Stereoselective Aldol Condensations via Boron Enolates. The Syntheses of (+)-Prelog-Djerassi Lactone and (+)-Tylonolide Citation Bartroli, Javier Francisco (1984) Stereoselective Aldol Condensations via Boron Enolates. The Syntheses of (+)-Prelog-Djerassi Lactone and (+)-Tylonolide. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/3v27-xh37. https://resolver.caltech.edu/CaltechTHESIS:11092018-094859390 Abstract The use of boron enolates of chiral N-acyl oxazolidinones i and ii in highly stereoselective aldol condensations is described. Mild base hydrolysis of the products affords optically pure erythro β-hydroxy acids and the chiral auxiliary, which can be reconverted into i or ii in one step. The utility and scope of these reactions is demonstrated by the total syntheses of (+)-Prelog-Djerassi lactone and (+)-Tylonolide, cyclic 5,20-hemiacetal . [Chemical structures included in scanned thesis' abstract, p. v.] Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: Chemistry Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Dougherty, Dennis A. Thesis Committee: Evans, David A. (chair) Collins, Terrence J. Dervan, Peter B. Dougherty, Dennis A. Defense Date: 9 December 1983 Record Number: CaltechTHESIS:11092018-094859390 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:11092018-094859390 DOI: 10.7907/3v27-xh37 Related URLs: URL URL Type Description https://doi.org/10.1021/ja00398a058 DOI Article adapted for Chapter I. https://doi.org/10.1016/s0040-4039(00)86954-3 DOI Article adapted for Chapter II. https://doi.org/10.1016/s0040-4039(00)85658-0 DOI Article adapted for Chapter II. Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 11268 Collection: CaltechTHESIS Deposited By: INVALID USER Deposited On: 09 Nov 2018 19:17 Last Modified: 11 Aug 2022 17:33 Thesis Files Preview PDF - Final Version See Usage Policy. 141MB Repository Staff Only: item control page

STEREOSELECTIVE ALDOl CONDENSATIONS VIA BORON ENOLATES. THE SYNTHESES OF {+)-PRElOG-DJERASSI LACTONE AND {+)-TYlONOliDE Thesis by Javier Bartrol i In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy California Institute of Technology Pasadena, California 1984 (Submitted December 9 , 1983) ;; Als Meus Pares iii ACKNOWLEDGEMENTS I want to deeply thank Dave Evans for the transformation he has effected in my scientific career. His enormous knowledge in chemistry together with his desire to communicate it to the people that surround him has made my tenure at Caltech a constant learning experience in all aspects. I would also like to thank the Evans' group in general for all their help and friendship and for making my time in this country truly unforgettable. In particular I wish to thank John Nelson and Scott Biller for their help during my first months in the lab, my coworkers Tom Shih and Thierry Godel, and Joel Morris and Mike Ennis for being two very good friends. I would like to thank the people that have helped me in the preparation of this report: Joel Morris, Professor Harry Ottenheijm, Kevin Chapman and Dave Mathre for reading the rough drafts, providing invaluable comments and correcting my English, and Carl Illig, Eric Sjogren and Bob Dow for recording the FX-90Q and some of the 500 MHz spectra. A special acknowledgement goes to Larry and Millie Brinn for their financial support during my complete tenure through an L and L fellowship, and for their personal concern. Without their help I never would have been able to come to graduate school in the United States. iv I also would like to thank my beloved roommates Paolo, Vicente, Marisa and Julia for their deep friendship. Finally, I would like to thank Carol Chojnowski for the excellent typing job. v ABSTRACT The use of boron enolates of chiral N-acyl oxazolidinones 1 and ii in highly stereoselective aldol condensations is described. Mild base hydrolysis of the products affords optically pure erythro - e-hydroxy acids and the chiral auxiliary, which can be reconverted into i or ii in one step. The utility and scope of these reactions is demonstrated by the total syntheses of (+)-Prelog-Djerassi lactone (34) and (+)-Tylonolide, cyclic 5,20-hemiacetal (87). 0 0 0 0 ~NJl.O fN)l_O R':-1 R K ~ Me ii 0 0 Me0<? yYcooH Me 34 HO Me 87 Ph vi TABlE OF CONTENTS CHAPTER I. ERYTHRO-SELECTIVE CHIRAL ALDOL CONDENSATIONS VIA BORON ENOLATES............................... 1 I. Introduction........................................ 2 II. Background.......................................... 4 III. Results and Discussion •••••••••••••••••••••••••••••• 11 1. Synthesis of Starting Materials ••••••••••••••••••••• 11 2. The Aldol Condensation using Chiral Propionyl Oxazolidinones............................ 15 The Aldol Condensation using Chiral, Functionalized Acyl Oxazolidinones •••••••••••••••••• 25 4. Chiral Auxiliary Removal •••••••••••••••••••••••••••• 28 5. Discussion •••••••••••••••••••••••••••••••••••••••••• 32 IV. SurTITia ry. • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • 38 3. Experimental Section ••••••••••••••••••••••••••••••••••••••••• 40 General ••••••••••••••••••••••••••••••••••••••••••••••••• 40 Di-n-butylboryl trifluoromethanesulfonate ••••••••••••••• 42 Di-n-butylboryl methanesulfonate •••••••••••••••••••••••• 43 General Procedure for the Preparation of 3-acyl-2-oxazolidinones ••••••••••••••••••••••••••••••••• 43 {S)-3-{2-Methoxy-1-oxoethyl)-4{1-methylethyl)-2-oxazolidinone {21) ...•................ 44 {4R,5S)-3-{2-Methoxy-1-oxoethyl)-4methyl-5-phenyl-2-oxazolidinone {23) .•..•............... 45 {S}-4-{1-Methylethyl}-3-{1-oxo-2-{phenylmethoxy}-ethyl)-2-oxazolidinone {22) ......•.•...•....... _ 45 vii TABLE OF CONTENTS(continued) (S)-4-(1-Methylethyl)- ,2-dioxo-3-oxazolidinebutanoic acid, ethyl ester (28) •••••••••••••••.••• 46 General Procedure for the Formation of the Boron Enolates of Acyloxazolidinones and Subsequent Condensation with Aldehydes •••••••••••••••••••••••••••••••••••••••••• 47 General Procedure for the Formation of the Lithium Enolates of Acyloxazolidinones and Subsequent Condensation with Aldehydes •••••••••••••••••••••••••••••••••••••••••• 48 (3Z,4R,5S)-3-(((1,1-Dimethylethy1) dimethylsilyl)oxy)-1-propenyl)-4methyl-5-phenyl-2-oxazolidinone (33) .................... 49 (3(2S,3S),4S)-3-(3-Hydroxy-2-methyl-1oxo-3-phenylpropyl)-4-(1-methylethyl)2-oxazolidinone (11) .............................•...... 50 (3(2R,3S),4S)-3-(3-Hydroxy-2-methyl-1oxo-3-phenylpropy1)-4-(1-methylethyl)2-oxazolidinone (11T) ...•...•........................... 51 (3(2S,3R),4S)-3-(3-Hydroxy-2,4-dimethyl-1oxopentyl)-4-(1-methylethyl)-2-oxazolidinone (13) .......................•.......•.......•..•.... 52 (3,(2S,3R),4S)-3-(3-Hydroxy-2-methyl-1oxohepty1)-4-(1-methylethyl)-2-oxazolidinone (15) ............................................. 54 (3(2R,3R),4R,5S)-3-(3-Hydroxy-2-methyl1-oxo-3-phenylpropyl)-4-methyl-5-phenyl2-oxazolidinone (12) .................................... 55 (3{2R,3S),4R,5S)-3-(3-Hydroxy-2,4-dimethyl1-oxopentyl)-4-methyl-5-phenyl-2-oxazolidinone (14). ............ ............... ...... ....... .... 56 (3{2R,3S),4R,5S)-3-{3-Hydroxy-2-methyl-1oxoheptyl)-4-methyl-5-phenyl-2-oxazolidinone {16) ............................................. 57 viii TABLE OF CONTENTS(continued) (3(2R,3R),4R,5S)-3-(3-(2-Furanyl)-3hydroxy-2-methyl-1-oxopropyl)-4-methyl5-phenyl-2-oxazolidinone (17) •••••••••.••••••••••••••••• 58 (3(2S,3R),4S)-3-(3-Hydroxy-2-methoxy1-oxo-3-phenylpropyl)-4-(1-methylethyl)2-oxazolidinone (25) •••••••••••••••••••••••••••••••••••• 59 (3(R(R)),4R)-a-(Hydroxyphenylmethyl)4-(1-methylethyl)-a,2-dioxo-3-oxazolidinebutanoic acid, ethyl ester (29) ••••••••••••••••••••• 60 General Procedure for the Hydrolysis of Chiral Imide Aldol Adducts to a-Hydroxy Acids. . . . . . . . . . • . . • . . . . . . . . . . • . . . . . . . . . . . • . . . • . . . . . . • • • . 61 General Procedure for the Esterification of Acids. . . . . . . . . . . . . . . . . . . . . . . . . . . • . • . . . . . . . . . . . . . . . . . . 62 References and Notes •••••••••••••••••••••••••••••••••••• 63 CHAPTER II. THE TOTAL SYNTHESIS OF (+)-PRELOG-DJERASSI LACTONE. 1,3-ACYCLIC INDUCTION IN HYDROBORATION PROCESSES ••••••••••••••••••••••••• 67 I. Introduction and Strategy ••••••••••••••••••••••••••• 68 II. Results and Discussion •••••••••••••••••••••••••••••• 74 1. The Total Synthesis of (+)-PrelogDjerassi lactone •••••••••••••••••••••••••••••••••••• 74 Acyclic 1,3-Asymmetric Induction in the Hydroboration Process ••••••••••••••••••••••••••• 86 2. III. Sul11llary ••••••••••••••••••••••••••••••••••••••••••••• 101 Experimental Section ••••••••••••••••••••••••••••••••••••••••• 102 General ••••••••••••••••••••••••••••••••••••••••••••••••• 102 ix TABLE OF CONTENTS(continued) Page (3(S),4R,5S)-3-(2,4-Dimethyl-l-oxo4-pentenyl)-4-methyl-5-phenyl-2oxazolidinone (37) •••••••••••••••••••••••••••••••••••••• 104 (S}-2,4-Dimethyl-4-penten-1-ol (45) ••••••••••••••••••••• 105 (S}-2,4-Dimethyl-4-pentenal (46) •••••••••••••••••••••••• 106 (3{2R,3S,4S),4R,5S)-3-{3-Hydroxy-2,4,6trimethyl-1-oxo-6-heptenyl)-4-methyl5-phenyl-2-oxazolidinone (36) ••••••••••••••••••••••••••• 107 (3(2R,3S,4S,6R),4R,5S)-3-(7-Hydroxy2,4,6-trimethyl-1-oxo-3-((trimethylsilyl}oxy)heptyl)-4-methyl-5-phenyl-2oxazolidinone (50) and the Corresponding (3(2R,3S,4S,6S),4R,5S)-Isomer {51) •••••••••••••••••••••• 109 (3(R(2S,3S,5R)},4R,5S}-4-Methyl-3{1-oxo-2(tetrahydro-3,5-dimethyl-6oxo-2H-pyran-2-yl)propyl}-5-phenyl2-oxazolidinone (53} •••••••••••••••••••••••••••••••••••• 111 (2S(R),3S,5R}-Tetrahydro-a,3,5trimethyl-6-oxo-2H-pyran-2-acetic acid (34) ••••••••:-•••••••••••••••••••••••••••••••••••••• 113 (2S(R},3S,5R)-Tetrahydro-a,3-5trimethyl-6-oxo-2H-pyran-2-acetic acid, methyl ester (54} ••••••••••••••••••••••••••••••••• 115 {3{2S,3R,4S),4S}-3-(3-Hydroxy-2,4,6trimethyl-1-oxo-6-heptenyl-4{1-methylethyl)-2-oxazolidinone (48) •••••••••••••••••••• 116 Mixture of (3{2S,3R,4S,6R},4S)-3(7-hydroxy-2,4,6-trimethyl-1-oxo3-((trimethylsilyl)oxy}heptyl)-4{1-methylethyl)-2-oxazolidinone {60) and the Corresponding (3(2S,3R,4S,6S), 4S)-Isomer (73) ••••••••••••••••••••••••••••••••••••••••• 117 Determination of the Absolute Configuration of Compounds 60 and 73 .•••••••••.•.•••.••.••••.••••••••••••••••••••.. 118 X TABLE OF CONTENTS(continued) (2R,4S)-5-({Triethylsilyl)oxy)-2,4,5trimethylhexanol (62), and the Corresponding {2S,4S}-Isomer (79} ••••••••••••••••••••••••••••• 121 Determination of the Absolute Configuration of Compound 62 •••••••••••••••••••••••••••• 122 References and Notes •••••••••••••••••••••••••••••••••••• 124 CHAPTER III. THE TOTAL SYNTHESIS OF {+)-TYLONOLIDE, CYCLIC 5,20-HEMIACETAL •••••••••••••••••••••••• 129 I. Introduction •••••••••••••••••••••••••••••••••••••••• 130 II. Retrosynthetic Analysis ••••••••••••••••••••••••••••• 132 III. Discussion and Results •••••••••••••••••••••••••••••• 140 1. The Synthesis of the . c11 -c 15 Fragment ••••••••••••••• 140 2. Macrocyclization Studies •••••••••••••••••••••••••••• 149 3. The Construction of the C1 -c 10 Fragment and the Final Steps of the Synthesis of Tylonolide ••••••••••••••••••••••••••••••••••••••• 152 IV. Summary ••••••••••••••••••••••••••••••••••••••••••••• 168 Experimental Section General ••••••••••••••••••••••••••••••••••••••••••••••••• 169 {S,E)-4-{1-Methylethyl)-3-{1-oxo-2butenyl )-2-oxazolidinone {92) ••••••••••••••••••••••••••• 171 {3{2S,3R),4S)-3-{2-Ethenyl-3-hydroxy1-oxopentyl)-4-{1-methylethyl)-2oxazolidinone {93) ••••••••••.••.••••••••••••.•.••••••••• 172 {3R,4R)-4-Hydroxy-3-{({{1,1-dimethylethyl)dimethysilyl)oxy)methyl)-1hexene {98) ••••••••••••••••••••••••.••••••••••••••.••••• 174 xi TABLE OF CONTENTS(continued) (2E,4R,5R)-5-Hydroxy-4-((((1,1-dimethylethyl)dimethylsilyl)oxy)methyl)-2-methyl2-heptenoic acid, ethyl ester {100) ••••••••••••••••••••• 176 (2E,4R,5R)-4-((({1,1-Dimethylethyl) dimethylsilyl)oxy)methyl)-2-methyl2-heptene-1,5-diol (101) •••••••••••••••••••••••••••••••• 178 (2E,4R,5S)-5-Hydroxy-4-((((1,1-dimethylethyl)dimethylsilyl)oxy)methyl)-2-methyl2-heptenal (102) •••••••••••••••••••••••••••••••••••••••• 179 (4R,5S(S))-3-((4-Ethyl-2,2-dimethyl-1,3dioxan-5-yl)carbonyl)-4-(1-methylethyl)2-oxazolidinone (94) •••••••••••••••••••••••••••••••••••• 180 1 (4R,5S)-4-Ethyl-2,2-dimethyl-1,3-dioxan5-methanoic acid, phenylmethyl ester {95) ••••••••••••••• 181 (4R,5S)-4-Ethyl-5-hydroxymethyl-2,2dimethyl-1,3-dioxane (96) ••••••••••••••••••••••••••••••• 183 (11E,13E,15R,16R)-14-((((1,1-Dimethylethyl)dimethylsilyl)oxy)methyl)-16ethyl-12-methyl-oxacyclohexadeca-11,13diene-2,10-dione {108) •••••••••••••••••••••••••••••••••• 184 (4R,5S)-4-Methyl-3-(1-oxo-4-phenylmethoxybutyl)-5-phenyl-2-oxazolidinone (109) •••••••••••••••••••••••••••••••••••••••••••• 186 (3(R),4R,5S)-4-Methyl-5-phenyl-3(2-(2-(phenylmethoxy)ethyl)-1-oxo4-pentenyl)-2-oxazolidinone (110) ••••••••••••••••••••••• 188 (R)-4-Methyl-2-(2-{phenylmethoxy) ethyl)-4-pentenol (111) ••••••••••••••••••••••••••••••••• 190 (R)-4-Methyl-2-(2-(phenylmethoxy) ethyl)-4-pentenal {112) ••••••••••••••••••••••••••••••••• 191 (3(2R,3S,4R),4R,5S)-3-(3-Hydroxy2,6-dimethyl-1-oxo-4-(2-(phenylmethoxy)ethyl)-6-heptenyl)-4-methyl5-phenyl-2-oxazolidinone (113) •••••••••••••••••••••••••• 192 xii TABLE OF CONTENTS(continued) (3(2R,3S,4R),4R,5S)-3-(2,6-Dimethyl1-oxo-4-(2-(phenylmethoxy)ethyl)-3((triethylsilyl)oxy)-6-heptenyl)-4methyl-5-phenyl-2-oxazolidinone (114) ••••••••••••••••••• 195 (2R,3S,4R)-2,6-Dimethyl-4-(2-(phenylmethoxy)ethyl)-3-((triethylsilyl)oxy)6-heptenoic acid, phenylmethyl ester (115) •••••••••••••• 196 (2S,3S,4R)-2,6-Dimethyl-4-(2-(phenylmethoxy)ethyl)-3-((triethylsilyl)oxy)6-heptenol (116) •••••••••••••••••••••••••••••••••••••••• 197 (2R,3S,4R)-2,6-Dimethyl-4-(2-(phenylmethoxy)ethyl)-3-((triethylsilyl)oxy)6-heptenal (117) •••••••••••••••••••••••••••••••••••••••• 199 (3(2R,3S,4S,5S,6R),4R,5S)-3-(3-Hydroxy4,8-dimethyl-2-methylthio-1-oxo-6-(2(phenylmethoxy)ethyl)-5-((triethylsilyl)oxy)-8-noneyl)-4-methyl-5-phenyl2-oxazolidinone (118) ••••••••••••••••••••••••••••••••••• 200 The Aldol Condensation of the Di-nbutylboron Enolates 120 and 121 wTth Aldehyde 117. A Cram-antiCram Selection Study ••••••••••••••••••••••••••••••••••••••••• 202 (3(3R,4S,5S,6R),4R,5S)-3-(3-Hydroxy4,8-dimethyl-1-oxo-6-(2-(phenylmethoxy)ethyl)-5-((triethylsilyl)oxy)-8-noneyl-4-methyl-5-phenyl-2oxazolidinone (122) ••••••••••••••••••••••••••••••••••••• 205 (3R,4S,5S,6R)-3-Hydroxy-4,8-dimethyl6-(2-(phenylmethoxy)ethyl)-5-((triethylsilyl)oxy)-8-nonenoic acid, phenylmethyl ester (126) •••••••••••••••••••••••••••••••• 206 xiii TABLE OF CONTENTS(continued) (3R,4R,5S,6R,8R)-3-(((1,1-Dimethylethyl)dimethylsilyl)oxy)-9-hydroxy4,8-dimethyl-6-(2-(phenylmethoxy) ethyl)-5-((triethylsilyl)oxy)nonanoic acid, phenylmethyl ester (70) and the Corresponding (3R,4R,5S,6R,8S)-Isomer (127) .......•................... 207 (3R,4R,5S,6R,8R)-3-(((1,1-Dimethylethyl)dimethylsilyl)oxy)-4,8-dimethyl9-oxo-6-(2-(phenylmethoxy)ethyl)-5((triethylsilyl)oxy)-nonanoic acid, phenylmethyl ester (128) ................................ 210 (3R,4R,5S,6R,8R)-10-(Dimethoxyphosphinyl)3-(((1,1-dimethylethyl)dimethylsilyl)oxy)4,8-dimethyl-9-oxo-6-(2-(phenylmethoxy) ethyl)-5-((triethylsilyl)oxy)-decanoic acid, phenylmethyl ester (133) .......................... 212 (3R,4R,5S,6R,8R)-10-(Dimethoxyphosphinyl)3-(((1,1-dimethylethyl)dimethylsilyl)oxy)4,8-dimethyl-9-oxo-5-((triethylsilyl)oxy)6-(2-((triethylsilyl)oxy)ethyl)-decanoic acid (134) .............................................. 214 (3R,4R,5S,6R,8R)-10-(Dimethoxyphosphinyl)3-(((1,1-dimethylethyl)dimethylsilyl)oxy)4,8-dimethyl-9-oxo-5-((triethylsilyl)oxy)6-(2-((triethylsilyl)oxy)ethyl)-decanoic acid, (1R,2R,3E)-2-((((1,1-dimethylethyl) dimethylsilyl)oxy)methyl)-1-ethyl-4methyl-5-oxo-3-pentenyl ester (135) ....•............•... 215 20-Deoxy-3,23-di-0-((1,1-dimethylethyl) dimethylsilyl)-5,20-di-0-(triethylsilyl)tylonolide (136) .......: ...•....••............•.•....•.. 216 3,23-Di-0-((1,1-dimethylethyl)dimethylsilyl)-5~Q-(triethylsilyl)-tylonolide (138) ............. 217 Tylonolide, cyclic 5,20-hemiacetal (87) ••••••••••••••••• 219 References and Notes •••••••••••••••••••••••••••••••••••• 222 xiv TABLE OF CONTENTS(continued) APPENDIX I. APPENDIX II. APPENDIX III. IR and 1H NMR Spectral Catalog for Chapter I ••••••••••••••••••••••••••••••••••••• 227 IR and 1H NMR Spectral Catalog for Chapter II •••••••••••••••••••••••••••••••••••• 249 IR and 1H NMR Spectral Catalog for Chapter III ••••••••••••••••••••••••••••••••••• 282 PROPOSITIONS ••••••••••••••••••••••••••••••••••••••••••••••••• 357 -1- CHAPTER I Stereoselective Aldol Condensations Via Boron Enolates 1 -2- I. Introduction The aldol condensation is one of the oldest carbon-carbon bond forming reactions known in chemistry. It has not been until recent years, however, that organic chemists have learned how to control its intrinsic stereochemistry when performed in acyclic systems. 2 Today, this reaction constitutes a powerful tool in the synthesis of macrolide and polyether antibiotics. Before the reaction achieved practicability, one problem needed to be addressed: the selective formation of the desired product stereochemistry. The issue can be approached in two different ways: a), Via induction by the molecule's intrinsic chirality, for example the final aldol condensation of the Ireland and Kishi syntheses 3 of lasalocid A (eq. 1); or b), via induction by a removable, chiral Me + 1 . LOA, Me Me ZnCI 2 2 . RCHO OH HO C02 Bn Me Me (major) (1) '...,, Et Me (ref. 3) -3- auxiliary (eq .2). 4 Due to its wider scope, the latter method interested us more. + 2 . RCHO • ~oTYOoMEM V Me Me (ref. 4) denotes either the (R)-isomer or the (S)-isomer. Because an aldol condensation involves the creation of two sp 3 carbons, four possible stereoisomers principle be formed (eq. 3). can in In planning the selective formation of only one of them, two separate issues need to be addressed: The 5 control of the reaction erythro:threo selection (E ~ T), and the control of the reaction enantioselection (E 1 ~ E2 or T1 ~ T2). present here a practical way of preparing either E1 or E2-type products in a highly selective fashion. We -4OH 0 0 R1 ~R2 R,¥R3 + OH 0 AA R1 ; R2 R2 El Tl R3 (3) R3CHO OH 0 R1 II. ~ : R3 - OH 0 R¥R3 1 R2 R2 [2 T2 Background In 1957 Zimmerman and Traxler proposed a six membered cyclic transition state to rationalize the diastereoselection of the Reformatsky and Ivanov reactions of phenylacetic acid with benzaldehyde. 6 In this model, the enolate and the aldehyde are held by the metal, forming a chair-like structure. More recently, Dubois 7 and subsequently Heathcock 8 have demonstrated the tog~ther role of enolate geometry on the kinetic product distribution in the aldol condensation. Thus, the magnesium and lithium (Z) enolates of a variety of ketones afford erythro adducts with very good selection, whereas the corresponding (E) enolates give mainly three products. With this information in hand, a more elaborated cyclic aldol transition state was proposed by Evans in 1979 (Scheme I). 9a This model strongly emphasizes the role of the enolate geometry and nonbonding interactions in determining the product stereochemistry. -5Scheme I L IF-\ R, }-~o'/M~L 2 R ~j~o~}~L R,{r-oe '(C00 2 C1 H L E Cz H threo t 1 R, L I }1:-:0'/M~ L Hy:-::=00 R2 R3 CHO L R,JyRz _j + .,..M H z c4 • -6- For example, the (Z) enolate is predicted to give the erythro product via transition state c4, in which 1,3-diaxial interactions have been minimized. The (Z) enolate derived transition state c3 which leads to the threo product, has two additional diaxial 3 interactions (R ~R 1 and R ~L) thus raising its heat of formation 3 relative to transition state c4 • The observed enhancement of the reaction diastereoselection upon increasing the size of R1 is in full agreement with this model. A high level of aldol diastereoselection has been observed with boron enolates. 9 , 10 Whereas most metals (M= Li, Mg, Zn, Al) have a M-0 bond length in the range of 2 A, the B-0 and the B-C bond lengths are 1.4 A and 1.5 A respectively. This shorter bond distance is presumably translated into a tighter, more compact transition state, thereby enhancing the nonbonding interactions. This creates larger differences in the energies of the corresponding transition state structures c1 , c 2 , c3 and c4 (Scheme I). Although chair transition states are more generally appealing, in some cases the related boat transition states are equal, or even favored energetically. Thus, the opposite erythro:threo ratios observed for the magnesium (Z) enolates 1 and 2 (Scheme II) upon condensation with pivaldehyde 7d has been rationalized by the participation of boat transition state 5 for enolate 2. In this transition state the c2 enolate substituent and the aldehyde substituent have avoided the gauche interaction present in the -7- OMgBr OMgBr tsu ~Me tsuCHO tsu ~tsu z 1BuCHO z 2 1 I I I I l I \ H -~ ' - '0 .., ,\-;: --~-1 ~ ~ ~ 2--- I' H \I ·"' 3 4 I OH 0 OH 0 lsu~tBu lsuVIsu R tsu erythro threo R=Me E:T= 100:0 R=tBu E:T= 0:100 -8- diastereomeric chair 4. 2a Boat transition states are more likely to occur with lithium and magnesium enolates, where the M-0 and M-L bond distances are long and, consequently, the bowsprit-flagpole interaction is relatively small. Nonetheless, this latter assertion is difficult if not impossible to prove. Up to this point, we have discussed the elements that control the erythro:threo selection. We address now the architectural features necessary for control of the reaction enantioselection (i·~· E1 ~ E2 , T1 ~ T2 , see eq. 3). In principle, there are three approaches to the preparation of a chiral aldol adduct: a), Condensation of a chiral aldehyde with an achiral enolate; b), condensation of an achiral aldehyde with a chiral enolate; and c), condensation of a chiral aldehyde with a chiral enolate. In this chapter we will deal exclusively with the second class of reactions. In designing a chiral enolate, one must pursue one principal goal. The enolate must induce an effective n-facial differentiation through an organized, conformationally rigid transition state. An example that satisfies these criteria is illustrated in eq. 4. In this case, a sterically differentiated enolate w-face is established via chelate formation, which provides a fixed topology between the chiral and prochiral centers. Encouraged by the high levels {>97.3) of erythro:threo selection obtained upon condensation of the boron enolate of oxazolidinone 6 with a variety of aldehydes (eq. 5), 12 we decided to -9Br I 1. t BuMgBr 2. R5 CORL j AI-Hg (ref. 11) 70-98% ee 70-90% yield study the aldol condensation of its chiral counterpart 7. Oxazolidinone 7 has been efficiently prepared from (S)-valine in three 1. Bu 2 80Tf 2. iPr 2 NEt 3. RCHO HO 0 RYNJlO Me 6 E:T >97:3 7 0 8 (s) \_j (ref. 12) -10- steps. 13 Although we expected the erythro:threo selection to be maintained, a priori we did not have a feeling for either the magnitude or sense of the chirality transfer (i-~· E1 1i E2 ). By the time this project was started, however, the lithium enolate of 7 had already shown very high levels (120:1) of diastereoselection upon alkylation with benzyl bromide (eq. 6). 13 Although not 0 0 0 rN)lO ~ 1. LOA 2. PhCH 2 Br 0 Ph~N}-_0 (6) Me~ (ref. 13) 7 120:1 intimately related to our aldol reaction, this constituted an encouraging result. Concomitantly with oxazolidininone 7, we studied the reactions of its chiral antipode 8, derived in three steps from commercially available (1R,2S)-norephedrine hydrochloride. Both, (S)-valine and norephedrine hydrochloride are inexpensive chiral starting materials. -11- III. Results and Discussion 14 1. Synthesis of Starting Materials (a) Preparation of 3-acyl-2-oxazolidinones. Our two starting materials 9 and 10 were prepared from commercially available (S)-valine and (1S,2R)-norephedrine hydrochloride respectively. As indicated in Scheme III, (S)-valine was reduced to (S)-valinol with 1.15 equivalent of borane in the presence of 1.15 equivalents of boron trifluoride etherate {THF, reflux, 18 h; then aq. NaOH, reflux, 2 h) in 81% yield. 16 Subsequent treatment with diethyl carbonate (1.1 equiv.) in the presence of a catalytic amount of potassium carbonate (neat, 120°C, 24 h) gave oxazolidinone 9 in 74% yield after recrystallization. In a similar way, 10 was obtained from norephedrine hydrochloride by neutralization (aq. NaOH, 100% yield) and reaction with diphenylcarbonate (1.2 equiv.) in the presence of 1 equivalent of potassium carbonate (neat, 130°C, 5 h) in 73% yield after recrystallization. Both materials could be prepared in molar quantities without changes in the reaction yields. Their enantiomeric excess was shown to be ~99% by gas chromatography analysis of their corresponding Mosher imides. 17 The desired acyl derivatives were prepared in high yields by lithiation (n-Buli, THF, -78°C) and subsequent reaction with the corresponding acid chloride or anhydride. (b) Preparation of the Boron Reagents. Di-n-butyl- boryl trifluoromethanesulfonate (di-n-butylboryl triflate) was -12Scheme III _f;OH l-valine 0 )( HN 0 )---\ Me Ph mp 121°C 10 e e Cl NH 3 OH h Me Ph (1S,2R)-norephedrine hydrochloride NaOH NH 2 H Me OH Ph -13- obtained by the reaction of tri-~-butylborane and trifluoromethanesulfonic acid, according to Mukaiyama•s procedure. 18 Although di-~-butylboryl triflate was the common boron source used in this aldol study, we also investigated the effect that other di-~-butyl­ boryl sulfonates have on the yields and product distribution of this reaction. In an attempt to prepare di-~-butylboryl methanesulfonate by mixing tri-~-butylborane and methanesulfonic acid, decomposition (black tar ~ ) was observed and no product could be isolated. Our eventual solution to a successful synthesis of boryl sulfonate esters utilized the mechanistic observations of Dessy on the protonolysis of triethylborane by carboxylic acids. 19 He observed that the log of the reaction rate constant increased linearly with the pKa of the carboxylic acid. This, together with an observed primary isotope effect of 3.3, suggested that the reaction proceeds by a preequilibrium step, consisting of nucleophilic carbonyl coordination of the acid to the borane, followed by a rate determining proton transfer (eq. 7). R R \I ee 9 R/ 'o H II 'o/'.........R. -14- We do not have an explanation to our observation that the stronger acid trifluoromethanesulfonic acid reacts with tri-nbutylborane whereas the milder methanesulfonic acid does not. Sulfonic acids and carboxylic acids might well react via different mechanisms. Based on Dessy•s observations, we envisioned an altern- ative way to obtain the desired sulfonates. In presence of a catalytic amount of a mild carboxylic acid (like benzoic acid, for example), formation of the corresponding di-n-butylboryl carboxylate might take place (eq. 8). This compound, in turn, would be displaced by the sulfonic acid giving product and regeneration of the carboxylic acid. This approach proved to be successful using 0.05 equivalent of benzoic acid, tri-n-butylborane and methanesulfonic acid or chlorosulfonic acid. ~30%) Although low yields (~. were obtained in these first attempts, distillation afforded the desired boryl sulfonates. (a) HOS0 2 R 0 II Bu 2 BOCPh + BuH -15- 2. The Aldol Condensation Using Chiral Propionyl Oxazolidinones The reaction of the di-~-butylboron enolates of 7 and 8 with a variety of aldehydes was investigated. (a) Results. The di-~-butylboron enolates of imides 7 and 8 were prepared by the successive addition of 1.1 equivalents of di-~-butylboryl triflate and 1.2 equivalents of diisopropylethyl- amine to cooled (-78°C) solutions {1 to 0.25 M) of 7 or 8 in dichloromethane. The mixtures were stirred at -78°C for 0.5 h and at 0°C for 1 h. To these solutions, neat aldehyde {1 to 1.1 equiv.) was added at -78°C and the reactions were stirred for 0.5 h, then allowed to warm up to 0°C and stirred for 1 h. Oxidative workup {H 2o2 , MeOH, pH 7) and product isolation afforded the corresponding aldol adducts {eq. 9, 10). Although direct gas chromatography (GC) analysis of the reaction mixtures resulted in product decomposition, analysis of their corresponding trimethylsilyl ethers proved to be successful. For this purpose, a small sample of the isolated, unpurified reaction mixture was silylated (excess TMSNEt 2 , DMAP, CH 2cl 2). When TLC analysis showed complete reaction, the mixture, without purification, was analyzed by GC. The peaks were assigned by comparison with authentic diastereomeric mixtures obtained by the corresponding lithium aldol condensations. 20 As observed with chiral amides, 4 the lithium enolates of 7 and 8 reacted with aldehydes (-78°C, 5 sec) in high yields but with poor -16- overall selectivity, thus affording a valuable authentic isomeric mixture. When monitored, the erythro:threo ratios obtained by GC analysis were shown to be identical with those obtained by integra' tion of the carbinol proton (-C~OH) in their NMR spectra proving the authenticity of the GC data. The results are summarized in Table I. In all cases, the boron enolates showed remarkably high levels of both erythro:threo selection (E 1 + E2 ~ T1 + T2 ) and enantioselection in the erythro manifold (E 1 ~ E2 ). In some cases, especially in the norephedrine series, the ratio E2:(Ei + Ti + T2) was ~1000:1. Recrystallization or flash chromatography afforded the adducts in high yield. As a representative example, the boron and lithium reaction GC traces of Entry C of Table I are shown in Scheme IV. Scheme IV 1) enolization F M = Li i-1 !::::----- • I I~============~------- • 0 0 rN)l_O ---( 0 )l_ RY_tl 7 0 0 HO 0 HO (lNJlO 0 E2 E 1' Me ( 10) 1 Ph E; 8 Table 1. T; • T' 0 Me-}-{ )---{Ph (9) E, R~N)l_O Me T2 T1 • Aldol Condensations of 7 and 8 with Representative Aldehydes. Boron-aldol kinetic ratios Product RCHO Lithium-aldol kinetic ratios I El(E2) E1 (E 2 )(% yield)a E2(El) Tl(T2) T2(Tl) El(E2) E2(El) T1(T2) T2(Tl) c6H5CHO c6H5CHO 11 99.8 (88%) 0.04 0.14 0.06 9.8 29.5 59.0c 1.7 12 >99.9 (89%) <0.1 8.5 28.6 7 Me 2CHCHO 13 99.4 (78%) 0.2 10.6 11.0 D 8 Me 2CHCHO 14 99.8 (91%) 0.04 13.2 8.1 E 7 _!!-C 4H9CHO 15 99.0 (75%) 0.7 14.3 3.7 F 8 _!!-C 4H9CHO 16 99.9 (95%) 0.1 16.7 18.0 G 8 Furaldehyde 17 Entry Imide A 7 B 8 c ~99.3 I ~ ......, <0.1 b 0.2 0.2 0.15b 0.1 0.1 <0.1 b 62.7b 71.4 7.0 78.7b 24.4 57.6 65.3b (91%) a Isolated yields, except for Entries Band F where the yield is referred to the unpurified crystalline product. b The second threo isomer either was not formed or did not resolve on the GC. c The absolute stereochemistry of T1(R=Ph, liT) was determined to be (2R,3S) by hydrogenolysis, following the method used for compound 11 (Scheme V). -18- (b) Absolute Configuration. The erythro relative stereochemistry of the major isomers E1 and E2 obtained in the boron series was first suggested by the presence of small c2-H, c3-H coupling constants (~. 3-5Hz). This is typical for erythro-a- hydroxy-a-alkyl carbonylic compounds that have relatively small substituents at the c2 and c3 positions. 21 The absolute stereochemistry of the a-carbon of 11 was determined by its transformation into 18 (Scheme V) via hydrogenolysis {H 2 , 10% Pd-C, EtOH, cat. HC10 4 ) and subsequent comparison with an epimeric mixture obtained via alkylation of the lithium enolate of 7 with benzyl bromide. Since the absolute configuration of products 18 and 19 was already known, 13 we were able to deduce that the c2 stereocenter of 11 possessed the {S) configuration. This conclusion, together with the small erythro coupling constant recorded for 11 (4.5 Hz) defined its absolute stereochemistry as (2S,3S). More generally, the absolute configuration of compounds 11-17 was proven by the conversion of the imides into the corresponding methyl esters (vide infra), the absolute stereochemistry of which had already been determined. 4 , 25 In one case (12), an X-ray structure analysis was carried out, revealing the relative stereochemistry of all chiral centers. in Fig. 1. The ORTEP drawings in two different perspectives are shown Since the absolute stereochemistry of the chiral auxiliary was known, this constituted an unequivocal proof of the absolute stereochemistry of 12. In addition, the X-ray analysis -19Scheae V 1) Bu BOT f 2 2 ) PhCHO 0 1) LDA 2) PhCH 2 Br 0 ~-Po 7 19 332:1 revealed the expected anti conformation of the imidic carbonyl moiety as the result of allylic strain (vide infra) and dipole minimization. Finally, the analysis indicated an approximately 120° angle between the c2-H bond and the c1-carbonyl. This geometry has also been observed in a-keto imide 20, where the X-ray structure showed the c2-H bond to be in a similar orientation. 22 -20- Fig. 1. ORTEP Drawings of 12 -210 0 Me' H y Et¥~-'1 )--o 0 20 The surprisingly high resistence to epimerization observed for these a-keto imide systems has been rationalized in the following way. 22 A1 ' 3-strain arguments suggest that the c1-c 2 bond rotation might be severely restricted (Fig. 2), making the enolization required perpendicular relationship between the aC-H bond and the c1=o system difficult to reach (Fig. 2). The same kind of restrictions are believed to account for the aldol adducts, hence preventing epimerization under relatively strongly acidic or basic conditions. Fig. 2. Enolization Transition States of an Imide Aldol Adduct * ~ L '-.N,...., L ., .. " B R~_H' '\ ,...... L RYH N Me Me / l ~ X-Ray confonnat 1on enol ate 0 R~~:~ Me 1 ~L , "' "' B enol ate -22- {c) Reaction Variables. In conjunction with the present study, a systematic evaluation of the reaction parameters was undertaken in order to define optimal conditions for carrying out these transformations. The results of this study are summarized in Table 2. i) Temperature. When the reaction shown in eq. 13 was performed at -78°C throughout the whole process (Table 2, Entry 3) no difference in the observed ratios was observed. The GC yield (i.e.% conver- sion) was similar to that of the parent case (Entry 2). On the other hand, when the reaction was carried at 0°C, (Entry 4) a slight decrease of specificity was observed. ii) Solvent. The reactions carried out in ether or toluene proved 1) Bu BOR 0 0 (lN_J(O -r 2 2) R'N 3 3) R'CHO HO 0 R"~xv Me 7 E1 HO 0 Idem. Ph.J0XN Me 8 + E2 + T1 + (11) R• = Me CH (12) 2 R" = Ph T2 Table2. The Influence of Reaction Variables on the Ald o l Process (Eq . 11-1 3) . a Bu 2BOR Enol. Temp . Condens. Temp. E1 : E2 : T1 : T2 HB Bu 2BOTF -7S°C- ooc -?soc - ooc 99.S : 0.04 : 0.14 : 0.06 CH 2c1 2 HB Bu 2BOTF -7S°C - ooc -7S°C - ooc >99.9 : <0 .1 : <0.1 13 CH 2Cl 2 HB Bu 2BOTF -7S°C -7S°C >99.9 : <0. 1 : <0.1 13 CH 2c1 2 HB Bu 2BOTF ooc ooc 97.6 : 0.75 : 0. 75 : 0.9 Bu 2BOTF -7S°C - 0°( -?soc -o oc 99.3 : <0 .1 : 0.20 : 0.5 equation Solvent Amine 11 CH 2Cl 2 2 13 3 4 Entry I N 5 13 Et 20 HB 6 13 Toluene HB Bu 2BOTF -7S°C - ooc -78° ( - ooc 99.3 : <0 .1 : 0. 34 : 0. 36 7 12 CH 2c1 2 TEA Bu 2BOTF RT RT 99.9 : 0.07 : <0 .1 : <0 .1 s 11 CH 2Cl 2 HB Bu 2BOS0 2Me 0°C -RT ooc -RT 9 11 CH 2c1 2 TEA Bu 2BOS0 2Cl -7S°C -o oc -?soc -ooc : 0.32 10 13 CH 2c1 2 TEA Bu 2BOS0 2Cl -?soc- ooc -7S°C- ooc a HB= Huni g 's bas e = diisopropylethylamine; TEA = triethylamine b The absolute stereoch emistry of T was det e rmined to be (2R , 3S) by hydrogen o lysis, foll owing the metnod used for compound ll( Sc he me V) . NO REACTION 1. 31 ca. 2 : 57.76 : : 76 : 40.06 b 22 w I -24- to be equally clean, giving essentially the same product distribution with dichloromethane (Entries 5 and 6), the solvent of choice. iii) Amine Structure. Replacement of diisopropylethylamine by the less hindered base triethylamine did not affect yields or product ratios (entry 7). iv) Boron Reagent. The reaction response to the di-n-butylboryl sulfonate reagent was, on the other hand, very dramatic. Thus, the use of di-n-butylboryl methylsulfonate resulted in starting material recovery, even after warming up the reaction mixture to room temperature (Entry 8). On the other hand, when the corresponding chlorosulfonate reagent was used, a very surprising result was obtained. GC analysis indicated the predominance of the E and the T1 isomers (Entries 9, 10). results. v) 2 We do not have an explanation for these Aldehyde Electronic Characteristics. The reaction of the boron enolate of 7 with p-anisaldehyde and p-nitrobenzaldehyde was also investigated. Both reactions were equally selective (~99.5%) and proceeded in similar GC yield (i.e.% conversion). In a competition experiment, 1 equivalent of the boron enolate of 7 was condensed with a mixture containing 1 equivalent of each of the two mentioned aldehydes. 1H NMR analysis of the unpurified reaction mixture revealed a 65:35 ratio of compounds, in favor of the p-nitro phenyl adduct. The low selectivity observed in this competition experiment suggests that the aldehyde coordination to the boron is a rapid equilibrium process (vide infra). -25- 3. The Aldol Condensation of Chiral, Functionalized Acyl Oxazolidinones Up to this point we have discussed the use of the propionyl imides 7 and 8 in the aldol condensation. We were pleased to find that the reaction works equally well with imides having other, more functionalized acyl substituents. One such family of compounds is the alkoxyacetyl oxazolidinones 21, 22 and 23. 0 BnO~ 0 )l ~0 21 22 23 The success obtained in these reactions constitutes an invitation to future applications in the construction of sugars and other compounds such as polyether and macrolide antibiotics. results are shown in Table 3. The Unlike 7 or 8, the use of this family of oxazolidinones requires low temperatures or the diastereoselection drops noticeably (compare Entries A and B). This reaction has recently found application in efforts directed toward the synthesis of the macrolidic antibiotic Macbecin, where the boron enolate of 21 0 0 HO 0 0 Ph~N)l_O !-j(o RO~ -r RO 21: R=Me + E2 + T1 + T2 + E' + T'1 + T' 2 E1 22: R=Bn 0 0 HO (l)t.o MeO 0 PhA_)lN)lO )----\. Me Ph Meb 23 Table 3. 0 1 )-{ Ph Me I N 0"1 I e; Aldol Condensations of Imides 21-23 with Benzaldehyde. Boron-aldol Kinetic ratios Product El(E2) E1(E 2 )(% yield)b E2(El) Tl(T2) T2(Tl) Entry Imide Enoliz. Temp. Cond. Temp A 22 -7S°C- ooc 24 S0.9 {62%) 3.6 4.2 11.3 B 22 -7S°C -?soc- 0°C -?soc 24 9S.O (76%) 0.5 1.3 0.3 c 21 -7S°C -7S°C 25 99.2 {SO%) 0.4 0.1 0.3 oa 23 -7S°C -?soc- ooc 26 9S.6 {S9%) 0.6 0.3 0.5 a Experiment performed by Or. R. Conn. b Isolated yields. -270 MeO 0 MeO -r OMe <?Me O:N~: CHO I~ ~ ~ 0 Ar~xv II )( ~N 0 2. HO (14) Me MeO (ref. 22) Me OMe 21 27 was condensed with chiral aldehyde 27 in 80-85% yield, with excellent diastereoselection (eq. 14). 22 The aldol condensation of the functionalized oxazolidinone 28 was also investigated (eq. 15). Succinyloxazolidinone 28 has the interesting feature of possessing two enolizable carbonyls. Although we knew in advance that esters do not enolize with boryl triflates and diisopropylethylamine, the role of an additional chelation site on the product stereochemistry remained uncertain. However, as in the other cases, only one isomer was formed. Best results were obtained when low temperatures (-78°C) were maintained throughout the reaction. Product isolation and chromatography afforded 29 in 67% yield. The 90 MHz 1H NMR spectrum revealed a 5.0 Hz c 2 -H~c 3 -H coupling constant, indicative of an erythro 0 0 If...-.._ Jl""'N )( 0 EtO ... o-r -......,r 28 1) Bu 2BOTf 1 2) ( Pr) NEt 2 3) PhCHO OH 0 0 Ph~N)l_O EtO~ ~ 0 29 -28- relationship between substituents. The absolute stereochemistry of c2 was proven by hydrogenolysis and hydrolysis to (2R)-benzylsuccinic acid, the absolute configuration of which has already been established. 23 In view of the high levels of asymmetric induction observed in the cases cited above, it was surprising that the di-n-butylboron enolates of imides 30 and 31 behaved in a nonselective fashion, giving nearly 1:1 mixtures of products. 24 These results turned out to be of great utility when we elaborated the transition state model (vide infra). 30 4. 31 Chiral Auxiliary Removal The role of the chiral oxazolidinones in the boron enolate aldol condensation has been to provide good reaction stereospecificity. Once the desired stereocenters have been formed, the chiral auxiliary must be removed. This removal needs to be -29- site-specific and, preferentially nondestructive of the auxiliary, thus allowing its recovery. We were very pleased to find that treatment of a methanolic solution of the aldol adducts with a 2N aqueous solution of potassium hydroxide and subsequent acidification gave the corresponding acids and the chiral oxazolidinone 9 or 10, thus meeting our two initial requirements. Under these conditions direct TLC analysis indicated that the reaction proceeded by the very rapid displacement of the chiral auxiliary by the methoxide ion, to form the methyl ester which smoothly hydrolized to the acid. A minor byproduct was consistently formed in these reactions in ca. 5-15% yield. Spectral analysis suggested it to be the product resulting from attack at the oxazolidinone carbonyl (eq. 16). OH aq. KOH R~C0 2 H • Me OH 0 Rv~~OH Me The acids were esterified with diazomethane and the corresponding methyl esters purified by bulb-to-bulb distillation. 25 Table 4 summarizes the results obtained in this process. Y The rotations recorded for each pair of enantiomers were consistently 0 1) Bu 2BOTf 0 fN)(o HO 2) (iPr) NEt 2 --r 0 0 HO 1) aq. KOH-MeOH RV)l.o Me-r 3) RCHO 2) CH2N2 0 RVoMe Me 7 0 0 Jl Jl.o 0 HO RJyJl)lo r )--~ Me 0 HO II Me Ph II H Ph 0 RVoMe Me Me 8 I w 0 I Table 4. Base Hydrolysis of Imide Aldol Adducts. Entry Imide RCHO ester% overall yielda ester [a] 25 ester erythro/threo ratio A 7 82 -23.1° (~ 3.2, CHC1 3 ) 99.5 : 0.5 B 8 c6H5CHO c6H5CHO 60 +23.2° (~ 3.2, CHC1 3 ) 99.4 : 0.6 c 7 Me 2CHCHO 69 -7.9° (~ 5.7, CHC1 3 ) 99.4 : 0.6 D 8 Me 2CHCHO 78 +7.7° (~ 5.4, CHC1 3 ) 99.1 : 0.9 E 7 ~-C H CHO 4 9 68 +14.9° (~ 6.6, CH 2Cl 2 )b 98.9 : 1.1 b F 8 ~-C H CHO 4 9 71 -15.0° (~ 5.0, CH 2Cl 2 )b 99.8 : o. 2b a These yields are based on the imide 7(8) and refer to distilled methyl ester. the aldol adducts into the methyl esters. b Values obtained from methanolysis of -31- equal in magnitude and opposite in sign. 26 Diastereomeric analysis (GC) of the methyl esters revealed that hydrolysis proceeded, in general, with ~1% epimerization. A somewhat higher percentage of epimerization (1 to 2%) was consistently found for Entries E and F. Direct conversion of the aldol adducts into the methyl esters could be achieved by transesterification, that is, by adding 1 equivalent or a catalytic amount of K2co 3 , NaOMe or CH 3MgBr to methanolic solutions of the substrates. These and other examples have shown that the exocyclic carbonyl of these and other related compounds has a reactivity somewhat greater than that of an ester. Although hydrolysis or transester- ification of the aldol adducts hereby presented proceeded in high yields, later examples have shown that these reactions, as well as other nucleophilic additions (i·~· reductions), are highly substrate dependent. Indeed, aldol adducts having a slightly bulkier a-substituent are much more resistant to displacement of the chiral auxiliary and proceed with a consider.able degree of ring opening and/or retroaldol reaction. For some of these cases, we have found that the desired carbonyl regioselectivity can be recovered by formation of the boron aldolate prior to the addition of the nucleophile. Simultaneous hydroxyl protection and carbonyl complexation by the boron atom both, prevents retroaldol reaction and selectively activates the exocyclic carbonyl for nucleophilic attack. This alternative method will be discussed in more detail in Ch. 3 (section 3) of this thesis report. -32- 5. Discussion On the basis of the results obtained in the aldol condensation, we present and discuss in this section our proposed transition state models. As we mentioned earlier, the stereoselectivity of these reactions is believed to be caused by two factors: the enolate geometry and the enolate n-facial differentiation. a} The Enolate Geometry. Although we do not have a definite proof of the geometry of our imide enolates, there is strong evidence supporting the (Z) configuration. For example, experimental data strongly suggest that enolization of N,N-dialkylpropionamides with LOA in THF proceeds stereoselectively to afford the (Z) enolate. 27 , 28 It appears reasonable to assume that the closely related propionimides behave in a similar way. The large precedent for correlation between (Z) enolates and erythro products in the aldol condensation of propionyl derivatives, 2a also supports the (Z) enolate geometry. Finally, the sense of induction observed in the alkylation reaction of lithium enolates of these propionyl oxazolidinones, is in complete agreement with the participation of the chelated (Z) enolate 32 (eq. 17). 13 In an attempt to gain some further information concerning this issue, imide 8 was enolized with LOA (1.1 equiv, THF, -78°C, 30 m) and quenched with t-butyldimethylsilyl chloride (1 equiv, -78°C~25°C) (eq. 18). The 500 MHz 1H NMR spectrum of the unpurified mixture revealed the presence of only one quartet plus -33e Li eo"' 'o A '~ CH3 0 N~ \_/ ,... ,, ,, ,, Ph Me 32 1 LOA 0 0 ~!'t~ ', 'Me ,... Ph 8 some minor resonance in the vinylic region (4.86 ppm), and clearly one single doublet in the vinylmethyl region (1.64 ppm), suggesting exclusive formation of one geometrical isomer. An 1H NMR study of 8 LOA TBSCI 32 33 mp 88-89°C lithium enolate 32 (or the boron enolate) was not performed. an experiment would rule out the possibility of an equilibrium between enolates, where the (Z) enolate reacts faster towards ( 18) Such -34- electrophiles than the (E) enolate. Chromatography and recrystal- lization afforded 33 as white needles. An X-ray structure analysis that could unambiguously determine the structure of 33 remains to be done. The selective enolization of these systems can be rationalized as depicted in Scheme VI, by the same argument that we used to Scheme VI B B I I I I He I --_ri\ 0 t T, z .:- L =:;xy:::::CHJ N" ~ L Tt F HA 2 E -35- explain the epimerization resistance of these imides. Thus, stereoelectronic constraints demand that the transition states for enolization must possess a colinear geOmetry between the C-HA(B) bond and the carbonyl11·system. In addition, we will make the assumption that the partial delocalization of the nitrogen lone pair into the forming enolate locks the N-substituents in the u-plane. With these two reminders, the transition states corresponding to the enolization of each diastereotopic depicted in Scheme VI. proton will look like the ones The unfavorable developing 1,3-allylic interaction between the methyl group and the nitrogen substituent in the transition state leading to the {E) enolate,{T 2*), could be then the reason for the selective formation of the (Z) enolate. In summary, we believe that the structure of our enolate is the one dipicted in Fig. 3 where the olefin has a (Z) configuration and the boron is chelated to the ring carbonyl, in analogy to the lithium enolate. Fig. 3. Proposed Structure of the Di-n-butylboron Enolate of 8. Bu Bu .&:1 Jl 0 'se o,..... 'o<t> CH 3 ~N H Me Ph -36- {b) The Sense of As~tric Induction. In order to reach the required reactivity, the aldehydic carbonyl needs to be activated by coordination to boron. That precoordination might be a requirement is substantiated by the non-reactivity of these boron enolates towards acid chlorides. Although the intrinsic reactivity of acyl chlorides towards nucleophiles is higher than that of aldehydes, the electron-withdrawing character of the chlorine atom might prevent coordination, and consequently lower the reactivity. If this coordination was the rate determining step, p-anysaldehyde would have reacted much faster than p-nitrobenzaldehyde in the competition experiment (seep. 24), due to the higher lewis basicity of the former over the latter. Instead, very poor aldehyde selec- tion was observed (1.7:1), favoring, in fact, the p-nitro adduct. Before reaction takes place, then, the boron must switch its coordination site from the ring carbonyl to the aldehydic carbonyl (Scheme VII), leaving the c1-N bond free for rotation. Assuming the aldehyde approaches from the less hindered side (the face opposite to the ring substituent R) and that the aldehyde substituent bears an equatorial position (see Section 2) we can envision two chairlike transition states, E2 * and E1* (Scheme VII) in which the ring has adopted either one of the two resonance-stabilized conformations. The selective formation of the erythro-1 product might then be caused by the developing CH 3~R allylic strain interaction present in the transition state E2• leading into the erythro-2 -37Scha~e VII J * J * E 1* e*2 erythro-2 erythro-1 -38- product. The related interaction in E1* would be anticipated to be smaller, then offering a lower energy pathway to the reaction. If these transition states are the only ones that account for the reaction erythro enantioselection, their difference in energy would be 2.6 kcal/mol, as deduced from the observed E1 :E2 product distribution obtained in Entry 4, Table 2. 29 To the best of our knowledge, this is one of the largest transition state energy differences ever recorded in an enantioselective process. Support for this model is given by the loss of selectivity observed in the related reaction of acetyloxazolidinones 30 and 31, where the lack of the a-substituent makes both transition state ring conformers similar in energy. In summary, based on the chair models presented in Section 2 of this chapter, and assuming the aldehyde approaches from the * enolate's least hindered side, we propose the structure E1 depicted in Scheme VII for the transition state of the present aldol condensation. * The main difference between structures E1 and E2* is the orientation of the oxazolidinone ring (transoid ~ cisoid) which is translated into a difference in energy due to allylic interactions. IV. Slmlary The boron enolates of chiral oxazolidinones 7 and 8 have been demonstrated to react with aldehydes to afford erythro aldol adducts with excellent diastereoselection and high yields. The reaction can -39- also be performed with more functionalized oxazolidinones, such as 21 or 28. Mild base hydrolysis of the adducts leads to optically pure (~99% ee) a-hydroxy acids, along with the chiral auxiliary, which can be reused. The reaction is believed to go through a pericyclic, chair transition state in which 1,3-diaxial and A-strain interactions have been minimized. -40- Experimental Section General. Melting points were determined with a BHchi SMP-20 melting point apparatus and are uncorrected. Infrared spectra were recorded on a Beckman 4210 spectrophotometer. 90 MHz 1H NMR spectra were recorded on a Varian Associates EM-390 spectrometer and are reported in ppm on the o scale, from the indicated reference. Data are presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, m =multiplet, br =broad), coupling constant (in Hz), integration and interpretation. 500 MHz 1H NMR spectra were recorded on a Bruker WM-500 spectrometer at the Southern California Regional NMR facility. 13 c NMR spectra were recorded on a JEOL FX-90Q (22.5 MHz) spectrometer and are reported in ppm on the o scale from the indicated reference. Combustion analyses were performed by Spang Microanalytical Laboratory (Eagle Harbor, Michigan), Galbraith Laboratories, Inc. (Knoxville, Tennessee), or Mr. Lawrence Henling (California Institute of Technology). Optical rotations were recorded on a Jasco DIP-181 digital polarimeter at the sodium D line (589 nm) and are reported as follows: [a] 25 , solvent, and 0 concentration (£ = g/100 ml). Analytical gas-liquid chromatography (GC) was carried out on a Hewlett Packard 5880 A level 3 gas chromatograph equipped with a split mode capillary injection system and a flame ionization detector, using a 25m x 0.2 mm flexible fused silica capillary -41- column wall-coated with Carbowax 20M or Methyl Silicone (SP-2100), or a 30m x 0.32 mm fused silica capillary wall-coated with SE-54. Unless otherwise noted, injector and detector temperatures were 250°C. Data are reported as follows: column type, oven tempera- ture, and retention time (tr). Liquid chromatography was performed using a forced flow (flash-chromatography) of the indicated solvent system on EM Reagents Silica Gel 60 (230-400 mesh). follows: Data are reported as column diameter, weight of silica and eluent composition. Medium pressure liquid chromatography (MPLC) was carried out using EM Reagents LoBar Silica Gel 60 prepacked columns (column size indicated) on a Chromatronix MPLC apparatus equipped with a Fluid Metering Inc. Model RP-SY Lab Pump. Analytical thin layer chromatography (TLC) was performed using EM Reagents 0.25 mm silica gel 60-F plates. When necessary, solvents and reagents were dried prior to use. Tetrahydrofuran, diethyl ether, benzene and toluene were distilled from sodium metal/benzophenone ketyl. Dichloromethane, diiso- propylethylamine, diisopropylamine, triethylamine and boron trifluoride etherate were distilled from calcium hydride. Dimethyl sulfoxide and dimethylformamide were distilled under reduced pressure from calcium hydride and stored over activated 4 ~ molecular sieves. -42- Unless otherwise specified, all non-aqueous reactions were conducted under a rigorously dried argon atmosphere, using oven-dried glassware. Di-n-butylboryl trifluoromethanesulfonate 18 (Di-n-butyl boryltriflate). To rapidly stirred tri-~-butylborane (22.3 ml, 16.7 g, 91 ITITlOl, Callery Chemical) in a dry, three-necked, 100-ml flask, connected to an argon bubbler was added ca. 2 ml of anhydrous trifluoromethanesulfonic acid (triflic acid). The reaction was initiated by the application of heat (heat gun) and monitored by the evolution of butane. The remaining triflic acid for a total of 8.05 ml (13.76 g, 91 mmol) was added dropwise at a rate that maintained a steady evolution of butane. Caution: Do not allow the accumulation of large amQunts of unreacted triflic acid evidenced by formation of a two phase mixture, as the reaction may become violent. In order to prevent this from occurring, additional heating may be required. When the addition was complete, the resulting orange solution was then stirred at room temperature for 1 h and distilled at reduced pressure through a Vigreux column (15 em) to afford the title compound as a colorless, highly air-sensitive liquid (bp 70°C at ca. 2 mm; d = 1.1). The product was stored at ambient temperature under an argon atmosphere. Although the product often developed an orange coloration upon storage, it seemed not to affect the yields of subsequent reactions. -43- Di-n-butylboryl methanesulfonate. Into a dry 50-ml, three- necked flask connected to an argon bubbler was introduced tri-~­ butylborane (4.4 ml, 18.3 mmol) followed by a catalytic amount of benzoic acid (0.11 g, 0.9 mmol, 0.05 equiv). The solution was heated with a heat gun until butane was evolved. Methanesulfonic acid (1.18 ml, 18.3 mmol, 1 equiv) was then introduced in portions, with the careful control of heating. After the addition was completed, the orange solution was stirred at room temperature for 1 h, then distilled through a short-path distillation head to afford methanesulfonate as a colorless oil which was stored under an argon atmosphere at 4°C: bp 84°C at 0.5 mm; 1H NMR di-~-butylboryl (90 MHz, CDC1 3) o (TMS) 3.13 (s, 3H,-so 2 c~3 ), 1.5-1.0 (m, 12 H, 3 2 2 2 2 (CH c~ c~ c~ ) ), 1.0-0.7 (m, 6H, (CH 3CH 2) 2). General Procedure for the Preparation of 3-acyl-2-oxazolidinones. In a dry, 1-L flask was placed 130 mmol of oxazolidinone 9 or 10. The flask was flushed with argon and charged with tetra- hydrofuran (300 mL). The solution was cooled to -78°C and a 1.65 M solution of ~-butyllithium in hexane (79 mL, 130 mmol, 1 equiv) was added slowly. When 10 was used as the starting material, appearance of a red coloration, due to dianion fonmation, indicated that one equivalent of base had been added. The acid chloride (156 mmol, 1.2 equiv, neat) was then added in one portion, and the reaction mixture was allowed to wanm slowly to room temperature (45 min). The -44- reaction was quenched by the addition of saturated aqueous ammonium chloride and the organic volatiles removed in vacuo. The remaining aqueous slurry was extracted with dichloromethane (2 x 150 ml), and the combined organic layers were washed subsequently with 5% aqueous sodium hydroxide, and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified by molecular distillation (KUgelrohr, vacuum) followed by flash chromatography (when necessary) or recrystallization. (S)-3-(2-Methoxy-1-oxoethyl)-4-(1-methylethyl)-2-oxazolidinone (21). Freshly distilled methoxyacetyl chloride (1.51 ml, 16.5 mmol) was added dropwise into a cooled (-5°C) solution containing the lithium salt of 9 (15 mmol) in anhydrous tetrahydrofuran, following the previously described general acylation procedure. The resulting oil was purified by bulb-to-bulb distillation (KUgelrohr, 140°C, 0.005 mm), followed by flash chromatography (50 mm, 150 g silica, 40% ethyl acetate:hexane) to afford 2.31 g (76%) of compound 21 as a colorless oil: IR (CH 2cl 2) 3060, 2985, 1783, 1722, 1390, 1203, 892 cm- 1 ; 1H NMR (90 MHz, CDC1 3) II II I o (TMS) 4.58 (s, 2H, O=CC~2 ), 4.55-4.25 (m, 3H, -NC~C~2 ), 3.45 (s, 3H, c~3 0), 2.42 (qn of d, Jd = 3, Jqn = 7, lH, (CH 3 ) 2 t~). 0.92 (d, I I 25 J = 7, 3H, C~3 CHCH 3 ), 0.87 (d, J = 7, 3H, CH 3 CHC~3 ); [a] 0 = +92.6° (CH 2Cl 2 , £ 5.5). -45- Anal. calcd. for C9H15 o4 N: C, 53.72; H, 7.51; N, 6.96. Found: C, 53.56; H, 7.45; N, 6.82. (4R,5S)-3-(2-Methoxy-1-oxoethyl)-4~thyl-5-phenyl-2- oxazolidinone (23). To a stirred, cooled (-5°C) solution of the lithium salt of 10 (40 mmol) in anhydrous tetrahydrofuran was added methoxyacetyl chloride (4.02 ml, 42 mmol) following the previously described general procedure for acylation. The unpurified, solid product was recrystallized (ether: pet. ether) to afford 8.65 g (87%) of the title compound as colorless needles: mp 61-63°C; IR (CH 2Cl 2) 3050, 2990, 1782, 1720, 1350, 1200, 1125, 890 cm- 1 ; 1H NMR (90 MHz, CDC1 3) o (TMS) 7.5-7.2 (m, 5H, aromatic H), 5.74 (d, J = I I 7.0, 1H, PhC~-), 4.78 (qn, J = 7.0, 1H, CH 3 C~-), 4.63 (s, 2H, I CH 0c~ ), 3 2 I I 3.49 (s, 3H, c~3 0CH 2 ), 0.93 (d, J = 7.0, 3H, C~3 CH-); 13 C NMR (CDC1 3) o 169.15, 152.38, 132.69, 128.08, 125.09, 79.34, 78.36, 71.54, 58.74, 53.73, 13.90; [a]~5 = +30.8° (CH 2c1 2 , ~ 5.0). Anal. calcd. for c 13 H15 No 4 : C, 62.64; H, 6.07; N, 5.62. Found: C, 62.70; H, 6.01; N, 5.59. (S)-4-(1-Methylethyl)-3-(1-oxo-2-(phenylmethoxy)-ethyl}-2oxazolidinone {22). Phenylmethoxyacetyl chloride (3.32 g, 18 mmol, 1 equiv) was added to a cooled (-10°C) solution of the lithium salt of 9 (18 mmol), according to the previously described general procedure. The unpurified, crystalline product was recrystallized -46- from ether-pet. ether. 1H NMR analysis indicated the presence of unreacted starting material 9. The product was dissolved in dichloromethane, washed twice with water to remove 9, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 3.10 g (62%) of the title compound as a white solid: mp 86.5-87.0°C; IR (CH 2Cl 2 ) 2970, 1785, 1723, 1488, 1390, 1213, 1122 cm- 1 ; 1H NMR (90 MHz, CDC1 3) b (TMS) 7.5-7.25 (m, 5 H, aromatic H), 1 I I I 4.65 (d, J = 3.5, 2H, Phc~2 ), 4.53-4.20 (m, 3H, -NC~c~2 ), 2.42 I (qn of d, Jd = 3, Jq = 7, 1H, (CH 3 ) 2 C~), 0.93 (d, J = 7, 3H, I c~ CHCH ), 3 3 I 0.89 (d, J = 7, 3H, CH 3 CHC~3 ). Anal. calcd. for c15 H19 N0 4 : C, 64.97; H, 6.91. Found: C, 65.12; H, 7.04. (S)-4-(1-Methylethyl)-~,2-dioxo-3-oxazolidinebutanoic ethyl ester (28}. acid, Ethyl succinyl chloride (5.4 ml, 37.7 mmol, 1.2 equiv) was added into a solution containing the lithium salt of 9 (31.4 mmol) in anhydrous tetrahydrofuran, following the previously described general procedure. Flash chromatography (50 mm, 220 g silica, 30% ethyl acetate:hexane) afforded 6.75 g (83%) of the title compound as a colorless oil: Rf 0.28 (70% ethyl acetate:hexane); IR (film) 2975, 1785, 1735, 1705, 1390, 1210, 1170 cm- 1 ; 1H NMR (90 MHz, CDC1 3) o (TMS) 4.55-4.00 (m, 5H, -NC~C~O; CH 3 c~2 0-), 3.34 I I I I I (m, 2H,-CH 2Ctl 2CON-), 2.65-2.55 (m, 2H,-CH 2cH 2CON-), 2.38 (qn of d, t Jd = 3, Jqn = 7, 1H, CH 3 C~CH 3 ), 1.25 (t, J = 8, 3H, CH 3CH 20-), 0.90 -47- (d, J = 7.5, 3H, c~3 CHCH 3 ), 0.88 (d, J = 7.5, 3H, CH 3 cHc~ ); [a]~5 = 3 +73.2° (CH 2c1 2 , ~ 3.7). Anal. calcd. for c12H19 o5 : C, 56.02; H, 7.44; N, 5.44. Found: C, 56.17; H, 7.39; N, 5.36. General Procedure for the Fonaation of the Boron Enolates of Acyloxazolidinones and Subsequent Condensation .rtth Aldehydes. The following reactions were done on a scale ranging from 0.5 mmol to 300 mmol, at concentrations of starting oxazolidinones of 0.25 ~to 1 M. All reagent additions were made via hypodermic syringe. Method A: In a dry, two-necked, 25-ml flask equipped with a magnetic spin bar was introduced 1.0 mmol of the indicated oxazolidinone. The flask was purged with argon, charged with freshly distilled dichloromethane (2-4 mL), and the solution cooled to -78°C. Di-n-butylboryl triflate (0.27 ml, 1.1 mmol) was added dropwise, often resulting in a yellow solution, and partial freezing of the reagent. dissolved. The cooling bath was removed until the triflate The solution was recooled (-78°C) and freshly distilled diisopropylethylamine (0.21 ml, 1.2 mmol) (or freshly distilled triethylamine (0.17 ml, 1.2 mmol)) was then added dropwise resulting in a colorless, clear solution. The mixture was stirred at -78°C for 0.5 h, then at 0°C for 1 h. The solution was recooled to -78°C, and anhydrous aldehyde (neat, 1.0 mmol of non-enolizable aldehyde, or 1.1 to 1.2 mmol of enolizable aldehyde) was added in one portion. -48- The solution was stirred at -78°C for 0.5 h and then at 0°C for 1 h. The reaction was quenched by the successive addition of aqueous phosphate buffer (pH 7) (1 mL), methanol (sufficient to afford a homogeneous solution) and a solution of 30% aqueous hydrogen peroxide (1 mL) in methanol (2 mL). for 1 h. The mixture was stirred at 0°C Volatiles were removed in vacuo and the remaining aqueous mixture was extracted with ether (2 x 30 mL). The combined ethereal phases were washed with 5% aqueous sodium bicarbonate, and with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting aldol adduct was purified either by recrystallization or flash chromatography. Method B: nones. This method was used for a-alkoxyacetyloxazolidi- It is identical to method A, except that the temperature was maintained at -78°C during both the enolization and condensation processes. The reactions were quenched at -78°C. General Procedure for the Fonmation of the lithium Enolates of Acyloxazolidinones and Subsequent Condensation .rtth Aldehydes. In a dry, argon-filled, two-necked, 25-ml flask equipped with a magnetic spin bar, a rubber septum and an argon gas-inlet, was introduced 3 ml of anhydrous tetrahydrofuran and 0.15 ml (1.1 mmol) of diisopropylamine. The solution was cooled to -78°C and 0.68 ml (1.1 mmol) of a 1.6 M solution of n-butyllithium in hexane was added dropwise. After 20 min a solution of 1.0 mmol of the indicated -49- oxazolidinone in 1 ml of tetrahydrofuran was added dropwise (1 x 1 ml rinse). The solution was stirred 30 min and then treated with 1.0 mmol of non-enolizable aldehyde (or 1.1 to 1.2 mmol of enolizable aldehyde) in one portion. The reaction was quenched after 5-10 seconds by the addition of 2 ml of saturated aqueous ammonium chloride, and allowed to warm to room temperature. Volatiles were removed in vacuo and the remaining mixture was extracted with ether or dichloromethane (2 x 30 ml). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to slightly yellow oils. (3Z,4R,5S)-3-((((l,l-Dimethylethyl)di.ethylsilyl)oxy)-1propenyl)-4~thyl-5-phenyl-2-oxazolidinone (33). Enolization was performed according to the previously described procedure for the generation of lithium enolates. To a cooled (-78°C) solution of LOA (1.1 equiv, 1.1 mmol) in tetrahydrofuran (3 ml) was added dropwise a solution containing imide 8 (233 mg, 1 mmol) in tetrahydrofuran (1 ml). The mixture was stirred for 30 min, and then 1-butyldi- methylsilylchloride (151 mg, 1 mmol, 1 equiv) was added. The reaction mixture was slowly warmed up to room temperature, then stirred for 1 h and finally quenched by the addition of pH 7 phosphate buffer solution. The mixture was diluted with water and extracted with ether, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to 300 mg of a colorless oil. Flash -50- chromatography (30 mm, 45 g silica, 30% ethyl acetate:hexane) afforded 254 mg (73%) of the title compound as a white solid. Recrystallization (ether:pet. ether) afforded pure material as white needles: mp 88-89°C; IR (CHC1 3) 3022, 2965, 2941, 2870, 1756, 1687, 1390, 1055, 840 em -1 ; 1H NMR (500 MHz, CDC1 3) o (TMS) 7.42-7.24 (m, I I I 5H, aromatic H), 5.57 (d, J = 7.0, 1H, -NCHCH1, 4.86 (q, J = 7.0, I I I I 1H, H 3 CC~=), 4.290 (qn, J = 6.5, -NC~CH-), 4.284 (qn, J = 6.5, I I I I I 1.64 (d, J = 7.0, 3H, C~3 CH=), 0.99 (s, 9H, (C~3 ) 3 CSi), I I. 13 0.771 (d, J = 6.5, 3H, C~3 CHN-), 0.23 (s, 6H, (C~3 ) 2 Sl-); C NMR -NC~CH-), I (CDC1 3 ) o (CDC1 3) 143.12, 138.19, 135.07, 128.6, 120.1, 103.81, 55.46, 25.76, 18.16, 14.52, 11.01, -4.2, -4.6; [a]~ 5 = +106.9° (CHC1 3 , .£ 1.1). Anal. calcd. for c19 H29 N0 3Si: C, 65.67; H, 8.41. Found: C, 65.74; H, 8.37. (3(2S,3S),4S)-3-(3-Hydroxy-2~thyl-1-oxo-3-phenylpropyl)-4- (l~thylethyl)-2-oxazolidinone (11). (Table I, Entry A). Enoliza- tion, aldol condensation, oxidation and product isolation were performed according to the previously described method A. To a cooled (-78°C) solution of the boron enolate of 7 in 8 ml of anhydrous dichloromethane (prepared from 370.4 mg (2.0 mmol) of oxazolidinone 7, 0.54 ml (2.2 mmol) of di-~-butylboryl triflate, and 0.42 ml (2.4 mmol) of diisopropylethylamine) was added benzaldehyde {0.21 ml, 2 mmol, 1 equiv). The reaction was stirred at -78°C for 0.5 hand . -51- at 0°C for 1 h. Product isolation afforded 534 mg of a white solid. Diastereomer analysis (Carbowax, T = 200°C, tr E1 = 5.42 min, tr E2 = 7.17 min, tr T1 = 8.40 min, tr T2 = 9.23 min) of an unpurified, silylated sample (TMSNEt 2 , DMAP, CH 2c1 2 , 12 h) revealed a ratio of E1 :E2 :T1 :T2 = 99.8:0.04:0.14:0.04. Recrystallization (ether:pet. ether) gave 510.3 mg (88%) of the title product as white mp 97-98°C; IR (CH 2Cl 2) 3540 (br), 2970, 2880, 1780, 1680, 1385, 1300, 1205, 660 cm- 1 ; 1H NMR (90 MHz, CDC1 3 ) 8 (TMS) 7.5-7.2 I (m, 5H, aromatic H), 4.98 (d, J = 4.5, lH, HOC~-), 4.4-3.9 (m, 4H, needles: I I I I 1 O=CC~-, -NC~c~ 0 ·), 2 3. 5-3.2 ( br s, 1H, ~0-), 2.17 (qn of d, J d = 3. 5, I I I qn = 7 lH, CH 3CHCH - 3 ), 1.20 (d, J = 7.0, 3H, O=CCHCH- 3 ), 0.87 (d, J = I I 13 7, 3H, C~3 CHCH 3 ), 0.83 (d, J = 7, 3H, CH 3 CHC~3 ); C NMR (CDC1 3)o (TMS) 176.64, 153.44, 141.67, 128.15, 127.37, 126.21, 73.76, 63.43, J 58.42, 44.58, 28.53, 17.81, 14.75, 11.50; [a]~ 5 = +64.5° (CH 2c1 2 , £ 8.4). Anal. calcd. for c16 H21 No 4 : C, 65.96; H, 7.27; N, 4.81. Found: C, 66.04; H, 7.26; N, 4.71. (3(2R,3S),4S)-3-(3-Hydroxy-2~thyl-l-oxo-3-phenylpropyl)-4(l~thylethyl)-2-oxazolidinone (liT). Lithium enolate formation, aldol condensation and product isolation were performed according to the previously described procedure. To a cooled (-78°C) solution of the lithium enolate of 7 in 5 ml of anhydrous tetrahydrofuran (prepared from 185.2 mg (1 mmol) of 7, 0.15 ml (1.1 mmol) of -52- diisopropylamine, and 0.8 ml (1.1 mmol) of a 1.37 ~solution of ~-butyllithium), was added benzaldehyde (1 mmol). afforded a yellow oil. Product isolation Diastereomer analysis (Carbowax, 200°C, tr E1 = 7.71 min, tr E2 = 10.17 min, tr T1 = 11.86 min, tr 12 = 13.16 min) afforded a ratio of E1 :E2 :T1 :T2 of 9.8:29.5:59.0:1.7. Chromatography on silica gel (MPLC, Merck LoBar size~, 43% dichloromethane, 43% hexane, 14% ethyl acetate) afforded 50 ~g of the title compound as a white solid. Diastereomer analysis of a chromatographed, silylated sample (TMSNEt 2 , DMAP, CH 2c1 2 , 12 h) afforded a ratio of E1 :E2 :T1 :T2 = 0.1:i0.01:99.5:0.4: Rf 0.25 (43~ dichloromethane, 43% hexane, 14% ethyl acetate); mp 103-104°C; IR (CH 2C1 2) 3600, 3520, 2970, 1780, 1700, 1385, 1210 em -1 ; 1H NMR (90 MHz, CDC1 3) o (TMS) 7.5-7.25 (m, SH, aromatic H), 4.70 (t, J = I I I I I 1 8, 1H, HOC~-), 4.55-4.05 (m, 4H, O=CC~-, -NC~C~2 ), 3.40 (d, J = 7, I 1H, -HO), 2.23 (qn of d, Jd = 3, J qn = 7, 1H, (CH 3) 2CH), 1.06 (d, J = I I I 7, 3H, O=CCHC~3 ), 0.85 (d, J = 7, 3H, C~3 CHCH 3 ), 0.72 (d, J = 7, 3H, I 13 CH CHC~ ); C NMR (CC1 4 ) o (TMS) 175.66, 153.04, 142.71, 128.09, 3 3 127.24, 126.33, 77.14, 62.32, 58.16, 43.41, 28.01, 17.80, 14.49, 14.23; [a]~5 = -3.18° (CH 2C1 2 , £ 8.3). Anal. calcd. for c16H21 N0 4 : C, 65.96; H, 7.27; N, 4.81. Found: C, 66.22; H, 7.30; N, 4.76. (3(2S,3R),4S)-3-(3-Hydroxy-2,4-dimethyl-l-oxopentyl)-4{l~thylethyl)-2-oxazolidinone {13). (Table 1, Entry C). -53- Enolization, condensation, oxidation and product isolation were performed according to the previously described method A. To a cooled (-78°C) solution of the boron enolate of 7 in 12 ml of anhydrous dichloromethane (prepared from 555 mg (3 mmol) of oxazolidinone 7, 0.81 ml (3.3 mmol) of di-~-butylboryl triflate, and 0.63 ml (3.6 mmol) of diisopropylethylamine) was added 0.33 ml (3.6 mmol) of isobutyraldehyde. The reaction was stirred at -78°C for 0.5 h and at 0°C for 1 h. Product isolation gave 670 mg of a white solid. Diastereomer analysis (Carbowax, T = 180°C, tr E1 = 10.18 min, tr E2 = 11.29 min, tr T1 = 12.27 min, tr T2 = 12.87 min) of an unpurified, silylated sample (TMSNEt 2 , DMAP, CH 2c1 2 , 12 h) afforded a ratio of E1 :E 2 :T1 :T2 = 99.4:0.2:0.2:0.2. Recrystallization (ether:pet. ether) gave 604.1 mg (78%) of compound 13 as white mp 88-89°C; IR (CH 2Cl 2) 3550 (br), 2970, 1783, 1683, 1386, 1208 cm- 1 ; 1H NMR (90 MHz, CDC1 3 ) o (TMS) 4.55-4.1 (m, 3H, I I -NC~C~ 0), 3.93 (q of d, Jd = 3, Jq = 6.5, 1H, O=CC~-), 3.47 (d of 2 needles: 'I I I t, Jt = 3, Jd = 8.5, lH, HOC~-), 2.95 (d, J = 3, lH, HO-), 2.32 I (qn of d, Jd = 3.5, Jqn = 7, 1H, CH 3 C~CH 3 ), 1.85-1.45 (m, 1H, I HOCHC~(CH ) I I 3 2 1.21 (d, J = 7, 3H, O=CCHC~3 ), 1.1-0.8 (m, 12H, two I 25 (C~ ) CH); [a] 0 = +60.3° (CH Cl , £ 2.3). 3 2 2 2 Anal. calcd. for c13 H23 N0 4 : C, 60.68; H, 9.01; N, 5.44. Found: ), C, 60.52; H, 9.01; N, 5.38. -54- (3(2S,3R),4S)-3-(3-Hydro~-2~thyl-1-oxoheptyl)-4-(1~thyl- ethyl)-2-oxazolidinone (15). (Table 1, Entry E). Enolization, condensation, oxidation and product isolation were performed according to the previously described method A. To a cooled (-78°C) solution of the boron enolate of 7 in 16 ml of anhydrous dichloromethane (prepared from 741 mg (4 mmol) of oxazolidinone 7, 1.08 ml (4.4 lllTIOl) of di-n-butylboryl triflate and 0.84 ml (4.8 lllTIOl) of diisopropylethylamine) was added 0.44 ml (4.4 mmol) of freshly distilled pentanal. at 0°C for 1 h. The reaction was stirred at -78°C for 0.5 h and Product isolation afforded 952 mg of an oil. Diastereomer analysis (Carbowax, 170°C, tr E1 = 5.96 min, tr E2 = 6.16 min, tr T1 = 7.18 min; tr T2 = 7.78 min) of an unpurified, silylated sample (TMSNEt 2 , DMAP, CH 2c1 2 , 12 h) revealed at ratio of E1 :E 2:T1 :T2 = 99.0:0.76:0.18:0.06. A portion (322 mg) was flash chromatographed (25 mm, 35 g silica, 30% ethyl acetate:hexane) to afford 30 mg of starting material (7) and 274.6 mg (75%) of compound 15 as a colorless oil: IR (CH 2cl 2 ) 3560 (br), 2970, 1780, 1680, 1455, 1385, 1300, 1205 cm- 1 ; 1H NMR (90 MHz, CDC1 3) o (TMS) I I I I I I 4.55-4.05 (m, 3H, -NC~C~2 ), 4.0-3.55 (m, 2H, O=CC~C~-), 3.05 (br d, I J = 3, 1H, -HO-), 2.33 (qn of d, Jd = 3.5, J qn = 7, 1H, (CH 3 ) 2CH), I I I 1.7-1.0 (m, 6H, CH 3 c~2 c~2 c~2 ), 1.25 (d, J = 7, 3H, O=CCHCH 3 ), I I 25 1.0-0.7 (m, 9H, c~3 cH 2 , (CH 3 ) 2CH); [a] 0 = +75.2° (CH 2c1 2 , £ 3.4). Anal. calcd. for c14 H25 No 4 : C, 61.97; H, 9.29; N, 5.16. Found: C, 61.93; H, 9.35; N, 5.10. -55- (3(2R,3R),4R,5S)-3-(3-Hydroxy-2~thyl-1-oxo-3-phenylpropyl)- 4-methyl-5-phenyl-2-oxazolidinone (12). (Table 1, Entry B). Enolization, condensation, oxidation and product isolation were performed according to the previously described method A. To a cooled (-78°C) solution of the boron enolate of 8 in 40 ml of anhydrous dichloromethane (prepared from 2.33 g (10 mrnol) of oxazolidinone 8, 2.7 ml (11 mmol) of di-~-butylboryl triflate, and 2.1 ml (12 mmol) of diisopropylethylamine) was added 1.01 ml (10 mmol) of benzaldehyde. and at 0°C for 1 h. The reaction was stirred at -78°C for 0.5 h Product isolation afforded 3.04 g (89%) of compound 12 as a white solid, pure by TLC and proton NMR. Diastereomer analysis (SE-54, T = 225°C, 10 PSI, tr E1 = 10.22 min, tr E2 = 12.61 min, tr T = 13.62 min) of an unpurified, silylated sample (TMSNEt 2 , DMAP, CH 2c1 2 , 12 h) afforded a ratio of E1 :E2 :T = >99.9:<0.1:<0.1. Recrystallization (ether:pet. ether) provided an analytical sample of 12: mp 138-139°C; IR (CH 2C1 2) 3500 (br), 1770, 1675, 1352, 1183 cm- 1 ; 1H NMR ( 90 MHz, CDC1 3) o (TMS) 7.5-7.15 (m, 10H, aromatic H), 5.40 (d, J = 7, 1H, -NCHC~O-), 5.04 (d, J = 4.5, I I I I I I 1H, HOC~-), 4.62 (qn, J = 7, 1H, -NC~-), 4.11 (q of d, Jd = 4.5, I I Jq = 7, 1H, O=CC~-), 3.2-3.0 (br, lH, ~0-), 1.22 (d, J = 7, 3H, I I 25 0=CCHC~ ), 0.88 (d, J = 7, 3H, -NCHC~ ); [a] = +5.5° (CH 2Cl 2 , 0 3 3 £ 6). I I Anal. calcd. for c20 H21 N0 4 : C, 70.78; H, 6.24; N, 4.13. Found: C, 70.78; H, 6.21; N, 4.10. -56- (3(2R,3S),4R,5S)-3-(3-Hydroxy-2,4-di.ethyl-l-oxopentyl)-4methyl-5-phenyl-2-oxazolidinone (14). (Table 1, Entry D). Enolization, condensation, oxidation and product isolation were performed according to the previously described method A. To a cooled (-78°C) solution of the boron enolate of 8 in 40 ml of anhydrous dichloromethane (prepared from 2.33 g (10 mmol) of oxazolidinone 8, 2.7 ml (11 mmol) of di-~-butylboryl triflate, and 2.1 ml (12 mmol) of diisopropylethylamine) was added 1.1 ml (11 mmol) of isobutyraldehyde. The reaction was stirred at -78°C for 0.•5 h and at 0°C for 1 h. Product isolation gave 3.51 g of a thick oil. Diastereomer analysis (SE-54, 200°C, 10 PSI, tr E1 = 11.88 min, t r E2 = 13.09 min, t r T = 13.50 min) of an unpurified, silylated sample (TMSNEt 2 , DMAP, CH 2c1 2 , 12 h) afforded a ratio of E1 :E 2 :T = 99.8:0.15:0.05. A portion (243 mg) was flash chromatographed (25 mm, 32 g silica, 40% ethyl acetate:hexane) to afford 226.1 mg {91%) of the title compound as a colorless, thick oil: IR (film) 3700-3100 (br), 2970, 1782, 1700, 1455, 1200, 1120 cm- 1 ; 1H NMR (90 MHz, CDC1 3) o (TMS) 7.5-7.2 (m, 5H, aromatic H), 1 5.67 (d, J = 7, lH, -NCHC~O), 4.76 (qn, J = 7, lH, -NC~-), 3.95 I I 1 I I I I (q of d, Jd = 3.5, J q = 7, lH, O=CCH-), 3.56 (d of d, J = 3.5, J = I I 8.5, lH, HOC~-), 3.25-3.1 (br, 1H, ~0)-, 1.9-1.45 (m, 1H, (CH 3 ) 2 C~), I I I 1.22 (d, J = 7, 3H, O=CCHC~3 ), 1.02 (d, J = 7, 3H, c~3 CHCH 3 ), 0.93 t 25 (d, J = 7, 3H, CH 3CHCH 3), 0.88 (d, J = 7, 3H, -NCHC~3 ); [a] 0 = +30.2° (CH 2c1 2 , £ 5.9). II -57- Anal. calcd. for c17 H23 No 4 : C, 66.86; H, 7.59; N, 4.59. Found: C, 66.94; H, 7.73; N, 4.44. (3(2R,3S),4R,5S)-3-(3-Hydro~-2~thyl-1-oxohepty1)-4~thyl- 5-phenyl-2-oxazolidinone (16). (Table 1, Entry F). Enolization, condensation, oxidation and product isolation were performed according to the previously described method A. To a cooled (-78°C) solution of the boron enolate of 8 in 40 ml of anhydrous dichloromethane (prepared from 2.33 g (10 mmol) of oxazolidinone 8, 2.7 ml (11 mmol) of di-~-butylboryl triflate, and 2.1 ml (12 mmol) of diisopropylethylamine) was added 1.17 ml (11 mmol) of freshly distilled pentanal. at 0°C for 1 h. The reaction was stirred at -78°C for 0.5 hand Product isolation afforded 3.02 g (95~) of compound 16 as a white solid, pure by TLC and proton NMR. Diastereomer analysis (SE-54, 200°C, tr E1 = 12.71 min, tr E2 = 14.04 min, tr T = 14.87 min) of an unpurified, silylated sample (TMSNEt 2 , DMAP, CH 2c1 2 , 12 h) gave a ratio of E1 :E2 :T = 99.9:~0.01:0.1. Recrystal- lization from ether:pet. ether afforded an analytical sample of 16: mp 98-100°C; IR (CH 2C1 2) 3700-3400 (br), 2970, 2950, 1785, 1685, 1458, 1347, 1200, 1123 cm- 1 ; 1H NMR (90 MHz, CDC1 3) o (TMS) 7.5-7.2 I I I (m, 5H, aromatic H), 5.68 (d, J = 7, 1H, -NCHC~O), 4.79 (qn, J = 7, 1 I I I I I 1H, -NCHCHO), 4.1-3.8 (br, 1H, HOCH-), 3.89 (q of d, Jd = 3.5, J q = I I 7, 1H, O=CC~-), 3.05-2.85 (br s, 1H, ~0-), 1.7-1.1 (m, 6H, I 3 2 2 2 CH c~ c~ c~ ), II 1.25 (d, J = 7, 3H, O=CCHC~3 ), 1.1-0.85 (m, 3H, -58- c~3 cH 2 ), 0.90 (d, J = 7, 3H, -NCHC~3 ); [a]~5 = +12.2° (CH 2c1 2 , £ 3.5). Anal. calcd. for c18 H25 No 4 : C, 67.69; H, 7.89; N, 4.39. Found: C, 67.54; H, 7.88; N, 4.31. {3{2R,3R),4R,5S)-3-{3-(2-Furanyl)-3-hydroxy-2~thyl-1-oxo­ propyl)-4-methyl-5-phenyl-2-oxazolidinone (17). {Table 1, Entry G). Enolization, condensation, oxidation, and product isolation were performed according to the previously described method A. To a cooled (-78°C) solution of the boron enolate of 8 in 3 ml of anhydrous dichloromethane (prepared from 700 mg (3 mmol) of oxazolidinone 8, 0.81 ml (3.3 mmol) of di-n-butylboryl triflate, and 0.50 ml (3.6 mmol) of triethylamine) was added 0.27 ml (3.3 mmol) of freshly distilled furaldehyde. 0.5 h and at 0°C for 0.5 h. The mixture was stirred at -78°C for Product isolation afforded a colorless Gas chromatography analysis (SE-54, 200°C, 15 PSI, tr = 11.07 oil. min) of an unpurified, silylated sample (TMSNEt 2, DMAP, CH 2c1 2 , 12 h) indicated ~99.3 diastereomeric purity. Flash chromatography (40 mm, 130 g silica, 42% ethyl acetate:hexane) afforded 901.3 mg (91%) of the title compound as a white solid: mp 82-83°C; IR (CHC1 3) 3650-3300 (br), 3630, 1782, 1690, 1440, 1352, 1180, 945 cm- 1 ; 1H NMR (90 MHz, CDC1 3 ) o (TMS) 7.6-7.2 (m, 6H, C~-, furfuryl c -~), 6.4 (s, 2H, furfuryl c -~ and c -H), 5.65 (d, J = 7, lH, 5 3 4 I I I I -NCHC~O), I I I 5.11 {t, J = 5.5, 1H, HOCH-), 4.75 (qn, J = 7, 1H, -NC~-), -59- I I 4.25 (q of d, Jd = 5.5 J q = 7, 1H, O=CCH-), 3.1 (d, J = 5.5, 1H, ~0-), I I I I 1.35 (d, J = 7, 3H, O=CCHC~3 ), 0.90 (d, J = 7, 3H, -NCHCH 3); [a]~5 = +16.1° (CHC1 3 , £ 2.3). Anal. calcd. for c18H19 N0 5 : C, 65.64; H, 5.81. Found: C, 65.49; H, 5.88. (3(2S,3R),4S)-3-(3-Hydroxy-2~tho~-l-oxo-3-phenylpropyl)-4- (1-methylethyl)-2-oxazolidinone (25). (Table 3, Entry C). Enolization, condensation, oxidation and product isolation were performed according to the previously described method B. To a cooled (-78°C) solution of the boron enolate of 21 in 4 ml of anhydrous dichloromethane (prepared from 201 mg (1 mmol) of compound 21, 0.27 ml (1.1 mmol) of di-~-butylboryl triflate, and 0.21 ml (1.2 mmol)of diisopropylethylamine) was added 0.10 ml (1.0 mmol) of benzaldehyde. Product isolation afforded 245 mg (80%) of compound 25 as a white solid, pure by TLC analysis and proton NMR. Diastereomer analysis (SE-54, 200°C, 15 PSI, tr E1 = 4.58 min, tr E2 = 4.80 min; tr T1 = 5.53 min; tr T2 = 5.94 min) of an unpurified, silylated sample (TMSNEt 2 , DMAP, CH 2c1 2 , 12 h) afforded a ratio of E1 :E2 :T1 :T2 = 99.2:0.4:0.14:0.26. Recrystallization {ether:pet. ether) afforded an analytical sample of 25: mp 105-106°C; IR {CH 2cl 2 ) 3580, 3060, 2980, 1782, 1710, 1385, 1202, 1155, 891 cm- 1 ; 1H NMR {90 MHz, CDC1 3 ) o (TMS) 7.5-7.25 (m, 5H, aromatic H), 5.35 {d, J = 5.5, 1H, CH 3 oc~-), 4.87 {d, J = 5.5, 1H, I -60- I I -C~OH), 4.2-4.0 (m, 2H), 3.81 (q, J = 8.5, 1H), 3.38 (s, 3H, C~3 0), I 3.0-2.5 (br, 1H, ~0-), 2.6-2.2 (m, 1H, (CH 3 ) 2 C~), 0.88 (d, J = 7, I I 25 3H, C~3 CHCH 3 ), 0.83 (d, J = 7, 3H, CH 3 CHC~3 ); [a] 0 = +92.4° (CH 2c1 2 , £ 1.6). Anal. calcd. for c16 H21 N0 5 : C, 62.53; H, 6.89; N, 4.56. Found: C, 62.54; H, 6.82; N, 4.48. (3(R(R)),4R)-8-(Hydro~phenylmethyl)-4-(l~thylethyl)-a,2- dioxo-3-oxazolidinebutanoic acid, ethyl ester {29). Enolization, condensation, oxidation and product isolation were performed according to the previously defined method B. To a cooled (-78°C) solution of the boron enolate of compound 28 in 4 ml of anhydrous dichloromethane (prepared from 257.3 mg (1.0 mmol) of oxazolidinone 28, 0.27 ml (1.1 mmol) of di-~-butylboryl triflate, and 0.21 ml (1.2 mmol) of diisopropylethylamine), was added 1.0 ml (1.0 mmol) of benzaldehyde. After stirring at -78°C for 1.5 h, the reaction was quenched, oxidized, and the product isolated to give 311.4 mg of a thick oil. Flash chromatography (25 mm, 27 g silica, 30% ethyl acetate:hexane) afforded 242.3 mg (67%) of the title compound as a white solid. Recrystallization (ether:pet. ether) afforded an analytical sample: Rf 0.31 (30% ethyl acetate:hexane); mp 101-102°C; IR (CH 2Cl 2) 3600, 3060, 2990, 1781, 1730, 1695, 1387, 1205, 1055 cm- 1• 1H NMR (90 MHz, CDC1 3) o (TMS) 7.5-7.2 (m, 5H, I aromatic), 4.99 (t, J = 5.5, 1H, HOC~-), 4.58 (d oft, Jt = 4.5, -61- I I I I I I Jd = 10.5, 1H, -NC{=O)C~-), 4.45-3.85 (m, 5H, CH 3 c~2 o, -NC~C~2 0), I 2.97 (d of d, J = 10.5, J = 17.5, 1H, -OC{=O)C~{H)), 2.70 {d, J = I 3.5, 1H, ~0), 2.50 (d of d, J = 4, J = 17.5, 1H, -OC(=O)CH{~)), I I 2.5-2.2 (m, 1H, {CH 3 ) 2 C~), 1.17 (t, J = 7, 3H, C~3 cH 2 0), 0.89 {d, I 25 J = 7, 6H, {C~3 ) 2 CH); [a] 0 = +96.0° {CH 2c1 2 , £ 3.6). Anal. calcd. for c19 H25 N0 5 : C, 62.80; H, 6.93; N: 3.85. Found: C, 62.96; H, 6.90; N, 3.81. General Procedure for the Hydrolysis of Chiral Imide Aldol Adducts to a-Hydroxy Acids. The unpu1ified aldol adduct was dissolved in methanol (ca. 6 ml per mmol). Water was added until the aldol adduct started to precipitate. The solution was cooled to 0°C and 2 N aqueous potassium hydroxide {2 ml per mmol) was added dropwise. The reaction mixture was stirred at 0°C for 45 min. Concentration in vacuo {30°C, ~· 15 min) hydrolyzed any remaining methyl ester formed during the reaction. The remaining aqueous phase was extracted with dichloromethane {3x), and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to the corresponding, crystalline oxazolidinone 9 or 10. The alkaline aqueous phase was acidified to pH 1 with 6 N aqueous hydrochloric acid, and saturated with sodium chloride. The aqueous solution was extracted with ether (2x), and the combined ethereal layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to the corresponding acids. -62- General Procedure for the Esterification of Acids. A solution of diazomethane in ether was prepared by the slow addition of N-nitrosomethyl urea to a cooled (0°C), well stirred mixture of 50% aqueous potassium hydroxide and ether. 30 After the urea dissolved, the reaction mixture was gently warmed and the ethereal solution distilled in glass apparatus with Clear Seal glass joints. An aliquot of the collected ethereal diazomethane solution was added to a stirred solution containing the acid in dichloromethane, until a yellow coloration remained. Argon was bubbled through the solution until the yellow color disappeared. The solvent was removed in vacuo to afford the methyl esters in quantitative yields. Molecular distillation (KUgelrohr) afforded analytical samples. -63- References and Notes (1) Evans, D. A.; Bartroli, J.; Shih, T. J. Am. Chern. Soc. 1981, 103, 2127. (2) For an excellent review see (a) Evans, D. A.; Nelson, J. V.; Taber, T. R. Topics in Stereochem. 1982, ~' 1. (3) (a) Nakata, T.; Schmid, G.; Vranesic, B.; Okigawa, M.; Smith-Palmer, T.; Kishi, Y. J. Am. Chern. Soc. 1978, 100, 2933. (b) Ireland, R. E.; Thaisrivongs, S.; Wilcox, C. S. Ibid. 1980, 102, 1155. (4) Evans, D. A.; McGee, L. R. J. Am. Chern. Soc. 1981, 103, 2876. (5) Throughout this report we will use the erythro:threo nomenclature according to eq. 3, which follows the convention proposed by Heathcock. 8 (6) Zimmerman, H. E.; Traxler, M. D. J. Am. Chern. Soc. 1957, 79, 1920. (7) (a) Dubois, J. E.; Fort, J. F. Tetrahedron 1972, 28, 1653, 1665. (b) Dubois, J. E.; Fellman, P. C. R. Acad. Sci. 1972, 274, 1307. (c) Dubois, J. E.; Fellman, P. Tetrahedron Lett. 1975, 1225. (d) Fellman, P.; Dubois, J. E. Tetrahedron, 1978, 34, 1349. (8) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M. C.; Sohn, J. E., Lampe, J. J. Org. Chern. 1980, 45, 1066, and citations to earlier work. -64- (9) (a) Evans, D. A.; Vogel, E.; Nelson, J. V. J. Am. Chern. Soc. 1979, 101, 6120. (b) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chern. Soc. 1981, 103, 3099. (10) (a) Masamune, S.; Mori, S.; Van Horn, D.; Brooks, D. W. Tetrahedron Lett. 1979, 1665. Ibid. 1979, 2225. 2229. (b) Hirama, M.; Masamune, S. (c) Van Horn, D.; Masamune, S. Ibid. 1979, (d) Hirama, M.; Garvey, D. S.; Lu, L.; Masamune, S. Ibid. 1979, 3937. {11) Solladie, G.; Mioskowski, C. J. Chern. Soc. Chern. Commun. 1977, 162. (12) Cherpeck, R. E. Ph.D. Dissertation. California Institute of Technology, Pasadena, California, 1980. (13) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chern. Soc. 1982, 104, 1737. (14) A related enantioselective aldol condensation using boron enolates appeared after this work was submitted for . t•1on. 15 pu bl 1ca (15) Masamune, S.; Choy, W.; Kerdesky, F. J.; Imperiali, B. J. Am. Chern. Soc. 1981, 103, 1566. (16) Lane, C. F., U.S. Patent 3,935,280. Chern. Abstr. 1976, 84, 135101 P. {17) Mathre, D. J.; Evans, D. A. Unpublished results. {18) Inoue, T.; Mukaiyama, T. Bull. Chern. Soc. Jpn. 1980, ~, 174. -65- (19) Toporcer, L. H.; Dessy, R. E.; Green, S. I. E. J. Am. Chern. Soc. 1965, ~, 1236. (20) The GC peaks of the lithium aldol adducts were assigned in the following ways: (consider the valine series) a) E1 (see Table I) was assigned by comparison to the boron aldol major isomer; b) the threo isomers (note that we do not specify their absolute stereochemistry, except in entry A, Table 1) were differentiated from the other erythro isomer, E2 , by conversion of the unpurified lithium-aldol mixture into their methyl ester derivatives. A careful comparison of the (E 1 + E2):(T1 + T2) ratio obtained in the aldol and the E:T ratio observed for the methyl esters mixture allowed us then to assign the E2 peak. (21) Gaudemer, A. in Detennination of Configurations by Spectro11 metric Methods," Vol. I in "Stereochemistry, Fundamentals and Methods ... Kagan, H. B., Ed.; Georg Thieme, Stuttgart, 1977, pp. 69-71. (22) Ennis, M. D. Ph.D. Dissertation. California Institute of Technology, Pasadena, California, 1983. (23) Fredga, A. Arkiv. Kemi., Min. Geo. 1948, 268, N-11, 1. (24) Shih, T.; Evans, D. A. in ref. 1. (25) Full characterization of these compounds have been previously described in McGee, L. R. Ph.D. Dissertation. California Institute of Technology, Pasadena, California, 1981. -66- (26) We recorded the optical rotations on the methyl esters to avoid concentration dependencies with the acids. (27) Takacs, J. M. Ph.D. Dissertation. California Institute of Technology, Pasadena, California, 1981. (28) Woodbury, R. P.; Rathke, M. W. J. Org. Chern. 1978, 43, 888. (29) These values were calculated by using the commonly used equation ~Go = -RT ln K. (30) Arndt, F. Org. Synth., Coll. Vol. 2 1943, 165-167. -67- CHAPTER II The Total Synthesis of (+)-Prelog-Djerassi lactone1a. 1,3-Acyclic Induction in Hydroboration Processes 1b. -68- I. Introduction and Strategy In 1956, Prelog 2 and Djerassi 3 independently obtained compound 34 as a degradation product from the antibiotics narbomycin and methymycin respectively. One year later, 34 was also found to constitute part of the backbone of neomethymycin 4 and pycro- Its structure was established by Djerassi in 1958, 7 and the stereochemistry assigned by Rickards 8 in 1970. Compound 34, mycin.5'6 which soon became known as Prelog-Djerassi lactone, has since been a very popular target molecule among synthetic organic chemists, serving as a focal point for the development of a diversity of new stereoselective chemical operations. Indeed, by the end of 1982 there were 19 published total syntheses, including the one that is reported here. 1a, 9- 17 The following approaches have been undertaken: aldol condensation, 1a, 9 ring opening of cyclic precursors, 10 carbohydrate derivatization, 11 ene . 13 hydro bora t 1on, . 14 D1e . 1s- Al der 15 an d . 12 organomercura t 1on, reac t 1on, carbonyl additions. 16 Seven of the syntheses are enantioselective1a,9b,10c,11,16b and two are nonstereoselective. 17 Due to its stereochemical features, Prelog-Djerassi lactone was chosen as the target molecule for the first application of our imide chemistry, partially presented in Chapter I. analysis of 34 is shown in Scheme I. emphasized in this scheme: A retrosynthetic Three main disconnections are an alkylation reaction (A), an aldol condensation (B) and a hydroboration (C). The two former reactions -69- Scheme I 0 Me~ 0 3 2 Me ~ HO 0 HO~OH 0 5 COOH Me Me Me Me 35 34 8 ~~»Jl ~ Me T··T Me 37 36 y X Me 0 0 Me~ Jl N 0 H Ph Me 8 Me XN -70- would constitute the only carbon-carbon bond formations in the synthesis. By their execution, three of the four asymmetric centers present in 34 would be introduced. The fourth center would be established via hydroboration of an olefin like 36. Before the fact, we did not expect this last reaction to be stereoselective and we first planned to equilibrate the mixture of the diastereomers at a later stage. A. The c2-c3 Bond Construction We envisioned the stereoselective formation of chiral center at c3 by an alkylation reaction using chiral enolate 32 (Scheme II). The reaction of the lithium enolates derived from oxazolidinones 7 and 8 with a variety of electrophiles has been shown to give very good levels of diastereoselection. 18 The results are rationalized by an approach of the electrophile from the less hindered side of the highly organized (Z) enolates 38 and 32 to afford, respectively, adducts 39 and 40. Allylic and benzylic bromides give kinetic ratios in the range of 97 to 120:1 in high yields. Less sterically demanding electrophiles (CH 3 I) afford lower ratios (ca. 10:1) when reacted with the butyrate counterparts. However, when a >99:1 degree of diastereomer purity is desired, the small amounts of the minor diastereomer can generally be removed by chromatography. Like the aldol adducts, the alkylation products can be transformed into valuable synthons by the nucleophilic, nondestructive displacement of the chiral auxiliary. -71Scheme II 8 7 Li Me0 0 o"" 'o Me~}( N major 0 -{ ..... El<t> ...... ...... 38 ...... ,, ...... , , Xc El 39: xc=Xv / minor / , li o"' 'o Me~)l N / ...... ...... ...... ..... "0 major }-{ Me ...... / / 0 Me~ ~ XC El Ph 40: Xc=XN 32 B. The Ca-c 2 Bond Construction We envisioned the establishment of the chiral centers Ca and c2 by means of an aldol condensation using the chiral boron enolate derived from oxazolidinone 8. 19 A detailed study on this general reaction is presented in Chapter I of this thesis. Although a priori we did not know what the effect of the resident chirality in the aldehyde on the overall stereochemical outcome would be, we -72- anticipated it to be small based on literature precedence. 31 This additional stereochemical point was planned to be elucidated in this work. C. The Establis~nt of the C5 Chiral Center In our first plan, we envisioned the elaboration of center c5 in a nonstereoselective way. The desired 5 (R) stereochemistry would be accomplished by equilibration of a cyclic intermediate. Thus, hydroboration of olefin 36 (or 41) (Scheme III), followed by oxidation, would presumably afford an epimeric mixture of aldehydes 42. Upon deprotection of the hydroxylic functionality, the cyclic 2,6-hemiacetal would be spontaneously formed. Submitting this 6-membered ring lactol to equilibrating conditions would proceed through the enol form to give, ultimately, the most stable chair 43, in which the c5 methyl adopts an equatorial position (Scheme III). Using C-C and C-OH skew interaction values of 0.8 and 0.45 kcal/mol respectively 20 and assuming that, due to the anomeric effect, the c6-hydroxyl adopts the axial configuration, compound 43 was calculated to be 0.8 kcal/mol more stable than 44. At 25°C, this difference in energy represents an equilibrium ratio of roughly 4:1. The mixture would then be separated and the minor isomer resubmitted to equilibration. We were happy to discover, however, that the hydroboration itself proceeded with good diastereoselection when hindered boranes were used. This unexpected result gave birth to a series of -73ScheE III Mey Me ~R ~ 0 1'('-N)(o Me Me 2. (ox) Me )---\ Me Ph Me 42 36: R=H 41 : R=Si Me 3 1. -R 9 2. H HO Me Me Me 43 H H 44 43 calculated bG = 0.8 kcal/mol 1 Ca-H: 0.8 kcal/mol 1 Ca-0: 0.45 kcal/mol -74- experiments aimed at a better understanding of the control elements in this reaction, and culminated in the proposal of a transition state model. II. Results and Discussion 1. The Total Synthesis of (+}-Prelog-Djerassi Lactone The first step of the synthesis (Scheme IV) involved the construction of the c3 chiral center. We planned to establish the 3(5) stereochemistry by means of an alkylation using chiral imide 8, easily prepared from (1S,2R)-norephedrine. 21 Thus, addition of propionyl oxazolidinone 8 to a LDA solution (1.1 equiv, THF, -78°C, 30 min) resulted in the formation of lithium enolate 32. Reaction with methallyl iodide 23 , 24 (neat, 2 equiv, -50°C~-20°C, 3 h) afforded crystalline oxazolidinone 37, as a 97:3 mixture of c2-epimers (determined by GC analysis). Chromatography (MPLC) afforded 37 in 73% yield, with a diastereomeric purity of 500:1. For large scale operations, however, it was found most convenient to carry the mixture of diastereomers as obtained and to separate the minor diastereomeric contaminant by recrystallization of a more advanced intermediate. The reaction with methallyl bromide was found to give the same 97:3 ratio, but due to its lower reactivity, the reaction mixture needed to be warmed up resulting in some enolate decomposition. -75- Scheme IV 0 0 (lQ Me a Y'' Ph Me 8 37 (73%) b c YYCHO Me Me YJoH Me 46 (91%) 45 BuBO Me H,C~NAyPh )-o 47 0 36 (86%) Me (85%) -76- The preparation of aldehyde 46 was carried out by a two step sequence from oxazolidinone 37. Thus, 37 was reduced (LAH, 1 mol equiv, Et 20, 0°C, 5 min) to the corresponding alcohol 45 in 85% yield after distillation. The remaining crystalline oxazolidinone 10 (for structure see footnote 21) was purified by recrystallization and stored for further use. oxidation of alcohol 45. this transformation: Aldehyde 46 was then obtained by Two problems were anticipated regarding first, the chiral center could potentially racemize under the reaction conditions, and second, the product would probably have a relatively low boiling point, making its isolation rather difficult. The second point was solved by limiting our oxidation choice to the methods that involved the use of a low-boiling solvent, preferably ether or dichloromethane. zation, however, turned out to be a more tricky issue. Epimeri- This was monitored by GC analysis of the aldol adduct obtained upon condensation of the freshly prepared aldehyde and the boron enolate 47. For this purpose, an authentic mixture of epimers at c4 of aldol adduct 36 was prepared by condensation of 47 with the racemic aldehyde. With this test in hand, we found that celite supported Collin's oxidation (6 equiv of Cr0 3 .2py, celite, CH 2c1 2 , 25°C, 3 h) 25 proceeded with 2.5 to 1.5% epimerization, and in moderate yields (50-70%). Oxidation using chromic acid suspended on silica gel (Et 2o, RT, 15 m) 26 afforded ca. 30% yield of aldehyde 46, with 11% epimerization. We were gratified to find, however, that the -77- Parikh modification of the Moffat oxidation 27 (3 equiv of so 3 .py, 7 equiv of Et 3N, DMSO, 25°C, 1 h) gave aldehyde 46 not only in high yields (85-91%) but with negligible epimerization (0.3 to 0.1,). This method has since been applied with similar success to the preparation of a variety of a-branched optically pure aldehydes. For very sensitive aldehydes, however, a considerable degree of epimerization under the mentioned reaction conditions has still been observed. 28 For these exceptional cases, best results were obtained . by us1ng the Swern procedure. 28 29 ' With aldehyde 46 in hand, we were ready to form the second and last carbon-carbon bond. In doing so we simultaneously established the Ca and c2 stereochemistries of Prelog-Djerassi lactone. As mentioned in the introduction, by the time we planned this synthesis, we already had a full body of information concerning the aldol condensation of chiral boron enolates with simple aldehydes. 19 We had demonstrated that these reactions proceeded with very high levels of diastereoselection to afford erythro adducts. However, the mutal influence of the chirality of these enolates and that of an asymmetric aldehyde on the product ratio distribution, was a matter that remained to be tested. The results obtained in this area are reported below. Formation of the boron enol ate of 8 (1.1 equiv of · di-~-butyl­ boryl triflate, 1.2 equiv of triethylamine, CH 2c1 2 , -78°C, 1 h) and subsequent condensation with freshly prepared aldehyde 46 (neat, -78- 1 equiv, -78°C~0°C) afforded the crystalline aldol adduct 36 in 86% yield. An authentic isomeric mixture was obtained for analysis purposes by an analogous condensation of the corresponding lithium enolate 32. The stereochemical control in this aldol process was truly remarkable. Diastereomeric analysis of the unpurified, silylated (TMSNEt 2 , DMAP) reaction mixture revealed that the total erythro:threo diastereoselection was 400:1, while the asymmetric induction within the erythro manifold was 660:1 (Scheme V). High levels of diastereoselection have been also observed in a similar reaction using boron enolates derived from (+)-mandelic acid (eq. 1). 9b 0-9BBN 0 Jl /".... .....-CHO MeO' 1 1 Me + 40:1 diastereoselection Me We also examined the aldol condensation of aldehyde 46 with the boron and lithium enolates of imide 7 (Scheme VI). Treatment of the boron enolate of 7 with 1.3 equiv of 46 gave a 73% yield of aldol adduct 48 after chromatography. Diastereomer analysis of an unpurified, silylated sample showed that the overall erythro:threo -79- Scheme V [ e M=L i r ) r i 1) enolization 2) 46 E 1' 8 Metal 36 E' E' 99.6 0.15 21.0 1.8 1 2 T' 1 T' 2 0.25 2.5 74.7 -80- Scheme VI M=L i ):-- i ~ c4-epimer 0 0 ~)(0 ~ HO 1) enolization 0 ~XV 2) 46 Me Me • E2 • T1 • T2 Me E1 7 48 Metal 98.76 7.6 0.67 0.25 81.6 0.32 10.8 -81- Scheme VII -. I i l- M=Li I HO 0 +~xo 1) enolizat i on 2) 46 Me Me Metal 35.5 63.4 1.1 27.4 57.0 12.6 1.2 Me -82- diastereoselection was 99:1, while the enantioselection within the erythro adducts was 395:1. Finally, a third aldol condensation was investigated, this time with the achiral oxazolidinone 6 (Scheme VII). It had previously been shown that the boron enolate of 6 reacts with aldehydes affording erythro adducts with excellent diastereoselection. 30 Therefore, its condensation with 46 was expected to give two erythro products (Cram and anti-Cram) in a ratio reflecting the aldehyde diastereoface selection. Indeed, upon condensation and diastereomer analysis of the silylated, unpurified reaction mixture, two products were obtained in a 64:36 ratio. The mixture was transesterificated (PhCH 20Li, THF) to a 63:37 mixture of benzyl esters and compared with the benzyl ester derived from 36. GC analysis indicated that the major isomer was the one corresponding to the anti-Cram addition. Although the Cram adducts usually predominate in the aldol condensation between achiral enolates and chiral aldehydes, reversed selectivity has also been noticed in some special cases. 31 In these systems, secondary effects must be taking place and the product ratio is somewhat unpredictable. In summary, these experiments suggest that in the aldol condensation of chiral boron imide enolates with chiral aldehyde 46, the diastereoface selection is dictated~ by the enolate chirality. Subsequent examples using other chiral aldehydes have extended the generality of this result. Similar conclusions had already been obtained for chiral zirconium amide enolates in our laboratories. 32 -83- Scheme VIII RO 0 Me Me HO~XN a ,b Me 36: R=H 50: R=TMS 41 : R=TMS 52: R=H 0 Me~'? ~ d 0 Y0xN C0 2 H 3 ; Me Me 51: 0 Me~ 5 + Me Me 34 53 The final asymmetric center was created via a hydroboration process (Scheme VIII). Based on an example showing moderate selectivity in the hydroboration of the josamycin synthon 49 with disiamylborane (eq 2), 33 we were not optimistic of obtaining good levels of selection in the hydroboration of olefin 41. oxo 0 - ~ Sia 2 BH OMe 0°C 2 • 5 : 1 mi xt ure OMe 49 (ref. 33) (2) R=TMS -84- We were surprised to discover, however, that this was not the case. Protection of the aldol adduct 36 {TMSNEt 2 , DMAP, CH 2c1 2 , 100% yield) followed by treatment with 2 molar equivalents of thexylborane {THF, 0°C, 5 h) and oxidative workup {H 2o2 , MeOH, H20, pH 8) afforded, after chromatography, a 79% yield of alcohol 50 and 11% yield of its c6 epimer, 51. Gas chromatography analysis of the unpurified, silylated mixture revealed a 85:15 ratio of epimers. The absolute configuration of alcohols 50 and 51 at c6 was assigned by their individual conversion into Prelog-Djerassi lactone and its c5-epimer, respectively. 34 A similar 1,3-induction was simultaneously found in the elaboration of the c1-c 10 tylosin fragment1b (vide infra). This observation led to a series of experiments which will be presented in the second part of this chapter. The final steps of the synthesis proceeded as follows. Cleavage of the trimethylsilyl ether 50 with oxalic acid (1.1 equiv, MeOH, 25°C, 30 min) proceeded cleanly to afford a 94% yield of unpurified diol 52. The next step required the selective oxidation of the primary alcohol to form the corresponding o -lactone. This was best achieved by means of the Sharpless' ruthenium-catalyzed oxidation 35 (4.2 equiv of N-methylmorpholine N-oxide, 1.6% of RuC1 2{PPh 3) 3 , acetone, 25°C, 4 h) which afforded crystalline lactone 53 in 78% yield after chromatography. Gas chromatography analysis of unpurified lactone 53 confirmed that it was 99% pure, contami- -85- Finally, base hydrolysis (aq. 1~ LiOH, MeOH, 0°C, 1 h) afforded a 62% yield of oxazolidinone 1021 and nated with 1% of its c5-epimer. 70% of (+)-Prelog-Djerassi lactone, 34. Gas chromatography analysis of the methyl ester (CH 2N2 , CH 2Cl 2) of the unpurified reaction mixture revealed that ca. 2% epimerization at c5 had occurred. 34 Recrystallization from hot ~-pentane:ether afforded 34 as white, amorphous crystals melting at 122-123°C, with a specific rotation of 25 = +41.3° (CHC1 , ~ 2.1). GC analysis of its unpurified methyl [a] 3 ester (54) (CH 2N2 , CH 2cl 2) indicated ~99.9% chemical and diastereomeric purity. A spectral (IR, 90 MHz 1H NMR, 13 c NMR) comparison of (+)-Prelog-Djerassi lactone obtained via the present route and that derived from the Ireland carbohydrate-based total synthesis 11 a established the identity of the two samples. -86- 2. Acyclic 1,3-Asymmetric Induction in the Hydroboration Process 1b Based on our preliminary observation concerning the 1,3-induction in the hydroboration process, we decided to initiate a detailed study of the general reaction depicted in equation 3. + (o) (3) (RL sterically larger than RM) Although by the time this project was started several cases of 1,2-induction had been reported for similar reactions, 36 very little information concerning the corresponding 1,3-induction was available. 33 In the course of trying to improve the observed 1,3-induction levels, we initially focused our attention on the structure of the borane. For this purpose, several mono and dialkylboranes were prepared. In an attempt to enhance the observed hydroboration diastereoselection by a cooperative effect of both, the olefin resident chirality and the borane ligand chirality, we also prepared the corresponding (a)-pinene-derived chiral reagents. 37 The results obtained upon reaction of olefin 41 with the different boranes are summarized in Scheme IX. In a typical experiment, the borane (2-4 -87- Scheme IX 50 41 51 Entry Solvent Borane Ratio (50:51) A THF BH 3 78:22 B THF (Sia) 2BH 85:15 c CH 2c1 2 (Sia) 2BH 85:15 D THF Thexyl-BH 2 85:15 E CH 2c1 2 (cyclohexyl) 2BH 81:19 F THF (+)-IPC-BH 2 79:21 G THF (-)-IPC-BH 2 83:17 H Et 20 (+)-IPC 2BH 79:21 I Et 2o (-)-IPC 2BH 82:1.8 -88- molar equivalents) was added to a solution of olefin 41 in the indicated solvent at 0°C. After 4-6 h, the reaction mixture was oxidized (H 2o2 , MeOH, pH 7-8, 0°C, 1 h) and the unpurified mixture silylated (TMSNEt 2 , DMAP) and analyzed by GC. Very little influence of the borane structure on the product diastereomeric ratio was observed. Even the use of the chiral mono and dialkylboranes derived from (+) and (-)-a-pinene, effected minimal changes on the reaction diastereoselection. 38 We therefore concluded that the diastereoselection noted in this process is derived almost exclusively from the structure of the olefin. Our next goal was then, to establish the influence of the structural features of the olefin. A general survey of a number of olefinic substrates (Schemes X and XI) with regard to diastereoselective hydroboration under the previously defined conditions (0°C) reveals several important points. A comparison of olefins 41 and 59 shows that preferential si-facial olefin hydroboration appears to be directed primarily by the proximal center of asymmetry. This result is corroborated by the hydroboration of olefin 61, which bears only one chiral center. The absolute configurations of the alcohols obtained in these cases were determined by spectral analysis of a meso derivative prepared as shown in Scheme XII. discussed later. Details for these transformations will be -89- Scheme X RO YTVN}(o Me Me Me HO 0 0 Sia 2 BH RO 0 lyyYxN Me Me )---\ Me Ph Me R:S ratio 36: R=H 52: R=H 87:13 41: R=TMS 50: R=TMS · 85:15 55: R=TES 56: R=TES 85:15 HO TMSO 0 TMSO 0 ~OBn Me Me Sia 2 BH ~OBn Me Me Me 58 57 TMSO 0 Me 87:13 0 ~NAO Me Me Me~ Me Me 60 59 Me 77:23 HO ~OTES Me 61 Me ~OTES Me Me 62 82:18 -90Sche11e XI 0 TMSO HO 0 NA_O XN /--{ Me OBn Me Me Ph OBn 63 64 0 Me ~Me OBn 75:15 (ref. 40) HO 0 NA_O ThxBH 2 XN )--\ Me Ph OBn 65 66 TES~TBS? 0 Me OBn HO 0 NAO 60:40 (ref. 40) TESQTBSO ThxBH 2 XN Me SMe }---\. Me Ph SMe OBn 67 68 TES~TBS? ~ 0 HO OBn 91:9 TESOTBSO 0 ThxBH 2 OBn Me Me OBn 69 TMSQ Thx BH 2 70 71 OBn 82:18 50:50 -91- The sense of induction observed for the substrates illustrated in Scheme X was maintained in the related olefins 63, 65, 67 and 69 (Scheme XI), where the methyl substituent at c4 had been substituted by a slightly larger ligand. Interestingly, conformational changes imposed by the presence of a ring seemed to play an important role in the degree of induction (cf 65 ~ 67). Finally, the lack of induction observed for olefin 37 suggested that there is a definite "size requirement" for the ligands on the asymmetric center. In 37, the trigonal substituent is not large enough to create a diastereofacial bias during hydroboration. A similar non-stereoselective process has been reported for the first step of the hydroboration of diene 72 (eq. 4). 14 b ~Me Me Me ~OTBS ~Me ~e ~e 'lOTBS 72 OH . OH ~OTBS Me Me 1:1 mixture Me -92- The absolute configuration of the major isomer obtained upon hydroboration of 59 was determined by the NMR spectrum of a derived product (Scheme XII). Thus, the unseparable alcoholic mixture 60 and 73 was converted into the corresponding aldehydic mixture and condensed with the boron enolate of imide 8 following the usual procedure to yield aldol adduct 74 as an unseparable 3:1 mixture (indicated by GC analysis of an unpurified, silylated sample). Silylation (TMSNEt 2 , DMAP, CH 2Cl 2) afforded a separable mixture of isomers 75 and 76. Finally, each isomer was transesterified (3 equiv of PHCH 20Li, THF, 0°C) independently and purified by chromatography. Diester 77, derived from 60, showed proton and 13 c NMR spectra consistent with a meso structure. Diester 78, derived from alcohol 73, showed, as expected, more complicated spectra, consistent with the structure lacking a mirror plane. Similarly, alcohol 62, the major isomer from the hydroboration of olefin 61, was converted into methyl ester 80 and treated with methyl magnesium bromide to afford the corresponding tertiary alcohol, which was treated with triethylsilyltriflate to afford 81. The 500 MHz 1H NMR spectrum of 81 revealed HA and Hx to be diastereotopic stereochemistry. (6o = 1.2 ppm), thus demonstrating the assigned If the stereochemistry of this final adduct had been (S,S), protons HA and Hx would have been magnetically equivalent. -93- Scheme XII 0 RO a,b Me 74: 60:6R 73:65 0 OTMSTMSO 0 BnO 0 + OBn Me Me Me Me Me 75 : R=H 6R; R=TMS 76 : 6S; R=TMS OTMS TMSO BnO OBn Me Me Me 77 major: Me Me 78 meso minor: dl (a) S0 .py, Et N, DMSO; (b) 47; (c) TMSNEt , DMAP; (d) Separate; 3 3 2 (e) BnOL i , THF. OH 0 MeO~OTES a,b Y00TES Me 62: Me Me Me 80 2R 79: 25 c,d HA Hx TESO X(;>< Me OTES Me 81 (a) Mel, KOH, DMSO; (b) Nai0 , RuC1 .H 0; (c) MeMgBr; (d) TESOTf, Et 3N. 3 2 4 -94- With these experimental data in hand, our next goal was to elaborate a working model capable of accommodating the observed results and, most importantly, able to predict the sense and degree of induction for other related hydroborations. According to Houk•s recent ab initio calculations on olefin addition reactions 41 the transition state structure of minimal energy corresponding to the reaction BH 3 + H2C=CHCH 3 has the conformation depicted in Fig. 1. This geometry has maximal staggering between the allylic bonds and the partially formed bonds. The rotational energy barrier for the methyl substituent was calculated to be 3 kcal/mol •41 b Fig. 1. Optimized (3-21G) Transition Structu4~bfor the Hydroboration of Propene with Borane * H H \iB-H ~H~H H~H H H -95- This perpendicular model proposed by Houk is comparable to that first suggested by Felkin 42 and then calculated by Anh 43 on the hydride addition to carbonyls. Houk also calculated the differences in energy of the corresponding propene transition states in which each allylic hydrogen, in turn, had been replaced by a standard methyl. 41 b The reported values are shown in Fig. 2. Fig. 2. ST0-3G Relative Energies of Model Transition Structures for Attack of Borane to 1-Butene. H H H \: B # HMe H I H H H outside Gout.-Ganti = 0.56 kcal/mol H H H )tJvH H~H Me anti \: B-H ~M~H Hr'P"H H H inside Gins.-Ganti = 5.41 kcal/mol -96- Whereas there is only a relatively small energy difference between the "outside" and the "anti" transition states, the "inside" structure is clearly disfavored, due to the non-bonding interactions of the methyl with the approaching borane and the partial double bond. Careful ab initio calculations carried out by Morokuma 44 have shown that in the transition state corresponding to the c2H4 + BH 3 reaction, the carbon to which the borane hydrogen is delivered has suffered very little pyramidalization. The reported optimized geometry is depicted in Fig. 3. Fig. 3. Optimized Geometry (4-31G SCF) for the Transition State C~4responding to the Reaction of Ethylene with Borane. H / H '/ H--~ Finally, simple MM2 calculations performed on the ground state of compound 82 (Scheme XIII) indicated that conformer B (R=H) is 1.05 kcal/mol more stable than conformer A (R=H). 45 We believe that -97- Scheme XIII Me ~2~4ls R' ~lrJ'J' "Me Me H R;c-y CH Me 82: R=H 83: R=Me H,, 3 CH 3 .,..~ ' H C3H7(i} A 8 8 this energy difference arises from the nonbonding CH 3~cH 3 interaction present in conformer A, but absent in B. The geometries were optimized for all substituents with the exception of the c4-c 5 bond (i.e., the isopropyl substituent). Based on this result, and on the theoretical background presented above, we can consider four possible transition states that would account for the observed induction: two of them would -98- i ) and two other to the be 1ong to the Houk 's "anti" type ( T1' and T * "outside" type (T 3 and r 4*)(Scheme XIV). Because of their anticipated higher energy, we disregarded the two corresponding "inside" transition structures (not illustrated). If we make the assumption that the low degree of pyramidalization calculated by Morokuma for the hydroboration transition state of ethylene applies to our system, we can draw two conclusions: first, the isopropyl ... methyl interaction in the "outside" structures will be more important than in the "anti" structures, thereby increasing their relative energy. Second, this interaction will be of comparable magnitude in both the ground and the transition states. Thus, the obtained 1.05 kcal/mol energy difference for the two ground state conformers A and 8 (Scheme XIII) should be very similar to that of the transition states T1* and r2*. Interestingly, a difference in energy of 1.05 kcal/mol corresponds, at 0°C, to an equilibrium mixture of 87:13, which is in very good agreement with the observed product distribution. In summary, we propose a transition state for this reaction in which the borane reagent bears an anti relationship with the allylic substituent, in full accord with the theoretical studies of Houk. The diastereofacial bias would then be created when the largest c4 substituent (RL) adopts the anti-confonmation. In this orienta- tion, we propose that the destabilizing feature which disfavors -99- Scheme XIV ,, * HH \~ B--H H--8 H3C CH 3 H... H 'H H CH~ R R T ("anti") 2 Tl ("anti") ! l H2B ~R H2B~R 1 Me Me * HH Me Me major 11inor • 1 I I I I I I I I I I * CH 3 R * H R c~,~ HH H r 3 ("outside") ... 'H H H T4 ("outside") -100- * transition state r 1 is the c 2 -methyl~c 4 -methyl nonbonding interaction. Based on Morokuma's calculations of the hydroboration transition geometries, we propose that this interaction is very close in magnitude to that of the ground state. Similar arguments might also apply to other olefin electrophilic additions. For example, when olefin 36 was treated with 1.5 equiv of N-iodosuccinimide (CHC1 3 , 0°C, 30 min) , an 83:17 mixture of tetrahydrofuranes was obtained (eq. 5) (the absolute configuration of the new center was not proved). ___N_IS____ ooc ~Me,~~ 0 WxN Me (s) Me 83:17 In more recent work, a related 1,3-induction has been observed upon epoxidation of a related olefin using MCPBA (eq. 6). 22 This result agrees with the related MM2 calculations performed on olefin 83 (Scheme XIII), which predicted a ~G = 1.1 kcal/mol for the ground state conformers. -101- Me HO 0 Et~xv Et Me Me 1) MCPBA -20°C (s) 2) AcOH 36 (6S,~):(6R,.zl) = 77:23 III• (ref. 22) Sl.lll1la ry The total synthesis of (+)-Prelog-Djerassi lactone has been described. The stereocenters Ca, c2 and c3 are introduced in an absolute fashion by means of an alkylation and an aldol reaction using chiral oxazolidinone 8. The remaining center, c5 , is created via a hydroboration reaction. The synthesis consists of 9 steps from 8, and proceeds with an overall yield of 13%. A study on the factors that regulate the 1,3-induction observed in the mentioned hydroboration process has been also undertaken. The sense and degree of induction is dictated by the size requirements of the substituents at the homoallylic position. -102- Experimental Section General. Melting points were determined with a BUchi SMP-20 melting point apparatus and are uncorrected. Infrared spectra were recorded on a Beckman 4210 spectrophotometer. 90 MHz 1H NMR spectra were recorded on a Varian Associates EM-390 spectrometer and are reported in ppm on the o scale, from the indicated reference. Data are presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, m =multiplet, br =broad), coupling constant (in Hz), integration and interpretation. 500 MHz 1H NMR spectra were recorded on a Bruker WM-500 spectrometer at the Southern California Regional NMR facility. 13 c NMR spectra were recorded on a JEOL FX-90Q (22.5 MHz) spectrometer and are reported in ppm on the o scale from the indicated reference. Combustion analyses were performed by Spang Microanalytical Laboratory (Eagle Harbor, Michigan), Galbraith Laboratories, Inc. (Knoxville, Tennessee), or Mr. Lawrence Henling (California Institute of Technology). Optical rotations were recorded on a Jasco DIP-181 digital polarimeter at the sodium D line (589 nm) and are reported as follows: [a] 25 , solvent, and 0 concentration (£ = g/100 ml). Analytical gas-liquid chromatography (GC) was carried out on a Hewlett Packard 5880 A level 3 gas chromatograph equipped with a split mode capillary injection system and a flame ionization detector, using a 25 m x 0.2 mm flexible fused silica capillary -103- column wall-coated with Carbowax 20M or Methyl Silicone (SP-2100), or a 30m x 0.32 mm fused silica capillary wall-coated with SE-54. Unless otherwise noted, injector and detector temperatures were 250°C. Data are reported as follows: column type, oven tempera- ture, and retention time (tr). Liquid chromatography was performed using a forced flow (flash-chromatography) of the indicated solvent system on EM Reagents Silica Gel 60 (230-400 mesh). follows: Data are reported as column diameter, weight of silica and eluent composition. Medium pressure liquid chromatography (MPLC) was carried out using EM Reagents LoBar Silica Gel 60 prepacked columns (column size indicated) on a Chromatronix MPLC apparatus equipped with a Fluid Metering Inc. Model RP-SY Lab Pump. Analytical thin layer chromatography (TLC) was performed using EM Reagents 0.25 mm silica gel 60-F plates. When necessary, solvents and reagents were dried prior to use. Tetrahydrofuran, diethyl ether, benzene and toluene were distilled from sodium metal/benzophenone ketyl. Dichloromethane, diiso- propylethylamine, diisopropylamine, triethylamine and boron trifluoride etherate were distilled from calcium hydride. Dimethyl sulfoxide and dimethylformamide were distilled under reduced pressure from calcium hydride and stored over activated 4 A molecular sieves. -104- Unless otherwise specified, all non-aqueous reactions were conducted under a rigorously dried argon atmosphere, using oven-dried glassware. (3(S),4R,5S)-3-(2,4-Dimethyl-1-oxo-4-pentenyl)-4~thyl-5- phenyl-2-oxazolidinone (37). To a stirred, cooled (-78°C) solution of freshly distilled diisopropylamine (3.0 ml, 21.5 mmol, 1.075 equiv) in anhydrous tetrahydrofuran (45 mL) was added a 1.57 M solution of ~-butyl lithium in hexane (13.5 ml, 21.2 mmol, 1.06 equiv). After 30 min a solution containing imide 8 in 5 ml of anhydrous tetrahydrofuran was added dropwise, resulting in a pale yellow coloration. After stirring for 30 min, methallyl iodide 23 , 24 (4.5 ml, 40 mmol, 2 equiv, neat) was added dropwise and the mixture stirred subsequently 1 h at -78°C, 2 h at -40°C and 15 min at -20°C. The reaction was quenched by the quick addition of saturated aqueous ammonium chloride. The volatiles were removed in vacuo and the resulting aqueous solution was extracted with dichloromethane (3 x 75 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to 6.75 g of a yellowish oil. Gas chromatography analysis (SE-54, T = 175°C, 15 PSI, t r 37 = 8.24 min, t r 2-epi-37 = 8.94 min) afforded a ratio of 37:2-epi 37 = 96.3:3.7. Chromatography on silica gel (MPLC, Merck Lobar f column, 5% ethyl acetate:hexane) of 6.19 g of -105- the unpurified reaction mixture afforded 4.21 g (73%) of the title compound as a white solid. >99% pure: Diastereomer analysis showed 37 to be Rf 0.52 (50% ethyl acetate:hexane); mp 42-44°C; IR -1 ( CH c1 ) 3062, 2998, 1780, 1700, 1342, 1195, 1120, 890 em • 1 H NMR 2 2 (90 MHz, CDC1 3) o (TMS) 7.35 (m, 5H, aromatic H), 5.60 (d, J = 7.5, I I I I I I I I 1H, -NCHC~O), 4.90-4.55 (m, 3H, -NC~CHO, ~2 C=), 4.00 (sextuplet, J = f I l l I 7.0, 1H, O=CC~-), 2.52 (d of d, J = 7.0, J = 14.0, 1H, O=CCHC~(H)), I I I 1 2.04 (d of d, J = 7.8, J = 14, 1H, O=CCHCH(~)), 1.75 (s, 3H, =CC~3 ), I I 13 1.14 (d, J = 7.0, 3H, O=CCHC~3 ), 0.84 (d, J = 7.5, 3H, -NCHC~3 ); C I I NMR (CDC1 3 ) o (TMS) 176.70, 152.72, 142.91, 133.42, 128.67, 125.62, 112.30, 78.70, 54.85, 41.66, 35.61, 22.29, 16.77, 14.49; [a] 25 = 0 +33.7° (CH 2c1 2 , £ 5.9). Anal. calcd. for c 17 H21 N0 3 : C, 71.06; H, 7.37; N, 4.87. Found: C, 70.94; H, 7.26; N, 4.76. (S)-2~4-Di•ethyl-4-penten-1-ol (45). To a cooled (0°C), well stirred suspension of lithium aluminum hydride (2.23 g, 58.8 mmol, 1' molar equiv) in 120 ml of anhydrous diethyl ether was added dropwise a solution of imide 37 (16.91 g, 58.8 mmol) in dry ether (25 mL). The ice bath was removed and the mixture let warm to ambient temperature. After 30 min, the reaction was quenched by the subsequent cautious addition of water (2.2 mL), 15% aqueous sodium hydroxide (2.2 ml) and water (6.6 mL). The mixture was filtered and the filtrate washed with brine, dried over anhydrous magnesium -106- sulfate, and filtered. distillation. Diethyl ether was removed by fractional Molecular distillation of the remaining oil (KUgelrohr, 73°C, 18 mm) afforded 5.10 g of product as a colorless liquid. The non-distilled residue was dissolved in warm ether and the oxazolidinone 10 was partially precipitated by addition of petroleum ether. Filtration followed by concentration and distillation as above gave an additional 568 mg of product (85% combined yield): Rf 0.44 (50% ethyl acetate:hexane); IR (CHC1 3 ) 3645, 3600-3200, 3090, 2940, 1649, 1453, 1375, 1123, 893 cm- 1 ; 1H NMR (500 MHz, CDC1 3) o (TMS) 4.75 (s, 1H, ~(H)C=), 4.71 {s, 1H, H(~)C=), I I 3.50 (m, 1H, HOC~(H)), 3.42 (m, 1H, HOCH(~)), 2.64 (br s, I I I 1H, ~0), 2.20-2.07 (m, 1H, HOCH 2 C~-), 1.92-1.74 (m, 2H, HOCH 2 CHC~2 ), I 13 1.72 (s, 3H, ~3 CC=), 0.90 (d, J = 6.5, 3H, ~3 CCH-); C NMR (CDC1 3 ) o (TMS) 144.34, 111.71, 67.98, 42.24, 33.60, 22.22, 16.57; [a] 25 = 0 I -3.9° (CH 2c1 2 , £ 4.1). Anal. calcd. for c7H14 o: C, 73.63; H, 12.36. Found: C, 73.58; H, 12.10. (S)-2,4-Dimethyl-4-pentenal (46). To a stirred solution containing alcohol 45 (2.66 g, 23.3 mmol), and freshly distilled triethylamine (22.7 ml, 163 mmol, 7 equiv) in 50 ml of dry dimethyl sulfoxide at 25°C, was slowly added (5 min) a solution of sulfur trioxide pyridine complex (11.11 g, 69.6 mmol, 3 equiv, Aldrich, 95% pure) in 50 ml of dry dimethyl sulfoxide. After 15 min, a mixture -107- of diethyl ether (250 mL) and water {150 mL) was carefully added. The mixture was transferred to a separation funnel, and the aqueous layer discarded. The remaining cloudy, ethereal layer was washed with saturated aqueous cupric sulfate (2 x 50 mL), and water {1 x 25 mL), then dried over anhydrous magnesium sulfate, filtered and concentrated by the fractional distillation of ether. Molecular distillation of the remaining liquid (KUgelrohr, 90°C, 140 mm) afforded 2.21 g {87%) of aldehyde 46: Rf 0.66 {50% ethyl acetate: hexane); IR {CHC1 3) 2985, 2955, 1715, 1460, 1383, 1235 cm- 1 ; 1H NMR {90 MHz, CDC1 3) o {TMS) 9.64 (d, J = 2, 1H,-C~O), 4.80 (br s, 1H, (H)C~=), 4.71 (br s, 1H, (~)CH=), 2.65-1.80 (m, 3H, C~2 c~-), 1.72 I I (s, 3H, ~3 CC=), 1.05 (d, J = 6.5, 3H, ~3 CCH-). {3{2R,3S,4S),4R,5S)-3-{3-Hydroxy-2,4,6-trimethyl-1-oxo-6heptenyl)-4~thyl-5-phenyl-2-oxazolidinone {36). To a cooled (-78°C) solution of imide 8 (1.75 g, 7.5 mmol) in 20 ml of anhydrous dichloromethane was added di-~-butylboryl triflate (2.02 ml, 8.25 mmol, 1.1 equiv). The dry ice bath was removed temporarily until the frozen triflate melted. After recooling the solution to -78°C, freshly distilled triethylamine (1.25 ml, 9 mmol, 1.2 equiv) was added dropwise. After 1 h, aldehyde 46 (0.98 ml, 7.5 mmol, 1 equiv, neat) was added in one portion. The solution was stirred 30 min at -78°C, 1 h at 0°C, and then quenched by the addition of 7 ml of aqueous phosphate pH 7 buffer solution. Enough methanol was added -108- to make the solution homogeneous. Then, a solution containing 7 ml of 30% aqueous hydrogen peroxide in 7 ml of methanol was slowly added and the mixture stirred at 0°C for 1 h. Volatiles were removed in vacuo and the remaining aqueous slurry was extracted with diethyl ether (2 x 100 ml). The combined ethereal layers were washed with 5% aqueous sodium bicarbonate, and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to a white solid (2.55 g). Diastereomer analysis (SE-54, T = 225°C, 5 PSI, tr E2 = 7.02 min, tr E1 = 7.35 min, tr 4-epi-E 1 = 7.60 min, tr T1 = 8.53 min) of an unpurified, silylated sample (TMSNEt 2 , DMAP, CH 2c1 2 , 6 h) afforded a ratio E2 :E1 :4-epi-E1 :T1 :T2 of 0.15:99.12:0.50:i0.1:0.22. The presence of 0.5% of 4-epi-E 1 was due to the fact that in this particular run, aldehyde 46 was obtained from a 99.5:0.5 epimeric mixture of oxazolidinone 37. A portion of the product (2.383 g) was chromatographed on silica gel (MPLC, Merck Lobar f col., 20%~30% ethyl acetate:hexane) to afford 2.093 g (86%) of pure imide 36 as white crystals: Rf 0.41 (50% ethyl acetate:hexane); mp 110-111°C; IR (CH 2Cl 2) 3695, 3550, 3060, 2980, 1785, 1685, 1346, 1198, 892 cm- 1 ; 1H NMR (90 MHz, CDC1 3) o (TMS) I 7.5-7.15 (m, 5H, aromatic H), 5.65 (d, J = 7, 1H, -NCHC~O), I I I I I I I 1 4.95-4.60 (m, 3H, -NC~CHO, ~2 C=C-), 3.98 (q of d, Jd = 2.5, Jq = I I I 7.3, 1H, O=CC~-), 3.62 (d of d, J = 2.5, J = 8.0, 1H, HOC~-), 3.00 t I (br, lH, HQ-), 2.57 (br q, J = 9, 1H, H 2 C=CC~(H)), 2.10-1.5 (m, 2H, 2 I I I H C=CCH(~)C~-), I 1.73 (s, 3H, ~3 CC=), 1.24 (d, J = 7.3, 3H, CH 3CH-), -109- I I I I 0.90 (d, J = 7, 3H, =CCH 2 CHC~3 ), 0.87 (d, J = 7, 3H, -NCHC~3 ); 13 C NMR (CC1 4 ) o (CC1 4 ) 176.84, 151.56, 144.09, 133.56, 128.43, 125.44, 111.86, 78.39, 75.27 (carbinol), 54.34, 41.61, 39.72, 33.74, 22.24, 14.96, 14.18, 9.37; [a]~ 5 = +17.0° (CH 2c1 2 , £ 2.6). Anal. calcd. for c20 H27 No 4 : C, 69.54; H, 7.88; N, 4.05. Found: C, 69.36; H, 7.75; N, 3.93. (3(2R,3S,4S,6R),4R,5S)-3-(7-Hydroxy-2,4,6-trimethyl-1-oxo-3((trimethylsilyl)oxy)heptyl)-4~thyl-5-phenyl-2-oxazolidinone and the corresponding (3(2R,3S,4S,6S),4R,5S)-Isomer, (51). (50), To a stirred solution of aldol adduct 36 (345.5 mg, 1 mmol) in 5 ml of anhydrous dichloromethane was added N,N-diethyltrimethylsilylamine (0.94 ml, 5 mmol, 5 equiv) and N,N-dimethyl-4-aminopyridine (45 mg, 0.36 equiv). The reaction mixture was stirred for 30 min at 25°C. The volatiles were removed in vacuo and the remaining yellow oil was chromatographed on silica gel (30 mm, 40 g silica, 10% ethyl acetate:hexane) to afford 417 mg (100%) of silylated product 41 as a pale slightly yellow oil: Rf 0.50 (30% ethyl acetate:hexane). Anal. calcd. for c23 H35 N0 4Si: C, 66.15; H, 8.45. Found: C, 66.18; H, 8.46. In another flask was placed a 1 M solution of borane tetrahydrofuran complex {2 ml, 2 mmol, Aldrich), and cooled to -15°C. A solution containing 2,3-dimethyl-2-butene (0.23 ml, 2 mmol) in 1 ml of anhydrous tetrahydrofuran was added dropwise (10 min) and the clear mixture stirred at 0°C for 2 h. -110- An aliquot (1.6 ml, ca. 2 molar equiv) was added to a cooled (0°C) solution containing the silylated aldol adduct 41 (210 mg, 0.503 mmol) in anhydrous tetrahydrofuran (2 ml). After stirring at 0°C for 5 h, 5~ aqueous sodium bicarbonate (2 ml) was added, followed by methanol (10 ml) and 30~ aqueous hydrogen peroxide (2 ml). The white slurry was stirred at 0°C for 1 h. Extraction with diethyl ether (3 x 50 ml) and concentration in vacuo afforded an aqueous solution which was extracted (2 x 50 ml) with diethyl ether. The combined ethereal layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to an oil. Diastereomer analysis (SE-54, T = 225°C, 13 PSI, tr 50= 4.82 min, tr 51 = 5.17 min) of an unpurified, silylated sample (TMSNEt 2 , DMAP, CH 2c1 2 , 15 min) afforded a 50:51 ratio of 84:16. Flash chromatography (20 mm, 25 g, 18~ ethyl acetate:hexane) afforded 173.0 mg (79~) of the major isomer, 50, (99.8~ diastereomerically pure), and 24.8 mg (11~) of the minor isomer, 51, (99~ diastereomerically pure), both as colorless oils. 50: Rf 0.29 (30~ ethyl acetate:hexane); IR (CH 2Cl 2) 3615, 3060, 2965, 2922, 1779, 1690, 1454, 1345, 1198, 841 em -1 ; 1H NMR (500 MHz, CDC1 3) o (TMS) 7.50-7.25 (m, 5H, aromatic H), 5.68 (d, I I I I I I I I J = 6.8, 1H, -NCHC~O), 4.71 (qn, J = 6.8, 1H, -NC~CHO), 4.05 (qn, I I I I I J = 7.2, lH, O=CC~-), 3.90 (d of d, J = 3.5, J = 7.2, lH, O=CCHC~-), I I I 3.52-3.42 (m, 2H, HOC~2 ), 1.83-1.50 (m, 5H, HO-, -C~C~2 c~-), 1.21 I I I (d, J = 6.8, 3H, O=CCHC~3 ), 0.960 (d, J = 6.5, -3H, C~3 CH-), 0.947 -111- I I I (d, J = 6.3, 3H, C~3 CH-), 0.87 (d, J = 6.8, 3H, -NCHC~3 ), 0.16 (s, 9H, (C~3 ) 3 Si-); [a]~5 = -20.6° (CH 2c1 2 , £ 5.0). Anal. calcd. for c23 H37 N0 5Si: C, 63.41; H, 8.56. Found: C, 63.35; H, 8.67. 51: Rf 0.24 (30% ethyl acetate:hexane); IR (CH 2Cl 2) 3670, 3600, 2945, 1768, 1685, 1331, 1183, 840 em -1 ; 1H NMR {90 MHz, CDC1 3) o (TMS) 7.55-7.15 (m, 5H, aromatic H), 5.60 (d, J = 6.5, 1H, I : I I -NC~CHO), I I I 1 4.72 (qn, J = 6.5, 1H, -NCHC~O), 4.20-4.75 (m, 2H, O=CC~C~-), 3.43 (d, J = 6.3, 2H, HOC~2 ), 1.9-1.4 (m, 4H, -c~c~2 c~-), I 1 I I 1.22 (d, J = 6.0, 3H, O=CCHC~3 ), 1.07-0.7 (m, 9H, c~3 CH-, C~3 CH-, C~3 CH-), 0.17 (s, 9H, (C~3 ) 3 Si-); [a];5 = -21.3° (CH 2c1 2 , £ 3.5). Anal. calcd. for c23 H37 N0 5Si: C, 63.41; H, 8.56. Found: C, 63.60; H, 8.42. (3(R(2S,3S,5R)),4R,5S)-4~thyl-3-(1-oxo-2-(tetrahydro-3,5- dimethyl-6-oxo-2H-pyran-2-yl)propyl)-5-phenyl-2-oxazolidinone (53). To a well stirred solution of alcohol 50 (234.0 mg, 0.537 mmol) in dry methanol (5 mL) was added oxalic acid (53 mg, 0.59 mmol, 1.1 equiv). After 30 min, the reaction was quenched by the addition of aqueous phosphate buffer solution. The volatiles were removed in vacuo and the remaining aqueous solution was extracted with diethyl ether (4 x 25 mL). The combined ethereal layers were dried over anhydrous magnesium sulfate, filtered and concentrated to afford 182.8 mg (94~) of pure dial 52 as a very thick oil: Rf 0.20 -112- (50% ethyl acetate:hexane); [a] 25 = +15.3° (CH 2c1 2 , £ 4.5). Anal. calcd. for c20 H29 N0 5: C, 66.09; H, 8.04. Found: C, 65.94; H, 8.05. To a solution of diol 52 (181.4 mg, 0.50 mmol) in dry acetone (8 ml, previously distilled and stored under drierite) was added anhydrous N-methylmorpholine-N-oxide (245 mg, 2.09 mrnol, 4.2 equiv) followed by a catalytic amount of tris-triphenylphosphinedichlororuthenium complex (8 mg, 8.3 ~mol, 1.6% equiv, Strem. Chern. Inc.), 35 resulting in a yellow solution that turned dark brown after 10 min. The reaction mixture was stirred for 4 h, concentrated in vacuo and purified by flash chromatography (30 mm, 40 g silica, 25% ethyl acetate:hexane) to afford 142.1 mg (78%) of compound 53 as a colorless foam, which crystallized on standing. Diastereomer analysis (SE-54, 225°C, 13 PSI, t r = 5.29 min) indicated 53 to be > 99.3% one diastereomer: Rf 0.29 (30% ethyl acetate:hexane); mp 123.5-124.5°C; IR (CH 2Cl 2) 3065, 2980, 2950, 1780, 1730 (br), 1457, 1348, 1200 cm- 1 ; 1H NMR (90 MHz, CDC1 3) o (TMS) 7.6-7.2 (m, 5H, I aromatic H), 5.68 (d, J = 6.5, 1H, -NC~CHO), 4.64 (qn, J = 7.0, 1H, I I I I 1 I I I I J.. -NCHCHO), 4.39 (d of d, J = 3.0, J = 10.0, 1H, O=CCHL~O-), 4.25-3.85 I I I I (m, 1H, O=CCHCHO-), 2.50 (sextuplet, J = 6.5, 1H, H3CCHC0 2-), I I I I 2.2-1.4 (m, 3H, -OCHCHC~2 ), 1.28 (d, J = 6.5, 3H, ~3 CCH-), 1.21 (d, I I J = 6.5, 3H, ~ CCH-), 1.09 (d, J = 6.0, 3H, ~3 CCH-), 0.93 (d, J = 3 I I 6.5, 3H, -NCHC~3 ). 13 C NMR (CC1 4 ) o (CC1 4 ) 172.81, 172.50, 152.54, 134.60, 128.17, 127.65, 125.57, 85.08 (carbinol), 78.58, 54.86, -113- 39.91, 37.31, 36.28, 31.21, 16.52, 16.25, 13.92, 8.01; [a] 25 = 0 +51.5° (CH 2c1 2 , £ 6.2). Anal. calcd. for c20 H25 N0 5 : C, 66.84; H, 7.01. Found: C, 66. 78; H, 6.99. (2S(R),3S,5R)-Tetrahydro-a,3,5-tri.ethyl-6-oxo-2H-pyran-2acetic acid (34). Imide 53 (78.7 mg, 0.219 mmol) in 5 ml of methanol, at -12°C, was treated with cold (0°C), 1 N aqueous lithium hydroxide (1 ml, 1 mmol). The mixture was stirred between -12°C and 0°C for 1 h, concentrated in vacuo and extracted with dichloromethane (2 x 30 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated afford 24 mg (62%) of norephedrine oxazolidinone 10. in vacuo to The alkaline aqueous phase was acidified to pH 1 with aqueous 10% hydrochloric acid, saturated with sodium chloride and extracted with diethyl ether (4 x 30 ml). The combined ethereal extracts were dried over anhydrous sodium sulfate, filtered and concentrated to 44.0 mg of an oil. A portion (4 mg) was esterified with diazomethane in dichloromethane and analyzed by GC. Diastereomer analysis (SE-54, T = 120°C, 10 PSI, tr 5-epi-54 = 5.53 min, tr 54= 5.76 min) of the unpurified methyl ester afforded a 5-epi-54:54 ratio of 4.3:95.7. The remaining acid (40 mg) was purified by chromatography on acidic silica gel (10 mm, 7 g of "Silicar CC-4 special" Mallinckrodt, 2:1 ether:pet. ether) to afford 30.4 mg (70%) of Prelog-Djerassi lactone -114- 34 as white crystals. A portion (28.3 mg) was recrystallized from ether:pet. ether to yield 21 mg of white crystals, as a 0.7:99.3 mixture of epimers at c5 , as indicated by diastereomeric analysis of the methyl ester (same conditions): mp 122-123°C (a sample generously provided by Dr. Ireland had amp 122-122.5°C) (lit. mp 123.5°C, 11 c mp 123.5-125°C, 10 c mp 123-125°C, 17 b 123.5-125°C, 11 a 124-125°C 16 b); IR (CH 2Cl 2) 3685, 3025, 1725, 1458, 1382, 1205, 907 cm- 1 ; 1H NMR (500 MHz, CDC1 3) o (TMS) 9.0-8.5 (br, 1H,-co 2~), 4.62 (d of d, J = 2.0, J = 10.8, 1H, c2-H), 2.78 (q of d, Jd = 2.0, Jq = 7.0, 1H, a-H), 2.53 (q of d of d, Jd = 6.3, Jq = 7.0, Jd = 12.5, 1H, c 5-H), 2.0-1.9 (m, 2H, c 3-H, c4-Heq), 1.32 (q, J = 13, 1H, c4-Hax), 1.30 (d, J = 7.0, 3H, a-CH 3 ), 1.22 (d, J = 6.9, 3H, c5-cH 3 ), 1.01 (d, J = 6.7, 3H, c 3-CH 3 ); 13 C NMR (CDC1 3 ) o (TMS) 177.62, 174.75, 86.43, 41.07, 37.17, 36.20, 30.87, 17.22, 16.90, 8.38; [a] 25 = 0 +41.3° (CHC1 3 , £ 2.1) (lit. [a];1 = +47.7° (CHC1 3 , £ 1.93), 11 a 5 5 [a] 0 = +38.6° (£ 1.92), 11 C [a]~ = +47.5° (CHC1 3 , £ 1.10), 9b [a]~ = +38.7° (£ 1.90), 10 c [a]~3 = +31.2° (CDC1 3 , £ 0.88). 16 b From 17b From degradat1on: . resolution: [a] 25 0 = +43.3° (CHC1 3 , £ 2.40). [a] 0 = +33° (CHC1 3 , £ 0.797), 2 [a] 0 = +38° (CHC1 3 ), 3 [a] 0 = +43° (CHC1 3 ) 5). Anal. calcd. for c10 H16o4 : C, 59.98; H, 8.05. 59.86; H, 7.91. Found: C, -115- (2S(R),3S,5R)-Tetrahydro-a,3,5-trimethyl-6-oxo-2H-pyran-2acetic acid, methyl ester (54). To a solution of acid 34 (27.4 mg, 0.137 mmol, recrystallized 2x from ether:pet. ether) in 3 ml of dichloromethane was added a solution of diazomethane in diethyl ether until the yellow color persisted. The solvents were removed in vacuo to afford 29.0 mg (100%) of methyl ester 54 as a white solid melting at 76-77°C. Recrystallization from pentane afforded 20.8 mg of white crystals: mp 91.5-92.5°C (lit. mp 78-78.5°c, 11 a 75.5-76.5°C, 2 79-81°C, 3 94-95°C 17 b). Diastereomer analysis (SE-54, 120°C, 4 PSI, t r = 9.99 min, then 200°C, 4 PSI, t r = 2.19 min) indicated both the chemical and diastereomer purity to be > 99.9%: IR (CHC1 3 ) 3025, 1729, 1457, 1233, 1095 cm- 1; 1H NMR (500 MHz, CDC1 3 ) o (TMS) 4.543 (d of d, J = 2.7, J = 10.6, c2-H), 3.733 (s, 3H, C~3 0), 2.730 (q of d, Jd = 2.7, Jq = 7.1, 1H, a-H), 2.508 (q of d of d, Jd = 6.5, Jq = 7.0, Jd = 12.5, lH, c5-H), 1.98-1.85 (m, 2H, c3-H, c4-Heq), 1.422 (q, J = 12.5, 1H, c4-Hax), 1.283 (d, J = 7.1, 3H, a-CH 3), 1.200 (d, J = 7.0, 3H, c5-CH 3 ), 1.007 (d, J = 6.5, 3H, c3-CH 3 ); 13 C NMR (CDC1 3 ) o (TMS) 173.71, 173.39, 86.30, 52.18, 41.33, 37.37, 36.26, 31.00, 17.29, 17.03, 8.77; [a]~ 5 = +37.0° (CHC) 3 , £ 0.9) (lit. [a] 0 =+38° (CHC1 3 , £ 1.03)lla). Anal. calcd. for c11 H18o4 : C, 61.66; H, 8.47. 61.42; H, 8.33. Found: C, -116- (3(2S,3R,4S),4S)-3-(3-Hydroxy-2,4,6-tri.ethyl-l-oxo-6heptenyl-4-(l~thylethyl)-2-oxazolidinone (48). Enolization, condensation, oxidation and product isolation were performed according to the preparation of compound 36. To a cooled (-78°C) solution of the boron enolate of 7 in 24 ml of anhydrous dichloromethane (prepared from 2.22 g (12 mmol) of oxozolidinone 7, 3.24 ml (13.2 mmol) of di-~-butylboryl triflate, and 2.0 ml (14.4 mmol) of triethylamine) was added 1.06 g (9.4 mmol, 0.78 equiv) of aldehyde 46. Product isolation gave 3.86 g of a yellow oil. Diastereomer analysis (SE-54, T = 170°C, 7 PSI, tr 4-epi-E 2 = 8.23 min, tr E2 = 8.82 min, tr E1 = 9.01 min, tr 11 = 9.10 min, tr 12 = 9.26 min) of an unpurified, silylated sample (TMSNEt 2 , DMAP, CH 2c1 2 , 12 h) afforded a ratio of 4-epi-E 2 :E2 :E 1 :T1 :T2 = 1.05:97.72:0.25:0.66:0.32. Flash chromatography (50 mm, 180 g silica, 20% ethyl acetate:hexane) afforded 2.06 g (73% based on aldehyde 46) of compound 48 as a colorless oil: Rf 0.25 (20% ethyl acetate:hexane); IR (CHC1 3 ) 3500 ( br), 3035, 2980, 2960, 1780, 1695, 1385, 1220 em -1 ; 1H NMR ( 90 MHz, I I CDC1 3 ) o (TMS) 4.75 (br s, 1H, (!!)HC=C-), 4.68 (br s, lH, (H)!!C=C-), I I I I 4.60-4.15 (m, 3H, -NC~C~2 0), 3.98 (d of d, J = 4, J = 7, 1H, I I I O=CCH-), 3.66 (q, J = 4.5, 1H, HOCH-), 2.58 (d, J = 4.5, 1H, -HO-), I I I I I 2.55-1.55 (m, 4H, (CH 3 ) 2C!!, HOCHCHC~2 ), 1.68 (s, 3H, !!3CC=), 1.27 I I I I I (d, J = 6.9, 3H, O=CCHC!!3 ), 1.0-0.8 (m, 9H, HOCHCHC~3 , (C!!3 ) 2CH); 13 C NMR (CC1 ) o (CC1 ) 176.52, 152.80, 143.38, 112.05, 74.03, 4 4 -117- 62.86, 57.98, 42.06, 40.18, 33.22, 28.22, 21.91, 17.75, 14.57, 14.38, 12.49; [a]~ 5 = +61.7° (CH 2Cl 2 , £ 3.3). Anal. calcd. for c16 H27 N0 4 : C, 64.62; H, 9.15. Found: C, 64 •48 ; H, 9 •04. Mixture of (3(2S,3R,4S,6R),4S)-3-(7-hydroxy-2,4,6-tri.ethyl1-oxo-3-((trimethylsilyl)oxy)heptyl)-4-(l~thylethyl)-2-oxazoli­ dinone (60) and the Corresponding (3(2S,3R,4S,6S),4S)-Isa.er {73). Aldol adduct 48 (911 mg, 3.06 mmol) was silylated (Et 2NSiMe 3 , DMAP, CH 2c1 2 , 4.5 h) following the procedure used for the preparation of compound 41. Flash chromatography (50 mm, 100 g silica, 10% ethyl I acetate:hexane) afforded 1,000 mg (84%) of silylated alcohol as a colorless oil. Hydroboration using thexylborane in tetrahydrofuran ( 2 equiv, 3.5 h, 0°C) was performed in the same way as for the preparation of compound 50. Diastereomer analysis (SE-54, 195°C, 5 PSI, t r 6R = 11.00 min, t r 65 = 11.36 min) of an unpurified, silylated sample (TMSNEt 2 , DMAP, CH 2c1 2 , 15 min) afforded a ratio of 60:73 = 75:25. Flash chromatography (40 mm, 85 g silica, 40% ethyl acetate:hexane) gave 1.00 g (96%) of a colorless oil as an inseparable, 3:1 mixture of epimers 60 and 73 as indicated by GC analysis: Rf 0.10 (30% ethyl acetate:hexane); 1H NMR (90 MHz, I I I CDC1 3 ) o (TMS) 4.5-4.1 (m, 3H, -NC~c~2 0), 4.1-3.75 (m , 2H, I I I O=CC~c~~), I 3.60-3.25 (m, 2H, HOC~2 ), 2.55-2.10 (m, lH, (CH 3 ) 2 C~-), I I I I 1.9-1.1 (m, 5H, ~OCH 2 C~CH 2 C~-), 1.22 (d, J = 6.0, 3H, O=CCHC~3 ), -118- I I I 1.05-0.85 (m, 12H, C~3 CHCH 2 CHC~3 , (C~3 ) 2 CH), 0.13 (s, 9H, (C~3} 3 Si). Anal. calcd. for c17 H37 No 5si: C, 58.80; H, 9.62. Found: C, 59.02; H, 9.52. Detenmination of the absolute configuration of compounds 60 and 73. (Scheme XII). A solution containing a 3:1 mixture of alcohols 60 and 73 (1.005 g, 2.72 mmol) and freshly distilled triethylamine (3.9 ml, 27 mmol, 10 equiv) in 10 ml of dry dimethyl sulfoxide, was treated with a solution of sulfur trioxide pyridine complex (1.91 g, 13.6 mmol, 5 equiv, Aldrich, 95% pure) in 10 ml of dry dimethyl sulfoxide. After 30 min, ether (100 mL) was added, and the mixture partitioned with water (25 mL). The ethereal layer was decanted and the aqueous phase was extracted with ether (1 x 25 ml). The combined organic layers were washed with saturated aqueous cupric sulfate (1 x 50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the corresponding mixture of aldehydes as a slightly yellow oil, pure by TLC analysis: Rf 0.36 (30% ethyl acetate:hexane). The oil was diluted in 1.5 ml of anhydrous dichloromethane and added dropwise into a cooled (-78°C) solution containing 3 mmol of boron enolate 47 in 12 ml of dichloromethane, prepared as described in p. 47. The mixture was stirred at -78°C for 0.5 hand then at 0°C for 1.8 h. General aldol workup (p. 47) and purification by flash chromatography (50 mm, 150 g silica, 35% ethyl acetate:hexane) -119- afforded 1.10 g (65% from alcohol 60) of product 74 as a 3:1 mixture at c6 • The mixture was then treated with an excess of N,N-diethyltrimethylsilylamine (2.6 ml, 13.6 mmol), in presence of DMAP {166 mg, 1.4 mmol) in anhydrous dichloromethane (10 mL), for 4.5 h. centration in vacuo afforded an oil. Con- Diastereomer analysis (SE-54, T = 275°C, Tinj = 285°C, 15 PSI, t r 75 = 7.67 min, t r 76 = 8~21 min) afforded a ratio of 75:76 = 72:28. Purification by flash chromatog- raphy (50 mm, 150 g silica, 10% ethyl acetate:hexane) resulted in a non-baseline separation of the epimers, affording 643.3 mg of 75 (Rf 0.52 in 50% ethyl acetate:hexane) (contaminated with 0.2% of 76) and 121 mg of 76 (Rf 0.46 in 50% ethyl acetate:hexane) (contaminated with 10% of 75). In another flask was placed benzyl alcohol (0.38 ml, 3.72 mmol, 4 equiv) and anhydrous tetrahydrofuran (4 mL). The solution was cooled to 0°C and a 1.7 ~solution of n-butyllithium in hexane (1.65 ml, 2.8 mmol, 3 equiv) was added dropwise. at 0°C for 20 min. The mixture was stirred Then, a solution containing 75 in ca. 1 ml of tetrahydrofuran was slowly added (1 ml rinse), and the resulting mixture stirred at 0°C for 3 h, after which period the reaction was quenched by the addition of aqueous ammonium chloride. The volatiles were removed in vacuo and the remaining aqueous slurry was partitioned between water and dichloromethane. The organic layer was decanted, dried over anhydrous sodium sulfate, filtered and -120- concentrated to an oil. Flash chromatography (5% ethyl acetate: hexane) afforded an analytical sample of 77, contaminated with only 0.2% of 78: Rf 0.62 (30% ethyl acetate:hexane); IR (CHC1 3 ) 3035, 2990, 1730, 1458 cm- 1 ; 1H NMR (500 MHz, CDC1 3 ) o (CHC1 3 ) 7.30-7.10 (m, 10H, aromatic H), 5.08 (d, J = 12.5, 2H, two PhC~(H)O), 4.99 (d, I I J = 12.5, 2H, two PhCH(~)O), 3.73 (d of d, J = 2.0, J = 8.3, 2H, two I TMSOC~-), I I I 2.61 (qn, J = 7.5, 2H, two O=CC~-), 1.50 (br q, J = 7, 2H, I I two TMSOCHC~CH 2 ), 1.34 (d of d of d, J = 7, J = 7, J = 13.5, 1H, I I I I 1.16 (d, J = 6.8, 6H, two O=CCHC~3 ), 0.97 (d of d of -CHC~(H)CH-), I f d, J = 7.0, J = 7.0, J = 13.5, 1H, -CHCH(~)CH-), 0.14 (s, 18H, two (C~3 ) 3 Si); 13 c NMR (CC1 4 ) o (CC1 4 ) 171.98, 134.10, 126.23, 125.91, 125.78, 75.02, 63.58, 41.88, 37.46, 32.33, 12.63, 11.92, -1.21. Compound 78 was obtained following the same procedure. Flash chromatography (same cond.) afforded a sample of 78 contaminated with 10% of 77: Rf 0.62 (30% ethyl acetate:hexane); 1H NMR (500 MHz, CDC1 3 ) o (CHC1 3) 7.3-7.16 (m, 10H, aromatic H), 5.10-4.96 (m, I I 4H, two PhC~2 0), 3.80-3.75 (m, 2H, two TMSOC~-), 2.65-2.57 (m, 2H, I I I I I two O=CC~-), 1.53-1.38 (m, 2H, two TMSOCHC~CH 2 ), 1.28 (d of d of d, I I J = 2.5, J = 13, J = 13, 1H, -CHC~(H)CH-), 1.15 (d, J = 7.0, 6H, two I I O=CCHCH 3 ), 0.99 (d of d of d, J = 2.5, J = 13, J = 13, 1H, I 1 I I 0.75 (d, J = 6.8, 3H, ~3 CCHCH 2 CHCH 3 ), 0.73 (d, 1• I I 13 J = 6.8, 3H, H 3 CCHCH 2 CHC~3 ), 0.10 (s, 18 H, two (C~3 ) 3 S1); C NMR -CHC~(H)CH-), (CC1 4 ) o (CC1 4 ) 171.72, 133.90, 126.10, 125.78, 124.67, 76.39, -121- 76.26, 63.52, 40.97, 40.77, 33.24, 32.78, 32.46, 14.45, 11.72, 11.07, 10.75, -1.34. (2R,4S)-5-{(Triethylsilyl)oxy)-2,4,5-trimethylhexanol (62), and the corresponding {2S,4S)-Isomer (79). To a cooled (-15°C), 5:1 mixture of anhydrous tetrahydrofuran and 10 ~ borane dimethyl sulfide complex solution (Aldrich), was added neat 2-methyl-2butene (2 equiv) dropwise. The solution was warmed to room temperature and stirred for 2 h. Into another flask containing olefin 61 (124 mg, 0.48 mmol) in anhydrous tetrahydrofuran (1 mL) at -10°C, was added dropwise an / aliquot of the disiamylborane solution (ca. 3 molar equiv). The solution was then warmed to 0°C and stirred at this temperature for 4 h. The excess borane was destroyed by the addition of aqueous phosphate buffer solution. Methanol was added, followed by a solution of 30% aqueous hydrogen peroxide (ca. 1 ml) in methanol. The slurry was stirred at 0°C for 1 h, concentrated in vacuo and the remaining aqueous solution extracted with ether (2 x 30 mL). The combined ethereal layers were dried over anhydrous sodium sulfate, filtered and concentrated to an oil. Neither the product, or its silylated (TMS) counterpart, proved to be suitable for GC analysis. Purification by flash chromatography (20 mm, 45 g silica, 10% ethyl acetate:hexane) afforded 61.9 mg (47%) of 62 and 13.4 mg (10%) of 79, both as colorless oils. -122- 62: Rf 0.52 (30% ethyl acetate:hexane); 1H NMR (90 MHz, CDC1 3)o I (TMS) 3.65-3.25 (m, 2H, HOC~2 ), 1.85-0.45 (m, 26H), 1.15 (s, 3H, I C~ ycH ), 3 3 I 1.10 (s, 3H, CH 3 yc~3 ). Anal. calcd. for c15 H34 o2si: C, 65.63; H, 12.48. Found: C, 65.53; H, 12.35. Rf 0.43 (30% ethyl acetate:hexane); IR (CHC1 3) 3645, 3480 (br), 2970, 2885, 1458, 1236, 1040, 710 cm- 1; 1H NMR (90 MHi, CDC1 3) o (TMS) 3.65-3.25 (m, 2H, HOC~2 ), 1.7-0.45 (m, 26H), 1.13 (s, 3H, 79: I 3 I c~ ~cH ), 3 1 1.11 (s, 3H, CH 3 yc~3 ). Anal. calcd. for c15 H34 o2Si: C, 65.63; H, 12.48. Found: C, 65.75; H, 12.42. Detenmination of the Absolute Configuration of Compound 62. Compound 62 (50 mg, 180 ~mol) was methylated (KOH, CH 3 I, DMSO, 48 h) according to the procedure of Johnstone. 46 The unpurified product was oxidized (Nai0 4 , RuC1 3 .H 2o, CC1 4 , CH 3CN, H20) according to the procedure of Sharpless. 47 The resulting unpurified (Scheme XII) methyl ester 80 was then treated with methyl Grignard (3M sol. in ether) in ether, at 0°C, for 4 h. The resulting alcohol treated with triethylsilyl trifluoromethanesulfonate (3.5 equiv) in presence of triethylamine (4.5 equiv) in dichloromethane. Flash chromatog- raphy (10 mm, 7 g silica, hexane) afforded 9 mg (12%) of compound 81. (The low overall yield is attributed to the loss of part of one of the intermediates upon concentration under low pressure.) Gas -123- chromatographic analysis (SE-54, 200°C, tr = 3.18 min) indicated 81 to be~ 99.8% pure: 1H NMR (500 MHz, CDC1 3) o (TMS) 1.91 (d of d of d, J = 4.0, J = 4.0, J = 14.0, 1H,-C~(H)-), 1.41 (q of d of d, Jd = I I 3.5, Jd = 7.0, Jq = 7.0, 2H, two -C~CH 3 ), 1.15 (s, 6H, two ~3 C~CH 3 ), I I 1.14 (s, 6H, two H 3 c~c~3 ), 0.95 (t, J = 8.0, 18H, two (C~3 cH 2 ) 3 Si), I 0.90 (d, J = 7.0, 6H, two -CHCH 3 ), 0.58 (q, J = 8.0, 12H, two I (CH c~ ) Si), 3 2 3 I 0.54 (d oft, J = 7.5, J = 7.5, J = 14.0, 1H,-CH(~)). -124- References and Notes (1) (a) Evans, D. A.; Bartroli, J. Tetrahedron Lett. 1982, 23, 807. (b) Evans, D. A.; Bartroli, J.; Godel, T. Tetrahedron Lett. 1982, 23, 4577. (2) Anliker, R.; Dvornik, D.; Gubler, K.; Heusser, H.; Prelog, V. Helv. Chirn. Acta 1956, 39, 1785. (3) Djerassi, C.; Zderic, J. A. J. Am. Chern. Soc. 1956, 78, 2907, 6390. (4) Anliker, R.; Gubler, K. Helv. Chim. Acta 1957, 40, 119. (5) (a) Djerassi, C.; Halpern, 0. J. Am. Chern. Soc. 1957, 79, 2022. (b) Djerassi, C.; Halpern, 0. Tetrahedron 1958, 1, 255. (6) Brockman, H.; Oster, R. Chern. Ber. 1957, 90, 605. (7) Djerassi, C.; Halpern, 0.; Wilkinson, D. I.; Eisenbraun, E. J. Tetrahedron 1958, !, 369. (8) Rickards, R. W.; Smith, R. M. Tetrahedron Lett. 1970, 1025. (9) (a) Masahiro, H.; Garvey, D. S.; Lu, L. D.; Masamune, S. Tetrahedron Lett. 1979, 3937. (b) Masamune, S.; Hirama, M.; Mori, S.; Ali, S. A.; Garvey, D. S. J. Am. Chern. Soc. 1981, 103, 1568. (c) Schlessinger, R. H.; Poss, M. A. J. Am. Chern. Soc. 1982, 104, 357. (10) (a) Masamune, S.; Kim, C. U.; Wilson, K. E.; Spessard, G. 0.; Georghiou, P. E.; Bates, G. S. J. Am. Chern. Soc. 1975, ~' 3512. (b) White, J. D.; Fukuyama, Y. Ibid. 1979, 101, 226. (c) Grieco, P. A.; Ohfune, Y.; Yokoyama, Y.; Owens, W. Ibid. -125- 1979, 101, 4749. (d) Stork, G.; Nair, V. Ibid. 1979, 101, 1315. (11) (a) Ireland, R. E.; Daub, J. P. J. Org. Chern. 1981, 46, 479. (b) Jarosz, S.; Fraser-Reid, B. Tetrahedron Lett. 1981, 22, 2533. (c) Isobe, M.; Ichikawa, Y.; Goto, T. Tetrahedron Lett. 1981, 22, 4287. (12) Wovkulich, P.M.; Uskokovic, M. R. J. Org. Chern. 1982, 47, 1600. (13) Bartlett, P. A.; Adams, J. L. J. Am. Chern. Soc. 1980, 102, 337. (14) (a) Morgans, D. J. Tetrahedron Lett. 1981, 22, 3721. (b) Still, W. C.; Shaw, K. R. Ibid. 1981, 22, 3725. (15) Danishefsky, S.; Kato, N.; Askin, D.; Kerwin, J. F. J. Am. Chern. Soc. 1982, 104, 360. (16) (a) Muruyama, K.; Ishihara, Y.; Yamamoto, Y. Tetrahedron Lett. 1981, 22, 4235. (b) Hoffmann, R.; Zeiss, H. J.; Ladner, W.; Tabche, S. Chern. Ber. 1982, 115, 2357. (17) (a) Bergel 'son, L. D.; Batrakov, S. G. Izv. Akad. Nauk SSR, Ser. Khim. 1963, 1259. (b) Nakano, A.; Takimoto, S.; Inanaga, J.; Katsuki, T.; Ouchida, S.; Inoue, K.; Aiga, M.; Okukado, N.; Yamaguchi, M. Chern. Lett. 1979, 1019. (18) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chern. Soc. 1982, 104, 1737. -126- {19) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chern. Soc. 1981, 103, 2127. {20) (a) Ell iel, E. L... Stereochemistry of Carbon Compounds" McGraw-Hill, 1962. (b) Stoddart, J. F... Stereochemistry of Carbohydrates" Wiley lnterscience, 1971. (21) The optical purity of oxazolidinones 9 and 10 was determined to be 299% by GC analysis of their Mosher imides. 22 0 HN~O Me 9 H Ph 10 (22) Evans, D. A.; Mathre, D. J. Unpublished results. (23) Prepared in two steps from methallyl alcohol (~: MsCl, Et 3N, CH 2c1 2 , 0°C; .Q. Li I, Et 20, 0°C-+ 25°C) in 85% yield after distillation. {24) Although the material showed no detectable decomposition when stored over cuper wire at 4°C for several months, a bottle that was stored at room temperature for ca. one year exploded violently. {25) Andersen, N. H.; Uh, H. Synth. Commun. 1973, 1, 115; Tetrahedron Lett. 1973, 2079. -127- (26) Santaniello, E.; Ponti, F.; Manzocchi, A. Synthesis 1978, 534. (27) Parikh, J. R.; Doering, W. J. Am. Chern. Soc. 1967, 89, 5505. (28) Ennis, M. D. Ph.D. Dissertation, California Institute of Technology, Pasadena, California, 1983. (29) Mancuso, A. J.; Huang, S.; Swern, D. J. Org. Chern. 1978, 43, 2480. (30) Cherpeck, R. E. Ph.D. Dissertation. California Institute of Technology, Pasadena, California, 1980. (31) For a review see Evans, D. A.; Nelson, J. V.; Taber, T. R. Topics in Stereochemistry 1982, Jl, 1. (32) Evans, D. A.; McGee, L. R. J. Am. Chern. Soc. 1981, 103, 2876. (33) Nicolaou, K. C.; Pavia, M. R.; Seitz, S. P. Tetrahedron Lett. 1979, 2327. {34) A sample of 34 and 5-epi-34 was generously provided by Dr. Ireland. (35) Sharpless, K. B.; Akashi, K.; Oshima, K. Tetrahedron Lett. 1976, 2503. (36) Schmid, G.; Fukuyama, T.; Akasaka, K.; Kishi, Y. J. Am. Chern. Soc. 1979, 101, 259. (37) (+) and (-)-mono and diisopinocampheylborane were prepared according to Brown, H. C.; Schwier, J. R.; Singaram, B. J. Org. Chern. 1978, 43, 4395. {38) This result truly contrasts a recently reported related hydroboration, using {+) and (-)-diisopinocampheylborane. 39 -128- (39) Masamune, S.; Kaiho, T.; Garvey, D. S. J. Am. Chern. Soc. 1982, 104, 5521. (40) Acknowledgement is due to Dr. Thierry Godel for the contribution of this result. (41) (a) Caramella, P.; Rondan, N. G.; Paddon-Row, M. N.; Houk, K. N. J. Am. Chern. Soc. 1981, 103, 2438. (b) Paddon-Row, M. N.; Rondan, N. G.; Houk, K. N. Ibid. 1982, 104, 7162. (42) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 2199, 2205. (43) Anh, N. T.; Eisenstein, 0. Nouv. J. Chim. 1977, l, 61. (44) Nagase, S.; Ray, N. K.; Morokuma, K. J. Am. Chern. Soc. 1980, 102, 4536. (45) We are indebted to Dr. William Scott for these calculations. (46) Johnstone, A. W.; Rose, M. E. Tetrahedron 1979, 35, 2169. (47) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, B. M. J. Org. Chern. 1981, 46, 3936. -129- CHAPTER III The Total Synthesis of (+)-Tylonolide, Cyclic 5,20-He.iacetal -130- I. Introduction In 1961, McGuire and coworkers reported the discovery of a new antibiotic from strains of Streptomyces fradiae. 1 !he compound was given the name of tylosin after its isolation from soils collected in Thailand. It was shown to be relatively nontoxic and highly active in vitro against gram-positive bacteria, certain gramnegative bacteria, and mycobacteria. 1a Today it is extensiv.e ly used both as a nutrient and as a treatment for respiratory diseases in poultry. Early studies 1b showed that tylosin (84) belongs to the growing class of macrolide antibiotics. 2 Hydrolysis experiments indicated that two neutral sugars (mycarose and mycinose) and one aminosugar (mycaminose) form part of the molecule. 1b, 3 In 1970 Morin and coworkers 4 elucidated the structure indicating that the antibiotic belongs to the 16-membered ring family of macrolides. There is no X-ray crystal struct~re analysis reported directly on tylosin; however, X-ray structures of two metabolites obtained from mutants of S. fradiae have recently appeared in the literature. Thus, the X-ray structures of protylonolide (85) and 5-0-mycarosyltylactone (86) were reported in 1980 and 1982 respectively.sa, 6 Because the absolute configuration of mycarose was already known, the absolute stereochemistry of 86 was unequivocally assigned as drawn in Scheme I. Furthermore, conversion of 86 into 85 by hydrolysis established the absolute configuration of 85. Since it was previously shown -131- Scheme I 0 mycarose mycaminose mycinose Tylosin (84) 0 0 '' '' Me ,ft ,Et ''' ''' Me Me 86 85 0 ,,~ ,, ~--OH '''0 HO 87 -132- that protylonolide, 85, is converted into tylosin by mutants of S. fradiae, 7 this constituted a proof of the absolute stereochemistry. It is significant to note that the stereochemistry at c14 proved to be opposite to that predicted by Celmer's empirical model for macrolide backbones. 8 Since the discovery of tylosin, several related antibiotics which block different stages of the biosynthetic pathway have been isolated from mutant strains. 9 ' 6 However, none of these has proved to be superior to tylosin in treating bacterial or mycoplasmal infections caused by sensitive organisms. 10 To date, four syntheses of compounds directly related to tylosin have been published. Two of them are based on carbohydrate starting materials, 11 , 12 , 15 one on aldol technologylJb,c and one on the chemistry of bicyclic systems. 14 Some of their relevant steps will be discussed in the next section. Here, we describe the total synthesis of the tylosin aglycone, tylonolide cyclic 5,20-hemiacetal, 87, using the methodology presented in Chapters I and II. II. Retrosynthetic Analysis In deriving a synthetic plan for tylonolide hemiacetal (87), or any other macrolidic molecule, two main issues need to be addressed: a) Macrocyclization, and b) Control of the stereochemistry. Examination of the structure of tylonolide quickly suggests two possible bond disconnections that would lead to a linear precursor: -133- the C1-0 bond and the c10 -c 11 bond (Scheme II). Due to the fact that both disconnections were envisioned in our overall plan, either route would ultimately lead to the same two fragments A and 8. An inspection of the large amount of literature concerning the C-0 closure (i.e. macrolactonization) 16 reveals that these reactions often proceed in rather low yields when carried on stereochemically complex substrates. Indeed, when some of these macrolactonization methods were applied to the syntheses of 16-membered-ring macrolides,yields in the range of 40 to 15% were obtained. Table 1 summarizes some of these results. Table 1. Macrolactonization yields. Target Activated carbonyl Conditions Yielda Ref Tylonolide R-C(O)SPh Hg(OS0 2Me) 2 ,NaHP04 17% 13a Tylonolide R-C(O)OP(O)(OPh) 2 DMAP, c6H6 32% 13b Tylonolide R-C(O)S-2-pyr Toluene 41% 11 Tylonolide R-C(O)S-2-pyr Toluene 19%b 14 Josamycin R-C(O)SPh Na 2HP0 4 ,AgOTF 17% 17 a The yields are based on the acid precursor. b Yield based on the corresponding methyl ester, and included is its basic hydrolysis to the acid. Based on our observations regarding the carbonyl reactivity of the acyl oxazolidinones towards nucleophiles, we did some preliminary Sche.e II 0 ( Me •' •' C1o- C11 •' OR ,, OH 0 OH 0 OH R Me ···,oH OR '·,·oH A 0 21 •' ,,Me I ~ w ~ I HO 87 0 ,•' Me •' c1-o HO ( OR ,, '•,,OH '•,,OH 0 OH H~Et ~e l__OH 8 -135- macrolactonization studies on a model compound (eq. 1). We were hoping that the oxazolidinone moiety would be internally displaced by the c15 -oxygen upon addition of a catalytic amount of a Grignard reagent. Unfortunately, no reaction was observed in the range of temperature indicated. This result, together with the low yields mentioned above led us to abandon this approach. 0 No reaction TBSO/''• 15 Me'''' By the time we were in the planning stages of our synthesis, Stork and Nicolaou 18 had independently reported model studies on macrocyclization wherein the Wittig-Harner reaction was employed in the intramolecular reaction leading to the macrocycle. Later, in an advanced stage of our work, Nicolaou published the synthesis of 23-Q-mycinosyltylonolide and reported an outstanding 80% yield for the ring closure using this reaction (eq. 2). 12 -136- 0 ''')=o '''0 Tol., 10 -3 !i 0 Me TBSO~~\ O ~' MeO Et''' ''''OTBS (801.) The relative facility observed in the formation of the c10 -c 11 bond in this study, encouraged us to direct our efforts towards an intramolecular macroaldol condensation connecting these two carbons. In the event this reaction failed, the corresponding phosphonate could be easily prepared from a common advanced intermediate and the ring would be formed via a Wittig-Harner reaction. -137- With the total synthesis of (+)-Prelog-Djerassi lactone presented in Chapter II, we demonstrated the utility of chiral acyl oxazolidinones in the creation of asymmetric centers by means of alkylation 19 and aldo1 20 reactions. In a similar way, we planned to use this powerful tool in the elaboration of {+)-tylonolide. As already mentioned, the two first main disconnections would lead us to two subunits A and 8 {Scheme II), possessing all the chiral centers present in tylonolide. A retrosynthetic analysis of fragments A and 8 is presented in Scheme III. The synthesis of this segment was envisioned to Subunit A: follow the basic steps used in the elaboration of the PrelogDjerassi lactone. Indeed, carbons 4, 5, 6 and 8 bear the same stereochemical relationships in both compounds. Therefore, the c6-c 7 bond would be created by means of an alkylation; an aldol reaction would set the c4 and c5 stereochemistry, and a hydroboration would create the c8 chirality. The remaining asymmetric center, c3 , would be introduced by an additional aldol condensation. Analysis of the absolute configuration of the centers indicates that our norephedrine-derived chiral auxiliary could be employed as the sole source of chirality. Subunit 8: Analysis of this segment revealed a pattern that we had not encountered before, namely, a threo hydroxy-hydroxymethyl relationship. imide 92. We envisioned its elaboration through the use of The boron enolates of chiral crotonate imides have been Scheme I II -138OH 9H R Et 0 : - CHO HO~ - OH Me HO/ OR' 8 A l ! .. Et :• I HO~ : XN o~xv OR' 0 Aldol-2 J HN''~o )-{ Me t Ph Aldol 0 ~xv I OR' Aldol-! I I 0 HNAO --{ HXv: I I 9 Alkylation 0 Ro~x N 10 _j -139- shown to react with aldehydes in high yields and with excellent diastereoselection (eq. 3). 21 Since olefin and carbonyl functionalities are easily interconvertible, these aldol adducts have the 0 ~X v 3) RCHO 92 (3) interesting property of leading eventually into threo or erythro relationships. The application of this reaction to our case would set the absolute stereochemistry of this subunit. Transformation into B would then be accomplished in a straightforward fashion. The chirality of this fragment requires the valine-derived oxazolidinone. Finally, a comment on protecting groups is worthwhile here. Since tylonolide has seven oxygens, their selection order of introduction is a critical aspect of the projected synthesis. We planned to generate the aldehyde oxidation state of c20 towards the end of the synthesis via an oxidation of the c20 primary alcohol. Throughout the synthesis, this alcohol functionality would be masked with a reasonable stable, mildly removable protecting group. We avoided the common protection of the c20 aldehyde and the c5 alcohol -140- as the methyl acetal because this would, presumably, generate undesirable anomeric mixtures. III. Discussion and Results 1. The Synthesis of the c11 -c 15 Fragment The e,e• dihydroxy carbonyl functionality present in this segment was stereospecifically introduced in the first step. Our first attempt at this problem was to carry out a direct aldol condensation between e-alcoxypropionate 88 and propionaldehyde which would lead to the desired adduct 90 (Scheme IV). However, enoliza- tion of 88 with di-~-butylboryl triflate and triethylamine (CH 2c1 2, -78°C) resulted in the clean formation of a very UV active spot in the TLC plate, presumably the acrylate imide 91. Such e-elimination had been observed before when the corresponding benzyl ether, 89, was submitted to the same conditions. 22 Scheme IV 0 RO 0 ?NYu -r 88: R=SiMe 2tBu 89: R=CH 2Ph Etyxv OH 1) Bu 2BOTf, Et 3N :liP 2) EtCHO 0 RO 90 0 ~X v 91 + ROH -141- This problem was solved by using crotonate imide 92 (eq. 4), obtained in 78% yield from oxazolidinone 9. 23 Thus, addition of di-n-butylboryl triflate (1.1 equiv) and triethylamine (1.2 equiv) to a cooled (-78°C) solution of 92 in CH 2c1 2 resulted in formation of its boron enolate, which was condensed with propionaldehyde (1.3 equiv, -78°C, 1 h, then 0°C, 45 min). Oxidative workup {H 2o2 , MeOH, 0°C, 1 h) and product isolation afforded imide 93 in 94% yield after chromatography. The 500. MHz proton NMR spectrum of this compound indicated a c2-H:C 3-H coupling constant of 3.5 Hz, supportive of the expe~ted erythro relationship between the substituents. 24 A sample of the unpurified mixture was converted into its triethylsilylether and was analyzed by GC. diastereomer. The product proved to be 98.6% of one The GC trace is shown in Fig. 1. OH 2) EtCHO 92 0 Etyxv 93 (94%) Fig. 1. GC Trace of the Triethylsilyl Derivative of the Unpurified Aldol Adduct 93. TESO 0 Et~XV -142- As we already mentioned, an interesting feature of this aldol adduct is that it contains a latent element of symmetry at c2 , due to the facile chemical interconversion of olefins and carbonyls. This is illustrated in Scheme V. Scheme V OR OR' EtA( CHO HO 0 ~ route a Et~XV 93 ~ (red) route b Since the same sequence of reactions could, in principle, be performed in the norephedrine series, all four diastereomers of this tylonolide fragment could be prepared. Although route a in Scheme V is the one that leads to the tylonolide c14 stereochemistry, route b was also undertaken. summarized in Scheme VI. The results are presented below and -143- Scheme VI Et9 0 93 94: R= XV 95: R= OBn R (82%) Et~oxo ~ Me (83%) C0 2 Et 97 96 (89%) (a) 03 , MeOH; (b) ZnBH 4 ; (c) Me 2C(OMe) 2 , H+; (d) PhCH 20Li, (94__.95); (e) LAH (95-.96); (f) so .py, Et N, DMSO. 3 3 Ozonolysis of olefin 93 in methanol (-78°C), followed by reductive workup (Zn(BH 4 ) 2 sol. in ether, -78°C, 20 h) 25 and protection of the diol (dimethoxypropane, CSA, acetone) afforded crystalline acetonide 94 in 82% overall yield after chromatography. -144- Reduction of 94 by treatment with a solution of lithium borohydride in tetrahydrofuran, at 0°C or 25°C resulted in very slow conversion. On the other hand, lithium aluminum hydride in tetrahydrofuran at -78°C gave mainly attack to the undesired oxazolidinone carbonyl. This problem was overcome by a two step sequence. Thus, imide 94 was converted into benzyl ester 95 (BnOLi, 1.7 equiv, THF, -15°C, 1.5 h) in 91% yield, along with a 92% yield of recovered oxazolidinone 9. Reduction of 95 (1~ LAH in Et 2o, -15°C, 15 min) proceeded cleanly to give alcohol 96 in 98% yield. GC analysis of the unpurified compounds 94, 95 and 96 showed that no detectable epimerization had occurred at any point. Finally, alcohol 96 was oxidized to the corresponding aldehyde (DMSO, so 3 .pyr, Et 3N, 0.5 h,) 26 and the latter, without purification, reacted with (carbethoxyethylidene) triphenylphosphorane (1.5 equiv, toluene, 60°C, 4 h) to afford unsaturated ethyl ester 97 in 83% yield. The configuration of the double bond was assumed to be E by analogy to a similar reaction reported in the literature. 12 a Although this product was not to be used in the synthesis of tylonolide, its elaboration demonstrated the versatility of aldol adduct 93, especially its threo:erythro duality. At this point, our efforts were directed to Route a (Scheme V) which would ultimately lead to the tylonolide fragment B (Scheme VII). Direct reduction of aldol adduct 93 with a variety of reducing agents proved to be difficult. Indeed, treatment of 93 with lithium borohydride {THF sol., 0°C~25°C) resulted in partial Sche.e VII -145- OH 0 Et~XV a,b l (94%) 93 92 c,d,e 98 99 OH OH Et}yyx (78%) 9 ,h .,l ~ ..,..CHO Et' y "I TBSOCH 2 Me TBSOCH 2 Me 100: X= C0 2 Et (91%) 101:X= CH 2 0H 102 (94%) (a) Bu BOTf, Et N; (b) EtCHO; (c) Bu BOAc; (d) LiBH ; (e) TBSCl, 4 2 3 2 Et N; (f) 0 , MeOH; SMe ; (g) DIBAL (100-+101); (h) Mn0 2 3 3 2 (101---.102). -146- retroaldol reaction. Conversion of the unpurified diol into the acetonide (dimethoxypropane, CSA) gave only a 52% overall yield of product. The use of lithium aluminum hydride (THF sol., 5 molar equiv, -78°C, 45 m) as the reducing agent followed by protection, gave a 32% yield of acetonide. Attempts to improve these yields using solutions of zinc borohydride in ether, lithium aluminum hydride in ether and aluminum hydride (A1H 3) in THF met with only partial success. Similarly, when reduction was performed after protection of the aldol adduct (TES and THP ether), reaction at the oxazolidinone ring carbonyl was the predominant mode of attack. After all these failures, we were gratified to discover that both, retroaldol and reaction at the undesired carbonyl were absent when the reduction was performed on the boron aldolate 10327 (Scheme VIII). . yxv Scheme VIII Bu 3 B • OH HOAc BuH 104 0 -147- Thus, treatment of a solution of 93 in THF with tri-n-butylborane (1.1 equiv) and glacial acetic acid (1.5 equiv) at room temperature for 1.5 h, followed by reaction with lithium borahydride (2 molar equiv, 1.3~ sol. in THF, 0°C, 1 h) afforded, after oxidative workup, (30% H2o2 , RT, 1.5 h) an 86% yield of diol 104, with a 99% recovery of the valine-derived oxazolidinone 9. This method for reducing aldol adducts has since found application in other examples encountered in these laboratories (Scheme IX). Scheme IX HO 1) Bu 2BOAc 0 2) LiBH ~ Ph : XN 4 Me Me HO OH 0 87% OH BnO~ Bno~Xv ~e ~ ~e ~ 92~ OH Ibid. R Et Me Me Me Me t (ref. 28) OH A) Et 83~ (ref. 29} -148- Selective protection of the primary hydroxyl of diol 104 as the !-butyldimethylsilylether {1.3 equiv of TBSCl, 1.3 equiv of Et 3N, 6% equiv of DMAP, CH 2c1 2 , 25°C, 3.5 h) 30 proceeded in 91% yield to give 98. GC analysis of both, the unpurified diol 104 and its correspending silyl ether 98, showed no observable epimerization. Ozonolysis of olefin 98 {MeOH, -78°C) followed by reductive workup (SMe 2 ), resulted in formation of s-hydroxyaldehyde 99, which without purification, was treated with 1.8 equiv of (carbethoxyethylidene)triphenylphosphorane (toluene, 70°C, 9 h). Chromatog- raphy afforded ethyl ester 100 in 91% yield from olefin 98. GC diastereomer analysis before and after purification showed 1.3% of a contaminant, presumably the (Z) olefin. Although the double bond geometry was not proved at this point, its further transformation into tylonolide hemiacetal corroborated our (E) geometry assignment. Because this material was unstable upon standing at room temperature for several days, it was immediately reduced to allylic alcohol 101 (DIBAL sol. in CH 2c1 2 , 3.5 equiv, CH 2c1 2 , -78°C, 15 min) in 96% unpurified yield. This crystalline material showed no decomposition after one year of storage at -20°C. The a,s-unsat- urated aldehyde 102 was obtained by oxidation of 101 using activated Mn0 2 (10 equiv, CH 2c1 2 , RT, 1 h) in 94-100% unpurified yield. Due to its instability, the aldehyde was prepared and used in the same day. -149- This completes the synthesis of the left hand side part of tylonolide which proceeded in seven steps from crotonate imide 92 with an overall yield of 63%, and, at least, 98.6% stereoselection. Compared to the other published routes, this is the shortest and the most efficient approach to the synthesis of this tylosin synthon. 2. Macrocyclization Studies Prior to committing ourselves to a macroaldol condensation strategy, the selective enolization of a methyl ketone in presence of a~-branched-a,a-unsaturated aldehyde had to be tested. For this purpose, alcohol 102 was acetylated (Ac 2o, pyridine, DMAP) to give 105, and an equimolecular mixture of 105 and methyl isopropyl ketone in ether was added into a solution containing di-~-butylboryl triflate (1.1 equiv) and diisopropylethylamine (1.1 equiv) in ether (-78°C, 2 h, then 0°C) (eq. 5). TLC analysis showed very clean, but Upon warming to 0°C no major change was incomplete, conversion. observed, indicating that very probably, the reaction mixture had been quenched by traces of moisture. 31 The aldol adduct was isolated OH ~eJCHO TBSO~-~-Et 105 0 0 + Jl /Me 1 Me' Me TBSO Me OAc (s) -150- in 40% yield after chromatography. Encouraged by this result, we decided to try the macroaldol on a model compound, prepared from methyl oleate in a straightforward fashion (Scheme X). Sche.e X 0 a,b MeO MeO (70%) ! methyl oleate c,d,e 0 0 OH __,l ~ _..CHO Et' y "I TBSOCH 1 Me HO 102 (65%) (51%) 106 (a) o3 , MeOH; SMe 2; (b) HCl, H2o, acetone, 25°C, 30m; (c) Me 2Culi, Et 2o, -78°C, 1.5 h; (d) Jones• oxid., acetone, 25°C; (e) 2~ LiOH, MeOH, 25°C, 4 h; (f) 102, DCC, DMAP. As shown in Scheme X, compound 106 includes the actual left hand tylonolide synthon, but has a nonsubstituted, polymethylene right fragment. Unfortunately, this material proved to be very unstable, -151- showing considerable decomposition one hour after its purification. However, when freshly purified 106 was diluted in ether and added into a cooled (-78°C) solution containing di-~-butylboryl triflate (1.2 equiv) and diisopropylethylamine (1.4 equiv) in ether under high dilution conditions (8 x 10- 3 M) (eq. 6), clean but partial conversion was observed. Oxidative workup and chromatography afforded an inseparable 1:1 mixture (GC) of epimers at c12 (107) in 0 0 TBSO ( 45%) 106 107 j (6) 0 TBSO 108 (50%) -152- 45% yield. This material was converted into the unsaturated ketone 108 by treatment with methyl sulfonyl chloride and triethylamine (excess, CH 2c1 2 , 25°C, 12 h) in 50% yield after chromatography (eq. 6). The olefinic portion of the 1H NMR of 108 greatly resembled the spectrum reported 32 for tylonolide. Like tylonolide, 108 showed an IR band at ca. 1680 cm- 1 , characteristic of an unsaturated ketone. 3. The Construction of the c1-c10 Frag.ent and the Final Steps of the Synthesis of Tylonolide The relatively high yield obtained in the model macroaldol reaction, together with its novelty, encouraged us to build methyl ketone 130 (Scheme XV). As was pointed out in the strate~ic plan, if the macroaldol reaction did not work on this substrate, the corresponding phosphonate would be easily prepared from a common intermediate, (see Scheme XI) and the ring would be formed via a Wittig-Harner reaction, as in the Nicolaou's synthesis. 12 b Following the basic strategy employed in the construction of the Prelog-Djerassi lactone, 35 compound 118 was synthesized in 9 steps from imide 109 in 33% overall yield 33 , 34 (Scheme XII). Thus, the starting imide 109 was prepared by the reaction of the preformed mixed anhydride of 4-benzyloxybutyric acid and pivaloyl chloride, with the lithium salt of oxazolidinone 10, in 72% yield after recrystallization. Treatment of imide 109 with 1.05 equiv of LOA (-78°C, THF, 0.5 h) followed by the reaction with methallyl iodide -153- Scheme XI 0 RQ 0 R" Me 1) "Me-" 2) [ox] / OBn 0 0 R" H 1) "(Me0) P(O)CH2" 2 ~x] OBn 0 II R'o 0 (Me0) 2 P R" Me OBn (5 equiv, -40°C, 12 h) afforded oxazolidinone 110 as a 95:5 mixture of epimers at c2 • The unpurified mixture was then treated with LAH (2 mol equiv, THF, -78°C~0°C) to afford alcohol 111 in 70% yield after chromatography and distillation. recovered in 73% yield. Oxazolidinone 10 was Oxidation with sulfur trioxide pyridine complex in dimethyl sulfoxide (3 equiv of so 3.py, 6.5 equiv of Et 3N, DMSO, 25°C, 30 min) afforded aldehyde 112. Aldol condensation of the unpurified aldehyde 112 with 1.1 equiv of boron enolate 47 (CH 2c1 2 , -78°C~0°C) gave aldol adduct 113. GC analysis indicated 4.5% of an isomer (presumably the c4-epimer) and less than 0.7% of any other observable epimer. Recrystallization afforded pure 113 in 89% yield based on alcohol 111. 0 Sche.e XII 33 -154- 0 BnO 0 II ~N ~ H Me 0 ~XN a 0 Y"· Ph '1 Me Me OBn 109 HO 110 0 1. c XN 2 · BuBO OBn 113 Me H,C~N~Ph 47 )-o 0 (89%) @+@ ~OH Me OBn 111 {70%) d,e.f.g TESO ~-A Me 1 ~e OBn 114: R= 115: R= 116: R= 117: R= HO 0 Me SMe TES? Me Bu 2 BO MeS~N~Ph )-o XN OBn 0 COXN C0 Bn 2 CH 0H 2 CHO @+@ 118 {75%) (a) LOA, THF, -78°C; (b) LAH, THF, -78°C; (c) S0 .py, Et N, DMSO 3 3 (111_.112); (d) TESOTf, Et N, CH c1 (113-.114); (e) PhCH 0Li, THF, 2 3 2 2 0°C (114-.115); (f) RED-AL, THF, -l0°C (115.-..116); (g) S0 .py, Et N, 3 3 DMSO (116.,..117). The results on this scheme are due to Dr. T. Godel. -155- Conversion of 113 into the desired aldehyde 117 involved the following series of reactions: {1) protection of the alcohol as the triethylsilyl ether (TESOTF, NEt 3 , CH 2c1 2 , 25°C) to afford 114; (2) transesterification into benzyl ester 115 {PhCH 20Li, THF, 0°C, 4 h, 88% yield from 112); (3) reduction to alcohol 116 (RED-AL, THF, -10°C, 20 min, 84% yield) and; (4) oxidation to aldehyde 117 (so 3 .py, Et 3N, DMSO, 25°C, 97% yield). Reaction of aldehyde 117 with 1.05 equiv of the preformed boron enolate of the thiomethylacetyl imide 119 (CH 2c1 2 , -78°C~0°C) afforded aldol adduct 118 in 75% yield after chromatography. 119 Before further elaboration of compound 118, we felt that the aldol condensation leading into the c2-c 3 bond formation needed to be studied in some more detail. We knew from early studies 20 that boron enolates 120 and 121 (Scheme XIII) react with poor selectivity when condensed with aldehydes not bearing a chiral center. However, their condensation with chiral aldehydes had never been tested. -156- Scheme XIII TESO 0 OBn 117 121 120 TESQ TESO 0 XC + OH 0 ~ Xc major OBn OBn 122: Xc=XN 124: Xc=XN 123: Xc=Xv 125: Xc=Xv Normally, the aldol condensation of chiral aldehydes with achiral enolates affords ratios of products that fall in the 1 to 4:1 range, the so called Cram-adduct being generally predominant. 36 -157- However, these ratios can be improved to high levels of diastereoselection if both the aldehyde and the enolate have consonant chirality, that is, when both favor one particular relative stereochemistry of the new asymmetric centers (double stereodifferentiation). In a similar way, we felt that the resident chiralities of aldehyde 117 and enolate 120 could cooperate in a consonant fashion to afford good diastereofacial selection. However, when aldehyde 117 was condensed with boron enol ate 120 (CH 2c1 2 , -78°C ~0°C) (Scheme XIII) compound 122 was formed only with moderate preference over 124 (122:124 = 75:25, as indicated by GC). Aldehyde 117 was also condensed under the same conditions with enolate 121, yielding a 123:125 ratio of 70:30. Thus, independently of the imide used in the reaction, we obtained the 3(R) adduct with a selection of ca. 3:1 in both cases. In this reaction the chirality transfer from the enolate was negligible, as we had previously observed with simpler, achiral aldehydes. 20 b The moderate selection was due almost entirely to the aldehyde's chirality. The absolute configuration of c3 in 122 was assigned (R) by an alternative preparation (see Scheme XIV). Transesterification (PhCH 20Li, THF) of 122 and 123 lead to the same benzyl ester 126. Transesterifica- tion of 124 and 125 gave also one ester, different from 126. These results proved the 3(R) and 3(S) stereochemistries of compounds 123 and 124 respectively. -158- The disappointing results described above, which were aimed at establishing the c3 hydroxyl stereochemistry, led us back to the utilization of our operationally effective chiral acetate enolate synthon 119. Thus, with compound 118 in hand, two main trans- formations needed to be accomplished: boration of the olefin. desulfurization and hydro- We found out that best yields on subsequent reactions were obtained when desulfurization was performed immediately after the aldol condensation. Indeed, the release of congestion at the c2 position facilitated in a great deal both, the c3 hydroxyl protection and the chiral auxiliary removal necessary for our synthesis. Thus, treatment of thioether 118 with a suspension of Raney-Nickel 47 (acetone, EtOH, 25°C) afforded 122 in 80% yield (Scheme XIV). A byproduct, tentatively assigned as the 3-dehydroxy-122, was isolated in 10% yield. This material was probably formed via elimination of water followed by the in situ reduction of the a,s-unsaturated imide. Transesterification of 122 with 1.8 equiv of lithium benzyloxide (THF, -50°C, 4 h) afforded benzyl ester 126 in 83% yield. As we already mentioned, the absence of an a substituent in 122 allowed this reaction to proceed at low temperatures, affording better yields. Benzyl ester 126 was protected as the 1-butyldimethylsilylether 69 (TBSOTF, 1.5 equiv, Et 3N, CH 2Cl 2) in 97% yield. The final asymmetric center, c8 , was constructed via a hydroboration process of 69 (2 equiv of thexylborane, THF, 0°C, 5 h; then H2o2 , pH 9.2, MeOH, 0°C) which gave a -159- Scheme XIV TESO OH 0 QH TESQ a 0 XN Me XN SMe Me OBn OBn (80%) 118 122 Jb TESQTBSQ -- -- 0 TESQ 9H 0 c OBn OBn Me Me OBn 69 {97%) ld OH OBn 126 @ TESOTBSO 0 e OBn Me OBn 70:8R (69%) {83%) TES?TBS? H 0 OBn Me OBn 128 (90%) 127:85 (15%) (a) Ni-Ra, acetone, 25°C; (b) PhCH 20Li, THF, -50°C; (c) TBSOTf, Et 3N, CH 2Cl 2; (d) ThxBH 2, THF, 0°C; H2o2; (e) so 3.py, Et 3N, DMSO. -160- 69% yield of alcohol 70 along with a 15% yield of its c8-epimer, 127. This 4.5:1 ratio was also supported by the careful integration of the c5-H in the 500 MHz 1H NMR spectrum of an unpurified reaction mixture. The conversion of alcohol 70 to methyl ketone 130 was accomplished in three steps. Thus, oxidation of 70 (S0 3 .py, NEt 3 , DMSO) gave aldehyde 128 in 93% yield, which upon treatment with lithium dimethyl cuprate (Et 2o, -78°C, 1.5 h) afforded an 87% yield (based on alcohol 70) of the corresponding secondary alcohol 129 (Scheme XV). Two-phase Jones• oxidation 37 (Na 2cr 2o7 , H2so 4 , H20-Et 2o, 25°C, 2 h) afforded 130 in 86% yield. This process occurred without any detectable epimerization by TLC analysis, as determined by monitoring the reaction with an authentic sample of the c8-epimer of 130, derived from alcohol 127. Selective hydrogenolysis of 130 (H 2 , 5% Pd-C, EtOAc, 25°C 45 min) afforded a quantitative yield of unpurified keto acid 131, which was coupled with alcohol 102 (1:1 mixt. of substrates, DCC (1.1 equiv), DMAP (catalytic), CH 2c1 2 , 25°C, 7 h) to give 132 in 73% yield, based on 130. This material showed a much lower rate of decomposition than the corresponding unsubstituted counterpart 106 (Scheme X). The setting for the projected macroaldol reaction was now completed. Thus, compound 132 was diluted in ether and added to a cooled (-78°C) solution containing 2.2 equiv of di-Q-butylboryl -161Scheme XV TESOTBSO : :- 0 0 0 - H TES<?TBS<? a,b OBn Me OR Me Me OBn (80%) OBn 128 130: R= Bn 131 : R= H HO Me~ 0 : - 129 c,d 0 ,,, No reaction. ( OBn ,Me e ,, \\ I I 11 132 0TES (73%) (a) Me 2Culi, Et 2o, -78°C (128~129); Jones• oxid., H20-Et 2o, 25°C (129--.130); (c) H2 (Pd-C), EtOAc, 25°C (130 ......131); (d) 102, DCC, DMAP (131~132); (e) Bu 2BOTf, (iPr) 2NEt, Et 20, 10- 3 M. triflate and 2.4 equiv of diisopropylethylamine in ether {concentration of 132 = 10 -3 ~). After 1.5 h, no reaction was observed by TLC. Subsequent additions of solutions containing 1:1.1 mixtures of -162- triflate and amine did not make any change. No transformation was observed after stirring the mixture at -20°C overnight. wor~up Oxidative and product isolation resulted in recovery of 132. A similar reaction carried out in CH 2c1 2 again failed to proceed at -78°C, and, upon warming to 0°C, afforded a complex mixture of unidentified products. In an attempt to understand the cause of this failure, we tested the reaction on its bimolecular counterpart. For this purpose, alcohol 102 was protected as the acetate, and acid 131 was transformed into the methyl ester. Then, when a 1:1 mixture of these compounds in CH 2c1 2 (0.06 ~) was successively treated with diisopropylethylamine (1.8 equiv) and di-~-butylboryl triflate (1.2 equiv), again TLC showed no reaction at -78°C, 0°C or 25°C for 0.5 h. Product isolation afforded starting materials. The mixture did not react even upon treatment with 2 equiv of LOA (THF, -78°C, 0°C, 25°C). These experiments indicated that, for some unknown reason, the substrate was very reluctant to enolize, or, in the case that it did, the enolate was very unreactive. The possibility existed that the reaction might have been quenched by adventious traces of moisture that might have been present in the large amount of solvent (ether) required for the intramolecular reaction. However, if this were the case, at least some reaction should have been observed in the bimolecular case, where the amount of solvent was much smaller. -163- Disappointed by these results, we decided to direct our efforts towards the synthesis of the macro-Wittig precursor, as depicted in Scheme XVI. Addition of a THF solution of aldehyde 128 into a cooled (-100°C) solution containing the lithium salt of dimethylmethylphosphonate38 resulted in attack at both the aldehyde and the ester carbonyls, affording only 54% yield of the desired secondary alcohol (based on alcohol 70). Attempts to improve the regiaselectivity using milder nucleophiles (organocuprate 38 and organozinc 39 derivatives) (-78°C~25°C) resulted in recovery of starting material. Fortunately, however, the organomagnesium derivative proved to have the desired reactivity, in that it reacted very selectively with the aldehydic functionality at -50°C. Thus, the lithium salt of dimethylmethylphosphonate in THF was treated with a solution of magnesium bromide (-78°C_.0°C), and an aliquot (1.6 equiv) was added to a solution of aldehyde 128 in THF (-78°C~-50°C). Collins• oxidation (7 equiv of Cr0 3.2py, CH 2Cl 2 )40 of the unpurified resulting e-hydroxyphosphonate afforded 8-ketophosphonate 133 in 79% overall yield from aldehyde 128 after chromatography. Both benzyl ester and benzyl ether groups of 133 were cleaved by hydrogenolysis (H 2 , 10% Pd-C, CH 2c1 2 , 25°C, 1 h). The unpurified resulting hydroxyacid was diluted in CH 2c1 2 and treated successively with triethylamine (4 equiv) and 1-butyldimethylsilyltriflate (2.5 equiv). The silyl ester functionality was selectively hydrolyzed (H 20, 3 h) to afford acid 134 in 61~ -164- Scheme XVI TESOTBSO 0 H 0 0 II (Me0) 2 P a,b OBn TESQTBS<? 0 OBn Me OBn OBn 133 128 (79%) c,d ,e OH 0 A ~ _...CHO "I Et' ' ( TBSOCH 2 Me TESQTBSQ 102 0 OH Me '•,,OTBS 135 OTES (61%) 134 (80%) 0 9 ,, ( OTES ,,Me ,,,, '•,,OTES TBSO '''•OTBS 136 (88%) (a) (Me0) 2P(O)CH 2MgBr, THF, -50°C; (b) Cr03.2py, CH 2c1 2 ; (c) H2 , 10% Pd-C, CH 2Cl 2; (d) TESOTf, Et 3N, CH 2Cl 2; (e) H20; (f) 102, DCC, DMAP; (g) K2co 3 ; 18-cr-6, 10 -3 ~' tol. -165- yield from 133. Acid 134 was esterified with freshly prepared alcohol 102 (1.15 equiv) (DCC, DMAP, CH 2c1 2 , 1~, 25°C, 6 h) affording ester 135 in 80% yield. When a 10 -3 M solution of 135 in anhydrous toluene was treated with anhydrous K2co 3 (12 equiv) in presence of 18-crown-6 ether at 60°C, 12 b formation of macrocycle 136 occurred very smoothly and cleanly (16 h). Aqueous workup and flash chromatography afforded a 88% yield of cyclized product, 136. Clearly, this rrethod developed by Nicolaou stands unique in its high efficiency. The last sequence of steps leading to our target molecule are shown in Scheme XVII. The primary triethylsilyl ether functionality in 136 was selectively hydrolyzed by treatment with mild acid (1:4 of 0.1% HCl :THF, 25°C, 1 h) and oxidized (10 equiv of Cr0 3 .2py) 40 to the crystalline aldehyde 138 in 93% yield. Finally, the three remaining silyl ethers were removed by treatment of 138 with hydrofluoric acid (1:5 of 48% aq. HF:CH 3CN, 25°C, 12 h). Crystal- line, (+)-tylonolide hemiacetal 87 was isolated in 92% yield after chromatography, as a mixture of anomers at c20 • A sample of 87 derived from natural tylosin 41 was prepared for comparison purposes, following the literature procedure. 2 , 32 Thus, mild acidic hydrolysis (2:1 THF:10% aq HCl, 25°C, 1 h) of tylosin detached the sugar mycarose affording desmycosin in 95% yield. Stronger acidic conditions (5% HCl, 90°C, 24 h) hydrolyzed the remaining neutral sugar linkage, delivering mycinose, and affording -166- ScheR XVII 0 0 ,,,M~HO ,,.Me (OR \\ TBSO ,, a,b \' \ TBSO ''''OTES J ''''OTES ,, ''''OTBS ''OTBS 138 136: R= TES 137: R= H c 0 HO 87 {93%) {92%) -167- 5-Q-mycaminosyltylonolide (OMT) in low yield (7%). Finally, the mycaminosyl moiety was removed via a Polonovsky reaction of the corresponding N-oxide (MCPBA, CH 2Cl 2; then TFAA, CH 2Cl 2 ; then NaOAc in THF:H 20). Chromatography afforded a sample of naturally derived 87, in 28% yield. The synthetic and the naturally derived materials showed identical physical properties (TLC, mp, IR, 500 MHz 1H NMR, 13 c NMR and specific rotation). Tylonolide hemiacetal presents some unexpected features. When a solution of 87 in chloroform was concentrated in vacuo, the material was semicrystalline and had no sharp melting point. On the other hand, crystallization from dichloromethane:hexane afforded a crystalline compound (mp synth: 154.5-156.5°C; nat: 155-157°C). The proton NMR spectrum of this material indicated that hexane had been occluded during crystallization in a proportion of ca. 2:1 of 87:hexane. The 500 MHz 1H NMR spectra of the synthetic and naturally derived tylonolide hexane complexes are showed in pages 351-356. Due to the presence of two isomers (ca. 3:1 anomeric mixture atC20) most of the signals are doubled. The peaks are assigned based on the reported spectrum of tylonolide 5b or by comparison with the reported spectra of tylosin derivatives. 6 ' 9 In p. 356, the peaks labeled "hex•• are due to the hexane occluded during recrystallization. In p. 350 is shown the spectrum of free tylonolide (i.e. without hexane) in presence of o2o. The changeable protons resonate at o 3.8, 3.2 (1/3 H) and 2.9 (2/3 H). The third -168- hydroxylic proton might be forming part of one of the multiplets, and therefore,difficult to visualize. IV. Sullnary The enantioselective total synthesis of (+)-tylonolide, cyclic 5,20-hemiacetal is reported. The utility of highly selective alkylation and aldol reactions, using norephedrine and valinederived oxazolidinones, is demonstrated by the construction of 6 of the 7 chiral centers present in the molecule. The remaining asymmetric center is created via hydroboration. The linear· precursor is closed to a 16-membered ring by means of a Wittig-Harner reaction. The longest sequence in the synthesis involves 24 steps (from oxazolidinone 109) and proceeds with an overall yield of 3%. -169- Experimental Section General. Melting points were determined with a BUchi SMP-20 melting point apparatus and are uncorrected • . Infrared spectra were recorded on a Beckman 4210 spectrophotometer. 90 MHz 1H NMR spectra were recorded on a Varian Associates EM-390 spectrometer and are reported in ppm on the o scale, from the indicated reference. Data are presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, m =multiplet, br =broad), coupling constant (in Hz), integration and interpretation. 500 MHz 1H NMR spectra were recorded on a Bruker WM-500 spectrometer at the Southern California Regional NMR facility. 13 c NMR spectra were recorded on a JEOL FX-90Q (22.5 MHz) spectrometer and are reported in ppm on the o scale from the indicated reference. Combustion analyses were performed by Spang Microanalytical Laboratory (Eagle Harbor, Michigan), Galbraith Laboratories, Inc. (Knoxville, Tennessee), or Mr. Lawrence Henling (California Institute of Technology). Optical rotations were recorded on a Jasco DIP-181 digital polarimeter at the sodium D line (589 nm) and are reported as follows: [a] 25 , solvent, and 0 concentration (£ = g/100 ml). Analytical gas-liquid chromatography (GC) was carried out on a Hewlett Packard 5880 A level 3 gas chromatograph equipped with a split mode capillary injection system and a flame ionization detector, using a 25m x 0.2 mm flexible fused silica capillary -170- column wall-coated with Carbowax 20M or Methyl Silicone (SP-2100), or a 30m x 0.32 mm fused silica capillary wall-coated with SE-54. Unless otherwise noted, injector and detector temperatures were 250°C. Data are reported as follows: column type, oven temperature, and retention time (tr). Liquid chromatography was performed using a forced flow (flash-chromatography) of the indicated solvent system on EM Reagents Silica Gel 60 (230-400 mesh). follows: Data are reported as column diameter, weight of silica and eluent composition. Medium pressure liquid chromatography (MPLC) was carried out using EM Reagents LoBar Silica Gel 60 prepacked columns (column size indicated) on a Chromatronix MPLC apparatus equipped with a Fluid Metering Inc. Model RP-SY Lab Pump. Analytical thin layer chromatography (TLC) was performed using EM Reagents 0.25 mm silica gel 60-F plates. When necessary, solvents and reagents were dried prior to use. Tetrahydrofuran, diethyl ether, benzene and toluene were distilled from sodium metal/benzophenone ketyl. Dichloromethane, diiso- propylethylamine, diisopropylamine, triethylamine and boron trifluoride etherate were distilled from calcium hydride. Dimethyl sulfoxide and dimethylformamide were distilled under reduced pressure from calcium hydride and stored over activated 4 A molecular sieves. -171- Unless otherwise specified, all non-aqueous reactions were conducted under a rigorously dried argon atmosphere, using oven-dried glassware. (S,E)-4-(1-Methylethyl)-3-(1-oxo-2-butenyl)-2-oxazolidinone {92). To a mechanically stirred, cooled (-78°C) solution of 9 (11.62 g, 90 mmol) and a trace amount of diphenylacetic acid (used as an indicator) in anhydrous tetrahydrofuran (250 ml), was added a 1.7 ~solution of n-butyllithium in hexane (52.5 ml, 90 mmol' 1 equiv) until appearance of a pink coloration (i.e. formation of the diphenylacetate dianion). The slurry was stirred at -78°C for 15 min, and then quenched by the quick addition of purified crotonyl chloride 42 (9.0 ml, 94.5 mmol, 1.05 equiv). The cooling bath was removed and the mixture was allowed to warm slowly (45 min) to room temperature, stirred an additional 1.5 h and quenched with 100 ml of saturated aqueous ammonium chloride. The volatiles were removed in vacuo, and the remaining mixture extracted with dichloromethane (2 x 200 mL). The organic phase was washed with saturated aqueous sodium bicarbonate (2 x 50 mL), and with brine (1 x 100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to 18 g of a yellowish solid. Recrystallization (ether-hexane) afforded 13.7 g {78%) of the title compound as white needles: mp 56.5-57.5°C; IR {CH 2Cl 2) 3060, 2975, 1780, 1685, 1640, 1340, 1210, 1038 cm- 1 ; 1H NMR {90 MHz, CDC1 3 ) o (TMS) 7.27-6.97 (m, 2H, olefinic -172- f I I 1 H), 4.56-4.13 (m, 3H, -NC~C~2 0), 2.60-2.23 (m, sym, lH, (CH 3 ) 2 C~), I I 1.95 (d, J = 5.5, 3H, C~3 CH=), 0.92 (d, J = 7, 3H, C~3 CHCH 3 ), 0.89 25 (d, J = 7, 3H, CH 3 CHC~3 ); [a] 0 = +109.9° (CH 2Cl 2 , £ = 2.5). Anal. calcd. for c10 H15 N0 3 : C, 60.90; H, 7.67. Found: C, I 60.99; H, 7.56. (3(2S,3R),4S)-3-(2-Ethenyl-3-hydro~-1-oxopentyl)-4-(l~thyl- ethyl)-2-oxazolidinone (93). To a cooled (-78°C) solution of imide 92 (5.85 g, 29.6 mmol) in anhydrous dichloromethane (50 mL) was added di-~-butylboryl triflate (8.00 ml, 32.6 mmol, 1.1 equiv) over 30 seconds, resulting in a yellow solution. After 5 min, anhydrous triethylamine (4.97 ml, 35.5 mmol, 1.2 equiv) was added over 2 min, resulting in the disappearance of most of the yellow color. The solution was stirred at -78°C for 30 min, then allowed to warm to 0°C slowly, and stirred at this temperature for 1 h. The solution was recooled (-78°C) and freshly distilled propionaldehyde (2.77 ml, 38.5 mmol, 1.3 equiv) was added in one portion. The clear solution was stirred at -78°C for 1.5 h, slowly warmed to ooc and stirred for 45 min. The reaction was quenched by the addition of 30 ml of phosphate buffer (pH 7), poured into a 500-ml flask containing 70 ml of methanol, cooled to 0°C, and treated with a solution of 25 ml of 30% aqueous hydrogen peroxide in 25 ml of methanol for 1 h. The organic solvents were removed in vacuo, and the aqueous residue extracted with ether (3 x 100 mL). The combined ethereal layers -173- were carefully washed with saturated aqueous sodium sulfite. The sulfite aqueous solution was back extracted with ether (1 x 50 ml), and the combined ethereal layers were washed with 5% aqueous sodium bicarbonate. The aqueous bicarbonate solution was back extracted with ether (3 x 20 ml). Pentane was added to the combined organic layers, and the cloudy solution was dried over anhydrous sodium sulfate, filtered and concentrated to a colorless oil. Gas · chromatography analysis (SE-54, 220°C, 5 PSI, tr = 3.63 min) of the silylated (triethylsilyltriflate, triethylamine, CH 2c1 2 , 5 min) unpurified aldol adduct indicated 93 to be > 98.6% diastereomerically pure. Flash chromatography {50 mm, 210 g silica, 50% ethyl acetate:hexane) afforded 7.09 g (94% yield) of pure 93 as a colorless oil: Rf 0.23 {30% ethyl acetate:hexane); IR {CH 2Cl 2) 3800-3400 (br), 3060, 2970, 1783, 1685, 1385, 1372, 1225, 1210, 750 cm- 1 ; 1H NMR (500 MHz, CC1 4 ) o (TMS) 6.000 (d of d of d, JAC = 18.0, JAB= 10.0, JAD = 9.1, 1H, HA), 5.376 {d of d, JCA = 18.0, JCB = 2.0, 1H, HC), 5.216 {d of d, JBA = 10.0, JBC = 2.0, 1H, H8 ), 4.654 (d of d, JOE= 3.5, JDA = 9.1, 1H, H0 ), 4.122-4.082 (m, 1H, HE), 3.853 (d of d of d, JIG= 8.5, JIH = 4.7, JIJ = 3.5, 1H, HI), 3.697-3.608 {m, 2H, HG, HH), 3.086 (br s, 1H, -0~), 2.125 {q of q of d, JJK = JJL = 7.0, JJI = 3.5, 1H, HJ), 1.610-1.514 (m, 1H, 3 I CH C~{H)), I 1.480-1.393 (m, 1H, CH 3 CH(~)), 0.993 (t, JMF = 7.5, 3H, I CHJ(M))' 0.618 (d, J = 7.0, 3H, C~3 CHCH 3 ), 0.600 (d, J = 7.0, 3H, 13 CH CHC~ ); C NMR {CC1 4 ) o (TMS) 173.65, 152.66, 131.99, 120.23, 3 3 I -174- 72.53 (carbinol), 62.58, 57.77, 51.47, 28.07, 26.84, 17.74, 14.49, 10.07; [a];5 = -12.4° (CHC1 3 , £ 3.2). Anal. calcd. for c13 H21 N0 4 : C, 61.16; H, 8.29. Found: C, 60.97; H, 8.38. 93 (3R,4R)-4-Hydroxy-3-((((l,l-di.ethylethyl)di.ethylsilyl)oxy)methyl)-l-hexene {98). A solution containing imide 93 {1.49 g, 5.83 mmol) in 20 ml of anhydrous tetrahydrofuran was treated successively with glacial acetic acid {0.5 ml, 8.7 mmol, 1.5 equiv) and tri-nbutylborane (1.75 ml, 6.4 mmol, 1.1 equiv). After stirring the colorless solution for 1.5 h at room temperature, the resultant boron aldolate 103 was cooled to 0°C and a 1.3 M solution of lithiumborohydride in dry tetrahydrofuran {8 ml, 2 molar equiv) was added over 30 sec, occasioning evolution of hydrogen. The reaction mixture was stirred at 0°C for 1 h, and quenched by the careful addition of a solution containing 20 ml of methanol, 20 ml of phosphate buffer (pH 7), and 10 ml of 30% aqueous hydrogen peroxide. The mixture was stirred for 10 min at 0°C followed by 1.5 h at room -175- temperature. The volatiles were removed in vacuo and the remaining aqueous solution extracted with dichloromethane 20x (i.e. until TLC analysis indicated the absence of dial 104 in the aqueous phase). The combined organic layers were washed with 40 ml of 5% aqueous sodium bicarbonate, and the aqueous layer back extracted with dichloromethane until TLC analysis indicated absence of dial 104 in the aqueous phase. The combined layers were dried over anhydrous sodium sulfate, filtered and concentrated to a colorless, clear liquid. Flash chromatography (50 mm, 140 g silica, diethyl ether) afforded 653 mg (86%) of dial 104 (Rf 0.26, ether) as a clear liquid, and 747.4 mg (99%) of valine oxazolidinone 9 (Rf 0.17, ether). A portion of dial 104 (338 mg, 2.6 mmol) was diluted in anhydrous dichloromethane (3.5 mL), and treated successively with dry triethylamine (0.47 ml, 3.35 mmol, 1.3 equiv), N,N-dimethyl4-amino pyridine (20 mg, 6% molar equiv) and 1-butyldimethylsilylchloride (509 mg, 3.35 mmol, 1.3 equiv) according to the procedure described by Hernandez. 30 After stirring the solution for 3.5 h at room temperature, saturated aqueous ammonium chloride was added. The layers were separated and the aqueous layer was extracted once with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to a colorless oil. Gas chromatography analysis (SE-54, 100°C, 15 PSI, tr = 2.76 min) showed 98 to be > 97% pure. Flash chromatography (40 mm, 70 g -176- silica, 20% ethyl acetate:hexane) afforded 578.0 mg (78% from 93) of alcohol 98 as a colorless oil: Rf 0.50 (30% ethyl acetate:hexane); IR (CHC1 3 ) 3500 (br), 3090, 3020, 1638, 1462, 1255, 1110, 1085, 838 em -1 1 ; H NMR (500 MHz, CDC1 3 ) o (CHC1 3 ) 5.907 (d of d of d, JAC = 17.5, JAB = 10.3, JAD = 9.2, 1H, HA), 5.165 (d of d, JBA = 10.3, JBC = 2.2, 1H, H8 ), 5.095 (d of d, JCB = 2.2, JCA = 17.5, 1H, He), 3.815 (m, 2H, HG, HG,), 3.743 (octuplet, J = 3, 1H, HE), 3.027 (d, J = 3.5, 1H, 0~), 2.252-2.204 (m, 1H, H0 ), 1.53-1.38 (m, 2H, ' HF,HF,), 0.926 (t, J = 7.5, 3H, CH 3 (H)), 0.880 (s, 9H, (C~3 ) 3 C), 0.058 (s, 3H, C~3 ~iCH 3 ), 0.054 (s, 3H, CH 3 ~iC~3 ); [a]~ 5 = -20.1° (CHC1 3 , f. 4.4). Anal. calcd. for c13 H28 o2Si: C, 63.87; H, 11.54. Found: C, 63.72; H, 11.27. 98 {2E,4R,5R)-5-Hydro~-4-((({l,l-di.ethylethyl)di.ethylsilyl)­ o~).ethyl)-2-.ethy1-2-heptenoic acid, ethyl ester (100). Into a cooled (-78°C) solution of olefin 98 (2.91 g, 11.9 mmol) in 50 ml of methanol, containing 10 drops of Sudan III ozonolysis indicator -177- solution (pink color), was bubbled ozone until the pink color disappeared. Argon was bubbled and then dimethylsulfide (15 ml, 240 mmol, 20 equiv) was added. The solution was slowly warmed to room temperature and stirred for 4 h. The volatiles were removed in vacuo, and the slightly yellow remaining oil diluted in 40 ml of freshly distilled toluene, under argon. The solution was then treated with (carbethoxyethylidene)triphenylphosphorane (7.76 g, 21 mmol, 1.8 equiv) which was added in portions into the reaction flask. The solution was stirred at 70°C for 9 h, then concentrated in vacuo. Most of the triphenylphosphine oxide formed during the reaction was removed by precipitation with ether first, then with 20% ethyl acetate:hexane. Filtration, concentration and flash chromatography (50 mm, 200 g silica, 20% ethyl acetate:hexane) afforded 3.57 g (91% from 98) of ethyl ester 100 as a slightly yellow oil. Diastereomer analysis before and/or after chromatog- raphy (SE-54, 150°C, 10 PSI, t r isa.er = 6.24 min, t r 100 = 6.48 min) revealed a ratio of isomer:100 of 1.3:98.7: Rf 0.44 (30% ethyl acetate:hexane); IR (CHC1 3) 3500 (br), 3015, 2862, 2840, 1700, 1460, 1355, 1090, 838 cm- 1 ; 1H NMR (500 MHz, CDC1 3) 8 (CHC1 3) 6.886 (d of q, Jq = 1.2, Jd = 10.5, 1H, olefinic H), 4.238-4.104 (m, 2H, I CH c~ 0C=O), 3 2 I 3.846 (octuplet, J = 2.5, J = 3.2, 1H, HOC~-), 3.808 I I (q, J = 10.0, 1H, TBSOC~(H)), 3.799 (q, J = 10.5, 1H, TBSOCH(~)), I 3.015 (d, J = 3.2, 1H, -0~), 2.634-2.586 (m, 1H, TBSOCH 2CH-), 1.854 I I (d, J = 1.2, 3H, CH 3C=), 1.500-1.330 (m, 2H, CH 3CH 2CH-), 1.271 (t, -178- 2 I 3 2 f J = 7.3, 3H, c~3 cH 0C=O), 0.932 (t, J = 7.5, 3H, c~ cH CH-), 0.881 I, I 25 (s, 9H, (C~3 ) 3 C), 0.046 (s, 6H, (C~3 ) 2 Sl-); [a] 0 = -11.6° {CHC1 3 , £ 2.2). Anal. calcd. for c17 H34 o4Si: C, 61.77; H, 10.37. Found: C, 61.83; H, 10.25. Note: This compound decomposed almost completely after two weeks of standing at room temperature. (2E,4R,5R)-4-(({(1,1-Di.ethylethyl)di.ethylsilyl)oxy)methyl)2-methyl-2-heptene-1,5-diol (101). To a well stirred, cooled (-78°C) solution of ethyl ester 100 (44 mg, 0.133 mmol) in 3 ml of anhydrous dichloromethane was added a 1 M solution of diisobutylaluminum hydride in dichloromethane {0.46 ml, 0.46 mmol, 3.5 equiv). The solution was stirred for 15 min and quenched by the addition of saturated aqueous ammonium chloride. The white slurry was carefully acidified with 1 ~aqueous hydrochloric acid, and the aqueous layer extracted with dichloromethane {3 x 20 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 36.0 mg (96%) of diol 101 as a white crystalline compound, pure by 1H NMR and TLC analysis. An analytical sample was obtained by recrystallization from ether:pet. ether: Rf 0.33 (50% ethyl acetate:hexane); mp 68-70°C; IR {CHC1 3) 3620, 3490 (br), 3020, 1465 (d), 1255, 835; 1H NMR {500 MHz, CDC1 3) 5 -179- (CHC1 3) 5.464 (br d of q, Jq= 1.5, ~ = 10.0, 1H, olefinic H), 3.986 I I (br s, 2H, HOC~2 ), 3.760-3.710 (br m, 1H, HOC~-), 3.700 (d, J = 5.5, I 2H, TBSOC~2 CH-), 3.073 (br s, 1H, -0~), 2.504 (decaplet, J = 2.5, I 1H, TBSOCH 2 c~-), 2.154 (br, 1H, -0~), 1.650 (br d, J = 1.2, 3H, I I I 1.47-1.34 (m, 2H, CH 3CH 2 ), 0.906 (t, 3H, C~3 cH 2 ), 0.860 (s, 3 1• 1. 13 9H, (C~3 ) 3 C), 0.030 (s, 3H, C~3 S,1CH 3 ), 0.025 (s, 3H, CH 3 ~,c~3 ); C ~ CC=), I NMR (CDC1 3) b (CDC1 3 ) 137.89, 121.52, 75.11, 68.49, 65.89, 43.86, 27.54, 25.79, 18.12, 14.22, 10.39, -5.60; [a]~ 5 = -19.3° (CHC1 3 , £ 1.5). Anal. calcd. for c15 H32 o3Si: C, 62.45; H, 11.18. Found: C, 62.34; H, 11.02. (2E,4R,5R)-5-Hydroxy-4-((({1,1-di.ethylethyl)dimethylsilyl)oxy)methyl)-2-.ethyl-2-heptenal {102). A solution containing diol 101 (40.7 mg, 0.14 mmol) in 1 ml of anhydrous dichloromethane was treated with activated manganese dioxide (126 mg, 10 equiv). The black slurry was stirred at ambient temperature for 1 h, and filtered through celite. The celite was washed several times with dichloromethane and the combined filtrates were concentrated to yield 40.0 mg (100%) of aldehyde 10~ as a colorless oil, pure by 1H NMR and TLC analysis: Rf 0.31 (30% ethyl acetate:hexane); IR (CHC1 3) 3500 (br), 3020, 1685, 1465 cm- 1 ; 1H NMR (90 MHz, CDC1 3) b . (CHC1 3) 9.39 (s, 1H,-C~O), 6.66 (br d, J = 10, 1H, olefinic H), I I 3.99-3.58 (m, 1H, HOC~-), 3.78 (d, J = 5, 2H, TBSOCH 2), 2.93 (d, -180- I J = 3, lH,-0~), 2.85-2.58 (decaplet, J = 3, lH, TBSOCH 2 C~-), 1.73 I I (d, J = 1, 3H, C~3 C=), 1.55-1.15 (m, 2H, CH 3 c~2 ), 0.85 (t, J = 7, I I I 3H, C~3 cH 2 ), 0.82 (s, 9H, (C~3 ) 3 C), 0.03 (s, 6H, (C~3 ) 2 Si-). A portion was chromatographed to afford an analytical sample: [a]~5 = -29.2° (CHC1 3 , £ 1). Note: This substance partially decomposed upon 1 day of storage at -20°C. {4R,5S{S))-3-{{4-Ethyl-2,2-di.ethyl-1,3-dioxan-5-yl)carbonyl)4-{l-.ethylethyl)-2-oxazolidinone (94). A cooled (-78°C) solution containing aldol adduct 93 (6.44 g, 25.2 mmol) and several drops of Sudan III ozonolysis indicator solution (pink color) in 300 ml of methanol was treated with ozone until the pinkish color disappeared. The solution was bubbled with argon to remove excess ozone and then treated dropwise with a 0.145 M solution of zinc borohydride in 25 diethyl ether (170 ml, 1 molar equiv). The solution was stirred at -78°C for 20 h, then slowly warmed to -20°C, and finally quenched by the slow addition of 5 ~aqueous phosphate buffer (pH 7). The volatiles were removed in vacuo, and the remaining white slurry acidified with 3 ~aqueous hydrochloric acid to pH 1 resulting in a clear solution, which was extracted with dichloromethane (3 x 100 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 7.58 g of an oi 1. -181- The unpurified product was dissolved in 60 ml of acetone and treated successively with 2,2-dimethoxypropane (35 ml, 283 mmol, 11 equiv) and a catalytic amount of camphorsulfonic acid. The reaction mixture was stirred at room temperature for 2 h, quenched by the addition of saturated aqueous sodium bicarbonate and concentrated in vacuo. The aqueous residue was extracted with dichloromethane (3 x 100 mL), and the combined extracts filtered and concentrated to give acetonide 94 as an oil. Gas chromatography analysis (SE-54, 160°C, 10 PSI, tr = 5.22 min) indicated 94 to be >99.7% diastereomeric pure. Flash chromatography (50 mm, 300 g silica, 26% ethyl acetate:hexane) afforded 6.19 g (82% from 93) of the title compound as white crystals: Rf 0.42 (30% ethyl acetate:hexane); mp 48.5°-49.5°C; IR (CHC1 3) 3055, 2970, 1782, 1690, 1385, 1367, 1205 cm- 1 ; 1H NMR (90 MHz, CDC1 3) o (TMS) 4.53-3.65 (m, 7H, -C~OC(Me) oc~ c~; -NC~C~ -), 2.50-2.05 (m, lH, CH C~CH ), 1.6-1.2 3 3 2 2 2 I I I I I I I I (m, 2H, CH 3 c~2 ), 1.45 (s, 3H, ~3 C~CH 3 ), 1.37 (s, 3H, H 3 C~C~3 ), 25 1.05-0.70 (m, 9H, C~3 CHC~3 , C~3 cH 2 ); [a] 0 = +142.0° (CHC1 3 , .£ 1.85). I I Anal. calcd. for c15H25 N0 5 : C, 60.18; H, 8.42. Found: C, 60.44; H, 8.57. (4R,5S)-4-Ethyl-2,2-di.ethyl-1,3-dioxan-5~thanoic acid, phenylmethyl ester {95). To a cooled (-15°C) solution of benzyl -182- alcohol (3.19 ml, 30.84 mmol, 1.9 equiv) in anhydrous tetrahydrofuran (20 mL), was added a 1.7 ~solution of n-butyllithium in hexane (16.2 ml, 27.6 mmol, 1.7 equiv). After stirring for 15 min, a solution containing acetonide 94 (4.86 g, 16.23 mmol) in 16 ml of dry tetrahydrofuran was added dropwise. The reaction mixture was stirred between -15°C and -5°C for 1.5 h, quenched with pH 7 phosphate buffer solution and concentrated in vacuo. The aqueous layer was extracted with dichloromethane (2 x 150 ml), and the combined organic layers dried over anhydrous sodium sulfate, filtered and concentrated to a yellow liquid. Gas chromatography analysis of the unpurified reaction mixture (SE-54, 150°C, 10 PSI, t r = 4.59 min) showed 95 to be>- 98.6 diastereomerically pure. Flash chromatography (50 mm, 250 g silica, 10% ethyl acetate:hexane) afforded 4.10 g (91%) of the title compound as a colorless oil (the column was then flushed with 1:1 ethyl acetate:methanol and 1.92 g (92%) of valine oxazolidone 9 was obtained): Rf 0.53 (30% ethyl acetate:hexane); IR (CH 2Cl 2 ) 3050, 2990, 1730, 1453, 1384, 1202, 1168, 1102, 1005 cm- 1 ; 1H NMR (500 MHz, CDC1 3 ) o (TMS) 7.58-7.25 (m, SH, aromatic H), 5.125 (s, 2H, PhC~2 o), 4.018 (t, J = 11.5, 1H, I I -OCH(~)), I 3.963 (d of d of d, J = 3.1, J = 8.1, J = 11, 1H; -OC~-), I 3.946 (d of d, J = 5.5, J = 11.2, 1H, -OC~(H)), 2.650 (d oft, I I I Jd = 5.2, Jt = 10.2, 1H, -C~C=O), 1.590-1.49 (m, 1H, C~(H)CH 3 ), -183- {TMS) 171.37, 135.56, 128.61, 128.35, 128.09, 98.52, 71.16, 66.42, 61.35, 46.53, 29.18, 27.36, 19.30, 9.16; [a]~5 = +30.8° {CHC1 3 , £ 2.1). Anal. calcd. for c16 H22 o4 : C, 69.04; H, 7.97. Found: C, 69.33; H, 7.94. (4R~5S)-4-Ethyl-5-hydro~thyl-2~2-di.ethyl-1~3-dioxane (96). To a well stirred, cooled (-15°C) solution of benzyl ester 95 {3.99 g, 14.33 mmol) in 50 ml of anhydrous diethyl ether was added a 1 ~ solution of lithium aluminum hydride in ether {14.3 ml, 14.3 mmol, 1 molar equiv, Aldrich) dropwise. After 15 min, the reaction was quenched by the careful, successive addition of 0.5 ml of water, 0.5 ml of 15% aqueous sodium hydroxide and 1.5 ml of water. was filtered and the precipitate washed with ether. The mixture The combined filtrates were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield a clear liquid. Gas chromatography analysis (SE-54, 80°C, 10 PSI, tr = 4.39 min) indicated 96 to be ~99% diastereomeric pure. Flash chromatography {50 mm, 200 g, 48% ethyl acetate:hexane) afforded 2.43 g {98%) of alcohol 96 as a colorless liquid: Rf 0.21 {30% ethyl acetate:hexane); IR {CHC1 3) 3630 (sharp), 3460 (br), 3010, 2940, 1460, 1380, 1368, 1195, 1000, 855 cm- 1 ; 1H NMR {500 MHz, CDC1 3) o (TMS) 3.887 (d of d, J = 5.0, I J = 11.5, 1H, -OCHax(~eq)), 3.775 (d of d, J = 9.5, J = 11.5, I I 1 -OCH~X (Heq)), 3.654-3.586 (m, 2H, HOCH{H),-OCH-), 3.560-3.495 (m, 1H, - -184- I I HOCH(~)), I 2.16 (br, 1H, ~0) 1.824-1.745 (m, 1H, CH 3 C~(H)), I I 1.728-1.638 (m, 1H, CH 3 CH(~)), 1.495-1.40 (m, 1H, HOCH 2 C~-), 1.426 I I (s, 3H, ~3 C~CH 3 ), 1.388 (s, 3H, H 3 C~C~3 ), 0.952 (t, J = 7.5, 3H, I 13 C~ CH ); C NMR (CDC1 3) o (TMS) 98.39, 77.01, 71.36, 61.87, 61.15, 3 2 41.52, 28.72, 26.45, 19.95, 9.29; [a]~5 = +22.3° (CHC1 3 , £ 2.1). Anal. calcd. for c9H18o3 : C, 62.04; H, 10.41. Found: C, 61.78; H, 10.50. {11E,l3E,l5R,16R)-14-((((-l,l-Dimethylethyl)dimethylsilyl)oxy).ethyl)-16-ethyl-12~thyl-oxacyclohexadeca-11,13-diene-2,10-dione (108). A solution containing di-~-butylboryltriflate (0.12 ml, 0.47 mmol, 1.2 equiv) and anhydrous diisopropylethylamine (0.095 ml, 0.55 mmol, 1.4 equiv) in anhydrous diethyl ether (30 mL) was stirred at room temperature for 10 min and then cooled to -78°C. A solution containing chromatographed, but partially decomposed, 43 ester 106 (178 mg, 0.39 mmol) in 20 ml of anhydrous diethyl ether, was added over a 10-minute period. After stirring at -78°C for 3 h, TLC analysis indicated that no further conversion was occurring. A solution containing an additional 0.12 ml (1.2 equiv) of triflate and 0.095 ml (1.4 equiv) of amine in 4 ml of ether was added slowly. The solution was stirred at -78°C for an additional 2 h, then slowly wanmed to -20°C. TLC analysis now indicated that other products were being formed, probably coming from decomposition of the starting material. The reaction was quenched by the addition of -185- aqueous phosphate buffer, diluted with methanol and then treated with 30% aqueous hydrogen peroxide (0.5 mL) at 0°C for 1 h. Volatiles were removed in vacuo, and the remaining aqueous slurry was extracted with ether (2 x 50 mL). The combined ethereal phases were washed with 5% aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated to an oil. Diastereomer analysis (SE-54, 215°C, 10 PSI, t r = 8.48 min, t'r = 9.07 min) of the unpurified product 107 indicated a 45:55 mixture of epimers at the new created asymmetric center. Flash chromatography (20 mm, 30 g silica, 25% ethyl acetate:hexane) afforded 80 mg (45%) of compound 107 as a very thick oil, as a 44:56 (GC ratio, same conditions) mixture of TLC non-resolvable isomers. storage. ~o occurred): (The material was unstable Even at -20°C for 24 h considerable decomposition Rf 0.19 (30% ethyl acetate:hexane); 1H NMR (90 MHz, I I I CDC1 3) o (CHC1 3 ) 5.6-4.8 (m; 2H, =C~, O=COC~-), 4.6-4.3 (m, 1H, I I HOC~-), 3.42 (br t, J = 8, 2H, TBSOC~2 ), 2.9-2.1 (m, 7H, ~0, I I I ~ CC(=O)C~ , O=CC~ ), 2 2 2 I I 1.8-1.2 (m, 13H), 1.70 (s, 3H, ~3 CC=), 1.0-0.7 I I (m, 12H, c~3 cH 2 , (C~3 ) 3 C), 0.0 (s, 6H, (C~3 ) 2 Si-). The mixture of isomers, 107, (75 mg, 0.16 mmol) was then dissolved in anhydrous dichloromethane (4 mL). Freshly distilled triethylamine (0.22 ml, 1.6 mmol, 10 equiv) and dry methanesulfonyl chloride (24 pl, 0.32 mmol, 2 equiv) were added subsequently. The reaction was stirred overnight at room temperature, and at 40°C for 1.5 h. Saturated aqueous ammonium chloride was -186- added and the organic layer separated. The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to an oil. Flash chromatography (20 mm, 28 g silica, 15% ethyl acetate:hexane) afforded 35.1 mg (50%) of the title compound as a colorless, thick oil: IR (CH 2cl 2) 3030, 2745, 1728, 1680, 1598, 1460, 1210, 837 cm- 1 ; 1H NMR (90 MHz, CDC1 3) b (CHC1 3) 7.05 (d, J = 16.5, 1H, O=CCH=C~), 6.15 (d, J = 16.5, 1H, O=CC~=), 5.77 I I I I I I I (br d, J = 12, 1H, O=CCH=CHC=C~), 4.95 (t of d, J = 3.5, J = 7.5, I I I 1H, O=COC~-), 3.64 (d, J = 5.0, 2H, TBSOC~2 ), 2.8-2.0 (m, 4H, I I I I -OC(=O)CH 2, O=CC~2 ), 1.80 (d, J = 2, 3H, ~3 CC=), 1.8-1.1 (m, 13H), I I I 1.05-0.75 (m, 12H, C~3 cH 2 , (C~3 ) 3 C), 0.05 (s, 6H, (C~3 ) 2 Si-); [a];s = +45.8° (CHC1 3, £ 1.7). (4R,5S)-4~thyl-3-(1-oxo-4-phenyl.ethoxybutyl)-5-phenyl-2- oxazolidinone (109). Into a dry, 3-necked, 5-L flask equipped with a constant pressure addition funnel, a septum and a mechanical stirrer was placed 4-phenylmethoxybutyric acid 44 (83.5 g, 0.43 mol), diethyl ether (2 L, freshly opened can), and triethylamine (62.2 ml, 0.44 mol, 1.03 equiv, freshly opened bottle). The solution was cooled to -78°C and pivaloyl chloride (54.6 ml, 0.44 mol, 1.03 equiv) was added over a 0.5-h period, resulting in the appearance of a white precipitate. 2.5 h. The slurry was warmed to ooc and stirred for -187- In another dry, 2-L flask was weighed oxazolidone 10 (72.6 g, 0.41 mol, 0.95 equiv). The flask was purged with argon and 1 L of tetrahydrofuran (freshly opened bottle) was introduced. The solution was cooled to -78°C and a 1.65 ~solution of ~-butyllithium in hexane (248 ml, 0.95 equiv) was added slowly, until a pink color appeared, indicating formation of the dianion, and thus that exactly 0.95 equivalents of base had been added. The mixture was stirred for 0.5 h, and then transferred via cannula into the cooled (-78°C), mixed anhydride mixture, over a 1-h period. The reaction mixture was slowly warmed up to room temperature (1 h), then quenched by the addition of saturated aqueous ammonium chloride. Volatiles were removed in vacuo, and the remaining aqueous slurry was extracted with dichloromethane. The combined organic phases were successively washed with 1 ~aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 144 g of a yellow oil. Recrystallization from hot ethanol afforded 104.4 g (72%) of compound 109 as white crystals: Rf 0.32 {30% ethyl acetate:hexane); mp 69-70°C; IR {CC1 4 ) 3080, 3045, 2950, 2870, 1795, 1705, 1455, 1345, 1195, 1120, 1028 cm- 1; 1H NMR {90 MHz, CDC1 3) o (TMS) 7.5-7.15 I (m, 10H, aromatic H), 5.50 (d, J = 7, 1H, -NCHC~O-), 4.66 {qn, J = I I I I I I 7, 1H, -NC~CHO-), 4.48 (s, 2H, PhC~2 ), 3.55 {t, J = 6, 2H, I PhCH 0c~ ), I I 2 2 3.06 (t, J = 8, 2H, O=CC~2 ), 2.01 (qn, J = 7, 2H, I I 13 O=CCH 2CH 2), 0.83 (d, J = 7, 3H, -NCHC~3 ); C NMR (CDC1 3) o (TMS) I I -188- 172.74, 152.98, 138.55, 133.42, 128.61, 128.35, 127.63, 127.50, 125.62, 78.83, 72.85, 69.28, 54.72, 32.62, 24.56, 14.56; [a] 25 = D +33.7° (CHC1 3 , £ 2.4). Anal. calcd. for c21 H23 N0 4 : C, 71.37; H, 6.56. Found: C, 71.43; H, 6.58. (3(R),4R,5S)-4-Methyl-5-phenyl-3-(2-(2-(phenylmethoxy)ethyl)1-oxo-4-pentenyl)-2-oxazolidinone (110). 33 a A dry, 3-necked, 1-L flask was fitted with a stirring bar, an additional funnel, a thermometer and a nitrogen inlet. The system was purged with nitrogen and charged with freshly distilled diisopropylamine (19.3 ml, 138 mmol, 1.1 equiv) and anhydrous tetrahydrofuran (125 ml). The solution was cooled to -78°C, and treated with a 1.63 ~solution of ~-butyllithium in hexane (80.3 ml, 131.2 mmol, 1.05 equiv) over a 1-h period. The mixture was stirred for 1 h and then a solution containing oxazolidone 109 (44.18 g, 125 mmol) in 125 ml of dry tetrahydrofuran was added at a rate which maintained the reaction temperature ~-65°C. The mixture was stirred at -78°C for 0.5 h and then methallyl iodide 45 (68.8 ml, 0.625 mol, 5 equiv) was slowly added. The mixture was allowed to wanm up to -40°C over a 2-h period, and stirred overnight at that temperature. The reaction was quenched by the addition of 125 ml of saturated aqueous ammonium chloride. Volatiles were removed in vacuo and the residue partitioned between dichloromethane and water. The organic phase -189- was washed with saturated aqueous sodium bicarbonate {100 mL), 1 ~ aqueous sodium thiosulfate (100 mL), and brine {100 ml), dried over anhydrous magnesium sulfate, filtered through celite and concentrated in vacuo to afford compound 110. The unpurified product was used in the next step without further purification. Gas chromatog- raphy analysis (SE-54, 225°C, rt 2-epi-110 = 9.02 min, rt 110 = 9.87 min) afforded a ratio of 2-epi-110:110 = 5:95. An analytical sample of 110 was obtained by chromatography on silica gel (MPLC, Merck-LoBar, 10% ethyl acetate:cyclohexane) as a colorless, viscous Rf 0.45 (30% ethyl acetate:hexane); IR (CC1 4 ) 3030, 2930, oil: 2862, 1775, 1690, 1340, 1194, 1120, 891, 693 em -1 ; 1H NMR ( 500 MHz, CDC1 3 ) o (TMS) 7.5-7.2 (m, 10H, aromatic H), 4.745-4.732 (m, 1H, ~(H)C=), I I I 4.712 (q, J = 1, 1H, H(~)C=), 4.672 (d, J = 7.5, 1H, -NCHC~O-), 4.433 (AB q, 60 = 0.051 ppm, J = 11.5, 2H, PhC~2 0-), I I I I 4.387 (qn, 1H, J = 7.5, -NC~-), 4.32-4.26 {m, 1H, O=CC~-), 3.70-3.59 I I 1 (m, 2H, PhCH 2 oc~2 ), 2.482 (d of d, J = 8, J = 13.5, 1H, =CC~(H)), I I I 2.235-2.125 (m, 2H, =CCH{~), PhCH 2 0C~(H)), 1.80-1.75 (m, 1H, I PhCH 0CH(~)), 2 I I 3 -NCHC~ ); 13 I 1.775 (br s, 3H, ~3 CC=), 0.705 (d, J = 6.5, 3H, C NMR (CDC1 3 ) o {TMS) 176.05, 153.05, 142.65, 138.75, 133.68, 128.48, 128.28, 127.57, 125.56, 112.69, 78.18, 72.79, 69.41, 54.59, 41.53, 38.86, 32.49, 22.35, 14.62; [a]~5 = +19.2° (CHC1 3 , £ 1.3). Anal. calcd. for c25 H29 N0 4 : C, 73.69; H, 7.17. 73.75; H, 7.18. Found: C, -190- (R)-4-Methyl-2-(2-(phenyl.ethoxy)ethyl)-4-pentenol (111). 33 a In a dry, 3-necked, 1-L flask fitted with a magnetic bar, addition funnel, thermometer and an argon gas-inlet was placed lithium aluminum hydride (9.40 g, 248 mmol, 2 molar equiv). The flask was purged with argon and charged with 400 ml of freshly distilled tetrahydrofuran. The slurry was cooled to -78°C and a solution containing 51.3 g (<125 mmol) of unpurified oxazolidone 110 ·in 200 ml of dry tetrahydrofuran was added at a rate which maintained the reaction temperature at i-65°C. The mixture was then allowed to warm to 0°C over a period of 2 h, and stirred at this temperature an additional 2 h. The mixture was cooled to -10°C and treated dropwise with 50 ml (0.5 mol, 4 equiv) of ethyl acetate. The mixture was stirred at 0°C for 15 min and then water (50 mL) was added. Concentrated hydrochloric acid was carefully added until the solution reached pH 1 and complete dissolution of the aluminum salts had occurred. The organic solvents were removed in vacuo and the aqueous residue extracted with ether. The combined ethereal phases were washed successively with 1 B aqueous hydrochloric acid (100 mL), saturated aqueous sodium bicarbonate (100 mL), and brine (100 mL), dried over anhydrous magnesium sulfate, filtered through celite and concentrated in vacuo to an oil. Flash chromatography (50 mm, 200 g silica, 10% ethyl acetate:cyclohexane) followed by molecular distillation (KUgelrohr, 180°C, mechanical pump), afforded 20.45 g (70% overall) of pure alcohol 111 as a colorless liquid. (16.28 g -191- (73%) of oxazolidone 10 was obtained after further elution of the Rf 0.19 (30% ethyl acetate:hexane); IR (CC1 4 ) 3600-3200 (br), 2920, 2865, 1430, 1360, 1090, 887, 691 cm- 1 ; 1H NMR (90 MHz, column): CDC1 3) o (TMS) 7.31 (s, 5H, aromatic H), 4.8-4.6 (m, 2H, ~2 C=), 4.49 I I (s, 2H, PhC~2 0-), 3.7-3.3 (m, 4H, HOC~2 CHCH 2 c~2 ), 3.05-2.70 (br, 1H, 13 ~0-), 2.2-1.5 (m, 5H,-OCH c~ c~c~ C=), 1.70 (s, 3H, ~ CC=); C NMR 2 3 2 2 I I I (CDC1 3 ) o (TMS) 143.95, 137.90, 128.41, 127.76, 112.10, 73.18, 68.82, 65.83, 40.62, 36.85, 31.84, 22.16; [a];5 = 6.5° (CHC1 3 , £ 2. 5). Anal. calcd. for c15 H22 o2 : C, 76.88; H, 9.46. Found: C, 76.67; H, 9.46. (R)-4-Methyl-2-(2-(phenylmethoxy)ethyl)-4-pentenal (112}. 33 a A dry, 3-necked, 250-mL flask was fitted with a stirring bar, addition funnel, thermometer and a nitrogen gas-inlet. Alcohol 111 (5.86 g, 25 mmol) was introduced, followed by dry dimethyl sulfoxide (62 mL) and freshly distilled triethylamine (22.6 mL, 162.5 mmol, 6.5 equiv). The solution was cooled to l5°C and then a solution of sulfur trioxide pyridine complex (11.94 g, 75 mmol, 3 equiv, Aldrich, 95%) in dry dimethyl sulfoxide (62 mL) was added at a rate which maintained the reaction mixture at ~20°C. After the addition was complete the mixture was stirred at room temperature for 0. 5 .h. The reaction was quenched by the addition of 100 mL of cold (0°C) water. The mixture was extracted with ether. The organic phase was -192- washed successively with diluted aqueous cupric sulfate (50 ml), saturated sodium bicarbonate (50 ml), and brine (50 ml), dried over anhydrous sodium sulfate, filtered through celite and concentrated in vacuo to afford aldehyde 112 as an oil. The unpurified product was used in the next step without further purification. An analytical sample of 112 was obtained by flash chromatography (silica, 10% ethyl acetate:cyclohexane) as a colorless liquid: Rf 0.41 (30% ethyl acetate:hexane); IR (CC1 4 ) 2920, 2860, 1720, 1435, 1355, 1095, 890, 690 cm- 1 ; 1H NMR (90 MHz, CDC1 3 ) o (TMS) 9.63 (d, J = 2, 1H, -C~O), 7.30 (s, 5H, aromatic H), 4.80 (br s, 1H, I ~(H)C=), 4.72 (br s, 1H, H(~)C=), 4.44 (s, 2H, PhC~2 ), 3.50 (t, J = I I I I 6, 2H, PhCH 2 oc~2 ), 2.9-1.65 (m, 5H, =CC~2 c~c~2 ), 1.68 (s, 3H, I 13 ~ CC=); C NMR (CDC1 3) o (TMS) 204.13, 142.13, 138.23, 128.35, 3 127.63, 112.88, 72.98, 67.59, 47.01, 37.17, 29.18, 22.29; [a] 25 = 0 -14.1° (CHC1 3 , £ 2.6). Anal. calcd. for c15 H20 o2 : C, 77.55; H, 8.68. Found: C, 77.38; H, 8.47. (3(2R,3S,4R),4R,5S)-3-(3-Hydro~-2,6-d;.ethy1-1-oxo-4-(2{phenylmetho~)ethyl-6-heptenyl)-4~thy1-5-phenyl-2-oxazol;d;none (113). 33 a Into a dry, 3-necked, 250-ml flask fitted with a stirring bar, thermometer and a n;trogen gas-inlet was introduced oxazolidone 8 (6.41 g, 27.5 mmol, 1.1 equiv). The system was purged with argon -193- and the flask charged with freshly distilled dichloromethane (60 mL). The solution was cooled to -78°C and di-~-butylboryl triflate (7.4 ml, 30.0 mmol, 1.2 equiv) was added dropwise, followed by freshly distilled triethylamine (4.5 ml, 32.5 mmol, 1.3 equiv) at a rate that maintained the reaction temperature at ~-65°C. The mixture was slowly warmed to 0°C and stirred at this temperature for 0.5 h, recooled to -78°C and treated by the slow addition of unpurified aldehyde 112 (5.85 g, ~25 mmol) in 10 ml of anhydrous dichloromethane. The mixture was stirred at -78°C for 30 min, then allowed to warm to 0°C over a 45-min period, and stirred at this temperature overnight. The reaction was quenched by the addition of 12 ml of aqueous phosphate buffer (pH 7) and 75 ml of methanol. The solution was oxidized by the slow addition of a cold (0°C) solution of 12 ml of 30% aqueous hydrogen peroxide in 50 ml of methanol. After 1 h of stirring at 0°C, the volatiles were removed in vacuo and the aqueous residue extracted with ether. The organic phase was decanted and washed with saturated aqueous sodium bicarbonate (25 mL) and brine (25 mL), dried over anhydrous magnesium sulfate, filtered through celite and concentrated in vacuo to a solid. Diastereomer analysis (SE-54, 250°C, Tinj = 275°C, tr 4-epi-E 1 = 9.80 min, tr E1 = 10.25 min, tr E2 = 11.7 min, tr T1 = 12.6 min, tr T2 = 14.3 min) of an unpurified, silylated sample (TMSNEt 2, DMAP, CH 2c1 2 , 12 h) afforded a 4-epi-E 1 :E1 :E 2 :T1 :T2 ratio of 4.5:94.5:~0.7:~0.7:0.7 Chromatography on silica gel (MPLC, -194- Merck-LoBar£ column, 20% ethyl acetate:cyclohexane) afforded 547.5 mg (4.7%) of an isomer, presumably the c4-epimer of 113, 46 and compound 113. Recrystallization of the latter (ether:cyclohexane) afforded 10.33 g (89% based on alcohol 111) of the title compound as a white solid. Diastereomer analysis (same conditions as above) indicated 113 to be 99.4% pure, contaminated with only 0.6% of 4-epi-113: Rf 0.21 (30% ethyl acetate:hexane); mp 98-99.5°C; IR (CC1 4 ) 3600-3400, 2943, 1795, 1690, 1341, 1196, 1122, 800, 730 em -1 ; 1H NMR (500 MHz, CDC1 ) b (TMS) 7.50-7.23 (m, 10H, aromatic H), 3 I I I 5.475 (d, J = 7.3, 1H, -NCHC~O-), 4.775 (br s, lH, ~(H)C=), 4.725 I I (br s, 1H, H{~)C=), 4.650 (qn, J = 6.5, 1H, -NC~-), 4.50 (AB q, I b. I I o = 0.018 ppm, J = 12, 2H, PhC~2 ), 4.070 {q, J = 6.5, 1H, O=CC!!-), I I 3.99-3.95 (m, lH, HOC!i_-), 3.63-3.50 (symmetric m, 2H, PhCH 20C!i_2), 3.220 (d, J = 4.1, 1H, ~0-), 2.350 (d of d, J = 3.0, J = 14.5, 1H, I I I I =CC!i_(H)), 2.030 (d of d, J = 10.0, J = 14.5, lH, =CCH{!!)), 1.97-1.87 I I I {m, 1H, =CCH 2C!i_-), 1.78-1.68 (m, J = 6.0, 2H, PhCH 20CH 2c!i_2 ), 1.725 I I I (s, 3H, !!3CC=), 1.320 (d, J = 7.1, 3H, O=CCHC!i_3 ), 0.855 {d, J = 6.9, I I 13 3H, -NCHC!!3 ); C NMR (CDC1 3 ) b {TMS) 176.71, 152.34, 144.54, 138.43, 133.23, 128.68. 128.35, 127.64, 127.51, 125.63, 111.98, 78.77, 74.22, 72.99, 67.92, 54.79, 40.56, 37.37, 36.36, 30.42, 22.35, 14.29, 13.12; [a]~5 = +4.9° {CHC1 3 , £ 2.4). Anal. calcd. for c28 H35 N0 5 : C, 72.23; H, 7.58. 72.24; H, 7.47. Found: C, -195- (3(2R,3S,4R),4R,5S)-3-(2,6-Di.ethyl-l-oxo-4-(2-(phenyl.ethoxy)ethyl)-3-((triethylsilyl)oxy)-6-heptenyl)-4~thyl-5- phenyl-2-oxazolidinone (114). 33 a To a stirred, cooled (15°C) solution containing aldol adduct 113 (5.82 g, 12.5 mmol) and freshly distilled triethylamine (5.2 ml, 37.5 mmol, 3 equiv) in anhydrous dichloromethane (62 mL), was added triethylsilyltrifluoromethanesulfonate (4.4 ml, 18.7 mmol, 1.5 equiv) dropwise. stirred at room temperature for 2 h. The mixture was The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (15 mL). The organic phase was decanted and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered through celite and concentrated in vacuo to an oil. Flash chromatography (50 mm, 100 g silica, 5% ethyl acetate:hexane) afforded 7.46 g of a mixture of the title compound and 14% of triethylsilyl alcohol. An analytical sample of 114 was obtained by heating at 150°C under vacuum for 5 h: Rf 0.50 (30% ethyl acetate:hexane); IR (CC1 4 ) 2950, 2880, 1782, 1688, 1338, 1225, 1192, 1120, 885, 693 em -1 ; 1H NMR {500 MHz, CDC1 3) h {TMS) 7.39-7.17 (m, 10H, aromatic H), 5.402 I I I (d, J = 7.5, 1H, -NCHC~O-), 4.761 {br s, 1H, ~(H)C=), 4.723 (br s, I I I 1H, H{~)C=), 4.509 (s, 2H, PhC~2 ), 4.493 (qn, J = 7.0, 1H, -NC~-), I 4.122 (d of d, J = 1.6, J = 8.5, 1H, TESOC~-), 4.042 {d of q, I I I Jq = 6.8, Jd = 8.5, 1H, O=CC~-), 3.602-3.488 {m, 2H, PhCH 2 oc~2 ), I I 2.244 {br d, J = 15.2, 1H, =CC~{H)), 1.886 (d of d, J = 9.8, J = -196- I I I I 1 15.2, 1H, =CCH(~)), 1.80-1.6 (m, 3H, =CCH 2 C~-, PhCH 2 0cH 2 c~2 ), 1.698 I I I (s, 3H, ~3 CC=), 1.248 (d, J = 7.0, 3H, O=CCHC~3 ), 0.995 (t, J = 8.0, I I I 9H, (C~3 cH 2 ) 3 Si), 0.816 (d, J = 6.8, 3H, -NCHC~3 ), 0.655 (q, upper field peak is doubled, J = 8.0, 6H, (CH 3 c~2 ) 3 Si); 13c NMR (CDC1 3 )o (TMS) 176.11, 152.53, 144.79, 139.20, 133.42, 128.74, 128.41, 127,44, 125.75, 111.71, 78.90, 75.64, 72.85,68.69, 55.11, 42.05, 37.95, 37.56, 31.45, 22.55, 15.40, 14.66, 7.21, 5.72; [a] 25 = +10.4° 0 (CHC1 3 , £ 2.6). Anal. calcd. for c34 H49 N0 5Si: C, 70.43; H, 8.52. Found: C, 70.39; H, 8.50. (2R,3S,4R)-2,6-Dimethyl-4-(2-(phenylmethoxy)ethyl)-3((triethylsilyl)oxy)-6-heptenoic acid, phenylmethyl ester (115). 33 a To a well stirred, cooled (-10°C) solution of benzyl alcohol (3.2 ml, 31 mmol) in anhydrous tetrahydrofuran (25 mL) was added a 1.61 ~ solution of ~-butyllithium in hexane (15.3 ml, 24.7 mrnol). The mixture was stirred at 0°C for 10 min. Then, a solution containing imide 114 (7.16 g of a mixture of 114 and triethylsilyl alcohol) in anhydrous tetrahydrofuran (25 mL) was added slowly. After the addition was complete, the mixture was stirred at 0°C for 4 h. The reaction was quenched by the addition of 15 ml of saturated aqueous sodium bicarbonate. The mixture was concentrated in vacuo and the residue partitioned between ether and water. The organic solution was washed with brine (15 mL), dried over anhydrous -197- sodium sulfate, filtered through celite, and concentrated in vacuo. Flash chromatography (50 mm, 100 g silica, 5% ethyl acetate: cyclohexane) afforded 5.56 g (88%, from 113) of ester 115 as a Rf 0.55 (20% ethyl acetate:hexane); IR (CC1 4 ) 3070, 3035, 2960, 2915, 2880, 1730, 1450 1088, 1055, 888 cm- 1 ; 1H NMR (500 colorless oil: MHz, CDC1 3 ) o (TMS) 7.8-7.4 (m, 10H, aromatic H), 5.050 (AB q, ~o = 0.0125 I ppm, J = 12.5, 2H, PhC~2 0C=O), 4.71 (br s, 1H, ~(H)C=), 4.64 (br s, 1H, H(H)C=), 4.439 (AB q, 6o = 0.016 ppm, J = 12, 2H, 2 I 2 PhC~ 0cH ), I 4.002 (d of d, J = 2.4, J = 7.0, 1H, TESOC~-), 3.48-3.35 I I I (m, 2H, PhCH 2 oc~2 ), 2.710 (qn, J = 7.0, 1H, O=CC~-), 2.138 (d of d, I I J = 2.5, J = 14.2, 1H, =CC(H)~), 1.967 (d of d, J = 9.3, J = 14.2, I I I 1H, =CC(~)H), 1.70-1.55 (m, 3H, PhCH 2 0CH 2 c~2 C~), 1.593 (s, 3H, 3 I ~ CC=), I I 1.193 (d, J = 7.0, 3H, O=CCHC~3 ), 0.939 (t, J = 8.0, 9H, 1 3 2 3 • (C~ cH ) Sl), 0.585 (q, J = 8.0, 6H, (CH 3 c~2 ) 3 Sl); 13 C NMR (CDC1 3 ) o '· (TMS) 175.21, 144.21, 138.68, 135.95, 128.48, 128.28, 127.57, 127.37, 112.10, 75.25, 72.85, 68.76, 66.16, 43.61, 38.41, 37.95, 30.41, 22.03, 14.04, 7.02, 5.46; [a]~ 5 = +12.7° (CHC1 3 , £ 2.4). Anal. calcd. for c31 H46 o4Si: C, 72.90; H, 9.08. Found: C, 72.90; H, 9.02. (2S,3S,4R)-2,6-Dimethyl-4-(2-(phenylmetho~)ethyl)-3- {(triethylsilyl)oxy)-6-heptenol {116). 33 a Into a three-necked, 100-ml flask equipped with a thenmometer, septum and an argon gas-inlet was placed ester 115 (5.45 g, 10.7 mmol). The system was -198- purged with argon and the flask charged with 40 ml of anhydrous tetrahydrofuran. The solution was cooled to -10° and a 70% solution of sodium bis(2-methoxyethoxy) aluminum hydride in toluene (Red-Al, 7.46 ml, 26.6 mmol, 2.5 molar equiv) was added dropwise, at a rate that maintained the reaction temperature below -5°C. was found to be rather difficult to stir. would have been a better choice. The mixture A mechanical stirrer The mixture was stirred at -10°C for 20 min, and then quenched very carefully by the addition of saturated aqueous ammonium chloride. The volatiles were removed in vacuo and the residue partitioned between ether and water. The aqueous, white slurry was decanted and the organic phase was washed with saturated aqueous sodium bicarbonate (10 ml), and brine (10 mL), dried over anhydrous sodium sulfate, filtered through celite and concentrated in vacuo. Flash chromatography (50 mm, 100 g silica, 10% ethyl acetate:cyclohexane) afforded 3.63 g (84%) of alcohol 116 as a colorless liquid: Rf 0.24 (30% ethyl acetate: hexane); IR (CC1 4 ) 3640, 3550-3400, 3070, 2960, 2940, 2875, 1450, 1235, 1085, 887, 722 cm- 1 ; 1H NMR (500 MHz, COC1 3) o (TMS) 7.32-7.23 (m, 5H, aromatic H), 4.754 (br s, 1H, ~(H)C=), 4.699 (br s, 1H, H(~)C=), 4.461 (AB q, 6o = 0.0145 ppm, J = 12, 2H, PhCH 20-), 3.775 I I I (t, J = 3.8, 1H, TESOC~-), 3.53-3.40 (m, 4H, PhCH 2 oc~2 , HOCH 2), 2.27-2.17 (br, 1H, ~0-), 2.181 (d of d, J = 4.5, J = 14.3, 1H, I I =CCH(~)), I I 1.942 (d of d, J = 9.3, J = 14.3, 1H, =CC~(H)), 1.90-1.81 I (m, 2H), 1.75-1.69 (m, 1H), 1.700 (s, 3H, H3CC=), 1.604 (sextuplet, -199- J = 6.5, 1H), 0.956 (t, J = 8.0, 9H, I 0.874 (d, J = 1• I 13 7.0, 3H, HOCH 2 CHC~3 ), 0.602 (q, J = ?.0, 6H, (CH 3 C~) 3 Sl); C NMR 3 2 3 (C~ cH ) Si), (CDC1 3 ) o (TMS) 144.53, 138.55, 128.28, 127.70, 111.97, 74.86, 72.92, 68.89, 66.35, 39.38, 38.80, 36.85, 30.61, 22.22, 12.54, 7.08, 5.46; [a]~ 5 = +3.0° (CHC1 3 , £ 3.0). Anal. calcd. for c24 H42 o3Si: C, 70.88; H, 10.41. Found: C, 70.90; H, 10.25. (2R,3S,4R)-2,6-Di.ethyl-4-(2-(phenylmethoXY)ethyl)-3-((triethylsilyl)oxy)-6-heptenal (117). 33 a To a cooled (15°C) solution containing alcohol 116 (2.03 g, 5.0 mmol) and anhydrous triethylamine (4.52 ml, 32.5 mmol, 6.5 equiv) in anhydrous dimethyl sulfoxide (12.5 ml) under argon, was added a solution of sulfur trioxide pyridine complex (2.39 g, 15 mmol, 3 equiv, Aldrich, 95%) in dry dimethyl sulfoxide (12.5 mL) at a rate that maintained the reaction temperature below 20°C. temperature for 1 h. The mixture was stirred at room The reaction was quenched by the addition of 10 ml of cold (0°C) water and the mixture extracted with diethyl ether. The organic phase was washed with saturated aqueous sodium bicarbonate (10 mL) and brine (10 ml), dried over anhydrous sodium sulfate, filtered through celite and concentrated in vacuo. Flash chromatography (50 mm, 100 g silica, 10% ethyl acetate:cyclohexane) afforded 1.96 g (97%) of aldehyde 117 as a colorless liquid: Rf 0.60 (30% ethyl acetate:hexane); IR (CC1 4 ) 3070, 2950, 2915, -200- 2878, 1722, 1095, 720, 690 cm- 1 ; 1H NMR (500 MHz, CDC1 3) o (TMS) 9.647 (d, J = 1.2, 1H,-C~O), 7.34-7.23 (m, 5H, aromatic H), 4.77-4.75 {m, 1H, ~{H)C=), 4.69-4.67 {m, 1H, H(~)C=), 4.464 {s, 2H, I 4.182 (t, J = 4.4, 1H, TESOC~-), 3.52-3.45 (m, symm., 2H, 2 PhC~ 0-), 2 I 2 PhCH oc~ ), I 2.564 (q of d of d, Jd = 1.5, Jd = 4.4, Jq = 7.0, 1H, I I O=CC~-), I 2.073 (d of d, J = 5.7, J = 14.0, 1H, =CCH(~)), 1.980 (d of I I I I d, J = 9.0, J = 14.0, 1H, =CC~(H)), 1.90-1.84 (m, lH, =CCH 2 C~-), I 1.783 (d of q, Jq = 6.6, Jd = 14.3, 1H, PhCH 2 0cH 2 C~(H)), 1.683 (s, I 3H, ~3 CC=), 1.560 (d of d of d, J = 6.6, J = 13.0, J = 14.3, 1H, I I I 1.086 (d, J = 7.0, 3H, O=CCHC~3 ), 0.934 (t, J = 2 2 8.0, 9H, (C~ cH ) Sl), 0.573 (q, J = 8.0, 6H, (CH c~ ) Sl); 13 C NMR PhCH 0cH CH(~)), 3 2 3 1 3 2 3 • '· (CDC1 3 ) o (TMS) 204.45, 143.88, 138.55, 128.35, 127.70, 112.43, 73.05, 72.79, 68.63, 50.04, 39.19, 37.89, 30.22, 22.03, 9.23, 6.95, 5.33; [a]~5 = -22.6° (CHC1 3 , £ 3.4). (3(2R,3S,4S,5S,6R),4R,5S)-3-(3-Hydro~-4,8-di.ethyl-2~thyl­ thio-l-oxo-6-(2-(phenylmethoxy)ethyl)-5-((triethylsilyl)o~)-8- noneyl)-4-methyl-5-phenyl-2-oxazolidinone (118). 33 a Into a 3-necked, 50-mL flask fitted with a thenmometer, septum and argon gas-inlet was introduced imide 119 (1.22 g, 4.6 mmol, 1.05 equiv). The system was purged with argon, and freshly distilled dichloromethane (11 mL) was introduced. The solution was cooled to -78°C, and di-n-butylboryl triflate (1.19 mL, 4.82 mmol, 1.1 equiv) and freshly distilled triethylamine (0.73 mL, 5.26, 1.2 equiv) were -201- successively added at a rate that maintained the reaction temperature below -60°C. After the addition was completed, the mixture was warmed up to 0°C and stirred for 0.5 h. The solution was recooled to -78°C and aldehyde 117 {1.77 g, 4.38 mmol, 1 equiv, neat) was added slowly. The mixture was stirred at -78°C for 0.5 h, allowed to warm slowly (45 min) to 0°C and stirred at this temperature overnight. The reaction was quenched by the addition of aqueous phosphate buffer {2.2 ml) and cold methanol (13 ml). The mixture was oxidized by the slow addition of a solution of 30% aqueous hydrogen peroxide {2.2 ml) in methanol {9 mL). The reaction was stirred at 0°C for 1 h, then concentrated in vacuo, and the residue partitioned between ether and water. The organic phase was separated and washed with saturated aqueous sodium bicarbonate (10 ml) and brine (10 ml), dried over anhydrous sodium sulfate, filtered through celite and concentrated in vacuo. Flash chromatography {50 mm, 100 g silica, 10% ethyl acetate:cyclohexane) afforded 1.61 g of compound 118 as a colorless oil. The impure fractions were rechromatographed (MPLC, Merck-LoBar, B column, 10% ethyl acetate: cyclohexane) to afford an additional 578 mg (78% combined yield) of product: Rf 0.51 (30% ethyl acetate:hexane); IR {CC1 4 ) 3600-3400, 2875, 2885, 1782, 1682, 1342, 1215, 1191, 1000, 691 em -1 ; 1H NMR (500 MHz, CDC1 3 ) o (TMS) 7.43-7.24 {m, 10H, aromatic H), 5.664 (d, I I I I I I I J = 7.5, 1H, -NCHCHO-), 4.873 {d, J = 10.3, 1H, CH 3 sc~-), 4.780 (qn, J = 7.0, lH, -NC~CHO-), 4.772 (br s, 1H, ~(H)C=), 4.749 {br s, 1H, -202- H(~)C=), 4.499 (AB q, 60 = 0.018 ppm, J = 12.0, 2H, PhC~2 0-), 4.072 I (d oft, Jt = 2.0, Jd = 10.3, 1H, HOC~-), 3.876 (d of d, J = 1.3, I I J = 7.3, 1H, TESOC~-), 3.565-3.500 (m, symmetric, 2H, PhCH 2 oc~2 ), 2.510 (d of d, J = 1.2, J = 2.1, 1H, ~0-), 2.151 (br q, J = 10, 1H), I 2.017 (s, 3H, C~3 S-), 2.02-1.95 (m, 2H), 1.756 (s, 3H, c~3 C=), 1.76-1.65 (m, 3H), 0.977 (d, J = 7, 3H), 0.970 (t, J = 8.0, 9H, ' (C~ CH ) Si), 3 2 3 0.874 (d, J = 6.8, 3H), 0.633 {q, J = 8.0, 3H), 0.631 13 C NMR (CDC1 ) o (TMS) 168.1, 152.3, {q, J = 7.7, J = 8.1, 3H); 3 144.7, 138.7, 133.2, 128.7, 128.3, 127.6, 127.4, 125.7, 112.0, 78.8, 76.5, 72.9, 69.1, 67.8, 54.6, 48.2, 38.3, 37.9, 36.1, 30.3, 22.2, 14.0, 11.2, 9.7, 7.1, 5.7; [a]~ 5 = +4.4b (CHC1 3 , £ 2.4). Anal. calcd. for c37 H55 N0 6SSi: C, 66.33; H, 8.27. Found: C, 66.42; H, 8.32. The Aldol Condensation of the Di-n-butylboron Enolates 121 and 120 .rtth Aldehyde 117. A Cram- antiCram selection Study (Scheme XIII).Enolate formation, aldol condensation, oxidation and workup were performed according to the general method A described in Chapter I. To a cooled (-78°C) solution containing the boron enolate 121 in 1 ml of anhydrous dichloromethane {prepared from 42.8 mg {0.25 mmol) of the corresponding acetyloxazolidinone, 6.7 pl of di-~-butylboryl trifluoromethanesulfonate, and 42 pl of triethyl- amine) was added a solution containing~· 0.25 mmol of unpurified -203- aldehyde 117 in 0.25 ml of anhydrous dichloromethane in one portion. The mixture was stirred at -78°C for 0.5 h and at 0°C for 1 h, oxidized and worked up to give an oil. Diastereomer analysis {SE-54, 280°C, Tinj = 320°C, 15 PSI, t r 125 = 5.29 min, t r 123 = 5.60 min) of an unpurified, silylated sample {TMSNEt 2 , DMAP, CH 2cl 2), afforded a ratio of 125:123 = 30:70. Flash chromatography {20 mm, 25 g silica, 20% ethyl acetate:hexane) afforded an analytical sample of each isomer. 125: Rf 0.30 {30% ethyl acetate:hexane); IR {CHC1 3) 3020, 2960, 1778, 1685, 1381, 1220 cm- 1 ; 1H NMR {90 MHz, CDC1 3) o {TMS) 7.29 (s, 5H, aromatic H), 4.8-4.65 (br s, 2H, ~2 C=), 4.44 (s, 2H, I PhC~ ), 2 I I II I 4.5-3.7 (m, 5H, TESOC~-, HOC~-, -NCHCH 2 ), 3.47 {t, J = 7, I 2H, PhCH 2 0c~2 ), 3.21 (d, J = 5.5, 1H), 3.1-3.0 (m, 2H), 2.5-1.5 {m, I I I I I I 1 7H, =CC~2 CHC~2 , {CH 3 ) 2 c~, HOCHC~-), 1.70 (s, 3H, ~3 CC=), 1.1-0.8 (m, I I I I 18H, (C~3 cH 2 ) 3 Si, HOCHCHC~3 , (C~3 ) 2 CH), 0.8-0.4 (m, 6H, {CH c~ ) 3 Si); [a];5 = +20.1° {CHC1 3 , £ 1.27). Anal. calcd. for c32 H53 N0 6Si: C, 66.74; H, 9.28. Found: 3 2 C, 66.90; H, 9.37. 123: Rf 0.17 {30% ethyl acetate:hexane); IR {CHC1 3 ) 3020, 2960, 1780, 1685, 1385, 1220 em -1 ; 1H NMR {90 MHz, CDC1 3 ) o ( TMS ) 7.~0 I {s, 5H, aromatic H), 4.8-4.6 (br s, 2H, H2C=), 4.47 {s, 2H, PhC~ ), 2 I II I 4.5-4.1 (m, 4H, HOC~-, -NC~CH 2 ), 3.82 (d of d, J = 1.5, J = 1 I 5.5, 1H, TESOC~-), 3.47 (t, J = 7, 2H, PhCH 2 oc~2 ), 3.05 (d, J = 7, II I I I 2H, O=CC~2 ), 2.63 (d, J = 4, 1H, ~0-), 2.5-1.55 (m, 7H, =CC~2 CHC~2 , -204- I I 3 2 I HOCHC~-, (CH ) C~), 3 2 3 I I 1 I 1.70 (s, 3H, ~3 CC=), 1.1-0.8 (m, 18H, 3 (C~ cH ) Si, HOCHCHC~ , I I (CH 3 ) 2CH), 0.8-0.4 (m, 6H, (CH 3 c~2 ) 3 Si); [a];5 = +48.4° (CHC1 3 , £ 2.68). Anal. calcd. for c32 H53 N0 6Si: C, 66.74; H, 9.28. Found: C, 66.68; H, 9.02. In another flask containing the boron enolate 120 was added aldehyde 117 following the same procedure as described above. Diastereomer analysis (SE-54, 280°C, Tinj = 320°C, 15 PSI, t r 124 = 14.93 min, t r 122 = 15.73 min) of an unpurified, silylated sample (TMSNEt 2 , DMAP, CH 2Cl 2) afforded a ratio of 124:122 = 25:75. Flash chromatography (20 mm, 25 g silica, 20% ethyl acetate:hexane) afforded an analytical sample of each isomer: 122: Rf 0.37 (30% ethyl acetate:hexane); for the physical data of this compound see next experimental. 124: Rf 0.30 (30% ethyl acetate:hexane); IR (CHC1 3) 3030, 1783, 1696, 1375, 1225, 1150 em -1 ; 1H NMR ( 90 MHz, CDC1 3 ) u.t ( TMS ) I 1 I I 7.5-7.2 (m, 10H, aromatic H), 5.67 (d, J = 6.5, 1H, -NCHCHO), I I I I 4.9-4.7 (m, 3H, ~2 C=, -NC~CHO-), 4.48 (s, 2H, PhC~2 0-), 4.2-3.8 (m, 1 I I 2H, HOC~-, TESOC~-), 3.49 (t, J = 7, 2H, PhCH 2 oc~2 ), 3.27 (d, J = I I I I 4.5, 1H), 3.2-3.05 (m, 2H), 2.4-1.5 (m, 6H, =CCH 2 C~CH 2 , HOCHC~-), I I I I 1.70 (s, 3H, ~3 CC=), 1.1-0.8 (m, 15H, (C~3 cH 2 ) 3 Si, HOCHCHC~3 , 1• I I 25 -NCHCH 3), 0.8-0.45 (m, 6H, (CH 3 c~2 ) 3 S1); [a] 0 = +7.8° (CHC1 3 , £ 0.32). -205- Anal. calcd. for c36 H53 N0 6Si: C, 69.30; H, 8.56. Found: C, 69.80; H, 8.75. (3(3R,4S,5S,6R),4R,5S)-3-(3-HydroXY-4,8-di.ethyl-l-oxo-6{2-{phenylmethoxy)ethyl)-5-((triethylsilyl)oxy)-8-noneyl)-4.ethyl-5-phenyl-2-oxazolidinone (122). Raney-Nickel was prepared according to the published procedure. 47 To a cold (0°C) solution containing 16 g of sodium hydroxide in 60 ml of water was slowly added nickel alloy (12.5 g, No. 2813 Raney Catalyst Powder Alloy, Davison Speciality Chemical Co.) at a rate that maintained the reaction temperature at ca. 50°C. When the addition was complete, the resulting heterogeneous black slurry was stirred at 50-60°C for 1 h, and washed with water (10 x 100 ml) until the slurry showed a pH= 7. Absolute ethanol was added, the mixture centrifugated and the supernatant decanted (10 x 50 mL). immediately after preparation. The material was used Batches that were stored as the ethanolic mixture at -20°C proved to be inactive after 48 h. A well stirred solution of compound 118 (6.65 g, 9.93 mmol) in 50 ml of acetone (freshly opened bottle) was treated with an emulsion of the freshly prepared Raney-Nickel in ethanol. Batches were added until TLC analysis indicated complete disappearance of the starting material. Filtration through celite and concentration of the filtrate gave an oil which was flash chromatographed (60 mm, 350 g silica, 15% ethyl acetate:hexane) to afford 695 mg (11%) of -206- 3-dehydroxy-122 (Rf 0.66, 2% acetone:dichloromethane) and 4.93 g (80%) of the title compound: Rf 0.41 (2% acetone:dichloromethane); IR (CHC1 3) 3680 (sharp), 3550 (br), 3020, 1780, 1690, 1365, 1220, 1190, 700 em -1 ; 1H NMR ( 90 MHz, CDC1 3 ) o (TMS) 7.50-7.20 (m, 10H, I I aromatic H), 5.63 (d, J = 7, 1H, -NC~-), 4.8-4.6 (m, 3H, ~2 C=, I I I I -NCHC~O-), I 4.47 (s, 2H, PhC~2 0), 4.3-4.0 (m, 1H, -C~OH), 3.85 (d, I I 2 J = 6, 1H, -C~OTES), 3.50 (t, J = 7, 2H, PhCH 0c~ ), 3.3-3.0 (m, 2H, 2 I I O=CC~ ), 2 2.75 (d, J = 4, 1H, -0~), 2.2-1.20 (m, 6H, I I I I I PhCH 0CH c~ c~c~ , O=CCH CHC~-), 2 2 2 2 I 2 I I I 1.72 (s, 3H, H 2 C=CC~3 ), 1.2-0.8 I I (m, 15H, (C~3 cH 2 ) 3 s;, -NCHC~3 , HOCHCHC~3 ), 0.80-0.45 (m, 6H, (CH 3 c~2 ) 3 Si); [a]~ 5 = +30.0° (CHC1 3 , £ 2.15). Anal. calcd. for c36 H53 No 6s;: C, 69.30; H, 8.56. Found: C, 69.43; H, 8.77. (3R,4S,5S,6R)-3-Hydroxy-4,8-di.ethyl-6-(2-(phenylmetho~)­ ethyl)-5-((triethylsilyl)oxy)-8-nonenoic acid, phenylmethyl ester (126). To a cooled (-10°C) solution of benzyl alcohol (0.11 ml, 1.06 mmol, 2.3 equiv) in anhydrous tetrahydrofuran (2 mL) was added a 1.65 ~solution of n-butyllithium in hexane (0.51 ml, 0.84 mmol, 1.83 equiv). to -78°C. After stirring for ca. 10 min, the solution was cooled A solution containing imide 122 (288 mg, 0.46 mmol) in 1.5 ml of dry tetrahydrofuran was added dropwise {2 x 1 ml rinses). The colorless, clear solution was stirred between -60° and -50°C for 4 h, then quenched with saturated aqueous ammonium chloride, -207- concentrated in vacuo, extracted with dichloromethane {2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to an oil. Flash chromatography {30 mm, 68 g silica, 15% ethyl acetate:hexane) afforded 213.7 mg (83%) of the title compound Rf 0.45 (30% ethyl acetate:hexane); IR {CHC1 3 ) 3640, 3500 (br), 3025, 2965, 1726, 1452, 1025, 695 cm- 1• 1H NMR as a colorless oil: (500 MHz, CDC1 3 ) 8 (TMS) 7.38-7.30 (m, 10H, aromatic H), 5.159 (d, ' ' J = 12.5, 1H, PhC~(H)OC=O), 5.113 (d, J = 12.5, 1H, PhCH(~)OC=O), 4.740 (br s, 1H, ~(H)C=), 4.678 (br s, 1H, H(~)C=), 4.473 (s, 2H, 2 PhC~ 0-), 4.135 (d of d of d of d, J = 3.0, J = 3.3, J = 4.0, J = I I 9.3, 1H, HOC~-), 3.820 (d of d, J = 3.0, J = 5.4, 1H, TESOC~-), I 3.52-3.43 (m, 2H, PhCH 2 0c~2 ), 2.748 (d, J = 3.3, 1H, ~0-), 2.565 (d I I of d, J = 9.3, J = 16.0, 1H, O=CCH(~)), 2.435 (d of d, J = 4.0, J = I I I I 16.0, 1H, O=CC~(H)), 2.055 (d of d, J = 5, J = 13.5, 1H, =CC~(H)), I I I I 1.98-1.87 (m, 2H, =CCH 2 C~CHC~-), 1.754 (d of d, J = 7, J = 13.5, 1H, I I =CCH(~)), I I 1.70-1.54 (m, 2H, PhCH 20cH 2cH 2), 1.578 (s, 3H, ~3 CC=), I I 0.946 (t, J = 8.0, 9H, (C~3 cH 2 ) 3 Si), 0.93 (d, J = 7.1, 3H, C~3 CH-), 0.604 {q, J = 8.0, 6H, (CH 3cH 2 ) 3Si); [a];5 = +16.6° (CHC1 3 , .£ 2.8). Anal. calcd. for c33H50 o5Si: C, 71.44; H, 9.08. Found: C, 1 71.54; H, 9.23. {3R,4R,5S,6R,8R)-3-(((1,1-Di.ethylethyl)di.ethylsilyl)oxy)-9hydro~-4,8-di.ethyl-6-{2-(phenyl.etho~)ethyl)-5-((triethylsilyl)­ o~)-nonanoic acid, phenyl.ethyl ester, (70), and the Corresponding (3R,4R,5S,6R,8S)-Isamer (127). Benzyl ester 126 (2.62 g, 4.72 mmol) -208- was diluted in 10 ml of anhydrous dichloromethane. Freshly distilled triethylamine (1.65 ml, 11.8 mmol, 2.5 equiv) was added, followed by tert-butyldimethylsilyltrifluoromethanesulfonate (1.62 ml, 7.08 mmol, 1.5 equiv), resulting in a yellowish solution. The reaction mixture was stirred at room temperature for 20 min, and then quenched with saturated aqueous ammonium chloride. The organic layer was decanted and the aqueous solution was extracted with dichloromethane (2 x 50 ml). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and flash chromatographed (60 mm, 220 g silica, 5% ethyl acetate:hexane) to afford 3.04 g (96%) of the corresponding tert-butyldimethylsilyl ether, 69. In another flask was introduced a 1 M solution of borane tetrahydrofuran complex in tetrahydrofuran (14 ml, 14 mmol), cooled to -15°C, and treated dropwise with a solution of 2,3-dimethyl-2butene (1.64 ml, 4mmol) in anhydrous tetrahydrofuran (7 mL). The mixture was then warmed to 0°C and stirred for 2 h. In another flask was weighed compound 69 (2.27 g, 3.39 mmol), and was diluted with 12 ml of dry tetrahydrofuran. The solution was cooled to -5°C, treated dropwise with an aliquot of the previously prepared thexylborane solution (10.8 ml, 2 equiv), warmed to 0°C, and stirred for 5 h at this temperature. The reaction was quenched by the addition of 30 ml of an aqueous sodium carbonate-sodium bicarbonate solution (pH 9.2). Then, 80 ml of methanol was added -209- and the mixture treated with 10 ml of 30% aqueous hydrogen peroxide. The white slurry was stirred at 0°C for 4 h, after which period TLC analysis still indicated presence of unoxidized material. The mixture was neutralized with aqueous phosphate buffer, concentrated in vacuo and the remaining white slurry extracted with ether (2 x 30 mL). The combined ethereal layers were washed with aqueous 10% sodium hydroxide (1 x 30 ml), then with saturated aqueous sodium sulfite solution, dried over anhydrous sodium sulfate, filtered and concentrated to a colorless oil. This was dissolved in a mixture containing 20 ml of methanol, 12 ml of aqueous sodium carbonatesodium bicarbonate and 12 ml of tetrahydrofuran, cooled to 0°C and treated with 10 ml of 30% aqueous hydrogen peroxide for 0.5 h, after which time TLC analysis indicated no remaining organoborane. Workup as before gave an oil which was chromatographed (MPLC, Lo-bar, size C, 17% ethyl acetate:hexane) to afford 1.60 g (69%) of compound 70, and 338 mg (15%) of 127. 70: Rf 0.46 (30% ethyl acetate:hexane); IR (CHC1 3) 3700, 3560 (br), 3030, 2965, 1725, 1455, 1220, 1130, 835 em -1 ; 1H NMR ( 500 MHz, CDC1 3 ) ~ (CHC1 3 ) 7.38-7.24 (m, 10H, aromatic H), 5.078 (s, 2H, I I 4.502 (d, J = 11.7, 1H, PhC~(H)O), 4.446 (d, J = 11.7, PhC~ 0C=O), 2 I I 1H, PhCH(~)O), 4.133 (m, 1H, TBSOC~-), 3.681 (d of d, J = 2.5, J = I I 1 6.5, 1H, TESOC~-), 3.52-3.36 (m, 4H, HOCH 2 , PhCH 2 0~~2 ), 2.612 (d of I I d, J = 6.5, J = 15.5, 1H, O=CCH(H)), 2.503 (d of d, J = 5.7, J = II 15.5, 1H, O=CCH(~)), 2.038 (t, J = 6.0, 1H,-0~), 1.84-1.43 (five -210- I I I I I I multiplets, 7H, O=CCH 2 CHC~-, HOCH 2 c~c~2 c~c~2 ), 0.934 (t, J = 8.0, I I 9H, (C~3 cH 2 ) 3 Si), 0.925 (d, J = 7.0, 3H, ~3 CCH-), 0.885 (d, J = 7.0, I I 3H, ~3 CCH-), 0.830 (s, 9H, (C~3 ) 3 C), 0.591 (q, J = 8.0, 6H, I I I 0.003 (s, 3H, C~3 S iCH 3 ), -0.010 (s, 3H, CH 3S,iC.!:!_3 ); 3 2 3 [a]~ 5 = +6.9° (CHC1 3 , £ 1.8). (CH c~ ) Si), 1 Anal. calcd. for c39 H66 o6si 2 : C, 68.17; H, 9.68. Found: C, 68. 32; H, 9. 50. Rf 0.39 (30% ethyl acetate:hexane); IR (CHC1 3 ) 3690, 3500 (br), 3025, 2965, 1728, 1455, 1250, 1220, 833, 690. 1H NMR (90 MHz, 127: CDC1 3 ) o (CHC1 3 ) 7.35 (s, 5H, aromatic H), 7.32 (s, 5H, aromatic I I H), 5.10 (s, 2H, PhC~2 0C=O), 4.50 (s, 2H, PhC~2 0), 4.27-4.05 (m, 1H, I TBSOC~-), I 3.75 (d of d, J = 2.5, J = 5.5, 1H, TESOC~-), 3.65-3.30 I I I I (m, 4H, HOC~2 , PhCH 2 oc~2 ), 2.80-2.32 (m, 2H, O=CC~2 ), 1.95-1.00 (m, I I I I I 1 I 7H, O=CCH 2 CHC~-, HOCH 2 c~c~2 c~cH 2 ), 1.0-0.75 (m, 24H, ~3 CCH-, I I I I HOCH 2CHC.!:!_3 , (C~3 ) 3 C, (C~3 cH 2 ) 3 Si), 0.75-0.45 (m, 6H, (CH 3C.!:!_2)Si), 0.05 (s, 3H, C!!_3s;;cH 3 ), 0.03 (s, 3H, CH 3S:iC!!_3 }; [a]~ = +11.2° 5 (CHC1 3 , £ 1.4). Anal. calcd. for c39 H66 o2Si: C, 68.17; H, 9.68. Found: C, 68.08; H, 9.52. (3R~4R~5S~6R,8R)-3-(((1,1-Di.ethylethyl)di.ethylsilyl)o~}4,8-di.ethyl-9-oxo-6-(2-(phenylmethoxy)ethyl}-5-((triethylsilyl)o~) -nonanoic acid, phenyl.ethyl ester {128). To a solution of alcohol 70 (1.600 g, 2.33 mmol)in anhydrous dimethyl sulfoxide (30 mL) was -211- subsequently added freshly distilled triethylamine (2.93 ml, 21 mmol, 9 equiv) and a solution of sulfur trioxide pyridine complex (1.298 g, 8.15 mmol, 3.5 equiv, Aldrich, 95% pure) in dry dimethyl sulfoxide (10 ml). The orange solution was stirred at room temperature for 1 h, then poured into a separation funnel containing 100 ml of saturated aqueous solution of cupric sulfate and 200 ml of diethyl ether. The ethereal layer was decanted and the aqu~ous layer was extracted with diethyl ether (3 x 100 mL). The combined organic layers were washed with brine (3 x 25 ml). Pentane (100 mL) was added and the solution dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a colorless oil. Flash chromatography (45 mm, 160 g silica, 8% ethyl acetate:hexane) afforded 1.436 g (90%) of aldehyde 128 as a colorless oil: Rf 0.29 (10% ethyl acetate:hexane); 1H NMR (90 MHz, CDC1 3 ) ~ (CHC1 3 ) 9.58 I (d, J = 1.5, 1H, ~C=O), 7.35 (s, 5H, aromatic H), 7.30 (s, 5H, I I aromatic H), 5.10 (s, 2H, PhCH 20C=O), 4.46 (s, 2H, PhC~2 0), 4.13 (m, I I 1H, TBSOCH-), 3.75 (d of d, J = 1.5, J = 6.5, 1H, TESOC~-), 3.48 (br I I I t, J = 6, 2H, PhCH 2 0c~2 ), 2.80-2.32 (m, 2H, O=CCH 2), 2.55-2.25 (m, I I I I I I I I I 1H, O=CHC~-), 2.0-1.5 (m, 6H, O=CHCHC~2 CHCH 2 , O=CCH 2 CHC~-), 1.1-0.8 I I I I I I (m, 15H, O=CHCHC~3 ), O=CCH 2 CHCHC~3 , (C~3 cH 2 ) 3 Si), 0.88 (s, 9H, 3 3 I (C~ ) C), I I 0.8-0.4 (m, 6H, (CH 3 c~2 ) 3 Si), 0.03 (s, 6H, (CH 3 ) 2Si-). -212- (3R,4R,5S,6R,8R)-10-(Di.ethoxyphosphinyl)-3-(((l,l-di.ethylethyl)di.ethylsilyl)oxy)-4,8-dimethyl-9-oxo-6-(2-(phenylmethoxy)ethyl)-5-((triethylsilyl)oxy)-decanoic acid, phenylmethyl ester (133). A cooled (-60°C), 1.7 ~solution of Q-butyllithium in hexane (5.88 ml, 10 mmol) was diluted with 6 ml of anhydrous tetrahydrofuran, and treated dropwise with a solution containing methyldimethylphosphonate (1.2 ml, 11 mmol) in dry tetrahydrofuran (4 mL), resulting in a white slurry. 38 After stirring for 15 min between -60°C and -50°C, a 1.4 ~ solution of magnesium bromide in 5:4 ether: benzene (8.6 ml, 12 mmol) was added dropwise. The mixture was warmed up to 0°C and then anhydrous dichloromethane (2 mL) was added, resulting in a clear, homogeneous solution. An aliquot (9 ml, 3.36 mmol, 1.6 equiv) was then added very slowly into a well stirred, cooled (-78°C) solution containing aldehyde 128 (1.436 g, 2.1 mmol) in anhydrous tetrahydrofuran (50 mL). kept between -60°C and -55°C. The temperature was (Considerable attack at the ester carbonyl was observed in experiments where the temperature was raised to -45°C.) After 1.5 h, TLC analysis indicated almost complete disappearance of aldehyde. The reaction was quenched by the addition of saturated aqueous ammonium chloride, concentrated and the remaining aqueous slurry extracted with dichloromethane (5 x 30 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the corresponding B-hydroxyphosphonate as an oil. -213- To another flask containing dichloromethane (35 mL) and pyridine (2.58 ml, 32 mmol, 15.2 equiv) was added dry chromium trioxide (1.6 g, 16 mmol, 7.1 equiv). solution was stirred for 15 min. The resultant red burgundy The unpurified s-hydroxyphos- phonate in dry dichloromethane (2 mL) was then added in one portion resulting in the formation of a black tar. The mixture was stirred at ambient temperature for 3 h, after which period it was chromatographed directly through a florisil column containing ethyl acetate. The column was flushed thoroughly with ethyl acetate. Concentration and flash chromatography (50 mm, 180 g silica, 50% ethyl acetate:hexane) afforded 1.340 g (79% from 128) of the title compound as a colorless oil: Rf 0.27 (50% ethyl acetate:hexane); IR (CH 2Cl 2 ) 3020, 2960, 1730-1712, 1455, 1254, 1035, 835 em -1 ; 1H NMR (90 MHz, CDC1 3 ) o (CHC1 3) 7.35 (s, 5H, aromatic H), 7.32 (s, 5H, I I aromatic H), 5.09 (s, 2H, PhC~2 0C=O), 4.46 (s, 2H, PhC~2 0), II I 4.24-4.00 (m, 1H, TBSOC~-), 3.72 (d, J = 11.5, 3H, C~3 0~0CH 3 ), 3.69 I II I (d, J = 11.5, 3H, CH 3 0~0C~3 ), 3.7-3.3 (m, 3H, TESOC~-, PhCH 2 0c~2 ), I I I I 3.10 (d, J = 22.5, 2H, O=~C~2 ), 2.78 (br t, J = 2.5, 1H, O=CHC~-), I I I I I I 2.65-2.48 (m, 2H, O=CC~2 ), 2.0-1.3 (m, 6H, O=CHCHC~2 CHC~2 , I I I O=CCH CHC~-), 2 I 1 I I 1.3-0.75 (m, 15H, O=CHCHC~3 , O=CCH 2 ~HCHC~3 , 1 I I 0.84 (s, 9H, (C~3 ) 3 C), 0.8-0.4 (m, 6H, (CH 3CH 2) 3Si), 3 2 3 0.02 (s, 3H, C~3 ~1CH 3 ), 0.00 (s, 3H, CH 3 ~1CH 3 ); 13C NMR (CDC1 3) o (CDC1 3 ) 205.88, 205.62, 171.50, 138.36, 135.89, 128.41, 128.22, (C~ cH ) Si), 1 • '· 127.63, 127.44, 75.19, 72.92, 70.38, 68.82, 66.15, 52.96, 52.70, -214- 52.44, 45.43, 42.89, 41.59, 40.88, 37.37, 37.11, 33.01, 32.36, 25.86, 18.00, 17.35, 10.92, 7.08, 5.59, -4.42; [a]~ 5 = +8.85° (CHC1 3 , £ 2.26). Anal. calcd. for c42 H71 o9PSi 2 : C, 62.50; H, 8.87. Found: C, 62.30; H, 8.73. (3R,4R,5S,6R,8R)-10-(Di.ethoxyphosphinyl)-3-(((1,1-di.ethylethyl)di.ethylsilyl)oxy)-4,8-di.ethyl-9-oxo-5-((triethylsilyl)o~)-6-(2-((triethylsilyl)o~)ethyl)-decanoic acid {134). To a solution of compound 133 (586.8 mg, 0.72 mmol) in anhydrous dichloromethane (60 mL) was added 10% palladium on carbon (290 mg). The mixture was hydrogenated (1 atm) for 1 h, filtered through celite and concentrated in vacuo. The unpurified acid was dissolved in anhydrous dichloromethane (7 mL), and treated subsequently with anhydrous triethylamine (0.41 mL, 2.88 mmol, 4 equiv) and triethylsilyltrifluoromethanesulfonate (0.41 mL, 1.8 mmol, 2.5 equiv). After 15 min, water (15 mL) was added and the two layer mixture stirred vigorously for 2.5 h. The aqueous layer was carefully acidified to pH 3 with 5% aqueous hydrochloric acid and extracted with dichloromethane (2 x 30 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (1 x 20 mL), dried over anhydrous sodium sulfate, filtered, concentrated and chromatographed (40 mm, 80 g silica, 80% ethyl acetate:hexane) to afford 325.4 mg (61% from 133) of compound -215- 134 as a colorless, very thick oil: Rf 0.40 (ethyl acetate}; IR (CHC1 3} 3025, 2960, 1720 (br), 1457, 1225 (br), 1035 cm- 1 ; 1H NMR (90 MHz, CDC1 3 ) 5 (CHC1 3 ) 4.12-3.8 (m, 1H, TBSOC~-}, 3.81 (d, J = I II II 11.5, 3H, ~3 CO~OCH 3 ), 3.71 (d, J = 11.5, 3H, H 3 coroc~3 ), 3.8-3.4 (m, I I I I 3H, TESOC~-, TESOC~2 ), 3.19 (d, J = 21.3, 2H, O=CC~2 ~=0), 2.8-2.35 I I I I I I I I (m, 3H, O=CC~-, O=CC~2 CH-), 2.2-1.3 (m, 6H, O=CCHC~C~CH 2 , ! I I 2 I I O=CCH CHC~-), I I (C~ CH ) Si, (C~ cH ) Si), 3 2 3 I 1 1 1.2-0.75 (m, 24H, O=CCHC~3 , O=CCH 2 CHCHC~3 , I 3 2 3 I I 0.87 (s, 9H, (C~3 ) 3 C), 0.75-0.3 (m, 12H, 3 2 3 3 2 3 5 CH 3 S:ic~3 ); [a]~ = -16.7° (CHC1 3 , .£ 1.47). (CH c~ ) Si, (CH c~ ) Si), I 0.07 (s, 3H, C~3 S,iCH 3 ), 0.05 (s, 3H, Anal. calcd. for c34 H73 o9PSi 3 : C, 55.10; H, 9.93. Found: C, 55.10; H, 9.68. (3R,4R,5S,6R,8R)-10-(Di.etho~phosphinyl)-3-(((1,1-dimethyl­ ethyl)dimethylsilyl)oXY)-4,8-di.ethyl-9-oxo-5-((triethylsilyl)oXY)6-(2-((triethylsilyl)oxy)ethyl)-decanoic acid, {1R,ZR,3E)-2((((1,1-dimethylethyl)di.ethylsilyl)oxy)methyl)-1-ethyl-4~thyl- 5-oxo-3-pentenyl ester {135). To a well stirred solution of acid 134 (310 mg, 0.42 mmol) and alcohol 102 (137.7 mg, 0.48 mmol, 1.15 equiv) in anhydrous dichloromethane (0.2 mL) was added 0.27 ml of a solution 2.0 ~in dicyclohexylcarbodiimide, and 0.18 ~in N,N-dimethyl-4-aminopyridine (1.3 equiv of DCC, 12% molar equiv of DMAP), in dichloromethane. After approximately 2 min, dicyclo- hexylurea started to precipitate as a white cloud. The slurry was -216- stirred at room temperature for 5 h. TLC analysis indicated that the reaction had reached a point where no further conversion was An additional 50 ~1 (0.24 equiv) of the DCC solution was occurring. added and the mixture stirred another 1 h. Ethyl acetate (1 ml) was added and the mixture was concentrated under a flow of argon. · Flash chromatography (40 mm, 110 g silica, 30% ethyl acetate:hexane) afforded 336.1wng (80%) of compound 135 as a colorless, very thick oil: Rf 0.39 (50% ethyl acetate:hexane); IR (CHC1 3) 3010, 2965, 1730, 1715, 1685, 1639, 1460, 1255, 1175, 1038, 837 cm- 1 ; 1H NMR {90 I MHz, CDC1 3) o (CHC1 3 ) 9.43 (s, 1H, O=C~), 6.45 (br d, J = 10.5, 1H, I I I olefinic H), 5.25-4.95 (m, 1H,-C~OC=O), 4.25-4.00 (m, 1H, TBSOC~-), I I 3.77 (d, J = 11.5, 6H, (C~3 o) 2 P=O), 3.9-3.4 (m, 5H, TBSOC~2 , I I TESOC~-, TESOC~ ), I I 2 I I 3.13 (d, J = 22.5, 2H, O=CCH 2 ~=0), 3.25-2.7 (m, I I 1H, O=CC~-), 2.61-2.46 (m, 2H, O=CC~2 CH-), 2.05-1.3 (m, 9H, II 2 I I 2 I 2 I 1 2 I I 2 3 O=CCHC~ c~c~ , O=CCH CHC~-, TBSOCH C~CHC~ cH ), I II I I I I 1.78 (d, J ca. 2, I I 3H, =CC~3 ), 1.3-0.8 (m, 45H, O=CCHC~3 , O=CCH 2 CHCHC~3 , (C~3 ) 3 C, 1 3 3 I 3 2 3 I (C~ ) C, (C~ cH ) Si, (C~ cH ) Si, C~ cH CH I 3 2 3 3 2 6), 0.8-0.4 (m, 12H, I I 3 2 3 3 2 3 5 (s, 6H, C~3 s:iCH 3 , c~3 s:;cH 3 ); [a]~ = +22.7° (CHC1 3 , .£ 1.07). (CH c~ ) Si, (CH c~ ) Si), 0.05 (s, 6H, CH 3 ~;c~3 , CH 3 ~iC~3 ), 0.00 20-Deo~-3,23-di-0-((1,1-di.ethylethyl)di.ethylsilyl)- 5,20-di-0-(triethylsilyl)-tylonolide (136). To a solution of phosphonate 135 (308.1 mg, 305 pmol) in 300 ml of freshly distilled toluene, was added 18-crown-6 (967 mg, 3.66 mmol, 12 equiv) and -217- finely powdered anhydrous potassium carbonate (253 mg, 1.86 mmol, 6 equiv). The mixture was stirred at 60°C for 16 h, after which period it was washed with water (1 x 50 ml), brine (1 x 50 mL), and aqueous phosphate buffer solution (1 x 50 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and flash chromatographed (40 mm, 50 g silica, 4% ethyl acetate:hexane) to give 238.1 mg (88%) of the title compound as a colorless, very thick Rf 0.21 (5% ethyl acetate:hexane); IR (CHC1 3) 3020, 2065, 1741, 1678, 1593, 1460, 1253, 1095, 833 cm- 1 ; 1H NMR (90 MHz, CDC1 3 ) o I I (CHC1 3) 7.25 (d, J = 15.5, 1H, O=CCH=C~), 6.17 (d, J = 15.5, 1H, oil: I I I O=CC~=CH), I I 5.80 (d, J = 11.0, 1H, O=CCH=CHC=C~), 4.86 (t of d, Jd = I I I 3, Jt = 9.5, 1H, O=COC~-), 3.90 (d, J = 7.5, 1H, TBSOC~-), 3.85-3.3 I l I I I (m, 5H, TBSOC~2 , TESOc~-, TESOC~2 ), 2.85-2.2 (m, 3H, O=CC~2 , I I O=CC~-), I I 2.1-0.3 (m, 66H), 1.74 (s, 3H, ~3 CC=), 0.07 (s, 3H, c~ ~iCH ), I I 0.02 (s, 6H, C~3 S1 i-CH 3 , CH 3 S iC~3 ), -0.07 (s, 3H, 3 1 5 CH 3 ~;c~3 ); [a]~ = -32.5° (CHC1 3 , £ 0.8). 3 Anal. calcd. for c47 H94o7si 4 : C, 63.88; H, 10.72. Found: C, 63.88; H, 10.61. 3,23-Di-0-((1,1-di.ethylethyl)di.ethylsilyl)-5-0-(triethylsilyl)-tylonolide (138). To a solution of 136 (219.3 mg, 248 pmol) in 5 ml of tetrahydrofuran, was added dropwise a solution containing 15 ml of tetrahydrofuran and 5 ml of 0.1% aqueous hydrochloric acid. The mixture was stirred for 1 h, then neutralized with 6 ml of 2.5 M -218- aqueous phosphate buffer solution. The volatiles were removed in vacuo, and the remaining solution extracted with ethyl acetate (2 x 30 mL). Pentane was added and the combined organic layers, dried over anhydrous sodium sulfate. Filtration and concentration afforded 206 mg of alcohol 137 as a colorless, very thick oil (Rf 0.41 in 30% ethyl acetate:hexane). To another flask containing a solution of pyridine (0.4· ml, 4.96 mmol, 20 equiv) in anhydrous dichloromethane (25 mL) was added dry chromium trioxide (250 mg, 2.48 mmol, 10 equiv). After stirring the burgundy mixture for 15 min, a solution containing 206 mg of unpurified alcohol 137 in 0.5 ml of dry dichloromethane was added via cannula, in one portion. The black slurry was vigorously stirred for 7 min, then filtered through celite, washed thoroughly with 250 ml of dichloromethane, concentrated in vacuo, diluted in diethyl ether and passed through a florisil column. The column was flushed with ca. 0.5 L of diethylether, and the solution concentrated in vacuo to an oil which was flash chromatographed (30 mm, 50 g silica, 15% ethyl acetate:hexane) to afford 177.1 mg (93% from 136) of aldehyde 138 as a white solid. An analytical sample was obtained by recrystallization from hot methanol: Rf 0.75 (30% ethyl acetate:hexane); mp 139-142°C; IR (CHC1 3) 3025, 2960, 1740, 1725, 1678, 1591, 1456, 1252, 1100, 835 cm- 1 ; 1H NMR (90 MHz, CDC1 3) o I I I (CHC1 3) 9.68 (m, 1H, O=C~), 7.35 (d, J = 16.2, 1H, O=CCH=C~), 6.23 I I I I I (d, J = 16.2, 1H, O=CC~=), 5.87 (d, J = 10.5, 1H, O=CCH=CHC=C~), -219- I I 4.88 (t of d, .Jd = 3.5, Jt = 9.5, 1H, O=COC~-), 4.02 (d, J = 7.5, I I 1H, TBSOC~-), 3.69 (d, J = 5.0, 2H, TBSOC~2 ), 3.49 (d, J = 9.0, 1H, I I I I I II 2.9-2.3 (m, 5H, O=CHC~2 , O=CCH-, O=CC~2 ), 2.15-0.4 (m, TESOC~), I I I 62H), 1.78 (s, 3H, ~3 CC=), 1.20 (d, J = 6.5, 3H, O=CCHCH 3 ), 0.13 (s, I I I 3H, C~3 ~iCH 3 ), 0.05 (s, 6H, CH 3 ~iC~3 , C~3 S~CH 3 ), -0.04 (s, 3H, CH 3SiC_t!3); [a]~ 5 = 11.8° (CHC1 3 , .£. 1.54). 1 1 Anal. calcd. for c47 H94 o7si 4 : C, 64.18; H, 10.25. Found: C, 63. 90 ; H, 9. 90. Tylonolide, cyclic 5,20-he.iacetal (87). Aldehyde 138 (127.3 mg, 166 ~mol) was dissolved in 10 ml of a 1:5 mixture of 48% aqueous hydrofluoric acid:acetonitrile, in a polyethylene bottle. The mixture was stirred for 12 h, then quenched by the careful addition of 25 ml of saturated aqueous sodium bicarbonate. partitioned between chloroform and water. The mixture was The phases were separated and the aqueous layer extracted (3 x 30 mL) with chloroform. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a white solid. Flash chromatography (30 mm, 40 g silica, 10% hexane:ethyl acetate) afforded a semicrystalline solid. This was dissolved in chloroform and concentrated in vacuo 3 times in order to remove all the hexane, to afford 65.2 mg (92%) of tylonolide hemiacetal 87 as a white, semicrystalline solid, identical in all aspects (TLC, mp behavior, IR, 500 MHz 1H NMR, 13 c NMR, and optical rotation) to a sample -220- obtained by degradation of tylosin 2 , 32 : Rf 0.48 (ethyl acetate); the substance started to melt at 107°C and finished at 155°C; IR (CHC1 3 , c = 10 mg/ml) 3700, 3610, 3650-3150 (br), 3025, 2975, 2935, 2890, 1711, 1681, 1600, 1457, 1321, 1185, 1068, 706 cm- 1 ; 1H NMR (500 MHz, CDC1 3 , c = 16 mg/ml) o (TMS) 7.22 (d, J = 15.5, lH, c11 -H), 6.318 (d, J = 16.0, l/3 H, c10 -H), 6.268 (d, J = 15.5, 2/3 H, c10 -H), 5.735 (d, J = 10.5, 2/3 H, c13 -H), 5.728 (d, J = 10.5, l/3 H, c13 -H), 5.452 (q, J = 4.5, 2/3 H, c20 -H), 5.385 (d of d, J = 3.5, J = 6.2, l/3 H, c20 -H), 4.879 (t of d, Jd = 3.0, Jt = 9.7, 2/3 H, c15 -H), 4.872 (t of d, Jd = 3, Jt = 9.5, 1/3 H, c15 -H), 4.067 (d of d, J = 4.0, J = 10.5, lH, c5-H), 3.80-3.63 (m, 3H, c23 -H 2 , -OH), 3.588 (br d of d, J = 1.0, J = 10.5, 2/3 H, c3-H), 3.479 (br d, partially buried, 1/3 H, c3-H), 3.140 (d, J = 4.0, l/3 H, HO-), 2.860 (d, J = 4.5, 2/3 H, HO-), 2.846 (t of d of d, Jt = 10.0, Jd = 6.3, Jd = 4.5, 1H, c14 -H), 2.56-2.47 (m, lH, c8-H), 2.440 (d of d, J = 11.0, J = 16.5, lH), 2.138 (q, J = 7.0), 2.080 (d of d, J = 6.0, J = 14.0), 2.01-1.93 (m), 1.90-1.72 (m), 1.800 (d, J = 1.0, 3/3 H, c22 -H3 ), 1.792 (d, J = 1, 6/3 H, c22 -H 3 ), 1.65-1.40 (m), 1.206 (d, J = 7.0, 3/3 H, c21 -H 3 ), 1.183 (d, J = 7.0, 6/3 H, c21 -H 3 ), 0.965 (d, J = 6.7, 3/3 H, c18 -H 3), 0.957 (d, J = 6.7, 6/3 H, c18 -H 3 ), . 0.898 (t, J = 6.8, 3H, c17 -H 3 ); 13 C NMR (CDC1 3 ) o {TMS) 204.58 (m), 48 204.26, 174.43, 147.00, 140.24, 136.15, 120.68, 97.48 (m), 97.09, 83.90 (m), 81.69, 75.39, 67.13, 62.65, 47.18, 45.82 (m), 45.49, 40.75, 39.31 (m), 38.34, 38.02, 37.62 (m), 37.17, 35.80 (m), -221- 33.34, 32.81 (m), 25.80, 17.35, 13.19, 9.88, 9.62; [a]~5 = +21.9° (CHC1 3 , ~ 0.726, 36.3 mg in 5.00 mL). (Natural: [a]~ 5 = +21.4° (CHC1 3 , ~ 0.735, 14.7 mg in 2.00 mL)). A portion of the material was dissolved in dichloromethane (~. 0.1 ml/mg). remained. Then, hexane was added slowly until a slight cloud A stopper was placed into the flask and the mixture let stand for 2 h. Tylonolide hemiacetal crystallized as very small, amorphous white crystals. The mother liquors were removed and the crystals dried under high vacuum (25°C) to afford tylonolide hemiacetal, which had incorporated about 0.5 molecule of hexane per molecule of compound: mp 154.5-156.5°C (natural: mp 155.0-157.0°C; mixed mp 155.0-156.5°C); [a]~5 = +26.5° (CHC1 3 , ~ 0.550, 11.0 mg in 2.00 ml) (natural: [a]~5 = +26.3° (CHC1 3 , ~ 0.545, 10.9 mg in 2.00 ml). Anal. calcd. for c23 H36 o7.1/2 C6H12 : C, 66.92; H, 9.07. Found: C, 66.85; H, 9.33. (Natural: Found: C, 67.08; H, 9.02) Recrystallization from acetone:diethyl ether:hexane afforded a semicrystalline substance: in 5.00 mL) (natural: 2.00 mL). [a]~ 5 = +25.2° (CHC1 3 , ~ 0.524, 26.2 mg [a]~ 5 = +25.4° (CHC1 3 , ~ 0.530, 10.6 mg in -222- References and Notes (1) (a) McGuire, J. M.; Boniece, W. S.; Higgens, C. E.; Hohen, M. M.; Stark, W. M.; Westhead, J.; Wolfe, R. N. Antibiot. Chemother. (Washington D.C.) 1961, l!, 320. (b) Hamill, R. L.; Haney, M. E.; Stamper, M.; Willey, P. Ibid. 1961, l!, 328. (2) For a macrolide review see (a) Nicolaou, K. C. Tetrahedron 1977, 33, 683. (b) Masamune, S.; Bates, G. S.; Corcoran, J. W. Angew. Chern. Int. Ed. Engl. 1977, ~, 585. (c) Back, T. G. Tetrahedron 1977, 33, 3041. (3) Morin, R. B.; Gorman, M. Tetrahedron Lett. 1964, 2339. (4) Morin, R. B.; Gorman, M.; Hamill, R. L.; Demarco, P. V. Tetrahedron Lett. 1970, 4737. (5) (a) Omura, S.; Matsubara, H.; Nakagawa, A. J. Antibiot. 1980, 33, 915. (b) Matsubara, H.; Miyano, K.; Nakagawa, A.; Omura, S. Chern. Pharm. Bull. 1982, 30, 97. (6) Jones, N. D.; Chaney, M. 0.; Kirst, H. A.; Wild, G. M.; Baltz, R. H.; Hamill, R. L.; Paschal, J. W. J. Antibiot. 1982, 35, 420. (7) Omura, S.; Kitao, C.; Matsubara, H. Chern. Pharm. Bull. 1980, 28, 1963. (8) Celmer, W. D. Pure Appl. Chern. 1971, 28, 413. (9) Kirst, H. A.; Wild, G. M.; Baltz, R. H.; Seno, E. T.; Hamill, R. L.; Paschal, J. W.; Dorman, D. E. J. Antibiot. 1983, 36, 376 and references cited therein. -223- (10) Kirst, H. A.; Wild, G. M.; Baltz, R. H.; Hamill, R. L.; Ott, J. L.; Counter, F. T.; Ose, E. E. J. Antibiot. 1982, 35, 1675. {11) Tatsuta, K.; Anerniya, Y.; Kanernura, Y.; Kinoshita, M. Tetrahedron Lett. 1981, 22, 3997. {12) (a) Nicolaou, K. C.; Pavia, M. R.; Seitz, S. P. J. Am. Chern. Soc. 1982, 104, 2027. (b) Nicolaou, K. C.; Pavia, M. R.; Seitz, S. P. Ibid. 1982, 104, 2030. (13) (a) Masamune, S.; Hayase, Y.; Chan, W. K.; Sobczak, R. L. J. Am. Chern. Soc. 1976, 98, 7874. (b) Masamune, S.; Lu, L. D.; Jackson, W. P.; Kaiho, T.; Toyoda, T. J. Am. Chern. Soc. 1982, 104, 5523. (c) Masamune, S.; Kaiho, T.; Garvey, D. S. Ibid. 1982, 104, 5521. {14) Grieco, P. A.; Inanaga, J.; Lin, N.; Yanami, T. J. Am. Chern. Soc. 1982, 104, 5781. (15) Tatsuta, K.; Anerniya, Y.; Kanernura, Y.; Takahashi, H.; Kinoshita, M. Tetrahedron Lett. 1982, 23, 3375. {16) For a good review see Nicolaou, K. C. Tetrahedron, 1977, 33, 683. {17) Tatsuta, K.; Anemiya, Y.; Maniwa, S.; Kinoshita, M. Tetrahedron Lett. 1980, fl, 2837. (18) (a) Nicolaou, K. C.; Seitz, S. P.; Pavia, M. R.; Petasis, N. A. J. Org. Chern. 1979, 44, 4013. E. J. Org. Chern. 1979, 44, 4011. (b) Stork, G.; Nakamura, -224- {19) (a) Ennis, M. D. Ph.D. Dissertation, California Institute of Technology, Pasadena, California 1983. (b) Evans, D. A~; Ennis, M. D.; Mathre, D. J. J. Am. Chern. Soc. 1982, 104, 1737. (20) (a) Chapter I of this report. (b) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chern. Soc. 1981, 103, 2127. (21) (a) Evans, D. A.; Sjogren, E. Unpublished results. (b) Evans, D. A. Aldrichimca Acta 1982, ~' 23. (22) Evans, D. A.; Conn, R. E. Unpublished results. (23) The o~tical purity of oxazolidinones 9 and 10 was determined to be ~99% by GC analysis of their Mosher imides. 29 (24) Gaudemer, A. in "Determination of Configurations by Spectrometric Methods," Vol. I in "Stereochemistry, Fundamentals and Methods," Kagan, H. B., Ed.; Georg Thieme, Stuttgart, 1977, pp. 69-71. (25) Zinc borohydride was prepared according to Foerst, "Newer Methods of Preparative Organic Synthesis," Vol. IV, p. 268. (26) Parikh, J. R.; Doering, W. J. Am. Chern. Soc. 1967, 89, 5505. (27) A similar reaction has been reported in the literature: Narasaka, K.; Pai, H. C. Chern. Lett. 1980, 1415. (28) Evans, D. A.; Dow, R. L. Unpublished results. (29) Evans, D. A.; Mathre, D. J. (30) Chaudhary, S. K.; Hernandez, 0. Tetrahedron Lett. 1979, 99. Unpublished results. -225- (31) During the course of our aldol studies we have invariably found that these reactions do not go to full conversion when they are performed on <0.1 mmol scale due, very probably, to the virtual impossibility of eliminating all traces of moisture. (32) Grieco, P. A.; Inanaga, J.; Lin, N.J. Org. Chern. 1983, 48, 892. (33) (a) This section of the work was performed by my coworker Dr. Thierry Godel, to whom I am indebted. (b) The details concerning the preparation and physical properties of compounds 109- 118 are included in the experimental section of this chapter. (34) For a discussion and results of this section, see Godel, T. Research Report, California Institute of Technology, Pasadena, California. (35) (a) Chapter II of this report. (b) Evans, D. A.; Bartroli, J. Tetrahedron Lett. 1982, 23, 807. (36) For a review see Evans, D. A.; Nelson, J. V.; Taber, T. R. Topics in Stereochemistry 1982, ~' 1. (37) Brown, H. C.; Garg, C. P.; Liu, K. J. Org. Chern. 1971, 36, 387. (38) Mathey, F.; Savignac, P. Tetrahedron 1978, 34, 649. (39) The organozinc derivative was prepared by addition of a ZnC1 2 solution in tetrahydrofuran to the lithium salt of dimethylmethylphosphonate in tetrahydrofuran at -40°C. -226- (40) Ratcliffe, F.; Rodehorst, R. J. Org. Chern. 1970, 35, 4000. (41) A sample of 50 g of tylosin was generously provided by the Eli Lilly Company. (42) Prepared from crotonic acid (Aldrich, 98~ pure) and thionyl chloride, and distilled under reduced pressure (55-57°C, 60 mm). It contained approximately 2.3~ of the cis . 21a 1 somer. (43) Compound 106 was an unstable substance. TLC analysis showed partial decomposition 1 h after its purification. (44) Prepared in two steps from 1,4-butanediol: (1) NaH, PhCH 2Br, cyclohexane, 80°C, 3 h, 79%; (2) Jones' oxidation, 25°C, 15 min, 80%. (45) Although methallyl iodide showed no detectable decomposition when stored over cuper wire at 4°C for several months, a bottle that was stored at room temperature for ca. one year exploded violently. (46) The presence of this isomer is due to the fact that the alkylation adduct 110 was carried on without separation of the diastereomers. (47) Billica, H. R.; Adkins, H. Org. Synth. Coll. Vol. 3 176. (48) .. m.. stands for the resolved peaks of the minor anomer. -227- APPENDIX I IR and 1H NMR Spectral Catalog for Chapter I -228- CDC1 3 -.-- ,- 7~1.) ~15 I 150 · ~o :;uo 1:>0 30 ~+,~-- ! ---· t I i .. : I t· '----+-----,--.----r------ -- ----. -----· - ·j·· ! I - ~- ~- - ~- - lU - : --- ---T-- ------·-- --_-::.1 9 1~ I 1~0 -229- 21 CDC1 3 _, ~·JO t i L l:oO bUO 375 :~ov , ()\,) 1 ·.. 1) I I I 150 120 •~o i (;0 I 'f'.J 0 30 0 I · · ·I· --- - f--- --·- -·~ l__j --+-------- -- - - - - · - ·- ·- - - - --- ---· I r--- ! ! ------------------~'------------~~~ ~ ~ 1 .. . .a. l l I I 10 1 '. ~ :' '' I I i '' I I :' !!'I ! 'i ' I J II I: I! ' I i;. -'I I. v I l ' .. ' I ~,~:-~.~~ .,~- ~~.+:~:.+ !,~-~ !~ 4,rr,!. ~ i. ~r~,h:l~:ll~-~~~~~~~-.. t •.-+~-+.~:+ ..--~-tlvHr.,-~~r-~+-~~4:44u ,. . !1 1 '- '' , ,; 1 ' 1 I I 'l',.o ;;.: "'I· I !r\ I I j/ ·:11 ;'1. 'I ·, . ---~ - - ..:.,. . __ -1-4-4-4---+- 1--1--~1---l- • --l· -·I· I o _LLL.l . l - - A<;l) I J.W ---1--- --- -230- 23 CDC1 3 -_ I ,;00hl 7~0 bOO 4 50 I 375 )i I ! I Tr 75 1~~ I : T : ;__!__Y-- --, --~ -uo~ -- 150 180 I ~U mr ' ' i ' I ' ' I __ --! 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I 7~~ -~!-17r~· ~ - - -- . •. ,:, ·' I; 1:1111 ,J• 'i' 'I.. " --1--t:T' •. ,-+ , ,:ll :ra+.-r'--tr-M-~f---.1-t-1 .... . . ; 1100 10110 - 0 ,,,, MeCHO -344- ,,,,I TBSO 138 CDC1 3 Jl~ l -- -·- -- -- -·---T , II I I . ' CHC1 3 JC •u l •~o ,.,.., I~ 0 -345- ''''')--- / '''0 HO CDCl 87 3 IUv I - I CDCl 3 lliO i i I i i ! I I I I I I I 1- - i I I : ;~ynthet i'c I - l I OH -346- 87 (cont.) CHC1 3 10 1--t...'':-t·-:· + , ._. '' 10 ,· ' ' 'H•~ ' II :. ' ; I; I• I :L_ lOaD loOOO ,I ,:, ''! 'I :1100 'I l lOO lOOil l s ·' 1:!' J;; oil! t:' ,.tj! ,I I ~I ll. j, t !, · , . . ·• ,· ,, I I ,..... !I, ' ·-·--r-1""~ - .,r- · 2Ul lOOD noa lAIIO 1000 I, ' ..., 1100 I : I I ';' " il ,, 1000 ~- I .•• ' ,' '',•, 1000 IDI __:, L'·,":__ ~- "::· ·1. . :' :;, :, '!II.' ,, l•;i 0/ ~ ' ··i~~- ·1· !!· lit•' ' I ·, ........ - --~ .. .~.... I ., .. .,.,1 .... , ..:. - · - -· I I WAVtH.IMUI CM' 1 WAVfUNGIH.... .. . ,.... i!·' · r :- · ~·~-·· 1900 trif s --1-:.:..;t. :... -~ _:__,;.. .f~ ~ · ~f-::.- I !• CHC1 3 100 I 'I .. ' . I 1'1 : 0 ~--:-~rr r--- · ~-~ -- oooo ' ·: ,i IDI • ':1 : 'I ·I' ,. ,· 1100 I 1000 Jl! - -r-~ : - 100 I} ll . j,t• •• ·~I .. .... _ ·,· -' ..:. ~. -r. I ~L ~ !' It •l! I~ : - ': '!II !I ',I •,I ,I :iiJII' ' " · I~ : I ' :· . I . I : I ' ·' I ~I ·,, :''' ~ ~,. ; ~ : ·.L,..,. ,! ~:., ..;_ .... . '•. ,ii : lit• jl Il l,~:,': 'li j:i+ · I l!J! illi :II :1· ·ill :II' '" li' 'l!il ,, . ". -+rn rr:!: ' "]' ·rr ~ ::· --:-- -;;· - ,:'I :I! i'l l ;, 1:· ' ~ 1 '. i . •!' ~l ,· ~iif ·:: :: ' ' :i: l!lil :::r ·,, ::: i:! 1'1; ,i. ,r ·:t· 10 I! 111: ilil ,J, Iii' ill· 'illl!l: lliii ;II! :' t;l, !." '' ' ] ~~~',.,;,. ' · ~: I•· ,1 '1 :1'· 1!1r il!! :: 1 jit: ill;;,·,!' !Iii .I i!.' '!,: l'q: i~' :1• ,,:: .::: ·d· !!.· . 111!1111!' .. .. 111 t! n 1il' ,,. !!'· ··I · :I'' ·; I I·.I· P' l.~a."- ~~""' · · , .. .io' , , :,: 1, : ;1 . '''· :•. ·:r· 1:1: '"'''Ii p !!!: :il· , :i!III JI: III'I'! ~-~~ .II' 11:: ·<. _,., 70 'I! '!· , .: ,, !!' 1!1' '" .. · , u':'1''' Iii· oili li ~~ . r ~ . . .... ' '" il:lli:' ·.i j .: :1:· :!:· i r"w\· ··' 1 ,!tl l!l" . ::: .. ·: ! . :.,; :.;, !!, : ·1 ~ 11'1'1 1: :: 11 .a I Ji l.: .............. ~....MJ rt ·.:r'1.1'" :.;..~~~~.o. l~~· ~~...._ il l ,, Wll""'~l ·l • ' l 1"1 I• - MGO - ~ noo 1000 - lOOD !j'· 11 I'" "7• - 1 ,-;; :·:"'" , •' !!'I · 1:•t:''11'' 1!'1' •lj• I ,;,, . • I\1 ~ : , •1t .• 1'' "l i' ' n '• I'" 'lol•' 1 lAIIO nao 1000 ·- - .,. •WAVINUMIII CM" 1 1000 ' I: ~ · Vl~ ; 'l i ,• l\ ''',(:, t ' \ •· ·, '''1 ,,1' I' '' ",r, · '1' I • ''''·,· I' IDI •- 1100 •ooo - - 1110 1. -347- 87 (cont.) --o---- --------~~~~~~--1-~~~-7--~~--~ 1 --~~-~ ~--..:..._-+--....::...__:::._::_+----'--_::-:-::1'. _· . :. -. .· . - - -- - -- -· ·-, ~ --1 - - L~ -;___ f~j-~ji;~-::~ .. i - i :1 -- ~~~ ~ ..:....._ ;--~- ---+· -~ ---:- '~,:~~-~~~ !___-_-_- . - -· ! - i .. j . - -- ---- ---~ - - ·'--·- - . · · --~- . -- · - ·- - 1 ___ _ _:....__ . . . I , - - - - - ·- . I . : .,.i -- :--'--::- -·- I -- - ~ - -~ -----·- - ·· ·- ---· - ··· ______ . ·- - -i -; -· - ________ _____ ~---+-- -·-·- _;___;. I _; : -- . : - ·- ·--·--- -- i ---~---j . - ~ - ~- . - i --~-- .- ! ! - . ---··-- i -~ --T;-::-~ --:- -;- -·- : --! I --- __ . i : __:_ · - ··--- -~ - ~~ - -- . - - I . ----..:· - :..:...J _ _ ~ - . _ - ~-..:....._~-----I ' -=~-· :_~t~: ~·, -:=: -.:_ ,~~- -- -_,__- ---~ . ·.. -·-------- u u 0 ·- - · : : . . - : .. I . - . I t - - I ---- ~='~~~~:~ r ~ s~ o ~!:.~~ ~ ~~ ~ ~ ~ ~~ '="".C: ~QI.e ~ ~ ~ ~ __. _,-- - ~--::- :- -: -· ·- : - -·--· :: i lt~~,;!;:I"'T"~-~-..e.,.:-""§""",;=:~:::=""::·~--~----· ' --:------~ -- _-,--- r- - _ __.:....:_=.. ·-. .j ~--~~ .. -- - - - -j -.-. - · .:.:.·: :=-~'-=--·~---- - -348- 87 (cont.) ---- ~-~ ~ ~~ ~~--~~~-~~-~ ~- •n-=-­ x•~~-~ ~ -~·~-------------------~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~ -~ ~~ ~-·~--~-------~~-----~-­ ---~--~~··-~·--~--~~--~-~~-·~ - ·-·~ -~~":~~~·-----·----~~~- ----~-~-·~-----------~---~--- -·---~~-----"------------~----~~-----~---------------~~--- ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ----~~------~~~N-~a~~-~~-~~~~ ~~~~==~~~~----~~~~·~~~~~-cz: =... ...... J• ..&. . _ ,., -¢ · ~ .;,::, ·~ - 0 ..... -......:. ~ ·..;.:. z; --~ ----------N~N~~~~~N~ ~------------~---------~--~--­ % ·· ---9 - - ,___-c_-· ·=_ --==-~ _= ·- ~-=-~~= _ : -==~=i= .;==-~ - --~~-- _:_~i""'=t:E"._=:___ . ~= -. ~~ - ,~~~-~ =--_:== : = : __ :...._= = _ + J -= ·::":"'1 ·. ....:... . 11 :S?'J \ -- c ~ C/) - ("'') u c u -- · _ !_ _ _ _ _ _ _ __ / -349- 87 (cont.) Ill N Cll: · a.. a.. ;r 0 Ill u 0 u -350- 87 (cont.) 0 0 0 1: · D... ~D... 11'1 11'1 ON c + co ... C1 w 11'1 w :::J ~ co c:: - M u Cl u ,...~ -351- 87, hexane complex ~ ; ~ 0 "" "" ~ ~ ~ N ~ ~ N <r N (IJ ~ (T) ~ X: · 0... a._ X: ·0... C) 0 q- ~a._ • "" (.) (IJ C'J q- a.. Q) ::s ....C'J c: .... ....c: .J:. ~ t.n >o. U) en U) • U) - ("'") u 0 u ~ !D ~ ~ (IJ - ("'") u 0 u ui 87 , hexane complex (cant.) -352- 0 N u u 0 111 :I: 0 ·~? 0 0 u 0 :I: u M :I: (.) i - u :r T t.O i.D 87, hexane complex (cont.) -353- u M N u cO ,n 0 ~ r ii J: 0 0 1.1') u i:j 0 J:: '!i 0 T u c Lf) 0 L() -354- 87, hexane complex (cont.) 0 0 :I: ~ .,. ~ r-i N i = u ~~ ;!) ~>J :I: 0 I ~~ «l r-.i - ~ u ~ 0 cri (r) . c >. en -35587, hexane complex (cont.) I L~ c :- \ N N u """''!!: ~ rc_ Cl. -..... Cl N 0 N J: 0 ·~? 0 N N N 0 J: IN .... i ..... C'O c -356- 87, hexane complex (cont.) 10 ~ >< Q) .J::. L" c. c. r- u I I1 0 lo r....: CIC) u I II I I iI - N u ,..;) ~~ <I' ~ >< Q) .J::. X 0 •(\, 0 c c (/) m 0 X i . .., >a -357- PROPOSITION I Abstract: A test of the strength of the s-effect in determining the regiochemical opening of a,s-halogenonium- and a,e-epoxysilanes is proposed. ********** In the past fifteen years, silicon has become widely used in organic synthesis; 1 indeed, it is rather unusual today not to have a silicon atom as part of one of the intermediates in a synthesis. In particular, vinylsilanes and a,e-epoxysilanes have gained popularity as masked synthons. For example, vinylsilanes have been employed as a-vinyl anion equivalents for the stereospecific construction of diand tri-substituted olefins. 2 On the other hand, a,S-epoxysilanes have served as masked carbonyls or as precursors of heteroatomsubstituted alkenes. The utility of these compounds depends principally on two factors: regie and stereoselection. Take, for example, the case where a vinylsilane is converted into a vinyl halide. The overall substitution outcome will depend both on the regiochemistry of approach of the nucleophile to the intermediate halogenonium ion, and on the stereoselection of the addition and elimination processes (Scheme I). 3 Experimentally, the reaction occurs with overall inversion. Whereas the anti addition of -358- halogens to regular olefins and the anti elimination of 1,2-diheterosubstituted alkanes are well documented, the preferred attack to the carbon~ to silicon needs to be rationalized. It is well accepted that the trialkylsilylmethyl unit offers a strong Scheae I xe H Me ( SiMe H 3 Me H X j Me~ X H -359- stabilizing electron-donating effect to a B electron defficient center (B-effect). 4 Due to the polarization of the C-Si u-bond, the carbon atom bears a larger atomic coefficient. This enables good overlap in the hyperconjugation with the empty p-orbital of an adjacent carbocation (fig. 1). Furthermore, this polarization Fig. 1 puts the u-bond in a higher energy level, close to that of a Studies have shown that the Me 3SiCH 2- group has a up* intermediate between that of a methyl and a methoxy group. 5 p-orbital. Therefore, the a-effect will generally direct the approach of nucleophiles to the carbon a to silicon. Exceptions to this rule are observed when the a carbon itself has an electron donating group that can stabilize a positive charge, or in the chemistry of a,e-epoxysilanes. This latter family of compounds shows opening by nucleophiles at the a position, almost without exception. The two following examples 6 show the strength of silicon in directing a-opening, independently of other features. In eq. 2, steric -360- Me 3 Si~OH ~-hex' 1 OMe effects arguments would have led us to predict attack at the less substituted, B position. In eq. 1, a cationic pathway would have suggested formation of a very stable, tertiary cation stabilized by a silicon atom at the B position. However, only attack at the a position was observed in both cases. Why is thee-effect of silicon which dictated opening at the B position in halogenonium silanes, not operating with a,e-epoxysilanes? Is the e-effect the only cause of the observed regioselection in the former compounds? An explanation to this problem has been proposed by Thomas and Whitham. 7 According to them, the transition state leading to the opening of halogenonium silanes must be a fairly late one, in which the B-halogen bond is highly broken and the e-effect is stabilizing the partial positive charge. In contrast, the a,e-epoxysilane ring opening must have an early, reactant-like transition state in where the e-effect cannot be operating due to geometrical reasons. -361- However, the question why in this latter case the a-position is preferred remains still unaddressed. 8 Earlier work done by Eisch on the opening of a,e-epoxysilanes with lithium aluminum deuteride proved that the reaction occurs via direct attack to the a-position, and that no rearrangement takes place. He also studied the regiochemistry of the reaction using different p-substituted phenyl groups attached to the silicon and found that the mode of opening was insensitive to electronic effects. However, it should be noted at this point that if silicon stabilizes charges by hyperconjugation of the C-Si sigma bond, only inductive effects of the substituents will be relevant. These substituents will make the C-Si sigma bond to be more or less polarized, thus changing the orbital coefficients and therefore making the e-effect more or less effective. Eisch used, among others a highly negative inductive group (CF 3 ), which should have had enhanced the C-Si bond polarization and consequently favor the e-effect. However, a opening was still the only product observed. These results suggest that the reaction regioselection is insensitive to the extent of the e-effect. However, they do not indicate if a charge around the a carbon is ever formed. This could be tested by doing the substitution studies directly on this carbon. For this purpose, several p-substituted, 2'-trimethylsilylstyrenes should be prepared. Here, if a partial positive charge is formed at the a carbon in the transition state, electron withdrawing groups -362- would disfavor the a opening and some B opening product would start to appear. Lets focus now our attention in the a,S-halogenoniumsilanes. As mentioned earlier, anti opening at the a position is generally observed. Thus, when trans-1-trimethylsilyl-1-propene, 1, was treated with bromine, erythro dibromide 2 could be isolated from the reaction 9 (eq. 3). Product 2 is the result of an anti attack of the SiMe ~SiMe3 3 Br Br Me 2 Mer.H EtOH H20 I 20°C Me) Br (3) 2 1 nucleophile to a bromonium ion. In another case, vinyl silane 3 was treated with 12 and silver trifluoroacetate and adduct 4 was isolated 10 (eq. 4). The general explanation for this observed regie and stereochemistry is the following. The olefin reacts with the halide to form a halogenonium ion which is attacked at the B position by the nucleophile. This last step has an advanced transition state in which there is a net defficiency of charge at thee position, stabilized by hyperconjugation of the C-Si sigma bond (S effect). The maximum stabilization would be reached when -363- n-Bu SiMe 3 - \:::1 3 KF DMSO I, i.e.: inversion the empty p orbital and the Ca -Si bond are in the same plane. In this orientation (s* in Scheme II), the bottom face would be blocked by the trialkylsilicon group and the nucleophile would approach from the top face giving~ addition. This is observed in the cases where A orB are groups that can stabilize an adjacent positive charge. 11 However, when they are usual alkyl groups, only anti addition is experimentally observed. This suggests that in this -364- Scheme II anti A c ® I A c A s* syn c -365- latter case the transition state might be more reactant like than it was originally thought. That is, the Ca-CS bond has not rotated from its original conformation (A* in Scheme II), having the trialkylsilyl unit not aligned with the adjacent p orbital. In this orientation, the s-effect is not operating fully. At this point the question of how much of the overall regiachemistry is due to the s-effect comes into one•s mind. Is this the only fact that determines s-attack to be more favorable? One way to evaluate it could be by means of an adduct in where the s-effect could not operate due to geometrical restrictions. One of these systems would be compound 5. 5 Compound 5 has been synthesized by Manuel and coworkers. 12 The synthesis is straightforward and it is summarized in Scheme III. Treatment of 5 with ICl, or I 2;F 3cco 2 - should give an addition adduct which regiochemistry would afford very valuable information. -366- Scheme I I I + Br~ Br (60%) NBS CCI 4 LAH 5 (50%) If we look at the structure of a possible a-cation intermediate 9, we realize that the empty p ortibal is almost orthogonal to the Ca -Si bond, that is, no a-effect will be operating (Scheme IV). The ratio of regioisomers will be mainly caused by the direct effect of silicon to its vicinal carbon. The difference in hinderance between the a and the a position in 6 should be similar to the one existing in the corresponding iodonium ion of 3. -367- co + -368- Therefore, if the a-effect is the factor that is causing the observed regioselection in vinylsilanes, complete reversal should be observed and the system should behave like an a,B-epoxysilane, giving a-opening product 7. Furthermore, compound 5 could be easily epoxidized (MCPBA) and treated with a nucleophilic agent. In principle, the reaction should proceed like with other epoxysilanes, where we concluded that no a-effect is operating, and afford a-opening product. This would serve as control experiment providing us with information concerning potential variations due to steric effects not present in the acyclic cases. -369- References and Notes (1) For a general review see E. W. Colvin, "Silicon in Organic Synthesis," Butterworths, London, 1981. (2) For a review see Chan, T. H.; Fleming, I. Synthesis 1979, 761. (3) Jarvie, A. W. P.; Holt, A.; Thompson, J. J. Chern. Soc. (B) 1969, 852. (4) (a) Batt, R. W.; Eaborn, C.; Greasley, P.M. J. Chern. Soc. 1964, 4804. 237. (b) Berwin, H. J. J. Chern. Soc. Chern. Comm. 1972, (c) Eaborn, C. J. Chern. Soc. Chern. Comm. 1972, 1255. (d) Eaborn, C. J. Organomet. Chern. 1975, 100, 43. (5) (a) Hanstein, W.; Berwin, H. J.; Traylor, T. G. J. Jlrn. Chern. Soc. 1970, 92, 829, 7476. (b) Hartman, G. D.; Traylor, T. G. J. Am. Chern. Soc. 1975, ~' 6147. (6) Hudrlik, P. F.; Hudrlik, A.M.; Rona, R. J.; Misra, R.N.; Withers, G. P. J. hn. Chern. Soc. 1977, 99, 1993. (7) Thomas, E. J.; Whitham, G. H. J. Chern. Soc. Chern. Canm. 1979, 212. (8) (a) Eisch, J. J.; Trainor, J. T. J. Org. Chern. 1963, 28, 287~. (b) Eisch, J. J.; Galle, J. T. J. Org. Chern. 1976, ~' 2615. (9) Jarvie, A. W.; Holt, A.; Thompson, J. J. Chern. Soc. (B) 1969, 852. (10) Miller, R. B.; Reichenbach, T. Tetrahedron Lett. 1974, 543. {11) Brook, A. G.; Duff, J. M.; Reynolds, W. F. J. Organomet. Chern. 1976, 121, 293. -370(12) (a) Manuel, G.; Mazerolles, P.; Darbon, J. M. J. Organomet. Chern. 1973, 59, C7. (b) Manuel. G.; Mazerolles, P.; Florence, J. C. J. Organomet. Chern. 1971, 30, 5. -371- PROPOSITION II Abstract: An explanation for the observed steric effects in the selectivity of the Horner-Emmons reaction is presentd. Experiments for its corroboration are proposed. Transition state structures are discussed. ********** The Wittig reaction constitutes one of the most common means of constructing olefins. 1 Since the original discovery by Wittig and Geissler in 1953, 2 a great deal of effort has been directed towards the control of the reaction diastereoselection by modification of the organosphosphorus reagent and/or the reaction conditions. One of the most significant improvements in this aspect was the introduction of the phosphoryl-stabilized carbanions by Horner and Wippel in 1958. 3 The phosphonate carbanions have been the most commonly used due to their readily availability and easy workup. 4 ' 5 The method is now referred to as the Wadsworth-Emmons or the Horner-Emmons modification of the Wittig reaction. The general mechanism for the reaction of phosphonate carbanions with aldehydes to produce olefins is believed to be essentially identical to that of the Wittig reaction and it is summarized in Scheme I. Unlike the Wittig reaction itself, the mechanism of the Horner-Emmons reaction Sche~~e I -372- + R"CHO 0 R' -o ,, . R'' II .... ) ( R02p~' A A :CN H R' = H 3 R" =Ph k'T R'XA R" 5 4 -o ~RIA RO~r R' R" 6 Na• 0 0 II (Et0) 2 P~CN R 7a:R:H 7b: R :CH 3 H II (Et0) 2 P 1 coocH, R 8a:R=H 8b: R=CH3 -373- has been studied to a lesser extent. However, kinetic and mechanistic data exist for some particular cases. 6 Basically it consists of an initial aldol reaction of anion 1 (Scheme I) with the aldehyde to form, sometimes reversibly, the epimeric oxyanions 2 (erythro) and 3 (three). ~fashion These intermediates then eliminate in a to the corresponding olefin 4 or 5, respectively. This elimination is believed to occur via the oxaphosphetane intermediate 6. Direct proof for the existence of this latter intermediate exists for at least one case. 7 The reaction mechanism has been studied in detail for the condensations of carbanions 7 and 8 with benzaldehyde. 6 The first step proved to be reversible for both 7 and 8. the case of 7a, a further complication was observed: In the corresponding erythro and three oxyanions interconverted directly. However, no direct interconversion was detected in 7b. 6 a This was attributed to a deprotonation and protonation equilibration. This issue was not addressed in system 8. 6c In the case where no interconversion is occurring, a straightforward calculation, applying the steady-state approach to intermediates 2 and 3, leads to the following expression: + k_T/k'T + k_E/k'E -374Two limiting cases can be envisioned: (a) k_T/kT and k_E/kE <<1, that is, the aldol condensation is highly irreversible. The olefin ratio is then equal to the aldol rate constant ratio kE/kT. (b) k_T/kT and k_E/kE >>1, that is the aldol reaction is highly reversible, and the olefin ratio is given by the expression: 4 5 = KE k' E KT ~ The overall reaction diastereoselection will then depend on the response of these rate constants to each particular substrate or conditions employed. For example, in the reaction of phosphono- ester 8b with benzaldehyde, the ratio k_E/kE was found to be substantially higher than that of phosphononitrile 7b, whereas the k_T/kT coefficient proved to be similar. 6c As a result, more I olefin was formed in the former case (l:I = 3:97 for 8b ~ l=I = 15:85 for 7b). A very powerful method used in the elucidation of the mechanism of this reaction has been to study the product distributions derived from oxyanions 2 and 3 obtained by an independent way. These oxyanions have been obtained pure by base treatment of their corresponding conjugated acids 9 and 10 (eq. 1), 6 or as a mixture by the conjugated addition of hydroxide ion to a-cyanovinylphoshonoesters (eq. 2), 8 or by reduction of a a-ketophosphonate (eq. 3). 9 -375- 1.! PrMgCI 2. PhCHO + OH- I EtOH I 1 . o-C 5 H 11 COCI 2 . H2 3. NaOEt -376Their isolation (eq. 1) and conversion of their sodium conjugated bases into olefins constitutes a powerful proof of their existence as intermediates in the reaction. An analysis of the olefin distribution obtained upon treatment of each e-hydroxyphosphonate (erythro and threo) · with base, in presence of an excess of a competing aldehyde led, in the case of 7 and 8, to the mechanism mentioned above, and provided some rate constant . . t s. 6a,c coe ff 1c1en The stereoselection of the Horner-Emmons reaction, like the Wittig reaction, has shown to be highly dependent on the reaction conditions (temperature, solvent, counterion) and on the nature of the phosphonate, especially on its steric requirements. There is a large number of examples in the literature concerning the variability of the olefin distribution upon changes in the size of the groups of the reactants. However, no studies have been done to determine how these effects really modify the ratios. Some of these examples are presented below. In general, for phosphonates not bearing a substituent a to phosphorus (1, R'=H), the I isomer is formed predominantly, independent of the steric requirements (nonetheless, some exceptions occur as will be noted later). For phosphonates bearing an alkyl group a to phosphorus, the size of this substituent and that of the aldehyde have shown to influence the product distribution. Thus, , when phosphonate 11 was treated with sodium hydride and condensed -377with different aliphatic aldehydes, an increase of the Z olefin percentage was observed concomitantly with the increasing size of the aldehyde (Scheme 11). 10 Similar trends were observed when a given aldehyde was condensed with a variety of phosphonoesters having increasing sterically demanding a substituents. 11 Scheme II 0 II (EtO )2P I H C02Et 1. NaH 2. RCHO R H A r C 02Et CH 3 11 + R ArCH 3 CH 3 C0 2 Et E z R E: z Me 100:0 Et 84:16 .i_-C3H7 38:62 sec-C 4H9 33:67 -378- One interesting set of results is the influence of the size of the alkoxide groups attached at the phosphorus atom on the olefin distribution. When cyclic phosphonate 12 was treated with sodium hydride and condensed with different aldehydes, the l olefin was obtained with a selection of ca. 3:2 (eq. 4). 12 This has been Me Me 0 0,11 P'-""C02Et X o' 12 fC0 2Et 1· NaH 2. RCHO (C0 2 Et + R R minor major (4) attributed to an enhancement of the rate of oxaphosphetane formation, due to ring strain release upon going from a tetrahedral to a pentacoordinate phosphorus, in which the five-membered ring occupies an apical-equatorial position (eq. 5). This rate olefins (s) -379- enhancement would represent a decrease of the k-/k' factor, leading towards a more kinetically controlled reaction (see Scheme I). An interesting and synthetically useful control of the olefin distribution has been accomplished through the use of different sterically demanding alkoxide groups at the phosphorus. One of the earliest reports in this aspect is shown in Scheme 111. 13 Scheme I I I + RT E • Z R E : Z Me 65:35 83:17 99:11 -380- These results show that an increase in the E olefin selection correlates with an increase in the size of the alcoxide substituent of the phosphonate. Similar trends have been recently reported in other systems and are summarized in Scheme IV. 14 Interestingly enough, even the stereochemistry of the disubstituted olefins could be modified by this approach. The data however, were presented in a rather empirical way and were not accompanied by any kind of explanation. One possible rationalization of these steric effects could be that the rate of oxaphosphetane formation might be highly modified by the steric hinderance at the phosphorus atom. Thus, when R (eq. 6) is sterically demanding, the intramolecular alkoxide attack at the phosphorus would be slowed down and the k-/k' coefficient increased. Under these conditions, the olefin geometry will be dictated by the relative transition state energies of the oxaphosphetane formation. On the other hand, a small R group would k' olefins (s) -381- Scheme IV ~CHO I BnO E:Z + CH 3 Entry Phosphonate Conditions E:Z ratio A (Me0) 2P(O)CH 2co 2Me K!Bu0/THF/-78°C 1:3 B (1Pr) 2P(O)CH 2co 2Et K!Bu0/THF/-78°C 95:5 E:Z + Entry Phosphonate Conditions E:Z ratio c (iPr) 2P(O)CH(MeC0 2iPr K!BO/THF/-78°C 95:5 0 (iPr) 2P(O)CH(Me(C0 2Et K!_BO/THF/-78°C 90:10 E (Et0) 2P(O)CH(Me)C0 2Et K!BO/THF/-78°C 40:60 F (Me0) 2P(O)CH(Me)C0 2Et K!BO/THF/-78°C 10:90 G (Me0) 2P(O)CH(Me)C0 2Me K!BO/THF/-78°C 5.95 -382- make the phosphorus more accessible towards nucleophilic attack, increasing the relative rate of this step relative to the aldol step. Consequently, the olefin ratio would, in this case, reflect the aldol stereoselection. Relevant data supporting the proposed explanation are given by studies on phosphonate hydrolysis. The kinetics of the hydrolysis of different methyl phosphonates in water:dioxane with sodium hydroxide have been described. 15 The results are reported in Table 1. It is clear from these data that there exists a strong dependence of the rate of hydrolysis on the steric effects of the substrate. The dicyclohexyl ester for example, hydrolyzes as much as 1000 x slower than the corresponding dimethyl ester. Although the diisopropylester was not investigated, its relative rate value should be close to the one of the dicyclohexylester. 0 0 II NaOH (R0) PCH 3 2 II ROfCH 3 OH Table 1 R CH 3 Et n-prop n-but cyclohexyl CH(Me)CMe 3 rel. rate 1000 95 49.7 29.5 1 0.2 -383- Even if in our case the reaction proceeds intramolecularly, a similar trend should be expected for the formation of the oxaphosphetane intermediate. A factor of 1000 would be, indeed, more than enough to reverse the control of the reaction. One way of gaining further information about the proposed explanation would be through the study of the evolution of the independently generated oxyanion intermediates. For this purpose, e-hydroxyphosphonates 13-18 can be prepared following the 13: R=R'=Me 14: R=R'=Me 15: R=iPr R'=Me - ' R=Me, R'=H 16: R=iPr - , R'=Me 18: R=Me, R'=H 17: procedure described in the literature. 6a If the olefin ratio is indeed dictated by the alteration of the k-/k' ratio, treatment of each of these compounds with sodium hydride in presence of an excess of a competing aldehyde, for example (CD 3 ) 2CHCHO (readily available from acetone-d 6 ), should give different results (see Scheme V). Thus, the oxyanion derived from 13, which should have a small k-/k' coefficient according to our model, should show mainly formation of Scheme V 0 II 0 CH3 II (Ro), Pyco,cH, • NaH HO~ 13: 15: CH 3 (Ro),P"f-co,cH, k' CH 'l!co,cH y' -o~ R=Me 19 x~ R=_i_Pr ~ I 0 II (Ro),Pjco,cH, CH 3 )-cHO (co 3) CHCHO 2 ~ k_ k I w 00 0 II CH (R0)2 P~02CHJ -o 3 CD3 CD3 k' CH3 yeo, (C02 CH 3 CD 3 20 -385- the l olefin 19, and little of the cross-over product 20. On the other hand, the oxyanion derived from S-hydroxyphosphonate 15 would have a large k-/k' coefficient, that is, it would revert into starting materials much faster than it would form product. In this case, then, deuterated olefin 20 should be formed in large amounts. Same trends should be observed in the threo series, 14 and 16. An interesting case is the one where R'=H, leading to the formation of disubstituted olefins. As shown in Scheme IV, the l olefin selection using trimethylphosphonoesters is not as good in the synthesis of disubstituted olefins as it is in the trisubstituted counterparts. Is this due to a poorly diastereoselective aldol condensation (1st step) or is it due to a direct equilibration of oxyanions of the type observed for 7a? Again, this could be tested by the study of the evolution of oxyanion 21, derived from s-hydroxyphosphonate 18, in presence of an excess of deuterated aldehyde (Scheme VI). be checked first. Formation of the cross-over olefin 23 should According to our model, oxyanion 21 should eliminate faster than revert to the starting trimethylphosphonoacetate anion 22, because of the little hinderance around the phosphoryl group. We should not observe, therefore, formation of the cross-over olefin 23. Assume the experiment has been done and that this has been found to be the case. Then, if there is direct epimerization between oxyanions, 21 should lead into a mixture of olefins 24 and 25. Comparison of the olefinic ratio obtained this way and the olefinic ratio obtained in the direct reaction (that is, Scheme VI 0 II (Me0) 2 P~C0 2 CH 3 yeo, /CHO (CD3) 2 CHCHO ·~ 1122 co 3 23 0 0 (Meo)J _..c~,CH, ( NaH HO:s: ~II C02CH 3 Me0 P:r; 2 ~co,cH, -o I 21 18 E w 24 !1 0 II H ( MeO),PrC0 2 CH, ~~CH, -oJ z 25 00 0"1 I -387using 22 and isobutyraldehyde as the starting materials) would indicate how fast equilibration is relative to olefin formation (Curtin-Hammett principle 16 ). If, on the contrary, 21 does not epimerize directly, it should afford only I olefin 24, since the elimination is known to proceed stereospecifically ~. 6 a In this case, then, the olefinic ratio obtained in the direct reaction of phosphonate 22 and isobutyraldehyde (which by comparison to the data presented in Scheme IV should be around 3:1 Z:£) would be reflecting the aldol stereoselectivly. Then, we would conclude that, according to the data on Scheme IV, an a-alkyl group is necessary to reach high (>>3:1 erythro:threo) diastereoselection in the aldol step. As we will see in a moment, this would be unlikely. So far we have talked about the influence of the size of the R group attached to the phosphorus. Examination of the data in Scheme IV shows that, in addition, there is a small effect on the olefinic ratio caused by the size of the ester attached to the carbonyl of the phosphonoester molecule. Lets assume that the experiments mentioned above proved that when the alcoxide group of the phosphorus is small the reaction is kinetically controlled, that is, the aldol step is the rate determining step. Seyden-Penne has demonstrated that the potassium enolate of triethylphosphonoacetate is 100% in the I form in THF. 17 Then, assuming that the aldol reaction goes through a pericyclic transition state 18 with the metal chelating the three sp 2 oxygens, we can think of two possible structures -388Scheme VII 11 • R CHO I Ill ,----0 \ - ---0-M.-L / R"' I R" P=o \.RO /~ OR - - - _Q \ /'/ R"' H --- 0-M.-L I P=O /\ RO OR j threo-oxyanion erythro-oxyanion j ! E-olefin Z-olefin -389- for the l enolate: T~, leading to the threo oxyanion and E~, leading to the erythro oxyanion (Scheme VII). Transition state T~has a disfavored 1,3-diaxial interaction between the aldehyde substituent R" and the phosphorus substituent OR. Transition state E*, on the other hand, lacks this particular interaction but has a 1,3-diaxial interaction between the aldehyde substituent R.. and the carbon ester group OR'. One can anticipate that the 1,3-diaxial interaction * should be more severe in T* than in E as the phosphorus is tetrahedral whereas the ester carbon is planar. However, if R'O is cons i de r ab1y 1a rg e ( i •e • R' =j_P r) , then the i nt era ct i on R..,.a R' i n E* might become more important putting this transition state somewhat closer in energy toT~, therefore decreasing the reaction selection. This could account, then, for the selection improvement observed in entry G (Scheme IV). According to this model, the size of the a-substituent R' 11 should not influence the stereoselection in the aldol condensation since it would be affecting the energies of E~ and T* in a comparable way. The observed dependence of the olefin ratios on the size of R' .. (vi de supra) must then be caused by a different rate of oxaphosphetane formation. The reason for the differences in olefinic ratios observed in entries C and D of Scheme IV remains, at this point, unknown. The proposed transition states predict a higher percentage of erythro oxoanion formation as the phosphorus substituents increase in size. If this was the only effect on the diastereoselection of -390- the reaction, higher percentages of I olefin should be observed. However, concomitantly with this increasing erythro selection, the rate of the oxaphosphetane formation should be decreased by large size substituents (vide supra) and this last step would then eventually become the rate determining step, favoring I olefin formation. The experimental results indicate that sterics must be felt in a more dramatic way in the oxaphosphetane formation than in the aldol reaction. This is supported by the strong steric dependance showed in the rate of the basic hydrolysis of phosphonates. -391- References and Notes (1) For a good review see Schlosser Topics in Stereoch. 1970 , ~' 1. (2) Wittig, G.; Geissler, G. Annalen, 1953. 580, 44. (3) Horner, L.; Hoffmann, H.; Wippel, H. G. Chern. Ber. 1958, 21, 61. (4) Wadsworth, W. S.; Emmons, W. D. J. Am. Chern. Soc. 1961, 83, 1733. (5) For a review see Wadsworth, W. S. Org. React. 1978, 25, 73. (6) (a) Deschamps, B.; Lefebvre, G.; Seyden-Penne, J. Tetrahedron 1972, 28, 4209. (b) Deschamps, B.; Lefebvre, G.; Redjal, A.; Seyden-Penne, J. Ibid. 1973, 29, 2437. T. Ibid. 1973, 29, 4199. (c) Bottin-Strazalko, (d) Redjal, A.; Seyden-Penne, J. Tetrahedron Lett. 1974, 1733. (7) Breuer, E.; Zbaida, S.; Segall, E. Tetrahedron Lett. 1979, 2203. (8) Danion, D.; Carrie, R. Tetrahedron 1972, 28, 4223. (9) Durrant, G.; Sutherland, J. K. J. Chern. Soc., Perkin I 1972, 2582. (10) Kinstle, T. H.; Mandanas, B. Y. Chern. Comm. 1968, 1699. (11) Sasaki, K. Bull. Chern. Soc. Jpn. 1968, 11, 1252. (12) Brever, E.; Bannet, D. V. Tetrahedron Lett. 1977, 1141. (13) Sugiyama, T.; Kobayashi, A.; Yamashita, K. J. Agr. Biol. Chern. 1972, 36, 565. -392- (14) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873. (15) Christal, H.; Marty, C. J. Organomet. Chern. 1968, 1£, 471. (16) Eliel, E. L. "Stereochemistry of Carbon Compounds". McGraw-Hill 1962, p. 238. (17) Bottin-Strzalko, T.; Corset, J.; Froment, F.; Pouet, M.; Seyden-Penne, J.; Simonnin, M. J. Org. Chern. 1980, 45, 1270. (18) Evans, D. A.; Nelson, J. V.; Taber, T. J. Am. Chern. Soc. 1979, 101, 6120. -393- PROPOSITION III Abstract: proposed. A mechanism for the disassembly of microtubules is The use of [e- 32 P]-GTP to provide experimental evidence for the proposed mechanism is discussed. ********** Microtubules 1 are proteinaceous organelles, present in nearly all eucaryotic cells, made of subunits assembled into elongated tubular structures. Together with other proteins, they are the building blocks of complex assemblies like mitotic spindles, centrioles, cilia and flagella, oxonemes and neurotubules. Micro- tubules may be described as regular helical assemblies of two protein subunits, 2 tubulins a and e, each of about 55,000 daltons molecular weight. 3 It has been shown that one mole of purified tubulin binds two moles of GTP. 4 There are two sites: at one, GTP is tightly bound to the protein and does not exchange with exogenous GTP; at the other, GTP is weakly bound to the protein and exchanges with the GTP in the medium. These sites are called E (exchangeable) and N (non-exchangeable). Microtubules consist of chains (protofilaments) of the subunit protein, tubulin, aligned longitudinally along the axis of the cylinder with 13 protofilaments arranged around the circumference (see fig. 1). In 1972, Weisenberg 5 described the conditions for -394- Figure 1 -------- TRANSVERSE VIEW LONGITUDINAL VIEW THE HELIX NET -395microtubule polymerization in vitro using brain tubulin. that the following conditions were required: He found (1) a minimum tubulin concentration, (2) presence of GTP, (3) presence of Mg 2+ and absence of ca 2+, and (4) a temperature of 37°C. The evolution of microtubule polymerization can be followed by turbidimetry and visualized by electron microscopy. Tubulin isolated by cycles of temperature dependent polymerization-depolymerization copurified with some other proteins called MAP's (Microtubule Associated Proteins). two classes: The MAP's belong to one, with high molecular weight (~. 300,000 daltons) called MAP 2 ; the other, with lower molecular weight (55,000 to 70,000 daltons) called the r factor. Under physiologicai concentrations of Mg 2+ (1 mM) and GTP (1 mM), polymerization of tubulin into microtubules requires the presence of these MAP's. However, the role that these proteins play in the process remains unclear. Thermodynamically, the tubulin-microtubule system is in dynamic equilibrium. The free tubulin is always equal to the minimal concentration required for polymerization (called the critical concentration). Tubulin assembly occurs by a polymerization- condensation mechanism consisting of two different phases: nucleation and elongation (see fig. 2). Some of these nuclei have been isolated and purified, 6 and show the presence of ribbon precursors. This tendency of tubulin to self-associate and to form intermediate polymers complicates the study of the assembly -396F ·gure 2 1 ------- -397- mechanism. Once the assembly process has started, it proceeds until the tubulin-dimer concentration reaches the critical concentration. At this point the steady-state has been achieved and the weight of total microtubule stays constant. The system is then continually undergoing assembly and disassembly. These two different processes are occurring preferently at opposite ends of the microtubules at equal rates. Addition of ca 2+, antimicrotubular drugs such as colchicine or Vinca alkaloids, or low temperatures (0 - 4°C) results in complete depolymerization. An essential point in the process of microtubule assembly is the role played by GTP. It has been shown that the E-GTP was hydrolyzed to GOP during polymerization, while the N-GTP was not. 7 However, hydrolysis of the E-GTP into GOP was shown not to be required for polymerization, since non-hydrolyzable analogs of GTP (such as GMPP(CH 2 )P and GMPP(NH)P) have the capacity to promote assembly.lc,S The use of the a-a hydrolysis resistant GTP analogs (like GMP(CH 2 )PP and GMP(CH 2 )P) has also been investigated, 9 , 10 showing interesting properties. Microtubules polymerized with GMP(CH 2 )PP are assembled at lower tubulin concentrations than those with GTP, resulting in faster rates of microtubule nucleation. addition, these microtubules do not depolymerize when exposed to cold or ca 2+ ions. Experiments with GMP(CH 2)P, the a-a nonhydrolyzable analog of GOP, once again showed assembly, but to a lesser extent. 10 Its equivalent, GOP, however, did not induce . po l ymer1za . t"1on. 11 tu b ul 1n In -398- It seems, then, that a-B hydrolysis might play a critical role in the process of disassembly. Then, conversion of GOP into GMP could be a requirement for microtubule disassembly. In fact, incubation of GTP with tubulin under polymerization conditions results in production of GOP and GMP. 10 However, this GMP could be the product of the hydrolysis of GOP in the medium, due to the action of minor impurities of phosphatases that copurified with the tubulin. On the other hand, E-GMP bound to the tubulin at the microtubule stage has never been detected. One possible explanation for this apparent controversy could be the participation of the N-GTP. If one makes the assumption that a conformational change in the tubulin molecule is requiredin order to cleave the dimer from the microtubule (i.e. disassembly), then, this change could be the result of a rapid interchange of the N-GTP ~-phosphate and the E-GOP a-phosphate. Such an interchange, with the transferred phosphate stabilized by some amino acid, would provide the tubulin molecule with a conformation suitable for depolymerization. This would explain why no GMP is detected in the microtubule and why microtubules containing a-B non-hydrolyzable GTP analogs at the E-site are resistant to depolymerization. The hypothesis described above could be tested experimentally in the following manner. Tubulin would be polymerized in presence of [e- 32 P]-GTP in order to load the E-site with this nucleotide. It is important to point out that interchange of nucleotides between -399- the E and the N-sites has never been observed. The microtubules would then be broken by the exposure to cold temperatures (vide supra). Then, the labeled nucleotide at theE-site would be displaced by use of an excess of non-labeled GTP, and subsequently removed by chromatography. Thus, after this treatment, any radioactivity found in the tubulin molecule would be due to labeled phosphorus at the N-GTP, therefore showing that 32 P interchange has occurred. This would not only account for a mechanistic function of the N-GTP, but would also help explain some of the experimental facts mentioned above. -400- References and Notes (1) For a review, see (a) Dustin, P., "Microtubules" SpringerVerlag, 1978. (b) Timasheff, S. N.; Grisham, L. M. Ann. Rev. Biochem. 1980, 49, 565-591. (2) Shelanski, M. L.; Gaskin, F.; Cantor, C. R. Proc. Natl. Acad. Sci. U.S.A. 1973, 70, 765-768. (3) (a) Bryan, J.; Wilson, L. Proc. Natl. Acad. Sci. U.S.A. 1971, 68, 1762-1766. (b) Fine, R. E. Nat. New. Biol. 1971, 233, 283-284. (4) (a) Shelanski, M. L.; Taylor, E. W. J. Cell. Biol. 1967, 34, 549-554. (b) Shelanski, M. L.; Taylor, E. W. Ibid. 1968, 38, 304-315. (c) Weisenberg, R. C.; Taylor, E. W. Fed. Proc. 1968, 'Q, 299. (5) Weisenberg, R. C. Science, 1972, 177, 1104-1105. (6) Snyder, J. A.; Mcintosh, J. R. J. Cell. Biol. 1975, ~' 409a. (7) (a) Kobayashi, T. J. Biochem. Tokyo 1975, ll, 1193-1197. (b) Kobayashi, T.; Simizu, T. ibid. 1976, 79, 1357-1364. (c) Weisenberg, R. C.; Deery, W. J.; Dickinson, P. J. Biochemistry 1976, ~' 4248-4254. (8) Penningroth, S. M.; Kirschner, M. W. J. Mol. Biol. 1977, 115, 643-673. (9) Sandoval, I. V.; McDonald, E.; Jameson, J. L.; Cuatrecasas, P. Proc. Natl. Acad. Sci. U.S.A. 1977, 74, 4881-4885. -401- (10) Sandoval, I. V.; Jameson, J. L.; Niedel, J.; McDonald, E.; Cuatrecasas, P. Proc. Natl. Acad. Sci. U.S.A. 1978, ~' 3178-3182. (11) Carlier, M. F.; Pantaloni, D. Biochemistry 1978, Jl, 1908-1915. -402- PROPOSITION IV Abstract: The use of a Claisen rearrangement in the construction of vicinal quaternary centers is discussed. Its application to the total synthesis of (~)-Verrucarol is proposed. ********** The trichothecene antibiotics are a clinically promising family of compounds. 1 These sesquiterpene metabolites show antibiotic, antifungal, antiviral and cytotoxic properties as well as antileukemic activity. 2 Indeed, laboratory-derived oxygenated trichothecenes have proved to be the most potent antileukemic agents known to date against mouse P388 leukemia. 2 As a consequence, it is not surprising that a lot of effort has been directed towards the laboratory syntheses of these compounds. Structurally, they have interesting and challenging chemical features (Scheme I). The family can be divided in two groups. Both classes share a common, tetracyclic sesquiterpene, containing a spiro epoxide. However, one group contains an additional carbon chain forming a macrocyclic structure (Verrucarins and Roridins), whereas the other lacks this unit (Trichodermol and Verrucarol, among others). -403- xh~e I OH Verrucarol (1) 0 Verrucarin A Verrucarol, 1, contains the basic structure of nearly all the trichothecene members. It includes three cycles (named A, B and C going from left to right as represented in Scheme I), and an epoxide. The molecule has six oxygen functionalized carbons and one unsaturation. Finally, the carbon-carbon connection between rings A and C involves two vicinal quaternary centers. To date, three syntheses of Verrucarol have been published. 3 ' 4 ' 5 One key point in these syntheses and in those of related compounds is the stereoselective introduction of the aforementioned quaternary centers. Useful methods that have been used for the construction of quaternary carbons 6 involve electrocyclic reactions. Indeed, in the mentioned syntheses of verrucarol these centers are created via Diels-Alder reactions or Claisen rearrangements, in a stepwise -404- fashion. It is conceivable, however, to envision the construction of the two quaternary carbons in one step by means of one of these processes. Because the non-bonding interactions in the transition state of such a reaction must be very severe, the presence of some "equilibrium-pulling" factor is required. Two examples of this are the Claisen and oxy-Cope rearrangements. In these cases, the formation of a carbon-heteroatom bond is the driving force of the reaction. Indeed, a quick calculation on the energy of the Claisen rearrangement of vinyl allylether (based on bond energies) favors the formation of the rearranged product by ca. 30 kcal/mol. It is well accepted that, when possible, Claisen and Cope type rearrangements proceed via a cyclic, chair-like transition state, in which non-bonding interactions have been minimized. 7 This has been used for the stereospecific construction of substituted olefins or for chirality transfer along two points of a molecule. The energy difference between the corresponding chair and boat transition states for the Cope rearrangement of 1,5-hexadiene has been found to be 5.8 kcal/mol. This value is very close to the difference in energy of boat and chair cyclohexanes (5.5 kcal/mol). Furthermore, there has been found a correlation between the relative free energies of formation of the substituted Claisen chair transition states and those of the corresponding cyclohexanes. 8 This provides, then, a powerful tool to predict product distributions. -405- The kinetics of the Cope rearrangement of compounds 2 and 3 have been recently studied by Shea. 9 Both compounds lead to the same product 4 upon heating (Scheme II). However, the conformation Scheme II 6-D ..... 2(d1) . .9 ' ' ~/ / c• * ~ eY 4 / s• 3 (meso) of their transition states must be different due to geometrical constraints. Thus, the Ql compound can undergo rearrangement only through a chair transition state, whereas the meso counterpart can only rearrange via a boat. Analysis of the molecular models of the two transition states predicts serious non-bonding interactions between the two rings and the two vicinal hydrogens (see fig. 1) in -406Fig. 1 transition state B. The difference in energy for these transition states was calculated to be 9.1 kcal/mol. The equilibrium in this reaction lies completely towards product 4. However, the introduction of an heteroatom in a suitable place could shift completely the equilibrium position to the opposite direction. Indeed, compound 5 undergoes rearrangement to the ketone in 75% yield (eq. 1). 10 By the principle of 200°C, 0.5 h 5 (75%) microrreversibility one can think that the arguments presented above will hold for this process. Therefore, only one compound (the -407- Ql-type) should arise for this reaction. Unfortunately, the authors made no comment on the stereospecificity of the reaction. Data exist, however, on the stereospecificity of the rearrangement of compound 6 (eq. 2). 11 In this reaction, only the Ql compound was formed. 6 Taking into consideration the data above, we can envision then the rearrangement of a compound like 7 into keto-olefin 8 (eq. 3). In this process, the overall stereochemical outcome would be dictated by two independent factors: a) according to the arguments presented above, the rearrangement would proceed through a chair transition state to afford exclusively the Ql-type product; b) the chiral center in the molecule would ensure approach of the cyclohexene moiety from the less hindered side, that is, the a side. (3) 7 8 -408- The two transition states (chair c*, and boat s•) of this mode of approach are represented in fig. 2. Fig. 2 • c• * It is clear from molecular models that transition state B* should be highly disfavored by a) the developing 1,2 CH 3~cH 2 0R interaction~and b) the interaction between rings. *. absent in transition state C Both of these are -409- One aspect that has not been addressed up to this point is the potentially serious steric constraints of approaching two tetrasubstituted olefins. Although such a reaction has never been reported in the literature, a comparison with closely related systems indicates that yields are not substantially lowered when the degree of substitution is increased in sterically constrained systems. Scheme III summarizes one of these examples. 12 Scheme III Ph COO I I I Ph COO I ~::o R Yield R= R'= H R= Me, R'= H R= H, R'= Me R= Me, R'= Me 80% 84% 75% 77% It should be mentioned that in this particular example, all three carbons of the allylic moiety are part of a ring and therefore -410- the corresponding transition states for the rearrangement are even more crowded that the ones of the reaction it is being proposed here. A possible preparation of the Claisen precursor is outlined in Scheme IV. The ring that would ultimately become the A ring of Verrucarol would be synthesized via a Diels-Alder reaction of 2-methoxy-1,3-butadiene (9) and acetylene 10. Compound 10 could be easily prepared from commercially available dimethyl acetylenedicarboxylate by reduction and protection as the 1-butyldimethylsilylether. The Diels-Alder adduct 11, which should have the carboxylate and the methoxy substituents in a para relationship, would then be reduced to the alcohol (DIBAL, CH 2cl 2 ), and this protected as the triphenylmethylether. Deprotection of the silyl ether (Bu 4NF, THF) and transformation of the methylenolether functionality into a cyclic acetal (ethyleneglycol, TsOH) would afford compound 12. The vinylic portion of the Claisen precursor, which would ultimately become the C ring of our target molecule, could be derived from 2-methyl-1,3-cyclopentadione, 13. The coupling of the two pieces, 13 and 12, in presence of a catalytic amount of acid (CSA) should give compound 14. Reduction with sodium borohydride in presence of cerium cation, 13 and careful quenching (pH 7) to avoid elimination, followed by protection as the TBS ether (TBSOTf, Et 3N) would finally afford our desired product 15. Scheme IV -411- C0 2 CH 3 I CH,O~ + m ~ OTBS 9 10 11 I a,b,c,d OTr (_~ OH (a) DIBAL, CH Cl ; (b) TrCl, Et N, CH Cl ; (c) Bu NF, THF; 4 3 2 2 2 2 (d) HOCH CH 0H, TsOH. 2 2 0 Q: + 12 13 15 12 -412- Based on the arguments presented above, compound 15 should rearrange to ketone 16 upon heating. The final steps of the synthesis are outlined in Scheme V. Ozonolysis, followed by reduction (LiBH 4 , THF) would presumably afford a complex mixture of dials. Without purification, the mixture would be treated with POC1 3 in pyridine to afford bis olefin 17. Under mild acid conditions, selective deprotection of the acetal in presence of the other protecting groups should be feasible. The remaining steps leading into our final target would then proceed in analogy to Still's synthesis of Trichodermol •14 Thus, deprotection of the silyl ether {HF, pyridine) would regenerate the alcohol functionality needed for the stereoselective epoxidation of the five membered ring olefin. Treatment of this alcohol with t-BuOOH in presence of VO(acac) 2 would afford epoxide 19. Subjecting the epoxide to acid conditions {H 2so 4 , acetone) should proceed with the regioselective opening of the epoxide at the least hindered site, and consequent internal Michael addition to afford 20. Under these mild conditions the primary, but somewhat hindered trityl ether should not be affected. Reaction of 19 with methyllithium would form the corresponding tertiary alcohol. Selective protection of the c4 hydroxyl as the benzyl ester (PhCOCl, pyridine) and Collin's oxidation would then afford ketone 21. synthesis would proceed as follows: The four final steps of the the tertiary alcohol would be dehydrated to the desired olefin with POC1 3 in pyridine (7:1 ratio -413Scheme V TBSO A- ~OTr S< \_(0 0 a 0 \_} 15 16 b,c,d OTBS OH f,g X 0 X= OCH CH 0 2 2 e( 17: 0 X= 18: 19 h - : HOHOmOTr 1~ 0 : 'r_-- : PhCOO omOTr 0 0 II H H 21 20 ll,m,n,o verrucarol (a) heat; (b) 0 ; (c) LiBH 4 , THF; (d) POC1 , pyridine; (e) aq. HCl: 3 3 THF, 0°C; (f) HF, pyridine; (g) .!_BuOOH, VO(acac) ; (h) H so , 2 2 4 acetone; (i) Meli, THF; (j) PhCOCl, pyridine; (k) Cr0 .2py, CH Cl ; 2 2 3 (1) POC1 3 , pyridine; (m) aq. HCl :THF; (n) Ph P=CH , THF; (o) MCPBA. 3 2 OH -414- of olefins in Still's synthesis). Deprotection of both alcohol protecting groups (aq. HCl, THF) and methylenation (Ph 3P = CH 2), followed by c4 hydroxyl directed epoxidation (MCPBA) would then give (~)-Verrucarol. -415- References and Notes (1) For a recent review see (a) Jarvis, B. B.; Mazzola, E. P. Accts. Chern. Res. 1982, ~, 388. (b) Ong., C. W. Heterocycles 1982, _!2, 1685. (2) Doyle, T. W.; Bradner, W. T. in "Anticancer Agents Based on Natural Product Models," Cassidy, J. M., Douros, J. Eds., Academic Press, New York, 1980. (3) Schlessinger, R. H.; Nugent, R. A. J. Am. Chern. Soc. 1982, 104, 1116. (4) Trost, B. M.; McDougal, P. G. J. Am. Chern. Soc. 1982, 104, 6110. (5) Roush, R.; D Ambra, T. E. J. Am. Chern. Soc. 1983, 105,1058. (6) For a review see Martin, S. Tetrahedron 1980, 36, 419. (7) For a review see Rhoades, S. J. Org. Reactions 1974, 22, 1. (8) Faulkner, D. J.; Perrin, C. L. Tetrahedron Lett. 1969, 2783. (9) Shea, K. J.; Phillips, R. B. J. Am. Chern. Soc. 1980, 102, 1 3156. (10) Julia, S.; Julia, M.; Linares, H.; Blondel, J. Bull. Soc. Chim. Fr. 1962, 1947. (11) Tamuru, Y.; Harada, T.; Yoshida, Y. J. Am. Chern. Soc. 1978, 100, 1923. {12) Cave, R. J.; Lythgoe, B.; Metcalfe, D. A.; Waterhouse, I. J. Chern. Soc. Perkin I 1977, 1218; Lithgoe, B.; Metcalfe, D. A. Tetrahedron Lett. 1975, 2447. -416- ( 13) Louche, J. J . .Am. Chern. Soc. 1978, 100, 2226. (14) Still, W. C.; Tsai, M. J • .Am. Chern. Soc. 1980, 102, 3654. -417- PROPOSITION V Abstract: The classification of the Great Grebe (Podiceps major) as a non-Podiceps species is proposed on the basis of behavioral differences in the water courtship. ********** Ethology, or the study of animal behavior, is a relatively young science that has become very popular in the last two decades, especially since 1973 when the Nobel Prize in medicine was given to three scientists working in this field. 1 The science relies very heavily on one basic aspect: observation. 2 For many years ethologists have been compiling data on animal behavior. Since long ago, a class of behavior that has intrigued most biologists has been the innate or instinctive behavior. Instincts, just like physio- logical characteristics, are intrinsic to the species and are transmitted from generation to generation by genetic mechanisms. They are, therefore, subject to the laws of natural selection, as Darwin already pointed out in 1886 in his .. Origin of Species ... In trying to classify the animal kingdom, taxonomists put all their emphasis on the comparison of the physiological characteristics. Based on these features, they speculated about the origin and evolution (phylogeny) of the different families and orders of -418- animals. Recently, though, and coinciding with the development of ethology as an .. accepted .. science, behavior has been incorporated to these evolutionary and taxonomic studies. Indeed, by the comparative study of the innate behaviors of the species of a family, ethologists have been able to trace their evolutionary hi story. Grebes (Podicipediformes) constitute an order of birds particularly interesting for their primitive stage in the evolutionary scale. They are small to medium-large in size, foot-propelled diving birds, widely spread throughout the world. The order has a single family (Podicipedidae), formed by 20 species grouped in 5 genera, Tachybaptus, Podilymbus, Rollandia, Podiceps and Aechmophorus. 3 ' 4 The family has generally been divided into two tribes. The Podilymbini, which includes Podilymbus and Tachybaptus, are characterized by having a well developed Musculus flexor perforatus digiti II, and extra bony channels for its tendon in the hypotarsus 3 (see fig. 1), and by presenting a particular copulatory behavior. The other tribe, the Podicipedini, includes the remaining three genera. Its members are characterized by the lack of the mentioned canal in the hypotarsus (fig. 1), and by their copulatory behavior. The members of the genus Podiceps have one of the most interesting and sophisticated courtship displays observed in birds. The genus is formed by eleven species, one of them (gallardoi) -419- Figure 15 Tarsometatarsus of the Red-necked Grebe (Podiceps grisegen a) (left) and the Pie-billed Grebe (Podilymbus podiceps) (right). The arrow demarks the canal for the tendon of insertion of Musculus flexor perforatus digiti II, present in the Podilymbini tribe, but lacking in the Podicipedini. discovered as late as 1974 4 • Some of them are represented in fig. 2. 5 The six top birds are generally accepted as the six species of Podiceps, sensu stricto. The bird at the bottom (the Great Grebe) is the subject of this proposal. The remaining four species of the genus Podiceps (not represented) will not be considered here because of the lack of data concerning details of their behavior. The Great Grebe (Podiceps major) is a species that has been difficult to classify. This South American bird was originally thought to be closely related to the palearctic, Red-necked Grebe -420- A c D E F G Figure2 6 plumages: Head patterns of some Podiceps species in nuptial A, Taczanowski (P. taczanowski); 8, Great-necked (P. cristatus); C, Silver (P. occipitalis); D, Eared (P. auritus); E, Red-necked (P. grisegena); F, Black-necked (P. nigricollis); G, Great (P. major). -421- (P. grisegena) based on analogies in the head pattern. 9 These resemblances, however, might well be due to convergent evolution. Indeed, while based on morphological features one would quickly classify the Great Grebe as a Podiceps member, a close comparison of their courtship behavior will demonstrate that, in fact, it might not be as closely related as it is commonly accepted. The following is a series of water displays and ceremonies reported for the Great Grebe by Storer 10 and Greenquist. 11 In the present description of the displays, details have been ommitted to keep the text compact. The descriptions will rely heavily on the corresponding accompanying figures, which are based on the ones reported by the authors. (a) The Upright Mohawk Position (fig. 3A). In this position, the neck is stretched upward, and the crest (mohawk type) is fully erected. (b) It is used as part of the ceremonies (vide infra). The S-neck Position (fig. 38). The mohawk crest is partially erected and the neck forms an S-type curve. It is used in mildly aggressive situations. (c) Advertising (fig. 3C). The head is held high, the neck is nearly stretched vertically, the mohawk crest may or may not be spread, and a specific call is given while in this posture. This display is common throughout all the members of the family, with - minor differences. (d) The Gunner's Display (fig. 30). The neck is extended to the front and the head is held low over the water, while a call is -422- . ~I A c B E D Figure 3: Courtship displays of the Great Grebe: A. Upright Mohawk position; B. S-neck posi- F tion; C. Advertising; D. The Gunner's Display; E. The Nodding Display; F. The Ceremonial Flying Display; G. Progressive stages of the Ghostlypenguin Display, with G Nodding. -423- given. The meaning of this display is not well understood, since no reaction to it is observed by other individuals. (e) The Nodding Display (fig. 3E). In this display, two birds approach each other in the Upright Mohawk posture and start nodding their heads slowly. (f) Display. Their movements may or may not be synchronized. The Turning Display. It always follows the Nodding The birds, usually in the Upright Mohawk posture, perform rigid, synchronized, 90° turns to the same side swimming side by side for 1 to 2 feet, back and forth between 5 to 10 times. (g) The Turning-away Display. the Turning Display. It is the usual conclusion of The birds turn tail to tail and slowly separate, periodically "glancing" at each other. (h) The Ceremonial Flying-away Display (fig. 3F). A bird suddenly turns and flies away from its mate, with the mohawk crest partially raised, the head held down and wings flapping. (i) The Ghostly-penguin Display (fig. 3G). The bird dives, swims underwater past the other bird, and slowly emerges, adopting a risen posture, facing away from the second bird; the neck is extended upward, the bill is dipped about 45° below the horizontal and the mohawk crest is raised. In 10% of the displays, bill raising is quickly followed by a single, pronounced nod. The most common displays in a complete ceremony are Nodding, Turning and Turning-away, which are performed always in the stated order. The Ghostly-penguin and the Flying-away Displays appear less frequently. -424- When compared with the displays observed in the true Podiceps members (P. cristatus, grisegena, auritus, nigricollis, taczanowskii and occipitalis), the activities of the Great Grebe seem to be much more simple. 10 The true Podiceps have a large number of complicated ceremonies which are common, except for minor variants, to all members of the group. Some of the displays of the Great Grebe have been proposed to be homologous 12 to some displays used by the true Podiceps species in the so called Discovery Ceremony. This ceremony is performed by all members of the Podiceps genus in a strikingly similar way; only the New Zealand species P. poliocephalus and P. rufopectus have lost it to a certain degree. 13 It can be summarized as follows: 14 (1) one grebe dives while the other automatically changes its appearance from relaxed to the so-called Cat Display (see fig. 4); (2) at a distance of about 1m away from the second bird, the first bird emerges vertically, in an erected position, known as the Ghostly-penguin Display; (3) a penguin dance follows, in which both partners dance, breast to breast, in an erected position of the body; in the Great-crested Grebe (P. cristatus), this display is replaced by the Head-shaking Display, in which the birds perform a rapid side to side head movement; (4) the end of the ceremony is different between species and might include habit preening, where the head is turned away and the bird starts touching its back or wing feathers with its bill, or -425- . it might finish with the turning away, where the two birds slowly separate from each other in a stereotype fashion. This ceremony, which is common for the six top species shown in fig. 2, appears to be acting as a bond strengthner of the members of a pair. 3 As an example, figure 4 intends to show the similarities of the already mentioned ghostly-penguin display of four different species of the genus Podiceps (drawings based on ref. 14). In most of the Podiceps species, the Discovery Ceremony is either followed by repeating the same performance or by the completely different, Weeding Ceremony. This consists of either a penguin dance (or a side by side rush) performed with weeds in the bills of both partners (fig. 5) (P. cristatus, P. grisegena, P. auritus and Aechmophorus occidentalis), or in some kind of other weed-presentation display (P. occipitalis, P. gallardoi, P. nigricollis and presumably P. taczanowskii). 15 It is somewhat surprising that the Western grebe (Aechmophorus occidentalis) has a Weeding Ceremony, since the genus Aechmophorus is believed to have separated from the Pociceps branch a long time ago. However, no kind of weeding display has ever been recorded for the Great Gre be. 10,11 Once we have presented some of the more characteristic displays of both sides, the Great Grebe and the rest of the Podiceps grebes, we are ready to discuss their similarities and discrepancies, and to speculate about their common or independent origin. -426- . ~ ~1fl ~ ~. - -.-. ~ . _; __- ""-- ·~ ~ A --- --- -=--- - C . 8 -..> c --~ D Figure 4: The Ghostly-penguin and Cat Displays of four Podiceps species: A. Great-crested (cristatus); B. Red-necked (grisegena); C. Eared (auritus); D. Black-necked (nigricollis).(Drawings based on ref. 14). -427- A 8 Figure 5: The Weed-Ceremony. c A. Great-crested Grebe (Podiceps cristatus); B. Black-necked Grebe (Podiceps nigricollis); C. Western Grebe (Aechmophorus occidentalis) Contrary to the other Podiceps, the Great Grebe lacks a Discovery Ceremony. However, one of the displays of this ceremony, the Ghostly-penguin Display (fig. 4) has been proposed to have its counterpart in the Great Grebe (fig. 3H). Storer10 compared these two displays and concludedthat they were phylogenetically related. Nonetheless, he pointed out the following discrepancies: (1) the -428- long dive is not interrupted by emergences like in P. nigricollis, auritus and grisegena, nor is the bird close enough to the surface to make a ripple, as in P. cristatus; (2) in some cases, the emergent bird makes a nod; (3) during emergence, the bird does not bend its neck, contrary toP. nigricollis, auritus and grisegena; (4) the body of the emerging bird remains in a horizontal position. Although not mentioned by Storer, two other discrepancies should be added: (5) while in the other Podiceps species the display involves two partners (the diving bird and the Cat-displaying bird, see fig. 4), the Great Grebe performs it generally alone and unpredictably, during the ceremonies; 11 (6) finally, courting Great Grebe pair members might perform Ghostly-penguin Displays at the same time, 11 which is unprecedented for other Podiceps grebes. The above-mentioned differences in the execution of the Ghostly-penguin Display by the Great Grebe makes this display of questionable homology with the one observed in the other Podiceps members. The fact that the display is more or less similar in both counterparts might well be the consequence of a convergent evolution. Moynihan 16 defines a display as "any behavior especially adapted in physical form or frequency to function as a social signal." In other words, a display is, in one way or another, the consequence of a modified, "every day" behavior via natural selection. It would be logical, then, to believe that the Ghostly- -429- penguin Display of the grebes was originated through the ritualization of the normal fishing dive. Because all grebes dive for fish, it is perfectly possible that the Ghostly-penguin Display appeared independently in the Great Grebe and in the other Podiceps members after they separated in the evolutionary tree, and that their similarities are the result of convergent evolution. As the behavior transformed into a display, in one branch (true Podiceps) it became a uniformly consistent part of a ceremony, whereas in the other branch (Great Grebe) it became a single display, unpredictably performed. It has been proposed that the Nodding and Turning ceremonies are related to the Discovery Ceremony of the Podiceps grebes, but details were not given. 1 For example, it was pointed out that the ° Turning Display of the Great Grebe might be derived from the Headshaking of the Great Crested grebe (P. cristatus). 10 A close analysis of these two displays, however, shows important differences. Indeed, in the Great Grebe, it involves displacement of the whole body,lO,ll whereas in the Great Crested grebe it represents only a rapid side to side movement of the head. 14 The fact that the Great Grebe lacks any form of Weed Ceremony might be used as an indication of the age of this species. As we mentioned earlier, even the separate Western grebe (genus Aechmophorus) shows a Weed Ceremony, which suggests that the Great Grebe might have detached from the main Podiceps branch even earlier -430- than the Western grebe. One could argue, though, that in the same way that the Ghostly-penguin Display of the Great Grebe might be the result of convergent evolution (vide supra), the Weeding Ceremony of the Western grebe could also have appeared independently of the Weeding Ceremony of the other Podiceps members. However, contrary to the Ghostly-penguin Display, the Weeding Ceremony of both counterparts involves a sequence of different actions (Weed-trick, Weed-approach and Weed-dance). 14 It is highly improbable that the identical sequence had evolved independently in the two genera. In summary, the above mentioned differences in the courtship behavior of the Great Grebe (Podiceps major) seem to indicate that this species separated from the old Podiceps stock at an early stage in the evolutionary history of the family, before the Aechmophorus branch differentiated, and when the display behaviors of the members of the family were still very simple. The comparative analysis presented above suggests that the species should not be classified as a Podiceps member. -431- References and Notes (1) For a good text in ethology see (a) Eibl-Eibesfeldt, I • .. Ethology: the Biology of Behavior, .. 2nd ed. New York: Rinehart and Winston, 1975. Holt, (b) Lorenz, K. The Foundations of Ethology 11 Touchstone, 1st ed., New York, 1982. (2) For an excellent methodological review in this field see Lehner, P. N. 11 Handqook of Ethological Methods, .. Garland STPM Press, New York and London, 1979. (3) Storer, R. W. Proc. XIII Intern. Ornithol. Congr. 1963, 562. (4) Rumboll, M. A. E. Communicaciones del Museo Argentino de Ciencias Naturales, 1974, i, 33. (5) Drawings based on original Storer drawings. 3 Drawings of the top six birds based on Storer originals. 7 i Great Grebe figure based on Blake. 8 (6) (7) Storer, R. W. Condor 1969, ll, 188. (8) Blake, E. R. 11 Manual of Neotropical Birds .. Vol. 1, the University of Chicago Press, 1977, p. 87. (9) Simmons, K. E. L. Bull. Brit. Ornithol. Club 1962, 82, 109. (10) Storer, R. W. Condor 1963, 65, 279. (11) Greenquist, E. A. Condor 1982, 84, 370. (12) Homology: similar feature present in two or more species due to a common ancestor. Analogy: similar feature present in two or more species due to a convergent evolution. (13) Storer, R. W. Notornis 1971, 18, 175. -432- (14) Cramp, S.; Simmons, K. E. L... Handbook of the Birds of Europe, the Middle East, and North Africa: the Birds of Western Palearctic Vol. 1, Oxford University Press, Oxford, 1977. (15) Noechterlein, G. L.; Storer, R. W. Condor 1982, 84, 351. (16) Moynihan, M. Behaviour 1956, lQ, 126. 11