, 1H,
CH2CO2Et), 2.56 (dd, J = 15.3, 8.6 Hz, 1H, CH2CO2Et), 3.00 (s, 3H, CH3SO3), 3.52-3.55
(m, 2H, CH2OBn), 3.55-3.65 (m, 1H, CHCH2CH2OBn), 3.88 (ddd, J = 8.6, 5.1, 1.9 Hz,
1H, CHCH2CO2Et), 4.13 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.47 (s, 2H, OCH2Ph), 4.90 (ddd, J = 11.9, 4.9, 4.9 Hz, 1H, CHOMs), 7.26-7.36 (m, 5H, ArH); 13C-NMR (100 MHz,
CDCl3) δ 5.61 (q), 14.16 (q), 32.74 (t), 35.79 (t), 36.48 (d), 37.93 (t), 38.76 (d), 60.55 (t), 66.29 (t), 73.04 (t), 73.09 (d), 74.57 (d), 80.51 (d), 127.53 (d), 127.61 (d), 128.33 (d),
138.34 (s), 170.68 (s); exact mass calcd for C20H30O7S (M + Na) m/z 437.1604, found m/z 437.1606.
OBn CO2Et O
339
rel-(2R, 6R)-6-Benzyloxy-2-carbethoxymethyl-5,6-dihydro-2H-tetrahydropyran (339). A 10-mL two-necked round-bottomed flask equipped with a condenser and under argon atmospheres, was charged with 100 mg (0.241 mmol) of mesylate 374 and 0.8 mL of dry toluene. To the solution was added 232 mg (1.21 mmol) of cesium acetate and 14.8 mg (0.121 mmol) of 4-dimethylaminopyridine. The mixture was refluxed for 24h and concentrated in vacuo. The residue was diluted with 25 mL of ethyl acetate and washed with 10 mL of water. The organic phase was dried (MgSO4) and concentrated in vacuo to afford 14.6 mg (19%) of alkene 339. The 1H-NMR data for alkene 339 matched previously reported data. The yield was calculated based on the 1H-NMR of the crude.
193 OBn CO2Et O
OH
376
rel-(2R, 3R, 4S, 6S)-6-Benzyloxyethyl-2-carbethoxymethyl-4-hydroxy-3-methyl tetrahydropyran (376).67 A 5-mL round-bottomed flask under a nitrogen atmosphere was charged with 48.5 mg (0.100 mmol) of the tetrahydropyran 338 and 1 mL of absolute ethanol. To the colorless solution was added 7 mg (0.05 mmol) of anhydrous potassium carbonate. The mixture was stirred for 2 h and concentrated in vacuo to afford a cloudy residue. The residue was diluted in 25 mL of dichloromethane and washed with 5 mL of water and 5 mL of brine. The organic layer was dried (MgSO4) and concentrated in vacuo to afford 46 mg of a colorless oil. The oil was chromatographed over 10 g of silica gel (230-400 mesh, eluted with 40% ethyl acetate/60% hexanes) to give 28.4 mg (84%) of tetrahydropyran 376 as a colorless oil: IR (Neat) 3454, 1736 cm-1; 1H-NMR (400
MHz, CDCl3) δ 0.91 (d, J = 7.1 Hz, 3H, CH3), 1.24 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.47
(broad d, J = 14.2 Hz, 1H, CH2CHOH), 1.56-1.66 (m, 2H, CH2CHOH and CHCH3),
1.66-1.77 (m, 2H, CH2CH2OBn), 1.85 (broad s, 1H, OH), 2.28 (dd, J = 14.9, 5.2 Hz, 1H,
CH2CO2Et), 2.51 (dd, J = 14.9, 9.0 Hz, 1H, CH2CO2Et), 3.55 (dd, J = 6.5, 6.5 Hz, 2H,
CH2OBn), 3.88 (ddd, J = 2.6, 2.6, 2.6 Hz, 1H, CHOH), 3.96 (m, 1H, CHCH2CH2OBn),
4.12 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.33 (ddd, J = 8.5, 5.5, 2.6 Hz, 1H, CHCH2CO2Et), 13 4.57 (ABq, J = 12.6 Hz, 2H, OCH2Ph), 7.13-7.38 (m, 5H, ArH); C-NMR (100 MHz,
CDCl3) δ 10.92 (q), 14.21 (q), 34.00 (t), 36.19 (t), 37.96 (d), 38.36 (t), 60.36 (t), 66.90 (t), 69.74 (d), 70.50 (d), 70.85 (d), 73.01 (t), 127.44 (d), 127.63 (d), 128.29 (d), 138.54 (s),
171.55 (s); exact mass calcd for C19H28O5 (M + Na) m/z 359.1829, found m/z 359.1797. The relative stereochemistry for tetrahydropyran 376 was established by NOE studies.
194 O
O NH
CO2Me
414
Methyl (4R)-2-Oxooxazolidinone-4-carboxylate (414).69 A 100-ml three-necked round-bottomed flask equipped with a condenser and under argon atmosphere, was charged with 1.56 g (10.0 mmol) of D-serine methyl ester hydrochloride salt and 20 mL of dry THF. To the mixture was added a solution of 1.9 g (6.4 mmol) of triphosgene in 5 mL of dry THF in portions via syringe. The mixture was heated to reflux for 1 h. The oil bath was removed and the yellow solution was allowed to cool to room temperature. The mixture was concentrated in vacuo to a volume of about 3 mL and 3 mL of ethyl acetate was added. The resulting solution was passed through a short plug of silica gel (60 g). The pad was eluted with ethyl acetate to give 1.32 g (91%) of the 2-oxoozazolidinone 25 20 414 as a pale yellow oil: [α]D = +20.9 (c 1.08, CH2Cl2), [[α]D = -18.9 (c 0.972, 1 CH2Cl2), enantiomer data]; H-NMR (400 MHz, CDCl3) δ 3.83 (s, 3H, CO2CH3), 4.43
(dd, J = 9.4, 4.5 Hz, 1H, CHNH), 4.59 (dd, J = 9.0, 4.5 Hz, 1H, CH2O), 4.63 (dd, J = 9.4,
9.1 Hz, 1H, CH2O), 5.96 (broad s, 1H, NH).
195 O
O MeO2C NO O N CO2Me H3CCN Rh Rh NCCH3 N O MeO2C O N CO2Me O O
383
Dirhodium (II) tetrakis[methyl 2-oxooxazolidine-(4R)-carboxylate] acetonitrile complex (383).69 The 25-mL flask of the Soxhlet extraction apparatus was charged with
163 mg (1.12 mmol) of oxooxazolidinone 414, 60 mg (0.136 mmol) of Rh2OAc4 and 7 mL of dry chlorobenzene. The thimble was charged with 1.50 g of a 2:1 mixture of
Na2CO3 and sand (dried overnight in the oven). The blue-green solution was heated to reflux for 6 h. The resulting blue solution was allowed to cool to room temperature and concentrated in vacuo to afford 180 mg of a purple solid and oil mixture. The mixture was diluted with 1.0 mL of methanol. The solid was collected by filtration and washed sequentially with three 250-µL portions of cold methanol and pentane. The purple solid was allowed to dry to afford 70 mg of the rhodium compound. The solid was recrystallized from 0.7 mL of dry acetonitrile to give 60 mg (51%) of the rhodium 25 23 complex 383 as a red-orange crystalline solid: [α]D = +229 (c 0.130, CH3CN), [[α]D = 1 -222 (c 0.120, CH3CN), enantiomer data]; H-NMR (400 MHz, CDCl3) δ 2.10 (s, 3H,
CH3CN), 3.75 (s, 3H, CO2CH3), 3.76 (s, 3H, CO2CH3), 4.19 (dd, J = 8.2, 4.0 Hz, 1H,
CHCO2Me), 4.26 (dd, J = 7.6, 5.5 Hz, 1H, CHCO2Me), 4.35-4.47 (m, 4H, CH2O).
196 O S NH O N OH H O
415
Glyoxylic acid p-toluenesulfonylhydrazone (415).70 A 500-mL three-necked round- bottomed flask was charged with 9.94 g (108 mmol) of glyoxylic acid monohydrate and 108 mL of water. The aqueous solution was warmed to about 60 °C and a solution of 20.1 g (108 mmol) of p-toluenesulfonylhydrazide in 54 mL of 2.5 M aqueous HCl, also at 60 °C was added. The resulting mixture was heated for another 5 min. During this time, an oil that separated from the solution solidified as a white precipitate. The reaction mixture was allowed to cool to room temperature and then stand overnight (18 h) in the refrigerator. The solid was collected, washed with two 25-mL portions of cold water and dried in high vacuum for 24 h. The pale yellow solid was recrystallized by dissolving in 80 mL of boiling ethyl acetate and then diluting with 160 mL of carbon tetrachloride. The mixture was allowed to cool to room temperature and then stand in the refrigerator for 6 h. The precipitate was collected by filtration to afford 18.4 g (70%) of the carboxylic acid 415 as a white crystalline solid: mp 146-152 ºC [lit70 148-154 ºC]; 1H-
NMR (400 MHz, DMSO-d6) δ 2.37 (s, 3H, CH3), 3.31 (broad s, 1H, NH), 6.96 (s, 1H, HC=N), 7.42 (d, J = 8.0, 2H, ArH), 7.70 (d, J = 8.0, 2H, ArH), 12.44 (broad s, 1H,
CO2H).
197 O S NH O N Cl H O
384
p-Toluenesulfonylhydrazone Glyoxylic acid chloride (384).70 A 250-mL three-necked round-bottomed flask equipped with a condenser and under argon atmosphere, was charged with 90 mL of dry benzene and 18.4 g (76.0 mmol) of carboxylic acid 415. To the suspension was added 11.1 mL (18.1 g, 152.0 mmol) of thionyl chloride. The suspension was heated to reflux for 2 h (until only a very small amount of solid remained at the bottom of the flask). The orange solution was allowed to cool and was then filtered through a Celite pad. The filtrate was concentrated in vacuo to afford a brown solid. The solid was broken into small pieces and washed with 14 mL of warm benzene. The solid was recrystallized by dissolving in 30 mL of boiling benzene, followed by addition of 14 mL of low boiling petroleum ether to the hot solution. The solution was allowed to cool to room temperature and stand overnight in the refrigerator. The resulting crystals were collected by suction filtration and washed with cold benzene. The filtrate was concentrated in vacuo and the recrystallization process was repeated to afford a total of 13.18 g (67%) of the acyl chloride 384 as a yellow solid: mp 110-115 °C [lit70 101-112 1 °C] H-NMR (400 MHz, C6D6) δ 1.79 (s, 3H, CH3), 5.67 (s, 1H, HC=N), 6.74 (d, J = 8.1 Hz, 2H, ArH), 7.56 (broad s, 1H, NH), 7.81 (d, J = 8.3 Hz, 2H, ArH).
198 OBn CO2Et O
O N2 O
385
rel-(2R, 3R, 4S, 6S)-6-Benzyloxyethyl-2-carbethoxymethyl-4-(2’-diazoacetoxy)-3- methyltetrahydropyran (385).71 A 10-mL two-necked round-bottomed flask was charged with 100 mg (0.297 mmol) of alcohol 376 and 1.7 mL of dry dichloromethane. The colorless solution was cooled to 0 °C (ice-water) and 145 mg (0.555 mmol) of acyl chloride 384 was added dropwise, followed by 70 µL (66 mg, 0.544 mmol) of N,N- dimethylaniline. The resulting brown solution was stirred for 30 min and 210 µL (153 mg, 1.51 mmol) of triethylamine was added via syringe. The dark orange solution was stirred for 15 min at 0 °C and 20 min at room temperature. The mixture was diluted with 20 mL of dichloromethane and washed with three 3-mL portions of saturated aqueous citric acid, 5 mL of water and 5 mL of saturated aqueous sodium bicarbonate. The
organic layer was dried (MgSO4) and concentrated in vacuo to afford 202 mg of a brown oil. The oil was chromatographed over 15 g of silica gel (230-400 mesh, eluted with ethyl acetate/hexanes, 1:4) to give 104 mg (87%) of diazoacetate 385 as a pale yellow oil: -1 1 IR (Neat) 3090, 2112, 1737, 1690 cm ; H-NMR (400 MHz, CDCl3) δ 0.90 (d, J = 7.2
Hz, 3H, CH3), 1.18 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.55-1.60 (sharp m, 2H,
CH2CH2OBn), 1.60-1.70 (m, 2H, CH2CHOCO), 1.70-1.80 (m, 1H, CHCH3), 2.20 (dd, J
= 15.0, 4.9 Hz, 1H, CH2CO2Et), 2.44 (dd, J = 15.0, 9.0 Hz, 1H, CH2CO2Et), 3.48 (t, J =
6.1 Hz, 2H, CH2OBn), 3.70-3.80 (m, 1H, CHCH2CH2OBn), 4.06 (q, J = 7.1 Hz, 2H,
OCH2CH3), 4.13 (ddd, J = 9.0, 4.9, 2.5 Hz, 1H, CHCH2CO2Et), 4.39 (ABq, J = 12.1 Hz,
2H, OCH2Ph), 4.72 (broad s, 1H, HC=N2), 4.91 (ddd, J = 2.5 Hz, 1H, CHOCO), 7.19- 13 7.31 (m, 5H, ArH); C-NMR (100 MHz, CDCl3) δ 10.51 (q), 14.12 (q), 31.18 (t), 35.12 199 (d), 36.02 (t), 38.12 (t), 46.44 (d), 60.33 (t), 66.45 (t), 70.21 (d), 71.47 (d), 72.97 (t), 73.38 (d), 127.39 (d), 127.52 (d), 128.23 (d), 138.45 (s), 165.94 (s), 171.19 (s); exact
mass calcd for C21H28N2O6 (M + Na) m/z 427.1840, found m/z 427.1863.
OBn OBn CO Et OBn CO2Et 2 CO Et O 2 O O
O O ) O 2O O O O
387a 386 388
rel-(2S, 3R, 4R, 6S)-[8-(2-Benzyloxy-ethyl)-5-methyl-2-oxo-1,7-dioxaspiro[3.5]non-6- yl]-acetic acid ethyl ester (387a), rel-(2S, 3R, 4R, 6R)-[6-(2-Benzyloxyethyl)-3a- methyl-2-oxohexahydrofuro[3,2-c]pyran-4-yl]-acetic acid ethyl ester (386) and Ether (388). A 25-mL two-necked round-bottomed flask equipped with a condenser and under argon atmosphere was charged with 3.2 mg (0.00371 mmol) of Rh2(4R-
MEOX)4(CH3CN)2 (383) and 2.0 mL of dry dichloromethane. The purple solution was heated to reflux and a solution of 150 mg (0.371 mmol) of diazoacetate 385 in 3.7 mL of dry dichloromethane was added over a 10 h period via a syringe pump. The resulting orange-red solution was heated at reflux for an additional hour. The mixture was allowed to cool to room temperature. The catalyst was removed by filtration through a short a pad of silica gel (5 g) using ethyl acetate to wash the pad. The filtrate was concentrated in vacuo to afford an orange oil. The oil was chromatographed over 15 g of silica gel (230-400 mesh, eluted with 40% ethyl acetate/60% hexanes) to give 11 mg (9.4%) of β- lactone 387a as a colorless oil, and 70 mg of a mixture of lactone 386 and tetrahydropyran 388 as colorless oils. This mixture was chromatographed over 12 g of
200 silica gel (230-400 mesh, eluted with 4% acetone/96% dichloromethane) to give 24 mg (23%) of lactone 386 and 30 mg (21%) of ether 388 as colorless oils. β-Lactone 387a: 25 -1 1 [α]D = +13.3 (c 0.55, CHCl3); IR (Neat) 1824, 1732 cm ; H-NMR (400 MHz, CDCl3)
δ 0.95 (d, J = 7.1 Hz, 3H, CH3), 1.26 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.69-1.86 (two m,
4H, CH2CH2OBn and CH2 THP ring), 1.88 (q, J = 7.0 Hz, 1H, CHCH3), 2.33 (dd, J =
15.0, 5.5 Hz, 1H, CH2CO2Et), 2.54 (dd, J = 15.0, 6.4 Hz, 1H, CH2CO2Et), 3.06 (d, J =
16.2 Hz, 1H, CH2C=O), 3.17 (d, J = 16.2 Hz, 1H, CH2C=O), 3.56 (t, J = 6.8 Hz, 2H,
CH2OBn), 3.80-3.86 (m, 1H, CHCH2CH2OBn), 4.14 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.23
(ddd, J = 7.0, 6.4, 2.0 Hz, 1H, CHCH2CO2Et), 4.48 (ABq, J = 12.0 Hz, 2H, OCH2Ph), 13 7.20-7.40 (m, 5H, ArH); C-NMR (100 MHz, CDCl3) δ 8.91 (q), 14.18 (q), 35.73 (t), 36.18 (t), 38.00 (t), 39.38 (d), 46.91 (t), 60.57 (t), 66.35 (t), 71.41 (d), 71.48 (d), 73.05 (t), 79.65 (s), 127.55 (d), 127.64 (d), 128.35 (d), 138.34 (s), 167.49 (s), 170.53 (s); exact mass calcd for C21H28O6 (M + Na) m/z 399.1778, found m/z 399.1776. Lactone 386: 25 -1 1 [α]D = +23.6 (c 0.55, C6D6); IR (Neat) 1786, 1736 cm ; H-NMR (400 MHz, C6D6) δ
0.43 (s, 3H, CH3), 0.97 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.08 (ddd, J = 15.0, 11.7, 3.6 Hz,
1H, CH2CHOC=O), 1.49-1.72 (m, 3H, CH2CHOC=O and CH2CH2OBn), 1.56 (d, J =
17.3 Hz, 1H, CH2C=O), 1.78 (d, J = 17.3 Hz, 1H, CH2C=O), 1.83 (dd, J = 15.4, 3.4 Hz,
1H, CH2CO2Et), 2.22 (dd, J = 15.4, 10.3 Hz, 1H, CH2CO2Et), 3.33-3.45 (two m, 2H,
CH2OBn), 3.51 (dd, J = 2.8, 2.8 Hz, 1H, CHOC=O), 3.56-3.63 (m, 1H,
CHCH2CH2OBn), 3.88 (dd, J = 10.3, 2.3 Hz, 1H, CHCH2CO2Et), 3.95 (q, J = 7.1 Hz,
2H, OCH2CH3), 4.31 (ABq, J = 12.2 Hz, 2H, OCH2Ph), 7.09 (t, J = 7.4 Hz, 1H, ArH), 13 7.18 (t, J = 7.4 Hz, 2H, ArH), 7.28 (d, J = 7.4 Hz, 2H, ArH); C-NMR (100 MHz, C6D6) δ 14.24 (q), 15.26 (q), 30.72 (t), 36.04 (t), 36.21 (t), 39.59 (s), 40.04 (t), 60.47 (t), 66.85 (t), 70.63 (d), 73.12 (t), 75.42 (d), 82.50 (d), 127.58 (d), 127.76 (d), 128.52 (d), 139.32
(s), 170.37 (s), 173.80 (s); exact mass calcd for C21H28O6 (M + Na) m/z 399.1778, found m/z 399.1762. This material contains an small amount of an unknown impurity that exhibited a methyl doublet at δ 0.55. Thus, the specific rotation reported here is clearly off to some unknown degree (see text for discussion). Ether 388: IR (Neat) 1738 cm-1; 1 H-NMR (500 MHz, C6D6) δ 0.68 (d, J = 7.2 Hz, 6H, CH3), 0.96 (t, J = 7.1 Hz, 6H,
OCH2CH3), 1.32 (ddd, J = 14.5, 11.7, 2.8 Hz, 1H, CH2CHOC=O), 1.41 (dd, J = 14.5, 1.9
201 Hz, 2H, CH2CHOC=O), 1.57-1.70 (two m, 6H, CHCH3 and CH2OBn), 2.03 (dd, J =
15.2, 4.7 Hz, 2H, CH2CO2Et), 2.47 (dd, J = 15.2, 8.9 Hz, 2H, CH2CO2Et), 3.42-3.52 (two
m, 4H, CH2OBn), 3.90-3.98 (two m, 6H, CHCH2CH2OBn and OCH2CH3), 4.00 (s, 4H,
CH2O), 4.33 (ABq, J = 12.1 Hz, 4H, OCH2Ph), 4.38 (ddd, J = 8.9, 4.7, 2.4 Hz, 2H,
CHCH2CO2Et), 4.89 (ddd, J = 2.7, 2.7, 2.7 Hz, 2H, CHOC=O), 7.09 (t, J = 7.4 Hz, 2H, ArH), 7.20 (t, J = 7.4 Hz, 4H, ArH), 7.28 (t, J = 7.3 Hz, 4H, ArH); 13C-NMR (100 MHz,
C6D6) δ 10.92 (q), 14.68 (q), 31.68 (t), 35.66 (d), 37.04 (t), 38.70 (t), 60.61 (t), 67.16 (t), 68.64 (t), 70.95 (d), 72.06 (d), 73.55 (t), 74.16 (d), 127.99 (d), 128.94 (d), 128.17 (d),
139.81 (s), 169.27 (s), 171.15 (s); mass calcd for C58H68O5 (M + Na) m/z 793.3, found m/z 793.3.
HO OH OH 391
(R)-1,2,4-Butanetriol (391).72 A 1000-mL three-necked round-bottomed flask equipped with a pressure equilazer addition funnel and under argon atmosphere was charged with
48 mL (480 mmol) of 10.0 M BH3·SMe2 in tetrahydropyran and 190 mL of dry THF (to make a solution 2.0 M in borane). The mixture was cooled to 0 °C (ice-water) and 50 mL (447 mmol) of trimethylborate was added via syringe. Then, a solution of 19.6 g (146 mmol) of (R)–malic acid (390) in 100 mL of dry THF was added dropwise over a 1 h period. The colorless solution was stirred at 0 °C for 5 min. The cooling bath was removed and a white precipitate appeared. After 30 min of stirring the precipitate dissolved and the cloudy solution became colorless. The mixture was stirred overnight (18 h) and 120 mL of methanol was added dropwise at a rate to maintain control of the reaction. The solution was concentrated in vacuo. The residue was dissolved in 120 mL of methanol and concentrated in vacuo. This process was repeated one more time to afford 14.7 g of a yellow oil. The oil was chromatographed over silica gel (230-400
202 mesh, eluted with dichloromethane/methanol, 9:1 and 7:3) to give 13.3 g (86%) of the 21 85 23 triol 391 as a colorless oil: [α]D = + 25.9 (c 0.58, MeOH), [lit. [α]D = + 24 (c 0.57, 1 MeOH)]; H-NMR (400 MHz, pyridine-d5) δ 2.11-2.27 (two m, 2H, CH2CH2OH), 4.02
(d, J = 5.5 Hz, 2H, CH2OH), 4.19-4.27 (m, 2H, CH2CH2OH), 4.44 (ddd, J = 8.7, 4.9, 4.9, 4.9 Hz, 1H, CHOH), 6.12 (broad s, 3H, three OH).
BnO O O
392
(S)-1,2-O-3-Pentylidene-1,2,4-butanetriol (392).73 A 1000-mL round-bottomed flask equipped with a condenser and under nitrogen atmosphere, was charged with 13.0 g (122.5 mmol) of the triol 391 and 250 mL of dry THF, 250 mL of 3-pentanone, and 2.33 g (12.3 mmol) of p-toluenesulfonic acid monohydrate. The mixture was heated to reflux for 16 h. The pale yellow solution was allowed to cool to room temperature. The solution was partitioned between 400 mL of diethyl ether and 150 mL of saturated
aqueous NaHCO3. The organic layer was separated, dried (MgSO4) and concentrated in vacuo (40 mmHg, 40 °C bath temperature) to give 16 g (75%) of acetonide 392 as a pale 23 86 25 1 yellow oil: [α]D = - 1.61 (c 0.93, MeOH), [lit. [α]D = - 2.6 (c 0.935, MeOH)]; H-
NMR (400 MHz, CDCl3) δ 0.90 (t, J = 7.5 Hz, 3H, CH2CH3), 0.91 (t, J = 7.5 Hz, 3H,
CH2CH3), 1.63 (q, J = 7.5 Hz, 2H, CH2CH3), 1.66 (q, J = 7.5 Hz, 2H, CH2CH3), 1.80-
1.86 (m, 2H, CH2CH2OH), 2.28 (t, J = 5.5 Hz, 1H, OH), 3.55 (t, J = 7.9 Hz, 1H, CH2O),
3.82 (broad q, J = 5.7 Hz, 2H, CH2OH), 4.11 (dd, J = 7.9, 6.1 Hz, 1H, CH2O), 4.22-4.29 (m, 1H, CHO).
203 BnO OH OH 393
(R)-4-Benzyloxy-1,2-butanediol (393).74, 86 A 1000-mL three-necked round-bottomed flask equipped with a pressure equalizer addition funnel was charged with 6 g (150 mmol) of 60% dispersion in mineral oil NaH. The white solid was washed with 80 mL of hexanes. The solvent was removed via cannula. To the solid was added 290 mL of dry THF. The suspension was cooled to 0 °C (ice-water) and a solution of 17.4 g (99.9 mmol) of acetonide 392 in 40 mL of dry THF was added dropwise. The white suspension was stirred for 40 min and a solution of 23.8 mL (34.2 g, 200 mmol) of
benzyl bromide in 60 mL of dry THF contining 739 mg (2.00 mmol) of nBu4NI was added dropwise. The ice bath was removed and the yellowish suspension was stirred at room temperature for 14 h. The reaction mixture was poured into 80 mL of saturated aqueous ammonium chloride. The mixture was extracted with three 100-mL portions of ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford a yellow oil. The oil was diluted with 114 mL of methanol and 29 mL of 3.0 N aqueous HCl. The mixture was heated at 50 °C (oil bath temperature) for 2 h. The brown mixture was allowed to cool to room temperature and concentrated in vacuo to afford a brown residue. The residue was chromatographed over 700 g of silica gel (230- 400 mesh, eluted with chloroform/methanol, 9:1) to give 10.0 g (51%) of diol 393 as a 21 86 24 1 pale yellow oil: [α]D = - 5.64 (c 1.04, CHCl3), [lit [α]D = - 4.2 (c 1.1, CHCl3)]; H-
NMR (400 MHz, CDCl3) δ 1.74-1.79 (m, 1H, CH2CH2OBn), 1.82-1.91 (m, 1H,
CH2CH2OBn), 2.15 (broad s, 2H, two OH), 3.52 (dd, J = 11.2, 6.2 Hz, 1H, CH2OH), 3.65
(dd, J = 11.2, 6.2 Hz, 1H, CH2OH), 3.67-3.75 (m, 2H, CH2OBn), 3.91-3.96 (m, 1H,
CHOH), 4.54 (s, 2H, OCH2Ph), 7.29-7.39 (m, 5H, ArH).
204 BnO O O S O O 395
(R)-4-(2-Benzyloxyethyl)-[1,3,2]-dioxathiolane-2,2-dioxide (395).76 A 500-mL round-
bottomed flask, equipped with a condenser, a CaCl2 anhydrous trap and HCl trap, was charged with 10.0 g (51.0 mmol) of diol 393 and 52 mL of carbon tetrachloride, followed by 4.5 mL (7.28 g, 61.2 mmol) of thionyl chloride. The pale yellow solution was heated to reflux for 1h (oil bath at 95 °C) with vigorous stirring. The solution was allowed to reach to room temperature and then cooled to 0 °C (ice-water). To the cold solution was . added in sequence 52 mL of acetonitrile, 114 mg (0.505 mmol) of RuCl3 H2O, 16.4 g
(76.5 mmol) of NaIO4 and 80 mL of water. The ice bath was removed and the resulting brown solution was stirred for 1 h. The solution was diluted with 200 mL of diethyl ether. The organic layer was separated, washed with 100 mL of water, 100 mL of
saturated aqueous NaHCO3 and 100 mL of brine, and dried (MgSO4). The mixture was passed through a small pad of silica gel (230-400 mesh). The pad was washed with two 200-mL portions of diethyl ether. The filtrate was concentrated in vacuo to afford 11.6 g 1 (81%) of cyclic sulfate 395 as a yellow oil: H-NMR (400 MHz, CDCl3) δ 2.15-2.27 (two
m, 2H, CH2CH2OBn), 3.58-3.69 (two m, 2H, CH2OBn), 4.49 (dd, J = 8.6, 8.6 Hz, 1H,
CH2O), 4.51 (s, 2H, OCH2Ph), 4.72 (dd, J = 8.9, 6.0 Hz, 1H, CH2O), 5.12-5.22 (m, 1H, CHO), 7.29-7.39 (m, 5H, ArH). This material contained some impurities by 1H-NMR, but was used without further purification in the next reaction.
205 BnO
OH (R)-334
(R)-1-Benzyloxy-5-heptyn-3-ol (334).77 A 1000-mL three-necked round-bottomed flask equipped with a low temperature thermometer under argon atmosphere was charged with
320 mL of dry THF. The solvent was cooled to –78 °C (CO2/acetone). A graduate cylinder was cooled to –78 °C and 12 mL of propyne was condensed therein. Then 10 mL of the 12 mL of propyne was transferred via cannula to the flask containing THF. To the resulting solution was added 56 mL (90.0 mmol) of 1.6 M nBuLi in hexanes at a rate such that the internal temperature did not exceed –65 °C. The cloudy solution was stirred for 30 min. Then a solution of 11.6 g (41.3 mmol) of cyclic sulfate 395 in 110 mL of dry THF was added slowly via cannula. The brown solution was stirred for 1 h. The cooling bath was removed and the mixture was stirred overnight (14 h) at room temperature. To the solution was added 3.0 mL of concentrated sulfuric
acid. The mixture was stirred for 2 h and 100 mL of saturated aqueous NaHCO3 was added very slowly. The mixture was extracted with three 150-mL portions of ethyl
acetate. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford 11 g of a brown oil. The oil was chromatographed over 400 g of silica gel (230- 400 mesh, eluted with 15% ethyl acetate/85% hexanes) to give 5.1 g (52%) of alkyne 334 20 1 as a yellow oil: [α]D = + 16.3 (c 0.78, MeOH); H-NMR (400 MHz, CDCl3) δ 1.79 (t, J
= 2.5 Hz, 3H, CH3), 1.83-1.94 (m, 2H, CH2CH2OBn), 2.34 (dq, J = 6.0, 2.5 Hz, 2H,
CH2C≡C), 2.96 (broad s, 1H, OH), 3.66 (ddd, J = 9.4, 7.6, 4.8 Hz, 1H, CH2OBn), 3.74
(ddd, J = 9.4, 6.1, 5.0 Hz, 1H, CH2OBn), 3.90-4.00 (m, 1H, CHOH), 4.50 (s, 2H,
CH2Ph), 7.18-7.35 (m, 5H, ArH).
206 BnO
OH (R)-335
(R)-(Z)-1-Benzyloxy-5-hepten-3-ol (335). A 100-mL of three-necked round-bottomed flask was charged with 33 mL of pyridine and 1.95 g of 5% Pd/BaSO4. The brown mixture was evacuated and prehydrogenated. To the resulting black mixture was added a solution of 5.0 g (22.9 mmol) of the alkyne 334 in 13 mL of pyridine. The mixture was hydrogenated at one atmosphere for 1 h. The mixture was flushed with argon and filtered through a Celite pad. The pad was washed with chloroform up to a total filtrate volume of 200 mL. The filtrate was washed with three 100-mL portions of 10% aqueous HCl.
The organic layer was separated, dried (MgSO4) and concentrated in vacuo to afford 5.05 20 1 g (100%) of alkene 335 as a yellow oil: [α]D = + 8.18 (c 1.02, MeOH); H-NMR (400
MHz, CDCl3) δ 1.65 (dd, J = 6.8, 0.8 Hz, 3H, CH3), 1.75-1.90 (m, 2H, CH2CH2OBn),
2.15-3.15 (m, 2H, CH2CH=CH), 2.30 (broad s, 1H, OH), 3.60-3.70 (m, 1H, CH2OBn),
3.70-3.80 (m, 1H, CH2OBn), 3.80-3.90 (m, 1H, CHOH), 4.57 (s, 2H, OCH2Ph), 5.45
(dqt, J = 10.9, 7.4, 1.7 Hz, 1H, CH=CHCH3), 5.63 (dqt, J = 10.9, 7.3, 2.0 Hz, 1H,
CH=CHCH3), 7.27 (m, 5H, ArH).
OBn
O EtO2C
(R)-336
(R)-(Z)-Ethyl 3-[(1-Benzyloxyethyl)pent-3-enyloxy]acrylate (336). A 250-mL three- necked round-bottomed flask under argon atmosphere was charged with 3.4 mL (3.32 g, 33.8 mmol) of ethyl propiolate, 40 mL of dry diethyl ether and 4.7 mL (3.42 g, 33.8
207 mmol) of triethylamine. To the resulting yellow mixture was added a solution of 4.95 g (22.5 mmol) of alcohol (R)-335 in 35 mL of dry diethyl ether via cannula. The brown solution was stirred for 43 h. The mixture was diluted with 200 mL of diethyl ether and
washed with 100-mL portions of 1M aqueous KHSO4, 100 mL of saturated aqueous
NaHCO3 and 100 mL of brine. The organic phase was separated, dried (MgSO4) and concentrated in vacuo to afford 7.7 g of a brown oil. The oil was chromatographed over 400 g of silica gel (230–400 mesh, eluted with 10% diethyl ether/90% hexanes) to give 20 1 4.2 g (59%) of enol ether 336 as a pale yellow oil: [α]D = + 68.7 (c 1.0, CH2Cl2); H-
NMR (400 MHz, CDCl3) δ 1.28 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.61 (ddd, J = 6.9, 0.9,
0.9 Hz, 3H, CH3), 1.80-2.00 (m, 2H, CH2CH2OBn), 2.28-2.42 (m, 2H, CH2CH=CH),
3.47-3.57 (m, 2H, CH2OBn), 4.17 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.14-4.21 (m, 1H,
CHO), 4.49 (ABq, J = 11.9 Hz, 2H, OCH2Ph), 5.27 (d, J = 12.3 Hz, 1H, CH=CHCO2Et),
5.38 (dtq, J = 10.7, 7.2, 1.9 Hz, 1H, CH=CHCH3), 5.61 (dqt, J = 10.7, 6.9, 1.6 Hz, 1H,
CH=CHCH3), 7.27-7.39 (m, 5H, ArH), 7.54 (d, J = 12.3 Hz, 1H, CH=CHCO2Et). The Z/E ratio was 14:1 based on the signals at 1.61 and 1.67 ppm. The 1H-NMR contains some small impurities.
OBn CO2Et O
OH 337a
(2S, 3S, 4S, 6R)-6-Benzyloxyethyl-2-carbethoxymethyl-4-hydroxy-3-methyl tetrahydropyran (337a). A 50-mL three-necked round-bottomed flask under nitrogen atmosphere was charged with 800 mg (2.51 mmol) of enol ether (R)-336 and 25 mL of dry dichloromethane. The solution was cooled to 0 °C (ice-water) and 1.9 mL (2.86 g,
208 25.1 mmol) of trifluoroacetic acid was added slowly via syringe. The ice bath was removed and the mixture was stirred for 2 h. The solution was cooled to 0 °C and 20 mL of saturated aqueous sodium bicarbonate was added very slowly. The mixture was extracted with three 25-mL portions of dichloromethane. The combined organic extracts
were dried (Na2SO4) and concentrated in vacuo to afford a yellow oil. The oil was dissolved in 25 mL of absolute ethanol and 191 mg (1.38 mmol) of anhydrous potassium carbonate was added. The mixture was stirred for 2 h at room temperature. The resulting solution was concentrated in vacuo and diluted with 100 mL of ethyl acetate. The solution was washed with 20 mL of water. The aqueous layer was separated and extracted with two 20-mL portions of ethyl acetate. The combined organic layers were
dried (MgSO4), and concentrated in vacuo to afford a yellow oil. The oil was chromatographed over 30 g of silica gel (230–400 mesh, eluted with 40% ethyl acetate/60% hexanes) to give 510 mg (60%) of tetrahydropyran 337a as a colorless oil: 22 1 [α]D = - 6.11 (c 1.02, MeOH); H-NMR (400 MHz, CDCl3) δ 0.90 (d, J = 7.1 Hz, 3H,
CH3), 1.27 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.39 (ddd, J = 12.1, 12.1, 12.1 Hz, 1H,
CH2CHOH), 1.59 (broad s, 1H, OH), 1.65 (ddd, J = 12.4, 4.6, 2.5 Hz, 1H, CH2CHOH),
1.70-1.88 (m, 2H, CH2CH2OBn), 1.89-1.96 (m, 1H, CHCH3), 2.37 (dd, J = 15.2, 5.1 Hz,
1H, CH2CO2Et), 2.59 (dd, J = 15.2, 8.6 Hz, 1H, CH2CO2Et), 3.50-3.60 (m, 3H,
CHCH2CH2OBn and CH2OBn), 3.85 (ddd, J = 7.9, 5.0, 2.0 Hz, 1H, CHCH2CO2Et), 3.96
(ddd, J = 11.6, 4.6, 4.6 Hz, 1H, CHOH), 4.15 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.67 (s, 2H,
OCH2Ph), 7.27-7.41 (m, 5H, ArH).
209 OBn CO2Et O
NO OBn 2 CO2Et O O
O
338a 339a
rel-(2S, 3S, 4R, 6R)-6-Benzyloxyethyl-2-carbethoxymethyl-3-methyl-4-(4’-nitro benzoyl)tetrahydropyran (338a) and rel-(2S, 6S)-6-Benzyloxy-2-carbethoxymethyl- 5,6-dihydro-2H-tetrahydropyran (339a).53 A 250-mL three-necked round-bottomed flask under argon atmosphere was charged with 3.04 g (9.04 mmol) of alcohol 337a, 120 mL of dry THF, 7.10 g (27.1 mmol) of triphenylphosphine and 2.27 g (13.6 mmol) of 4- nitrobenzoic acid. To the colorless solution was added 4.3 mL (4.72 g, 27.1 mmol) of diethyl azodicarboxylate dropwise via syringe at a rate to maintain control of the reflux. The mixture was stirred for 6 h at room temperature. The orange solution was diluted
with 150 mL of diethyl ether and washed with 100 mL of 5% aqueous K2CO3. The aqueous layer was separated and extracted with two 150-mL portions of diethyl ether.
The combined organic layers were dried (MgSO4) and concentrated in vacuo to a volume of about 20 mL. The resulting thick solution was chromatographed over 250 g of silica gel (230-400 mesh, eluted with 10% ethyl acetate/90% hexanes and 20% ethyl acetate/80% hexanes) to give 625 mg (14%) of the tetrahydropyran 338a as a colorless 22 oil and 1.58 g (55%) of alkene 339a as a colorless oil. Tetrahydropyran 338a: [α]D = 1 +2.25 (c 1.02, MeOH); H-NMR (400 MHz, CDCl3) δ 1.06 (d, J = 7.2 Hz, 3H, CH3),
1.27 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.70-1.85 (m, 4H, CH2CHOAr and CH2CH2OBn),
1.95 (qdd, J = 7.2, 2.5, 2.5 Hz, 1H, CHCH3), 2.33 (dd, J = 15.2, 5.2 Hz, 1H, CH2CO2Et),
2.57 (dd, J = 15.2, 8.8 Hz, 1H, CH2CO2Et), 3.50-3.61 (m, 2H, CH2OBn), 3.94-4.00 (m,
1H, CHCH2CH2OBn), 4.13 (qd, J = 7.1, 1.6 Hz, 2H, OCH2CH3), 4.37 (ddd, J = 8.8, 5.2,
2.4 Hz, 1H, CHCH2CO2Et), 4.50 (ABq, J = 11.9 Hz, 2H, CH2Ph), 5.21 (ddd, J = 2.4, 2.4, 2.4 Hz, 1H, CHOAr), 7.25-7.31 (m, 5H, ArH), 8.23 (d, J = 8.8 Hz, 2H, ArH), 8.30 (d, J = 210 22 1 8.8 Hz, 2H, ArH). Alkene 339a: [α]D = -33.7 (c 1.09, CHCl3); H-NMR (400 MHz,
CDCl3) δ 1.27 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.62 (s, 3H, CH3), 1.77-1.84 (m, 2H,
CH2CH2OBn), 1.85-2.05 (m, 2H, CH2CH=CCH3), 2.39 (dd, J = 14.5, 9.2 Hz, 1H,
CH2CO2Et), 2.66 (dd, J = 14.5, 4.0 Hz, 1H, CH2CO2Et), 3.56-3.61 (m, 2H, CH2OBn),
3.62-3.70 (m, 1H, CHCH2CH2OBn), 4.15 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.40-4.50 (m,
1H, CHCH2CO2Et), 4.49 (ABq, J = 12.1 Hz, 2H, CH2Ph), 5.52-5.55 (sharp m, 1H,
CH=CCH3), 7.27-7.37 (m, 5H, ArH).
OBn CO2Et O
OH 376a
rel-(2S, 3S, 4R, 6R)-6-Benzyloxyethyl-2-carbethoxymethyl-4-hydroxy-3-methyl tetrahydropyran (376a). A 50-mL round-bottomed flask under argon atmosphere was charged with 600 mg (1.24 mmol) of tetrahydropyran 338a and 12 mL of absolute ethanol. To the colorless solution was added 86 mg (0.62 mmol) of anhydrous potassium carbonate. The mixture was stirred for 2 h and an additional 86 mg (0.62 mmol) of anhydrous potassium carbonate was added and stirring was continue for 6 h. The solution was concentrated in vacuo to afford a mixture of a yellow oil and a solid. The residue was diluted in 50 mL of dichloromethane and washed with 10 mL of brine. The organic layer was dried (MgSO4) and concentrated in vacuo to afford a yellow oil. The oil was chromatographed over 15 g of silica gel (230-400 mesh, eluted with 40% ethyl acetate/60% hexanes) to give 340 mg (84%) of tetrahydropyran 376a as a colorless oil: 22 1 [α]D = +7.4 (c 1.02, MeOH); H-NMR (400 MHz, CDCl3) δ 0.91 (d, J = 7.1 Hz, 3H,
CH3), 1.24 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.47 (broad d, J = 14.2 Hz, 1H, CH2CHOH),
211 1.55 (broad s, 1H, OH), 1.60-1.70 (m, 2H, CH2CHOH and CHCH3), 1.70-1.85 (m, 2H,
CH2CH2OBn), 2.27 (dd, J = 14.8, 5.2 Hz, 1H, CH2CO2Et), 2.53 (dd, J = 14.8, 9.2 Hz,
1H, CH2CO2Et), 3.57 (dd, J = 7.5, 6.0 Hz, 2H, CH2OBn), 3.93 (ddd, J = 2.8, 2.8, 2.8 Hz,
1H, CHOH), 3.96 (m, 1H, CHCH2CH2OBn), 4.14 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.36
(ddd, J = 8.5, 5.5, 2.6 Hz, 1H, CHCH2CO2Et), 4.49 (ABq, J = 12.0 Hz, 2H, OCH2Ph), 7.25-7.37 (m, 5H, ArH).
OBn CO2Et O
O N2 O 385a
rel-(2S, 3S, 4R, 6R)-6-Benzyloxyethyl-2-carbethoxymethyl-4-(2’-diazoacetoxy)-3- methyltetrahydropyran (385a). A 25-mL three-necked round-bottomed flask under nitrogen atmosphere was charged with 320 mg (0.951 mmol) of alcohol 338a and 6 mL of dry dichloromethane. The colorless solution was cooled to 0 °C (ice-water) and 472 mg (1.81 mmol) of acyl chloride 384 was added, followed by addition of 220 µL (210 mg, 1.74 mmol) of N,N-dimethylaniline dropwise. The resulting brown solution was stirred for 30 min and 0.70 mL (491 mg, 4.85 mmol) of triethylamine was added via syringe. The dark orange solution was stirred for 15 min at 0 °C and 30 min at room temperature. The mixture was diluted with 40 mL of dichloromethane and washed with two 10-mL portions of saturated aqueous citric acid, 10 mL of water and 10 mL of saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO4) and concentrated in vacuo to afford 557 mg of a brown oil. The oil was chromatographed over 25 g of silica gel (230-400 mesh, eluted with ethyl acetate/hexanes, 1:4) to give 328 22 1 mg (85%) of diazoacetate 385a as a pale yellow oil: [α]D = +1.97 (c 1.02, CH2Cl2); H-
212 NMR (500 MHz, CDCl3) δ 0.99 (d, J = 7.2 Hz, 3H, CH3), 1.26 (t, J = 7.2 Hz, 3H,
OCH2CH3), 1.63-1.66 (sharp m, 2H, CH2CH2OBn), 1.67-1.78 (m, 2H, CH2CHOCO),
1.79-1.85 (m, 1H, CHCH3), 2.28 (dd, J = 15.1, 5.0 Hz, 1H, CH2CO2Et), 2.52 (dd, J =
15.1, 9.1 Hz, 1H, CH2CO2Et), 3.57 (t, J = 6.3 Hz, 2H, CH2OBn), 3.80-3.85 (m, 1H,
CHCH2CH2OBn), 4.14 (q, J = 7.2 Hz, 2H, OCH2CH3), 4.20-4.24 (ddd, J = 9.0, 5.0, 2.5
Hz, 1H, CHCH2CO2Et), 4.52 (ABq, J = 12.0 Hz, 2H, OCH2Ph), 4.80 (broad s, 1H,
HC=N2), 5.00 (ddd, J = 2.8 Hz, 1H, CHOCO), 7.19-7.31 (m, 5H, ArH).
OBn OBn CO Et OBn CO2Et 2 CO Et O 2 O O
O O ) O 2O O O O
387b 386 388
(2R, 3S, 4S, 6R)-[8-(2-Benzyloxyethyl)-5-methyl-2-oxo-1,7-dioxaspiro[3.5]non-6- yl]acetic acid ethyl ester (387b), (2S, 3R, 4R, 6R)-[6-(2-Benzyloxyethyl)-3a-methyl-2- oxohexahydrofuro[3,2-c]pyran-4-yl]acetic acid ethyl ester (386) and Ether (388). A 25-mL three-necked round-bottomed flask equipped with a condenser and under argon atmosphere was charged with 3.4 mg (0.00396 mmol) of Rh2(4R-MEOX)4(CH3CN)2 (383) and 2.2 mL of dry dichloromethane. The purple solution was heated to reflux and a solution of 160 mg (0.396 mmol) of diazoacetate 385a in 4.0 mL of dry dichloromethane was added over a 10 h period via a syringe pump. The resulting orange-red solution was heated to reflux for an additional hour. The mixture was allowed to cool to room temperature. The catalyst was removed by filtration through a short a pad of silica gel (5 g) using ethyl acetate to wash the pad. The filtrate was concentrated in vacuo to afford
213 280 mg of an orange oil. The oil was chromatographed over 15 g of silica gel (230-400 mesh, eluted with 40% ethyl acetate/60% hexanes) to give 11 mg (8.9%) of β-lactone 387b as a colorless oil, and 104 mg of a mixture of lactone 386 and tetrahydropyran 388 as colorless oils. This mixture was chromatographed over 10 g of silica gel (230-400 mesh, eluted with 4% acetone/96% dichloromethane) to give 39.8 mg (28%) of lactone 22 386 and 37 mg (24%) of ether 388 as colorless oils. β-Lactone 387b: [α]D = -15.8 (c 1 0.29, CHCl3); H-NMR (500 MHz, CDCl3) δ 0.95 (d, J = 7.1 Hz, 3H, CH3), 1.26 (t, J =
7.2 Hz, 3H, OCH2CH3), 1.71 (ddd, J = 14.2, 2.5, 1.6 Hz, 1H, CH2 THP ring), 1.74-1.86
(m, 3H, CH2CH2OBn and CH2 THP ring), 1.88 (qdd, J = 7.2, 1.6, 1.6 Hz, 1H, CHCH3),
2.33 (dd, J = 14.8, 5.7 Hz, 1H, CH2CO2Et), 2.55 (dd, J = 14.8, 8.5 Hz, 1H, CH2CO2Et),
3.06 (d, J = 16.2 Hz, 1H, CH2C=O), 3.17 (d, J = 16.2 Hz, 1H, CH2C=O), 3.54-3.58 (m,
2H, CH2OBn), 3.80-3.86 (m, 1H, CHCH2CH2OBn), 4.14 (q, J = 7.2 Hz, 2H, OCH2CH3),
4.23 (ddd, J = 8.2, 5.4, 2.2 Hz, 1H, CHCH2CO2Et), 4.48 (ABq, J = 12.0 Hz, 2H, 22 1 OCH2Ph), 7.27-7.35 (m, 5H, ArH). Lactone 386: [α]D = +42.0 (c 1.14, C6D6); H-
NMR (500 MHz, C6D6) δ 0.44 (s, 3H, CH3), 0.96 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.10
(ddd, J = 15.2, 11.8, 3.6 Hz, 1H, CH2CHOC=O), 1.50-1.66 (m, 3H, CH2CHOC=O and
CH2CH2OBn), 1.59 (d, J = 17.1 Hz, 1H, CH2C=O), 1.80 (d, J = 17.1 Hz, 1H, CH2C=O),
1.85 (dd, J = 15.4, 2.4 Hz, 1H, CH2CO2Et), 2.22 (dd, J = 15.4, 10.3 Hz, 1H, CH2CO2Et),
3.34-3.44 (two m, 2H, CH2OBn), 3.53 (dd, J = 3.0, 3.0 Hz, 1H, CHOC=O), 3.57-3.63 (m,
1H, CHCH2CH2OBn), 3.88 (dd, J = 10.3, 2.4 Hz, 1H, CHCH2CO2Et), 3.96 (qd, J = 7.1,
1.4 Hz, 2H, OCH2CH3), 4.31 (ABq, J = 12.1 Hz, 2H, OCH2Ph), 7.09 (t, J = 7.3 Hz, 1H, ArH), 7.18 (t, J = 7.4 Hz, 2H, ArH), 7.28 (d, J = 7.1 Hz, 2H, ArH); 13C-NMR (125 MHz,
C6D6) δ 14.25 (q), 15.28 (q), 30.73 (t), 36.06 (t), 36.22 (t), 39.63 (s), 40.07 (t), 60.49 (t), 66.87 (t), 70.64 (d), 73.13 (t), 75.45 (d), 82.55 (d), 127.59 (d), 127.77 (d), 128.53 (d), 22 1 139.34 (s), 170.43 (s), 173.89 (s). Ether 388: [α]D = +1.8 (c 1.85, C6D6); H-NMR
(500 MHz, C6D6) δ 0.68 (d, J = 7.2 Hz, 6H, CH3), 0.96 (t, J = 7.1 Hz, 6H, OCH2CH3),
1.32 (ddd, J = 14.5, 11.7, 2.9 Hz, 2H, CH2CHOC=O), 1.41 (dd, J = 14.5, 1.9 Hz, 2H,
CH2CHOC=O), 1.57-1.70 (two m, 6H, CHCH3 and CH2OBn), 2.04 (dd, J = 15.3, 4.8 Hz,
2H, CH2CO2Et), 2.47 (dd, J = 15.3, 9.0 Hz, 2H, CH2CO2Et), 3.42-3.54 (two m, 4H,
CH2OBn), 3.90-3.98 (m, 2H, CHCH2CH2OBn) 3.95 (qd, J = 7.1, 2.7 Hz, 4H, OCH2CH3),
214 4.02 (s, 4H, CH2O), 4.34 (ABq, J = 12.1 Hz, 4H, OCH2Ph), 4.38 (ddd, J = 9.0, 4.8, 2.3
Hz, 2H, CHCH2CO2Et), 4.89 (ddd, J = 2.7, 2.7, 2.7 Hz, 2H, CHOC=O), 7.10 (t, J = 7.5 Hz, 2H, ArH), 7.20 (t, J = 7.5 Hz, 4H, ArH), 7.29 (t, J = 7.5 Hz, 4H, ArH).
410
trans-Dec-5-en-2,8-diyne (410).80 A 5-L three-necked round-bottomed flask equipped with a mechanical stirrer, a pressure equalizing addition funnel and a low temperature thermometer under argon atmosphere was charged with 1.2 L of dry THF. The solution was cooled to –78 °C (CO2/acetone). A 250-mL graduated cylinder was cooled to –78 °C and 137 mL (2.4 mol) of propyne was condensed therein. The propyne was transferred to the 5-L flask via cannula. To the resulting solution was added 800 mL (1.6 mol) of 2.0 M EtMgCl in THF at a rate to keep the internal temperature below –65 °C. The black solution was stirred for 1.5 h and 3.9 g (0.026 mol) of anhydrous NaI and 5.94 g (0.060 mol) of CuCl was added. The ice bath was removed. The mixture was allowed to reach room temperature and a solution of 50 g (0.4 mol) of trans-1,4-dichloro-2-butene (409) in 300 mL of dry THF was added dropwise over a 1 h period. The addition funnel was quickly replaced by a condenser. The mixture was heated to a bath temperature of 55 °C for 20 h. The mixture was slowly poured in 400 mL of ice-water. The mixture was extracted with two 500-mL portions of diethyl ether. The combined extracts were washed with 100 mL of saturated aqueous ammonium chloride and 100 mL of brine. The
organic solution was dried (MgSO4) and concentrated in vacuo to afford a brown oil. The oil was distilled to give 22.4 g (42%) of hydrocarbon 410 as a pale yellow crystalline solid: bp 110 °C, 20 torr [lit 92-94 °C, 12 torr]; mp 52-55 °C, [lit80 52-54 °C]; 1H-NMR
215 (400 MHz, CDCl3) δ 1.82 (t, J = 2.4 Hz, 6H, CH3), 2.90 (s, 4H, CH2), 5.69 (sharp t, J = 2.7 Hz, 2H, CH).
OH
OH 411
Deca-2,8-diyn-5,6-diol (411).80 A 100-mL three-necked round-bottomed flask was charged with 1.66 g (12.4 mmol) of N-methylmorpholine N-oxide monohydrate, 1 mL of
t-butanol, 6 mL of water, 2.5 mL of acetone and 10 mg (0.0373 mmol) of OsO4. To the mixture was added dropwise a solution of 1.50 g (11.3 mmol) of olefin 410 in 8.0 mL of acetone over a 20 min period. During the addition a crystalline colorless solid formed, but partially dissolved as the addition proceeded. After 16 h of stirring, another equivalent (11.3 mmol) of N-methylmorpholine N-oxide and 10 mg (0.0373 mmol) of
OsO4 were added. The black solution was stirred for 18 h at room temperature. To the mixture was added 750 mg of NaHSO3, 2.25 g of Celite and 8 mL of water. The solution was filtered through a Celite pad and the solids were washed with two 10-mL portions of acetone and two 10-mL portions of water. The filtrate was acidified to a pH = 2.0 using 1N aqueous HCl. The mixture was extracted with three 50-mL portions of dichloromethane. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford a brown solid. The solid was chromatographed over 90 g of silica gel (230-400 mesh, eluted with ethyl acetate/hexanes, 1:1) to afford 900 mg (48%) of diol 80 1 411 as a white solid: mp 101-103 ºC, [lit 102-103 ºC]; H-NMR (400 MHz, CDCl3) δ
1.80 (t, J = 2.6 Hz, 6H, CH3), 2.30 (very broad s, 2H, OH), 2.40-2.53 (m, 4H, CH2), 3.75 (ddt, J = 9.6, 5.9, 2.6 Hz, 2H, CHOH).
216 OH
OH 412
trans, trans-Deca-2,8-dien-5,6-diol (412).80 A 500-mL three-necked round-bottomed flask equipped with a condenser and under nitrogen atmosphere was charged with 125 mL of diglyme. The flask was cooled to 0 ºC (ice-water) and 15.3 g (404 mmol) of
LiAlH4 was added very slowly, followed by 11 mL of dry THF. To the gray solution was added very slowly 12.9 g (77.6 mmol) of diol 411 using 75 mL of diglyme to help the solid integrate the gray suspension. The solution was allowed to reach room temperature and was then heated to a bath temperature of 146 ºC. The mixture was stirred for 6 h and allowed to cool to room temperature. The solution was poured into 200 mL of ice-water very slowly and then acidified to a pH of 2.0 using 1.0 N aqueous HCl. The mixture was extracted with four 300-mL portions of diethyl ether. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to a volume of about 200 mL. The solution was submitted to a high vacuum distillation to give 7.84 g (59%) of diol 412 as a white paste: bp 110-115 ºC, 0.45 torr, [lit.80 96-98 ºC, 0.15 torr]; 1H-NMR (400 MHz,
CDCl3) δ (d, J = 6.1 Hz, 6H, CH3), 2.03 (broad s, 2H,OH), 2.20-2.27 (m, 2H, CH2), 2.28-
2.32 (broad m, 2H, CH2), 3.46-3.50 (m, 2H, OH), 5.46 (dtq, J = 15.2, 7.3, 1.3 Hz, 2H,
CH3CH=CH), 5.58 (dq, J = 15.2, 6.1 Hz, 2H, CH3CH=CH).
217 O
O H O 398 401
trans-3-Pentenal (398) and 2-(2’-Butenyl)-2,3-dihydropyran-4-one (401).78, 80 A 10- mL two-necked round-bottomed flask was charged with 630 mg (2.94 mmol) of NaIO4 and 4.5 mL of water. The mixture was cooled to 0 °C (ice-water) and a solution of 500 mg (2.94 mmol) of diol 412 in 0.6 mL of diethyl ether was added in one portion. The mixture was vigorously stirred for 30 min. The resulting solution, containing a white precipitate, was extracted with three 5-mL portions of diethyl ether. The combined organic extracts were dried (Na2SO4) and concentrated by distillation of the solvent at one atmosphere to afford 202 mg (41%) of the expected aldehyde 398 as an ether 1 solution: H-NMR (250 MHz, C6D6) δ 1.40 (dd, J = 8.9, 2.4 Hz, 3H, CH3), 2.40-2.60
(broad m, 2H, CH2CHO), 5.09-5.28 (m, 2H, CH=CH), 9.19 (t, J = 2.0 Hz, 1H, CHO). This material was immediately used without any further any further purification due to its high unstability. A 50-mL three-necked round-bottomed flask under argon atmosphere was charged with the crude aldehyde 398 and 1.2 mL of 2-butanol. The mixture was cooled to 0 °C and 819 mg (3.60 mmol) of diene 399 was added dropwise via syringe. The orange solution was stirred for 45 min. The ice bath was removed and the mixture was stirred for another 30 min. The solvent was removed in vacuo (0.45 mmHg). The residue was dissolved in 10 mL of dry dichloromethane. The yellow-orange solution was cooled to – 78 °C (CO2/acetone) and a solution of 300 µL (337 mg, 4.32 mmol) of acetyl chloride in 7 mL of dry dichloromethane was added slowly. The red solution was stirred
for 30 min and 12 mL of saturated aqueous NaHCO3 was added. The mixture was extracted with three 30-mL portions of dichloromethane. The combined organic extracts
were dried (MgSO4) and concentrated in vacuo to afford a brown residue. The residue was chromatographed over 60 g of silica gel (230-400 mesh, eluted with 10% ethyl
218 acetate/90 % hexanes) to give 76.3 mg (38%) of ketone 401 as a pale yellow oil: 1H-
NMR (400 MHz, CDCl3) δ 1.64 (d, J = 6.3 Hz, 3H, CH3), 2.30-2.48 (m, 4H, CH2CO and
CH2C=C), 4.37 (dddd, J = 13.1, 6.1, 6.1, 4.0 Hz, 1H, CHO), 5.34 (d, J = 6.1 Hz, 1H,
OCH=CH), 5.37 (dtq, J = 15.2, 6.6, 1.0 Hz, 1H, CH3CH=CH), 5.54 (dq, J = 15.2, 6.1 Hz,
1H, CH3CH=CH), 7.31 (d, J = 6.1 Hz, 1H, OCH=CH). The NMR spectra contain some signals that might correspond to an isomeric cycloadduct from the Diels Alder reaction.
O
OH 413
2-(2’-Butenyl)-3,4-dihydro-2H-pyran-4-ol (413).81 A 25-mL round-bottomed flask was charged with 74 mg (0.486 mmol) of ketone 401, 1.5 mL of absolute ethanol, 2.4 mL of
water and 120 mg (0.486 mmol) of CeCl3. The mixture was cooled to –25 °C
(CO2/ethylene glycol) and 27.6 mg (0.729 mmol) of NaBH4 was added in one portion. The initially cloudy solution was stirred for 20 min. To the pale yellow solution was added 0.5 mL of acetone. The mixture was allowed to reach room temperature and was then extracted with three 15-mL portions of diethyl ether. The combined organic extracts
were dried (Na2SO4) and concentrated in vacuo to afford 61.2 mg of a yellow oil. The oil was chromatographed over 12 g of silica gel (230-400 mesh, eluted with 30% ethyl acetate/70% hexanes) to give 40 mg (53%) of alcohol 413 (mixture of isomers, 33:1) as a -1 1 colorless oil. Major isomer: IR (Neat) 3365, 1643 cm ; H-NMR (400 MHz, C6D6) δ
1.48 (ddd, J = 13.0, 11.6, 9.4 Hz, 1H, CH2CHOH), 1.54 (d, J = 4.2 Hz, 3H, CH3) 1.85
(broad ddt, J = 13.0, 6.3, 1.7 Hz, 2H, CH2CHOH and OH), 2.07-2.13 (m, 1H,
CH2CH=CH), 2.21-2.27 (m, 1H, CH2CH=CH), 3.68 (ddd, J = 8.9, 6.3, 1.8 Hz, 1H, CHOH); 4.22 (ddt, J = 9.0, 7.0 Hz, 1H, CHO), 4.66 (ddd, J = 6.2, 1.8, 1.8 Hz, 1H, 13 OCH=CH), 5.31-5.43 (m, 2H, CH=CHCH3), 6.27 (d, J = 6.2 Hz, 1H, OCH=CH); C- 219 NMR (100 MHz, C6D6) δ 18.18 (q), 37.81 (t), 38.76 (t), 63.22 (d), 75.10 (d), 106.35 (d), 126.85 (d), 128.06 (d), 145.1 (d). NMR spectrum showed small signals that correspond to the minor isomer.
220 LIST OF REFERENCES
1. Horton, P. A.; Koehn, F. E.; Longley, R. E.; McConnell, O. J. J. Am. Chem. Soc. 1994, 116, 6015-6016.
2. Lee, E., Song, H. Y.; Kang, J. W.; Kim, D-S.; Jung, C-K.; Joo, J. M. J. Am. Chem. Soc. 2002, 124, 384-385.
3. Lee, E., Song, H. Y.; Joo, J. M.; Kang, J. W.; Kim, D. S.; Jung, C. K.; Hong, C. Y.; Jeong, S. W.; Jeon, K.; Bioorg. Med. Chem.Lett. 2002, 12, 3519-3520.
4. Song, H. Y.; Joo, J. M.; Kang, J. W.; Kim, D-S.; Jung, C-K.; Kwak, H. S.; Park, J. H.; Lee, E.; Hong, C. Y.; Jeong, S. W.; Jeon, K.; Park, J. H. J. Org. Chem. 2003, 68, 8080-8087.
5. Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4992-4998.
6. Wittig, G.; Haag, W. Chem. Ber. 1955, 88, 1654-1666.
7. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408.
8. Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett. 1991, 32, 1175-1178.
9. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989-1993.
10. Blakemore, P. R.; Cole, W. J.; Kocieński, P. J.; Morley, A. Synlett 1998, 26-28.
11. Mitsunobu, O.; Wada, M.; Sano, T. J. Am. Chem. Soc. 1972, 94, 679-680.
12. Wadsworht, W. S. Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733-1738.
221 13. Kang, S. H.; Kang, S. Y.; Kim, C. M.; Choi, H.; Jun, H-S.; Lee, B. M.; Park, C. M.; Jeong, J. W. Angew. Chem. Int. Ed. 2003, 42, 4779-4782.
14. Kang, S. H.; Choi, H.; Kim, C. M.; Jun, H-S.; Kang, S. Y.; Jeong, J. W.; Youn, J-H. Tetrahedron Lett. 2003, 44, 6817-6819.
15. Kang, S. H.; Kang, S. Y.; Choi, H.; Kim, C. M.; Jun, H-S.; Youn, J-H. Synthesis 2004, 1102-1114.
16. Hart, D. J.; Patterson, S.; Unch, J. P. Synlett 2003, 1334-1338.
17. Hart, D. J.; Patterson, S.; Zakarian, A. Heterocycles 2000, 52, 1025-1028.
18. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818.
19. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
20. a) Baeyer, A.; Villiger, V. Ber. 1899, 24, 3625. b) Baeyer, A.; Villiger, V. Ber. 1900, 33, 858. c) Hassall, C. H. Org. React. 1957, 9, 73.
21. Gurjar, M. K.; Kumar, P.; Rao, B. V. Tetrahedron Lett. 1996, 37, 8617-8620.
22. Gurjar, M. K.; Chakrabarti, A.; Rao, B. V.; Kumar, P. Tetrahedron Lett. 1997, 38, 6885-6888.
23. Nowakowski, M.; Hoffmann, H. M. R. Tetrahedron Lett. 1997, 38, 1001-1004.
24. Beck, H.; Hoffmann, H. M. R. Eur. J. Org. Chem. 1999, 2991-2995.
25. Deba, T.; Yakushiji, F.; Shindo, M.; Shishido, K. Synlett 2003, 10, 1500-1502.
26. Oppolzer, W.; Blagg, J.; Rodriguez, I.; Walther, E. J. Am. Chem. Soc. 1990, 112, 2767-2772
27. a) MacMillan, D. W. C.; Overman, L. E.; Pennington, L. D. J. Am. Chem. Soc. 2001, 123, 9033-9044. b) Corminboeuf, O.; Overman, L. E.; Pennington, L. D. . J. Am. Chem. Soc. 2003, 125, 6650-6652.
222 28. Lolkema, L. D. M.; Hiemstra, H.; Mooiweer, H. H.; Speckamp, W. N. Tetrahedron Lett. 1988, 29, 6365-6368.
29. a) Roush, W. R.; Dilley, G. J. Synlett 2001, 955-959. b) Semeyn, C.; Blaauw, R. H.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1997, 62, 3426-3427. c) Lolkema, L. D. M.; Hiemstra, H.; Semeyn, C.; Speckamp, W. N. Tetrahedron 1994, 50, 7115- 7128. d) Lolkema, L. D. M.; Semeyn, C.; Ashek, L.; Hiemstra, H.; Speckamp, W. N. Tetrahedron 1994, 50, 7129-7140.
30. a) Miranda, P. O.; Díaz, D. D.; Padron, J. I.; Bermejo, J.; Martin, V. S. Org. Lett. 2003, 5, 1979-1982. b) Dobbs, A. P.; Guesné, S. J. J.; Martinovič, S.; Coles, S. J.; Hursthouse, M. B. J. Org. Chem. 2003, 68, 7880-7883. c) Dobbs, A. P.; Martinovič, S. Tetrahedron Lett. 2002, 43, 7055-7057. d) Jaber, J. J.; Mitsui, K.; Rychnovsky, S. D. J. Org. Chem. 2001, 66, 4679-4686.
31. a) Blumenkopf, T. A.; Bratz, M.; Castañeda, A.; Look, G. C.; Overman, L. E.; Rodriguez, D.; Thompson, A. S. J. Am. Chem. Soc. 1990, 112, 4386-4399. b) Winstead, R. C.; Simpson, T. H.; Lock, G. A.; Schiavelli, M. D.; Thompson, D. W. J. Org. Chem. 1986, 51, 277-279.
32. Nussbaumer, C.; Fráter, G. J. Org. Chem. 1987, 52, 2096-2098.
33. Nussbaumer, C.; Fráter, G. Helv. Chim. Act. 1987, 70, 396-401.
34. Kozmin, S. A. Org. Lett. 2001, 3, 755-758.
35. Hart, D. J.; Bennett, C. E. Org. Lett. 2003, 5, 1499-1502.
36. Díaz, D. D.; Betancort, J. M.; Crisóstomo, F. R. P.; Martín, T. Martin V. S. Tetrahedron 2002, 58, 1913-1919.
37. Adam, W.; Saha-Möller, C. R.; Schmid, K. S. Tetrahedron Asym. 1999, 10, 315-322.
38. Ewing, J. C.; Ferguson, G. S.; Moore, D. W.: Schultz, F. W.; Thompson, D. W. J. Org. Chem. 1985, 50, 2124-2128.
39. For similar reaction see: Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017-3020.
40. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480-2482.
223 41. For similar reaction see: Martin, S. F.; Dappen, M. S.; Dupré, B.; Murphy, C. J.; Colapret, J. A. J. Org. Chem. 1989, 54, 2209-2216.
42. Krishnamurthy, S.; Brown, H. C. J. Am. Chem. Soc. 1976, 98, 3383-3384.
43. Koch, G.; Kottirsch, G.; Wietfeld, B.; Küsters, E.; Org. Process Res. Dev. 2002, 6, 652-659.
44. For similar reaction see: Gruttadauria, M.; Meo, P. L.; Noto, R. Tetrahedron 1999, 55, 4769-4782.
45. Bieber, L. W.; de Sá, A. C. P. F.; Menezes, P. H.; Goncalves, S. M. C. Tetrahedron Lett. 2001, 42, 4597-4599.
46. Mikami, K.; Yoshida, A. Tetrahedron 2001, 57, 889-898.
47. For similar reaction see: Jaber, J. J.; Mitsui, K.; Rychnovsky, S. D. J. Org. Chem. 2001, 66, 4679-4686.
48. For similar reaction see: Chakraborty, T. K.; Hussain, K. A.; Thippeswamy, D. Tetrahedron 1995, 51, 3873-3880.
49. For similar reaction see: Johnson, C. R.; Bis, S. J. J. Org. Chem. 1995, 60, 615-623.
50. Plattner, J. J.; Gless, R. D.; Rapoport, H. J. Am. Chem. Soc. 1972, 94, 8613- 8615.
51. Martin, A. A.; Frauendorf, C. Enantiomer 1997, 2, 45-50.
52. Lygo, B. Tetrahedron 1988, 44, 6889-6896.
53. For a similar reaction see: Oishi, T.; Ohtsuka, Y. Chem. Pharm. Bull. 1988, 36, 4722-4736.
54. For a similar reaction see: Kabalka, G. W.; Hedgecock, H. C. Jr. J. Org. Chem. 1975, 40, 1776-1779.
55. For a similar reaction see: Atarashi, S.; Choi, J. K.; Ha, D. C.; Hart, D. J.; Kuzmich, D.; Lee, C. S.; Ramesh, S.; Wu, S. J. Am. Chem. Soc. 1997, 119, 6226-6241.
224 56. For similar reaction see: Muto, S.; Mori, K. Eur. J. Org. Chem. 2001, 4635-4638.
57. Kyburz, E.; Els, H.; Majnoni, S.; Englert, G.; von Planta, C.; Fürst, A.; Plattner, Pl. A. Helv. Chim. Acta 1966, 49, 359-369.
58. For a similar reaction see: Dobbs, A. P.; Guesne, S. J. J.; Martionic, S.; Coles, S. J.; Hursthouse, M. B. J. Org. Chem. 2003, 68, 7880-7888.
59. Brown, H. C.; Schwier, J. R.; Singaram, B. J. Org. Chem. 1978, 43, 4395-4397.
60. Brown, H. C.; Mandal, A. K.; Yoon, N. M.; Singaram, B.; Schwier, J. R.; Jadhav, P. K. J. Org. Chem. 1982, 47, 5069-5074.
61. Brown, H. C.; Jadhav, P. K.; Mandal, A. K. J. Org. Chem. 1982, 47, 5074-5083.
62. Tu, Y.; Frohn, M.; Wang, Z. X.; Shi, Y. Org. Synth. 2003, 80, 1-8.
63. Tu, Y.; Wang, Z-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806-9807.
64. Wang, Z-X.; Tu, Y.; Frohn, M.; Zhang, J. R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224-11235.
65. Shu, L.; Shi, Y. Tetrahedron 2001, 57, 5213-5218.
66. Hawryluk, N. A.; Snider, B. B. J. Org. Chem. 2000, 65, 8379-8380.
67. For a similar reaction see: Holloway, G. A.; Hügel, H. M.; Rizzacasa, M. A. J. Org. Chem. 2003, 68, 2200-2204.
68. Doyle, M. P.; Kalinin, A. V., Ene, D. G. J. Am. Chem. Soc. 1996, 118, 8837-8846.
69. Doyle, M. P.; Dyatkin, A. B.; Protopopova, M. N.; Yang, C. I.; Miertschin, C. S.; Winchester, W. R.; Simonsen, S. H.; Lynch, V.; Ghosh, R. Recl. Trav. Chim. Pays- Bas 1995, 114, 163-170.
70. Blankley, C. J.; Sauter, F. J.; House, H. O. Org. Synth. Coll. Vol. V., 1973, 258-263.
71. Corey, E. J.; Myers, A. G. Tetrahedron Lett. 1984, 25, 3559-3562.
225 72. Hanessian, S.; Ugolini, A.; Dubé, D.; Glamyan, A. Can. J. Chem. 1984, 62, 2146-2147.
73. Börjesson, L.; Csöregh, I.; Welch, C. J. J. Org. Chem. 1995, 60, 2989-2999.
74. Misiti, D.; Zappia, G.; Monache, G. D. Gazz. Chim. Ital. 1995, 125, 219-222.
75. Liu, Y. J.; Tropp, B. E.; Engel, R. Can. J. Chem. 1993, 71, 206-209.
76. For a similar reaction see: Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538-7539.
77. Pais, G. C. G.; Fernandes, R. A.; Kumar, P. Tetrahedron 1999, 55, 13445-13450.
78. Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 9662-9663.
79. Kozmin, S. A.; He, S.; Rawal, V. H. Org. Synth. 2002, 78, 152-159. The sample used in the experiment came from the checking of this procedure by Dr. David J. Hart and Ruth Figueroa.
80. Oppolzer, W.; Siles, S.; Snowden, R. L.; Bakker, B. H.; Petrzilka, M. Tetrahedron 1985, 41, 3497-3509.
81. Luche, J-L.; Gemal, A. L. J. Am. Chem. Soc. 1979, 101, 5848-5849.
82. Bates, R. W.; Maiti, B. T. Synthetic Comm. 2003, 33, 633-640.
83. a) Martin, A. A.; Frauendorf, C. Enantiomer 1997, 2, 45-50. b) Ohshiba, Y.; Yoshimitsu, T.; Ogasawara, K. Chem. Pharm. Bull. 1995, 43, 1067-1069.
84. Legraveend, M.; Boumchita, H.; Zerial, A.; Huel, C.; Lemaitre, M.; Bisagni, E. J. Med. Chem. 1990, 33, 2476-2480.
85. Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc. 1995, 117, 10805- 10816.
86. Sneddon, H. F.; Gaunt, M. J.; Ley, S. V. Org. Lett. 2003, 5, 1147-1150.
226 87. For a similar result see: Ireland, R. E.; Maienfisch, P. J. Org. Chem. 1998, 53, 640-651.
88. Clive, D. L. J.; Murthy, K. S. K.; Wee, A. G. H.; Prasad, J. S., da Silva, G. V. J. Majewski, M.; Anderson, P. C.; Evans, C. F.; Haugen, R. D.; Heerze, L. D.; Barrie, J. R. J. Am.Chem. Soc. 1990, 112, 3018-3028.
89. For a similar reaction see: Trost, B. M.; Seoane, P.; Mignani, S.; Acemoglu, M. J. Am. Chem. Soc. 1989, 111, 7487-7500.
90. Miller, R. B.; Reichenbach, T. Tetrahedron Lett. 1974, 15, 543-546.
91. VanRheenan, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 17, 1973-1976.
92. Lin, H.-S.; Paquette, L. A. Synth. Comm.1994, 24, 2503-2506.
93. For a similar procedure see: Owens, F. H.; Fellmann, R. P.; Zimmerman, F. E. J. Org. Chem. 1960, 25, 1808-1809.
227