I. The Stereochemistry of the [3,3] Sigmatropic Rearrangement of 1,5-Diene-3-Alkoxides. II. Stereoselective Aldol Condensations via Dialkylboron Enolates Citation Nelson, John Victor (1981) I. The Stereochemistry of the [3,3] Sigmatropic Rearrangement of 1,5-Diene-3-Alkoxides. II. Stereoselective Aldol Condensations via Dialkylboron Enolates. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/93mv-cf69. https://resolver.caltech.edu/CaltechTHESIS:09192025-213350260 Abstract A study was carried out on the [3,3] sigmatropic rearrangement of the potassium salts of the four diastereomers (both cis,trans and erythro,threo) of 1-(1-methoxy- 2-butenyl)-2-cyclohexen-l-o1. It was found that these rearrangements proceed in a concerted fashion predominately via chair-like transition states to give diastereomers of 3-(3-methoxy-l-methyl-2-propenyl)-cyclohexanone. The application of these modified oxy-Cope rearrangements to the synthesis of (±)-erythro-juvabione is reported. A detailed investigation of the enolization of a variety of ketones and carboxylic acid derivatives with dialkylboryl triflates in the presence of a tertiary amine and the subsequent aldol condensations of these boron enolates was conducted. The stereochemistry of the enolates formed from acyclic ketones was found to be dependent on the structure of the ketone, the dialkyl-boryl triflate, and the tertiary amine. A mechanism for the enolization involving initial coordination of the boryl triflate to the ketone carbonyl with subsequent deprotonation by the amine is proposed to explain the results . The boron enolates derived from these acyclic ketones undergo aldol condensation with a number of aldehydes in good yield, Consistently good correlation was observed between the enolate geometry and the product aldol stereochemistry for these acyclic ketones regardless of the structure of the ketone or the boron ligands. However, for the boron enolate derived from cyclohexanone the aldol stereoselectivity was dependent on the boron ligands and the solvent. In this case, the use of a cyclopentylthexylboron enolate in tetrahydrofuran as solvent resulted in complete stereocontrol in the condensation. Although simple esters and amides cannot be enolized with the triflate reagents, tert-butyl thio-propionate was readily converted to the trans-enolate. The stereoselectivity of the aldol condensations of this enolate are also dependent on the boron ligands and the solvent; again, the proper choice of these parameters allowed total stereocontrol of the condensation, It was found that carboxylic acids could be converted to the dialkyl boron enediolates and the aldol condensations of these species were used to probe the relative reactivity of cis- and trans-enolates. 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): Evans, David A. Thesis Committee: Unknown, Unknown Defense Date: 13 August 1980 Funders: Funding Agency Grant Number NSF UNSPECIFIED California Institute of Technology UNSPECIFIED Record Number: CaltechTHESIS:09192025-213350260 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:09192025-213350260 DOI: 10.7907/93mv-cf69 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 17693 Collection: CaltechTHESIS Deposited By: Benjamin Perez Deposited On: 04 Oct 2025 12:19 Last Modified: 04 Oct 2025 12:33 Thesis Files PDF - Final Version See Usage Policy. 49MB Repository Staff Only: item control page

I. THE STEREOCHEMISTRY OF THE [3,3] SIGMATROPIC REARRANGEMENT OF l,5-DIENE.,-3-ALKOXIDES II. STEREOSELECTIVE ALDOL CONDENSATIONS VIA DIALKYLBORON ENOLATES Thesis by John Victor Nelson In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy California Institute of Technology Pasadena, California 1981 (Submitted August 13, 1980) ii To My Parents iii II That is the only way I ever heard of research going. r asked a question, devised some method of getting an answer, and got a fresh question.'' H. G, Wells '-' ·The Island of Dr, Moreau'' ''The idea is like grass. It craves light, likes crowds, thrives on crossbreeding, grows better for being stepped on." U. K. Le Guin "The Dispossessed'' iv ACKNOWLEDGEMENTS r would like to thank Dave Evans for his guidance during my tenure at Caltech. Dave'-s endless interest in chemistry and his encouragement in times of adversity create a unique and stimulating research environment. Without the collaboration of a number of excellent colleagues the work described here could not have been accomplished. Therefore, I would like to thank my coworkers on the oxy-Cope project, Dave Baillargeon and Alan Golob, and on the aldol project, Ernst Vogel, Terry Taber, Steve Tanis, and Larry McGee, for their assistance. I would also like to thank Jim Takacs and Scott Biller for many helpful discussions and Bill Kleschick for provid~ng us with results from Heathcock's group prior to publication. I also wish to express my appreciation to the National Science Foundation for a graduate fellowship and to the California Institute of Technology for additional financial support. Finally, special thanks to Dot Lloyd for the excellent typing and drawings, including many last minute changes, in this thesis. V ABSTRACT A study was carried out on the 13,3] sigmatropic rearrangeme nt of the potassium salts of the four diastereomers (both cis,trans and erythro,threo) of 1-(1-methoxy2-butenyl)-2-cyclohexen-l-ol. It was found that these rearrangements proceed in a concerted fashion predominately via chair-like transition states to give diastereomers of 3-(3-methoxy-l-methyl-2-propenyl)?cyclohexanone. The application of these modified oxy-Cope rearrangements to the synthesis of (±)-erythro-juvabione is reported. A detailed investigation of the enolization of a variety of ketones and carboxylic acid derivatives with dialkylboryl triflates in the presence of a tertiary amine and the subsequent aldol condensations of these boron enolates was conducted. The stereochemistry of the enolates formed from acyclic ketones was found to be dependent on the structure of the ketone, the dialkylboryl triflate, and the tertiary amine. A mechanism for the enolization involving initial coordination of the boryl trif late to the ketone carbonyl with subsequent deprotonation by the amine is proposed to explain the results . The boron enolates derived from these acyclic ketones undergo aldol condensation with a number of aldehydes in good yield, Consistently good correlation vi was observed between the enolate geometry and the product aldol stereochemistry for these acyclic ketones regardless of the structure of the ketone or the boron ligands. However, for the boron enolate derived from cyclohexanone the aldol stereoselectivity was dependent on the boron ligands and the solvent. In this case, the use of a cyclopentylthexylboron enolate in tetrahydrofuran as solvent resulted in complete stereocontrol in the con~ densation. Although simple esters and amides cannot be enolized with the triflate reagents, tert~butyl thiopropionate was readily coriverted to the trans-enolate. The stereoselectivity of the aldol condensations of this enolate are also dependent on the boron ligands and the solvent; again, the proper choice of these parameters allowed total stereo~ontrol of the condensation, It was found that carboxylic acids could be converted to the dialkyl boron enediolates and the aldol condensations of these species were used to probe the relative reactivity of cis- and trans~enolates. vii TABLE OF CONTENTS PAGE LI ST OF TABLES . . . . . , . . , . ~ t •. • , . • • • • • • • • • • • • • • , • • • • • CHAPTER I. Stereochemical Study of the 13,3] Sigmatropic Rearrangement of 1,S .. Diene,-3~ alkoxides. Application to the Stereoselective Synthesis of (±)-3uvabione ... , ..... , .. ,..... xi i 1 Introduction ····················••11••······· Results and Discussion ., ... , .... ~ ... ~.. ... .. 6 Substrate Synthesis ... ,.. .. . ............ 6 Sigmatropic Rearrangements .............. 8 Alcohol Stereochemi cal Assignments •. . . . . . 14 Transition State Conformations ........ .. 15 Conclusions ...... , .. , ......_.. ,. ~,........... 16 A Stereoselective Synthesis of (±)-Juvabione 17 Experimental Section ............ ,........... 26 General . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . 26 1-(1-Methoxy-2-butynyl).,.2-cyclo.,. hexen-1-ol (11) ........................ , 27 1-(1-Methoxy-(E)-2-buteny1)~2 .. cyclo.,. hexen-1-ol (6a~6b) . ... ............ ...... 28 1-(1-Methoxy-(Z)-2-butenyl)-2-cyclohexen-1-ol (7a-;7b) .. .. . . .. . .. . .. .. .. .. . . 29 2 Qxy,-Cope Rearrangement of transDienols •••••••••••••• , • • • • • • • • • • • • • 30 Oxy-Cope Rearrangement of cisDienols Z~.t~ ...... , . , .... -:-:-:-........... , 31 ~~.?..~ viii TABLE OF CONTENTS (continued) 2-(3-Qxocyclohexyl)propanoic Acid (13) PAGE 32 7-Methylbicyclo[4.3.0]non-9-en-2-one ( 14) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Stereochemical Studies on the Oxy-Cope Rearrangement , ......................... . 34 trans-Dienol A (6a) 34 trans-Dienol B (6b) 34 cis-Dienol A CZ~) 35 cis-Dienol B CZ~) 35 Methyl 4-(3-Methoxy-l-methyl-(E,Z)-2propenyl)-2-oxocyclohexane-l-carboxylate (18) .................................... 35 Methyl 4-(3-Methoxy-l-methyl-(E,Z)-2propen y l)-l-cyclohexene-l-carboxylate (1~) . .... ... . . ... ..... . . .. . ... ... ... .. . . 36 3-(Methyl-4-carboxyl-3-cyclohexenyl)butanoic Acid (23a) . . . . . . . . . . . . . . . . . . . . . 39 (±)-erythro-Juvabione (1~~) . . .. . . . . .. . . . 40 References and Notes .. . .. . . . . . . ....... .. .. . . 42 CHAPTER II. Stereoselective Aldol Condensations via Dialkylboron Enolates . .. .... ... .. . ... . . . 46 Introduction . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . 47 Results and Discussion .......... ,..... .. . ... SO Selec ti ve Generation of Boron Enolates .. SO Stereoselective Aldol Condensations ..... 60 Conclusions ........... , .. , . . . . . . . . . . . . . . . . . . 73 Experimental Section ..... , .. , .. , .. , ........ , 74 General .. , ..... , ........................ 74 ix TABLE OF CONTENTS (continued) PAGE Preparation of Dialkylboryl trifluro• methanesulfonates ......... , .. , ........ , . General Considerations on Handling 76 ~ •••••••• , ••••• 76 Diethylboryl trifluoromethanesulfonate (4c) ................. , ... . 76 and Storage . t •• , ••••• Di~n-butylboryl trifluoromethane• sulfonate (~e) . , ........ ~ .. · · · · · · · · · 77 Dicyclopentylboryl trifluoromethanesulfonate (1~) .....•.• , • •·· •· • ·· · • · · 77 Cyclopentylthexylboryl trifluoro• methanesulfonate (4dJ ., .. , .. ,, ..... . 77 General Procedures for the Formation of Boron Enolates , .. , ..... , ...... ~ ... . .. 78 Kinetic Generation of Boron Enolates 78 Equilibration of Boron Enolates ... ,. 78 Silylation of_Boron Enolates ., .. , .. , 79 General Procedures for the Aldol Condensation of Dialkylboron Enolates 79 Hydrogen Peroxide Workup 79 MoOPH Workup , .. , ..... , ........... , . . 80 Silylation of the di-n-butylboron enolate of 3-pentanone (Table I, Entry B) ......................... , . . . . . . 80 $ilylation of the dicyclopentylboron enolate of 2-methyl-3-pentanone (Table I, Entry I ) ..... , ... •. . . . . . . . . : . . . . . . . . . . . . . 81 Silylation of the di-n-butylboron enolate of 2, 2-dimethyl-3-pentanone (Table I, Entry K)· ......... ~ ..... , .. ,. ........ _ . . . . 81 X TABLE OF CONTENTS (continued) Silylation of the di~n~butylboron enolate of 4..-methyl ... 3-;hexanone • Table I, Entry L) . ................ ...... PAGE 82 Silylation of the di..-n~butylboron enolate of propiophenone (Table I, ...... ~ .. , ..._.. ~ . . . . . . . . . . . . . . . . 82 Silylation of the di . . n~butylboron enolate of S-tert..-butil propanethioate (Table I, Entry"N) . .. .. . . . .. .. .. .. .. . . .. 83 Erythro-l-hydroxy-2-methyl-l-phenyl-3pentanone (Table II, Entry A) ... ; . . . . . . . 83 Erythro-5-hydroxy-4-methyl-3-octanone (Table II, Entry C) . . . . . . . . . . . . . . . . . . . . . 84 Erythro-5-hydroxy-4,6..-dimethyl-3heptanone (Table II, Entry D) ... :. . . . . . . 85 Erythro- and threo~S-hydroxy,,.4,6-dimethyl6-hepten-3..-one (Table II, Entry E) ..... . 86 Er}thro- and threoTS--hydroxy-4,6-dimethyl(E -6-octen-3-one (Table II, Entry F) . . 87 Erythro-l-hidroxy-5-methyl-l-phenyl-3-hexanone (Table II, Entry H) ............ 88 Erythro- and threo-l-hydroxy--2,4-dimethyll--phenyl-3--pentanone (Table II, Entry J) 88 Erythro-l-hydroxy-2,4,4-trimethyl-lphenyl-3-pentanone (Table II, Entry L) .. 89 Erythro-3-hydroxy-2--methyl-l,3-diphenyl1-propanone (Table II, Entry M) ,........ 90 Erythro-1-(1-t-butyloxycarbonyl-l-azacyclopenta-2,~-dien-2-yl)-3-hydroxy-2methyl-3-phenyl-l-propanone (Table II, Entry N) ..... ...... 1!_••~··--················ 91 Entry M) Erythro- and threo,,-3-hydroxy--2-methyl-1-tri~ethylsi1y1-1..-propanone (Table II, Entry Q) .... ~ .............. , ........ ~ . . . 92 xi TABLE OF CONTENTS (continued) PAGE Erythro- and threo-S-(1,l-dimethylethyl)-3-hy<lroxy-2-methyl-3-phenylpropanethioate (Table II, Entry S) ...... 93 Erythro- and threo-S-(1,l~dimethylethyl-3-hydroxy-2-methylhexanethioate (Table II, Entry U) .. .. ..... .. . . . . ...... 94 Erythro- and threo-S-(1,l-dimethylethyl)3-hydroxy-2,4-dimethylpentanethioate (Table II, Entry V) . . . . . . . . . . . . . . . . . . . . . 95 Erythro- and threo-S-(1,1-dimethylethyl)3-hydroxy-2,4-d1methyl-4-pentenethioate (Table II, Entry W) . . . . . . . . . . . . . . . . . . . . . 95 Erythro- and threo~S-(1,l-dimethyl~thyl)3-hydroxy-2,4-dimethyl-4-hexenethidate (Table II, Entry X) .. .... ............ ... 96 Threo-2-phenylhydroxymethyl-1-cyclohexanone (Table III, Entry F) . . . . . . . . . . . 97 Erythro- and threo-3-hydroxy-2-methyl3-phenylpro~anoic acid (18,19a) ......... 98 Threo-3-hydroxy-3-phenyl-2-phenylmethoxypropanoic acid (!~~) ..... .. . .......... .. 99 (Z)-2-Phenylmethoxy-1-phenylethene ...... 100 References and Notes ....... .... ... ... ... ... . 102 APPENDIX I. A Brief Review of the Methods for the Generation of Boron Enolates ..... .. . . . . . 107 APPENDIX II. IR and 1 H NMR Spectral Catalog for Chapter I ... . ................ , • . . . . . . . . . 118 APPENDIX III. IR and 1 H NMR Spectral Catalog for Chapter I I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 xii LIST OF TABLES PAGE CHAPTER I Table I. Rearrangement of Dienols . e: • • • • • , •• , • • • • • • • • • • • • • • , • • • • • • 1s Table I. Kinetic Enolate Formation With Triflates 4a and 4b (eq. 2) ................. 54 Table II. Kinetic Aldol Condensations With Representative Aldehydes at -78°C (Scheme III) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 Table III. Aldol Condensation of 13 ana 15 With Benzaldehyde (eq. 5, 6). Solvent and Ligand Effects . . . . . . . . . . . . . . . . . . . . . . . . . . 68 Table IV. Influence of Metal Center on Kinetic Aldol Reactions With .Benzaldehyde 72 ~ ~ , ~~ , Z ~ , Z12. CHAPTER II APPENDIX I Table I. Stereochemistry of the Boron Enolates Generated by the Addition of . Triethylboron to Enones ....... ... ........... 111 Table II. Stereochemistry of the Enolates Generated by the Reaction of Ketones and Diethylboron Pivalate ........... ... ...... ... 113 -1- CHAPTER I Stereochemical Study of the [3,3] Sigmatropic Rearrangement of 1,5-Diene-3-alkoxides. Application to the Stereoselective Synthesis of (±)-Juvabione -2- Introduction In 19 75 we 1 reported the ob servati on that the oxy-Cope rearrangement of diene alkoxide 1~ proceeded at approxi12 mately 10 times the rate of the corresponding alcohol 2 I 3 4 • • • lb ~~ ( eq 1) . n sub sequent 1nvest1gat1ons, we an d ot h ers hav e established that these initial alkoxide-promoted rate accelerations are generalizable to other systems (eqs 2 and 3) . !; H = (I) OM MeOW H Me a, M:K b, M:H I .£ :~ (2) 0 (3) 0- K+ R K+o-t X OM /4 X = H, OMe, SPh ¢ OK OK In spite of the ap parently " concerted" nature of these rearrangements, onl y one published experiment bears on this important issue. 2 In this regard, ~e 1 found that, under conditions in which la underwent rearrangement with a half-life of 1.4 min (THF, 60°C), the diastereoisomeric -3- alkoxide 3 was stable for ca. 24 h. While these experi- ments contribute permissive evidence for the concerted -- nature of the transformation of la+ 2a ,. it does not rule out a nonsynchronous mechanism. The observations could be equally well explained by assuming that single-bond cleavage occurs in both substrates via either a homolytic or heterolytic pathway 5 but that the rotational barrier for the interconversion of these intermediates (cf. 4 and ~) is large relative to the recombination barrier 5 + 3 (Scheme I, homolysis). Scheme I -------- - K+~ ? OMe K+o-:....lkf 9 .l. OMe 4 ti lt ito-K' OMe 3 - ? ~o-K+ 9 OMe 5 In the present study, two sets of diastereoisomeric dienols ~~,~~ and Z~,z~ were chosen as informative sub- -4- strates. In the rearrangement of dienols 6ab and ?ab, --- it should be possible to examine two structural featues associated with each reaction: transfer of chirality and creation of specific product olefin geometry. 6 R1 ~ ,R2 ITT I Me 7 ~- !; A1 • H, R2 9 -· -· Az ~ OMe R1 • OMe, .0 CH 3 = H t. Rz: H A 1 • H, Az • OM e c· A1 : OMe, Rz • H As illustrated in Scheme II, if any given dienol underwent concerted rearrangement, only two predictable ketonic products (product set I or II) would be produced via chair and boat ·transition states (e.g., 6a + 8t + 9c). In the event that all four dienols rearranged in a concerted fashion, the dienol pair 6a and -- Z~ will afford only ketones 8t and 9c (set I) , while dienols 6b and 7a will give only ketones 8c and 9t (set II). If the above situation were found to be the case, complete erythro- -5- Scheme II --------- Set I 2: Choir* Me HO 2Me Boat+ OMe HO OMe cb .fil.. cr\M, -, 60 Boot• - £;, Choir+ .1.!L Me Me= H ..2£. Set II o )J Choir+ Boot+ OMe Me HO 9Me ~ ct) d\M, ..fil?.. Me Boot* . 2: Me ~ ~ H • Choir+ 7o OMe .fil.. and threo-dienol stereochemical assignments can be unambiguously made for the diastereoisomeric trans-olefin pair 6a,6b and cis-olefin pair 7a,7b. ~~ ~~ -- ~~ ~~ On the other hand, from any given dienol, the co-occurrence of more than two ketone rearrangement products or a combination of any two -6- products derived from sets I and II constitutes unequivocal evidence for nonconcerted rearrangement from that substrate. Results and Discussion §~~~!Ee!~_§r~!h~~!~- The four dienols ~~'~ and z~,~ were prepared via stereoselective trans and cis reduction of the diastereoisomeric hydroxy acetylenes 11. Metallation of 1-methoxy-2-butyne 6 with n-hutyllithium (-79°C, 30 min) followed by the addition of zinc chloride (1 equiv) resulted in the formation of the presumed organozinc reagent !2 (eq 4). . The addition of cyclohexenone to 10 I) n-BuLi (4) 2) ZnCl 2 10 afforded the acetylenic alcohol 11 in 95% yield as a 65:35 mixture of diastereoisomers. A number of the advertised procedures for the reduction of acetylenes to trans-olefins were found to convert acetylene 11 ,.._ to a mixture of transolefin 6 and a compound whose spectra were consistent with the allene, 1-(1,2-butadienyl)-2-cyclohexen-l-ol (12). 8 For example, sodium/ammonia reduction gave an 80:20 ratio of 6:12 in 90% yield, while lithium aluminum hydride 9 afforded a 94 : 6 ratio of 6:12 in only 60% yield ~--- -7- cf\ u~~ Me '-,_Me II AJ:e . l,)Me) 7o,b due to over-reduction. However, it was found that a 1:2 10 molar ratio of LiAlH :cH 30Na completely suppressed 4 over-reduction and afforded an 85% yield of 6a,b containing only a trace (1%) of allene 12 and cis-alcohols 7a,b (<1%). Presumably, 12 is formed by elimination of methoxide from a vinyl anion intermediate; thus, the success of the mixed reagent may be due to delivery of the hydride predominantly to the acetylene carbon nearest the hydroxyl. Although these conditions are known to effect delivery of the hydride exclusively to the acetylene carbon proximal to the hydroxyl function in propargylic alcohols, 10 its success in a homopropargylic system was a -8- pleasant surprise and poses some interesting mechanistic questions. The diastereoisomeric mixture of cis-dienols Z~,~ was obtained in 76% yield by catalytic hydrogenation of 11 over palladium on barium sulfate poisoned with 11 quinoline (6a,b:7a,b = 3:97). The two sets of diastereo- -- isomeric alcohols 6a,b and 7a,b were cleanly separated by chromatography on silica gel impregnated with silver 12 nitrate. Although independent stereoGhemical assignments w~re not determined for the two sets of erythro-threoalcohols, the following study (vide infra) leads to the unambiguous stereochemical assignments for '6a, 6b, 7a, and 7b as denoted in Scheme II. ~ig~~!E~Ei£_~~~E!~~g~~~~!~· Initial rearrangements were carried out on the unseparated diastereoisomeric trans-dienol mixture 6a,6b to determine optimal conditions and yields. In numerous preparative runs, it was found that the potassium alkoxides derived from 6a,6b (65:35) completely rearranged in diglyme at 110°C over a 38-h period to the mixture of ketonic products~ and~ in 75-80% isolated yields. Under identical conditions, the potassium alkoxides derived from the diastereoisomeric cis-dieriols Z~,z~ (65:35) afforded, in addition to the desired ketones 8 and~' a 40% yield of an unstable trienol derived from the base-catalyzed elimination of methanol. Proton NMR analysis suggested its structure to -9- be 1-(1,3-b ut a dienyl)-2-cyclohexen-l-ol. In contrast, the attempted thermal rearrangement of trans-dienol mixture ~':?...~ (250°C, 4 h) was totally unsuccessful,yielding pro- ducts derived from s-hydr oxy olefin cleavage, recovered starting material and intractable polymeric byproducts. Structure determination of the ketonic rearrangement ~~' products~!, ~~' and~! was accomplished by combined degradation and spectroscopic techniques. Determination of the relative stereochemical relationships between the ring and methyl-bearing side chain stereocenters for sets of ketones 8 and 9 was accomplished by degradation (0 3 , CrO 3 ) of the respective ketones to the erythro- and threoketo acids 13a and 13b. The structures of these diastereo- isomeric acids have been unequivocally established by X-ray 0 R2:H 2 R I 2 13 analysis. 13 , 14 anal ysi s 95 R E.., R1 " H, R2 • CH 3 b, R1 = CH 3 , R2 " H R1 14 It was f ound th at product diastereoisomer (§! + ~~=~!+~~)was most conveniently carried out by gas chromatography on the bicyclic ketones 14a and ~'!"- 14b which were readily obtained from the respective ketones 8a,b and 9a,b in excellent yield by acid-catalyzed -10- aldol condensation. No single analytical technique was found to be suitable for complete reaction product analysis. Nonetheless, the pairs of diastereoisomeric trans-olefinic ketones (St+ 9t) could be readily resolved from the cis-olefinic ketones (Sc+ 9c) analytically by gas chromatography to give product ratio, R (8t + 9t):(8c + 9c), for each rearrange1 ment experiment. This ratio was also cross-checked by 1 H NMR analysis of the unpurified pr·oduct mixture. The vinyl protons (-CH=CHOMe) for the trans isomer pair appeared at 6.20 ppm (J = 13 Hz), while the cis isomer pair appeared at 5.88 ppm (J = 6 Hz). The successful determination of the diastereoisomer ratios, R2 -trans (~!=~!) and Rz-cis (~f:~£), was based on the observation that the traris-olefin pair (8t + ~!) could be separated ~~ from the cis-olefin pair (8c + 9c) by medium pressure column chromatography. Accordingly, for each experiment the diastereoisomer ratios R2 -trans {~!=~!) and R2 -cis (~~=~~) were determined by the following procedure: (a) preparative chromatographic separation of the trans and cis isomer pairs (8t + 9t) and (8c + 9c); (b) acid- catalyzed aldol condensation of each isomer pair to the diastereoisomeric ketones 14a and 14b which were readily resolved by GLC; (c) GLC analysis to determine the product ratios, ~ 2 -trans and R2 -cis (!~~=!~~ = ~:~) and consequently -11- (.!:!!. + 9t) ~.~.~.fil (~•~) (8t 9t) (Sc 9c) the ratios 8t:9t and 8c:9c. X 140 = 8 14b = 9 14a 14b 8 = ~ 9 Thus, for each experiment, the determination of ratios R1 ,R 2 -cis, and R1 ,R 2 -trans enabled the complete product analysis, ~~=~!=~~=~!, to be determined. The erythro and threo diastereoisomers of the transdienols 6a and 6b were separated by column chromatography. The first-eluted major isomer, called trans-dienol A, was treated with KH (diglyme, 110°C, 37.5 h). Product analysis by analytical GLC (Carbowax 20M) indicated a trans:cis ratio (8t + 9t): (8c + 9c) = 96:4. The trans isomers (St+ 9t) were separated from the cis isomers ~~ (~£ + g£) by medium-pressure chromatography; Treatment of the trans pair (~! + g!) containing 1% of cis pair with acid (THF, H2so 4 , 4 h) afforded a ratio of:~~=:~~ (~!=~:) = 98:2 by analytical GLC (Carbowax 20M). When corrected for the 1% cis pair contamiriation in (8t + 9t), -12- the ratio of St:9t was calculated to be 99:1. Similar treatment of the cis isomer pair (Sc+ 9c) afforded a ratio of I~~=!~~ (~£=~~) = 4:96. Therefore, the product ratio derived from trans-dienol A was found to be: (96%), ~~ (4%), ~~ (~1%), ~! (~1%). St Following the identical analytical procedure, the secqnd-eluted trans dienol isomer, called trans-dienol B, was subjected to the identical rearrangement conditions. Product analysis was carried out as described above for the diastereoisomeric trans-alcohol A. The product ratio derived from trans- dienol B was found to be: 9t (23%). St (~1%), 9c (~1%), Sc (77%), These results confirm that tran's-dienol A affords ~99% product set I (~!+~~),while trans-dienol B affords ~99% product set II (Sc+ 9t). -- ~- Because of the absence of crossover products (within experimental error), the product distribution obtained from the rearrangement of the diastereoisomeric trans alcohols A and B indicates that the stepwise rearrangement is not occurring (<1%). In a parallel series of experiments, the erythro and threo diastereoisomers of the cis-dienols 7a and 7b were separated by column chromatography. The first-eluted major 1somer, called cis _dienol A, obtained in 99% isomeric purity (1% trans-dienol A), was subjected to rearrangement and subsequent product analysis according to the identical format as described above. The ratio (~! -13- + ~!=~~ + 9c) was determined to be 98:2 by GLC analysis. Chromatographic separation of the trans (8t + 9t) and cis isomer (~~ described. Consecutive acid-catalyzed aldol condensation + 9c) pairs was carried out as previously and GLC analysis of the trans pair (~! + ~!) afforded a ratio of 14a:14b (8t:9t) = 2:98. After correction for the 1% trans-dienol A contaminant (vide infra), the ratio 8t:9t was calculated to be 1:99. Unfortunately, due to the small quantities of the cis pair (~£+~£)produced from cis-dienol A (2%), we were unable to determine the ratio 8c:9c. Nonetheless, the value of 8c + 9c = 2% indicated that the most conservative estimate for the extent of crossover is 2%. Therefore, the product ratio derived from cis-dienol A was found to be: Be (2-0%) ~~ §! ('2_1%·), 2£ (0-2%), 9t (98%) ~ Following the identical procedure, ' ~~ the second-~luted minor cis-dienol isomer, called .cisdienol B, was subjected to identical rearrangement conditions and product analysis. The observed product ratio derived from cis-dienol B was found to be: St (30%), 9c (70%), Sc .(~1%), 9t (~1%). These results confirm that cis-dienol A affords >98% product set II(~~+~!), while cis-dienol B affords >99% product set I (~! + ~~). Within the experimental error of our analytical scheme (±2%), no significant crossover was detected in the rearrangement of either cis-dienol A or B, again indicating -14- that the stepwise rearrangement is not occurring to an ap pre ciable extent. Alcohol Stereochemical Assignments. ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The foregoing data clearly indicate that all four isomeric dienol alkoxides rearrange via highly ordered transition states, and that no evidence for competing nonconcerted reaction pathways was observed. Based upon the conveyed stereo- chemical information in the reaction product (threo vs. erythro and cis vs. trans) and the unequivocally determined olefin geometry in each of the four dienols, it is possible to make unambiguous erythro and threo stereochemical assignments to all four dienols and to assign the transition state conformations (boat or chair) interrelating reactants and products. These stereo- chemical assignments in no way depend upon the a priori assumption of a preferred chair or boat transition state preference, but only upon the postulate that either chair or boat transition states are involved in these rearrangements. On this basis, trans-dienol A and cis-dienol A, both of which were derived from the major diastereoisomeric acetylene 11, are assigned as the threo isomers 6a and 7a, respectively. In a similar fashion, trans-dienol Band cis-dienol Bare assigned as the erythro isomers~~ and 7b. The results obtained for the product ratios derived from the four dienols are summarized in Table I. -15- Rearrangement of Dienols ~~' ~~' Table I. ------- z~, 7ba Product Composition, % 9c Sc Alcohol St 6a 96 4 <1 <1 7b 30 70 <1 <1 6b <1 <1 77 23 7a <1 o-2b b 0-2- 98 !conditions: KH, 110°C, diglyme . Transition State Conformations. 9t bsc + 9c = 2 9., 0 • In the rearrangements of all four dienols, chair transition states are preferred. As predicted from conformational analysis of chair and boat transition states, ~land ~l' the threo-trans - dienol 2~ (R 1 = H, R2 = OCH 3 ) should exhibit a larger ~~G~ between -16- ~land ~l than the erythro-trans-dienol ~~ (R 1 = OCH , 3 15 R2 = H). The smaller t.LiG =f observed in the rearrangement of 6b is to be expected as a result of the destabilizing influence of the _ pseudo-axial methoxy substituent, R , in 1 the transition state ~ . Likewise, in the rearrangements 1 of diastereoisomeric cis-dienols 7a and 7b, the chair transition state £2 for Z~ (R 1 = OCH 3 , R2 = H) is again destabilized by the pseudo-axial methoxy substituent. These arguments correlate well with the observations that alcohols 6a and possibly 7a exhibit a greater preference for the chair transition state (96:4 and 98:2) in the Cope rearrangement than do~~ and Z~ (77:23 and 70:30). Although the original studies by Doering and 16 Roth on the Cope rearrangement showed a large preference for the reaction to proceed via a chair transition state, later work, 17 mainly on Claisen rearrangements, has shown that hindered 3,3-rearrangements often proceed to some extent via boat transition states. Conclusions These results unequivocally demonstrate that the [3,3] sigmatropic rearrangements of l,S~diene alkoxides possess the stereochemical characteristics of a concerted process. Consequently, these reactions can be employed in a -17- rational fashion in the stereoselective generation of asymmetry . In addition, we have found that dienols which are normally plagued with competing side reactions CB-hydroxy olefin cleavage) can be induced to rearrange in good yield as the conjugate bases. These innovations in the oxy-Cope rearrangement considerably extend the scope of these reactions. Just as important from a mechanistic standpoint, these studies demonstrate that the large rate accelerations associated with the sub- + stituent modification (R =OH+ R = 0 M) do not change the reaction mechanism . It is quite obvious that the concepts embodied in these studies can be applied to numerous other systems. Nonetheless, prior to the association of any mechanistic significance to related rate accelerations, a commonality of mechanism must be demonstrated between the neutral and charged substituents. A Stereoselective Synthesis of (±)-Juvabione Numerous terpenoid natural products possess methylbearing stereocenters on side chains proximal to a ring -18- fusion. Examples of molecules embodying this structural feature are the sesquiterpenes erythro-juvabione (15a) and threo-juvabione (lSb), the sesterterpene ophiobolin C (!~), as well as steroids (cf. !Z) and numerous triterpenes. Recently, several methods have been developed to solve .!:!_, R1 = H, R2 = CH 3 E_, R1 = CH 3 , R2 = H HO !I this ubiquitous stereochemical problem among which have been the creative contributions of Trost 18 a,b and . . . 18c F 1c1n1. The present study reports an alternative protocol for the solution of this problem within the context of a synthesis of (±)-erythro-juvabione. Juvabione, originally isolated by Bowers and co-workers from Abies balsamea (L.) Miller, was assigned the structure 15b by analogy to the stereochemistry of todomatuic ~-.d 20 ac1 . However, Saucy and co-workers synthesized both 19 -19- enantiomers of 15a and 15b and found that comparison of their ORD spectra with that of the natural product, 21 provided by Cerny, juvabione. 22 indicated 12e as the structure of Although the source of Cerny's sample was originally believed to be a balsam fir, this identification . 23 h as b ecome uncertain . More recently, Manville 23 reexamined juvabione and related compounds isolated from Abies balsamea and determined the structure of juvabione to be 15b by comparison of his ORD spectra with those of Saucy et al. Sakai and Hirose 24 found that juvabione from Douglas fir [Pseudotsuga menziesii (Mirb.) Franco] also possesses structure!~~- Although the identity of the natural source of 15a is in question, it appears that both 15a and 15b are natural products. Due to the fact that both 15a and ~Sb have been extensively referred to as juvabtone and epi-juvabione, for clarity we shall refer to 15a and 15b as erythro- and threojuvabione, respectively. Although erythro-juvabione (15a) has been the target of numerous synthetic investigati6ns, 18 c, 2 l, 25 the only stereospecific synthesis has been that reported by Picini and co-workers . 18 c A general alternative strategy for the synthesis of 15a is illustrated in Scheme III . In both routes the desired contiguous stereocenters can, in principle, be -introduced via related [3,3] sigmatropic -20- Scheme III ------~--HO OHR @ (f~ (3,3] 6\CH3 C3H U R (3,3] rearrangements. • In the present study, path A was chosen in conjunction with the general stereochemical investigation of 1,5-diene a_lkoxide [3,3] sigmatropic rearrangements. Based on the results presented in the preceding section, the 2:1 mixture of threo,erythro-dienols ~~' ~~, upon conversion to their respective potassium alkoxides with KH, underwent rearrangement in diglyme (110°C, 37 h) to ketones 8 and 9 in a ratio of 91: 9 (77% yield) (Scheme IV). The ratio of 8:9 could be improved to 96:4 if pure threodienol 6a was employed in the reaction. During the course of this investigation, we have found that the conditions employed for these rearrangements -21- Scheme IV KH, 110°C o; R1 • H, R2 • OMe !_; R 1 • OMe , R2 • H .!_; Rt • H, R2 • OMe =,; Rt • OMe, R2 • H 8 88% 11.. are critical. In an attempt to optimize the product ratio 8:9, it was reasoned that the stereoselectivity of the Cope process could be improved if the reaction could be carried out at lower temperatures . this did not prove to be the case. Unfortunately, Employing conditions which are known to provide maximal rate enhancements for these reactions, we have observed some side reactions which become important under these hyperbasic reaction conditions. For example, the rearrangement of 6 at 70°C with KH in HMPT results mainly in the formation of the unstable trienol 20 whose structure has been tentatively • d by 1H NMR . Apparently, the alkoxide is a strong ass1gne -22- enough base under these conditions to effect elimination of methoxide from~- Alternatively, the rearrangement of 6 with KH in diglyme at 70°C in the presence of 2 equiv of 18-crown-6 was successful. However, the ratio of 8:9 in this instance was 87:13 as compared with a 91:9 ratio in diglyme (110°C) in the absence of crown reagent. It thus appears that there is a ligand effect associated with 18-crown-6 which decreases the stereoselectivity of this rearrangement. OH 6 ITT KH, HMPT 10°c 20 In the succeeding steps of the synthetic sequence, no effort was made to separate the undesired minor diastereoisomeric ketones (9t + 9c) (9 %) formed during -- the oxy-Cope rearrangement . -- Carbomethoxylation of 8 followed by reduction (NaBH ), esterification (CH so Cl), 4 3 2 and elimination afforded the a,S-unsaturated est~r in an overall yield of 38%. In an effort to improve the overall yield in this latter transformation, we have investigated the use of a variant of the recently reported . . . 26 b ase-cata 1 yze d S - k eto ester tosy lh y d razone e 1 1m1nat1on . Based on the premise that N-aminoaziridines are tosyl- -23- hydrazine equivalents (eq 5), 27 28 , the hydrazone 21 was prepared from the reaction of keto ester!~ with 1-amino29 2-phenylaziridine. The addition of 21 to 2.7 equiv of lithium diisopropylamide (THF, 0°C) resulted in the extrusion of styrene and nitrogen;. subsequent protonation gave B ,y-unsaturated ester 22 which was equilibrated in situ with sodium methoxide to a,B -unsaturated ester 19 in an overall yield of 49%. It is noteworthy that these N-amino- aziridines, which are somewhat more nucleophilic than tosylhydrazine itself, appear to be generally applicable to the Shapiro elimination reaction. (5) The latter stages of the synthetic plan were completed by acid hydrolysis of enol ether 19 followed by in situ oxidation of the resulting aldehyde to the carboxylic acid 23a with Jones reagent (77% overall). An attempt to effect both hydrolysis and oxidation simply by treat- _, 24- ment of!~ with Jones reagent was unsuccessful because the oxidative cleavage of the enol ether was found to be competitive with hydrolysis. The conversion of 23a to (±)-erythro-juvabione (15a) via acid chloride 23b and --30 diisobutylcadmium proceeded in 60% yield. Comparison of the spectra of (±)-!~~ above with spectra of an independently prepared sample of (±)-lSa provided by Professor Ficini indicated that the samples were identical in all respects. 0~ ,......OCH 3 C5I.4l C (Jb7.5), ( 24. !l) • (139.0) ( 26. 1) 8.4) 0. l) X CH 3 c22.5J 23 .9.; X = OH .E_; X = Cl The analysis of juvabione samples for stereochem1cal purity is complicated by the fact that both diastereo1 isomers have identical H NMR, IR, mass spectra, and chromatographic properties; however, Manville and Bock 31 recently published carbon-13 NMR data which show differences between the diastereoisomers. Analysis of the (±)-erythro-juvabione (!~~) prepared above indicates -25- the presence of 4-5% of (±)-threo - juvabione (!~~). · As discussed earlier, the source of this minor diastereoisomer has been identified with the oxy-Cope rearrangement step in the synthetic sequence . -26Experimental Section -------------------- Infrared spectra were recorded on a Beckmann 4210 spectrophotometer. 1 H magnetic resonance spectra were recorded on Varian Associates A-60A (60 MHz) and FM-390 (90 MHz) spectrometers and are reported in ppm from internal tetramethylsilane on the a-scale. Data are reported as follows: chemical shift, IIR.lltiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = IIR.lltiplet, b = broad), integration, coupling constant (Hz), and interpretation. 13 C magnetic resonance spectra were recorded on a Varian Associates XL-100 (25.2 MHz) spectrometer and are reported in ppm from tetramethylsilane on the a-scale. When nrultiplicities were determined on the 13 C spectra (by off-resonance decoupling) they are reported using the abbreviations given above. on a Dupont 21-492 B spectrometer. Mass spectra were recorded Mass spectral and combustion analyses were performed by the California Institute of Technology Microanalytical Laboratory . .Analytical gas-liquid chromatography was carried out on a Varian Aerograph model 1400 gas ·chromatograph equipped with a flame ionization detector using 6 ft by 0.125 in. stainless steel colurrms packed with 10% Carbowax 20M or 5% SE-30 on 60-80 mesh Chromosorb Wor using a 20 ft by 0.125 in . .Analabs Hi-Plate column with OV-17 packing. Preparative gas- liquid chromatography was performed on a Varian Aerograph model 90-P chromatograph using a 6ft by 0.25 in. copper column packed with 10% SE-30 on 40-60 mesh Chromosorb W. support. Meditm1 pressure chromatography was performed using EM Laboratories LoBar Silica Gel 60 prepacked columns on a Chromatronix MPLC apparatus equipped with a Fluid Metering Inc. Model RP Lab Pump. Silver nitrate impregnated silica -27- gel was made with Silica Gel 60 by the procedure of Djerassi, et. ai. 12 When necessary, solvents and reagents were dried prior to use: tetra- hydrofuran, diglyme, diethyl ether, benzene (distilled from sodium metal/ benzophenone ketyl); triethylamine (distilled from calcium hydride); methanesulfonyl chloride (distilled from phosphorus pentoxide); methanol (distilled from sodium methoxide); dichloromethane (passed through a column of Activity I Alumina); zinc chloride (fused four times 1.mder a 32 vacuum of 0.1 mm). n-Butyllithium was titrated by the procedure of 33 Watson and Eastham. Sodium and potassium hydrides 32 were purchased as dispersions in mineral oil, 50% and 22% respectively, and were not titrated before use. Reactions requiring an inert atmosphere.were rt.m 1.mder a blanket of nitrogen unless stated otherwise. All reaction temperatures refer to the reaction itself unless stated otherwise. clohexen-1-ol {11). To a -70°C solution of --""".,..,,...,..,,...,..,,....,..,,...,.._,..,.,..__,...,.._"".,..,,...,..__.,..,.._.,..,.._"""'""'"""'""'.,...,._,.._ 100 mL tetrahydrofuran ~d 31 mL (71 mmol) of 2.28 M n-butyllithium in hexane was added 6.0 g (71 mmol) of 1-methoxy-2-butyne. 6 After 30 min. stirring at -70°C a solution of 9.7 g (71 mmol) of zinc chloride in 50 mL of tetrahydrofuran was added to the dark orange reaction to fonn a cloudy white solution. After 10 min. stirring 5.7 g (59 mmol) of 2-cyclohexen-1one was added. The reaction was allowed to wann to room temperature where it was quenched with 10 mL of saturated aqueous ammonium chloride. After the addition of 150 mL ether the solution was filtered through Celite and concentrated in vacuo to approximately 50 mL of orange oil which was added to 100 mL ether. The ether solution was washed once with saturated aqueous sodium bicarbonate and twice with brine, dried (Na2S04), and concentrated -28- in vacuo to yield 10.8 g of orange oil. Molecular distillation at SS°C {O. 5 mm) yielded 10.2 g (95%) of pale yellow oil: IR (neat) 3500, 3030, 2940, 2300, 2230, 1650, 1450, 1375, 1085, 730 cm- 1 ; NMR (CDC1 3) 5.77 (m, 2, = CH-), 3. 75 (q, 1, propargylic methine), 3.40 (s, 3, - OCH3), 2.38 (b, 1, - OH), 2.14 to 1. 47 (m, 9, aliphatic including = C-CH 3 doublet at 1.85). Anal. 1-(1-Methoxy-(E)-2-butenyl)-2-cyclohexen-1-ol (6a, 6b). ------------- -------------------------------------- To a sus- pension of 1.3 g (33 rnmol) of lithium aluminum hydride and 3.6 g (67 rnmol) of sodium methoxide in SO mL of tetrahydrofuran was slowly added 4.0 g (22 nnnol) of acetylene 11. The mixture was heated at reflux for 45 min after which the reaction was quenched at 0°C by slow addition of 6.2 mL of water. The solution was filtered through Celite and concentrated in vacuo to yield 3.6 g of orange oil. The product was bulb-to-bulb distilled at 125°C (0.1 mm) to give 3.4 g (85%) of colorless oil: IR (neat) 3500, 3030, 2940, 1660, 1645, 1450, 1375, 1100, 970, 730 cm- 1 • .Analytical gas-liquid chromatography on the OV-17 column indicated the product contained no (<1%) cis-dienol 7. The diastereoisomers, ~~and~~' were separated by chromatography over silver nitrate impregnated silica gel (25% AgNO3 by weight; 100 g of silica gel/g of 6; 6a (trans-dienol A): 1 eluted with he.xane:ethyl acetate, 70;30). H M>1R (CDC1 3) o 5. 50 (m, 4, =CI_i-), 3. 25 (d, 1, allylic methine), 3.21 (s, 3, OCH3), 2. 61 (b, 1, -0!!), 2.11 to 1.30 -29- (m, 9, aliphatics including =CH-CH3 doublet at 1.72); 13 C NMR (CDC13) o 132.0 (d), 131.0 (d), 128.8 (d), 127.4 (d), 88.8 (d), 70.8 (s), 56.2 (q), 32.4 (t), 25.3 (t), 18.6 (t), 17.9 (q). ~~ (trans-dienol B): 1H NMR (CDC1 ) o 5.50 (m, 4, =CH-), 3.31 (d, 1, allylic methine), 3 3.25 (s, 3, cx::H3), 2.30 (b, 1, CH), 2.11 to 1.30 (m, 9, aliphatics including =CH-CH3 doublet at 1. 71) ; 1 3 C NMR {CDCl 3) o 131. 2 (d) , 130.9 (d), 129.6 (d), 126.8 (d), 88.8 (d), 70.8 (s), 56.5 (q), 31.6 (t), 25.4 (t), 18.3 (t), 17.9 (q). ~~~:~::~~~=c~):::~~:=~~!2:~:~:~~~~~~=~=~~-i~~!-~~A rapidly stirred suspension of 3.3 g (18 nmol) of acetylene 11, 600 mg of 5% palladium on barium sulfate, and 36 dr:ops of quinoline in 100 mL of methanol was hydrogenated at room temperature and atmospheric pressure until 400 mL (18 rnmol) of hydrogen had been consumed (1 h). The solution was filtered through Celite and concentrated in vacuo to give a crude product which was chromatographed at medium pressure over silica gel C™ Laboratories size C LoBar colUIIlll; eluted with hexane:ethyl acetate, 85:15) to yield 2.5 g (76%) of colorless oil: IR (neat) 3500, 3030, 2940, 1650, 1450, 1375, 1100, 730 cm- 1 . Analytical gas-liquid chromatography on the OV-17 colUIIlll revealed that 3% of the product was trans-dienol 6. Anal. (C11H1 a02): C, H. The diastereoisamers, z~ and Zlz, were separated (and all but 1% of trans-dienol 6,.., removed) by chromatography over silver nitrate impregnated silica gel (25% AgN0 3 by weight; of 7; 100 g of silica gel/g eluted with hexane:ethyl acetate, 70:30). 7a (cis-dienol A): -30- 1 HNMR (CDCla)o 5.50 (m, 4, =GI-), 3.82 (d, 1, allylicmethine), 3.25 (s, 3, OCH3), 2. 70 (b, 1, OH), 2.16 to 1.33 (m, 9, aliphatics); 13 c NMR (CDCl3) 8 131.0 (d), 130.2 (d), 128.5 (d), 127.3 (d), 81.8 (d), 71.2 (s), 56.2 (q), 32.2 (t), 25.4 (t), 18.5 (t), 13.5 (q). 1 Z~ (cis-dienol B): H NMR (CDC1 3 ) 8 5.50 (m, 4, =CH-), 3.82 (d, 1, allylic methine), 3.25 (s, 3, OCH 3), 2.43 (b, 1, OH), 2.16 to 1.33 (m, 9, aliphatics); 13 C NMR (CDC1 3 ) 8 131. 0 (d), 130. 3 (d), 129. 4 (d), 126. 5 (d), 81. 8 (d), 71. 3 (s), 56.3 (q), 31.3 (t), 25.4 (t), 18.4 (t), 13.7 (q). Oxy-Cope Rearrangement of trans-Dienols 6a,b. ------------------------- ------------- To a suspension of 2.0 g (SO mmol) of oil-free potassil.D'Il hydride (from 8.9 g of 22% oil suspension) in 110 mL of diglyme under an argon atmosphere was added 3.0 g (17 mmol) of trans-olefin 6. .,..., 37.5 h. The solution was heated at 110°C for The resulting dark brown solution was added to SO mL saturated aqueous arrnnonitm1 chloride and the aqueous phase extracted twice with pentane. The combined organic extrc3:cts were washed once with saturated aqueous arnmonitm1 chloride, twice with saturated aqueous soditm1 bicarbonate, and twice with brine. After drying (Na 2 SO 4 ) the organic phase was concentrated in vacuo to leave an orange oil which was bulb-to-bulb distilled at 0.05 mm first at 35°C to remove residual diglyme then at 100°C to obtain 2.3 g (77%) of colorless oil: IR (neat) 3030, 2940, 1705, 1650, 1450, 1375, 1100, 940, 760 an- l ; NMR (CDCl3) 6.20 (d, 0.6, J = 13, trans - CH= Gi-OCH3), 5.88 (d, 0.4, J = 6, cis - CH= CH-QCH3) 4.53 (m, 0.6, trans - CH= CH-OCH3), 4.11 (m, 0.4, cis - CH= CH-O0-h), 3. 51 and 3.47 (two s, 3, cis and trans - CH= CH-QCH3) 2.65 to 1.12 (m, 10, aliphatics), 0.99 and 0.94 (two d, 3, side chain methyl); 13 C NMR (CDCb) 212. 6 (s, C = 0), 147 .1 and 145. 9· (two d, -31- cis and trans - CH= CH-OQ-f3), 109 . 8 and 105.7 (two d, cis and trans CH= CH-O0-h), 59.4 and 55.9 (two q, cis and trans - CI-I= CI-I-OCI-!3), 46.2 (t), 45.1 (t, weak, other diastereomer), 44.9 (d), 44.7 (d), 41.4 (t), 37.7 (d), 33.5 (d), 29.6 (t, weak, other diastereomer), 29.1 (t, weak, other diastereomer), 27.7 (t), 25.3 (t), 19.2 and 18.3 (two q, side chain methyl). Anal . Q~:~~E~~~~~EE~g~~~~! ~ ~f cis-~i~~~l~~z~~~ - The rearrangement of 1.5 g (8. 2 rrnnol) of cis-olefin 7 was carried out by the same procedure as for - "" Jusing 0. 75 (19 rrnnol) of oil-free potassililn hydride (from 3. 4 g of 22 % oil suspension) and 100 mL of diglyme to yield 0.80 g (53%) of colorless oil which contained at least 40% of a side product identified (vide infra) as the triolefin 20. Pure oxy-Cope product was isolated by preparative gas-liquid chromatography and was folIDd to have identical spectral properties to that prepared from the trans-olefin 6. Anal . The side product could not be separated from the oxy-Cope product by any thin-layer or coll.mm chromatography methods examined. Comparison of the spectra of ,2___ isolated by prep GLC with the spectra of the mixture indicated the presence of a hydroxyl group and an approximate ratio of one olefinic proton for ead1 aliphati c proton. These data implied that the s i de product was triolefin 12_. The side product was separated from 2.._ by prep GLC; however, the highly lIDStable material (decomposed within 4 hat room temperature) thus obtained exhibited different spectral properties than those seen in the mixture: IR (neat) 3080, 3020, 2940, 1615, 1450, -32- 1000, 940, 890, 690 cm- 1 ; NMR (CDCl3) 6.80 to 4.80 (m, 8, olefins), 2.22 (m, 4, aliphatic). A mass spectn.nn was also obtained for this cornoormd. These results indicate the fonnation of 2~(1,3-butadienyl)-1,3-cyclo~ hexadiene from the trienol during separation. Exact mass calcd for C10 H12 : 132.094. 2-(3-0xocyclohexyl)propanoic Acid (13). -------------------------------------- Formd: 132.092. Ozone was bubbled into a -70°C solution of 250 mg (1.4 rrnnol) of a 91:9 mixture of 8:9 in 10 mL of acetone tmtil a blue-violet color developed. After flushing with nitrogen, the solution was wanned to 0°C, whereupon 2 mL (5 rrnnol) of 2.67 M Jones reagent and 2 mL of water were added. After stirring 2 hat room temperature, the reaction was quenched ~ith isopropyl alcohol. The solution was extracted three times with ether; the ether extracts were washed twice with brine and concentrated in vacuo to give a crude oil. The crude oil was dissolved in 25 mL of ether and the ether solution extracted three times with saturated aqueous sodit.nn bicarbonate. After neutralization (6 N HCl) and saturation with sodit.nn chloride, the aqueous solution was extracted three times with ether. The ether extracts were dried (Na 2so4) and concentrated in vacuo to yield 137 mg (59%) of tan oil, 94 mg of this oil was bulbto-bulb distilled at 100°C (0.01 rrnn) to yield 85 mg (53% overall) of colorless oil which crystallized on standing. One recrystallization from ethyl acetate-hexane afforded pure erythro acid 13a, mp 77-78°C (lit. 13 76°C) which was identical in all respects with an authentic sample of l~~ independently synthesized by Ficini: 14 IR (neat) 3200, -33- 2940, 1700 cm- 1 ; NMR (CDC1 3 ) o 9.78 (b, 1, CO 2H), 2.55-1.30 (m, 10, aliphatics), 1.17 (d, 3, methyl). The NMR spectTI.llll of the tmre- crystallized sample revealed a small doublet at o 1. 20 for the threo 14 acid 13lz (lit. o 1. 21) . Exact mass calcd for C8 H1 ~O 3 : 170.094. Found: 170.089. 7-Methylbicyclo[4.3.0]non-9-en-2-one (14). A solution of 150 mg (0.82 mmol) of a 91:9 mixture of 8:9 and 5 mL of 4 N sulfuric acid in 10 mL of tetrahydrofuran was heated at reflux for 4 h. The reaction was quenched by very slow addition of solid sodium bicarbonate until no additional gas evolution was seen. three times with ether. The solution was extracted The combined ether extract~ were washed with saturated aqueous sodium bicarbonate and brine, dried (Na2SO~), and concentrated in vacuo to give a quantitative crude yield of yellow oil. Bulb-to-bulb distillation of the crude product at 125°C (4 nun) yielded 83 mg (67%) of colorless oil: 1670, 1605, 1450, 1375 cm- 1 ; IR (neat) 3030, 2960, NMR (CDC1 3 ) cS 6.59 (m, 1, =CH), 3.15 to 1.10 (m, 10, aliphatics including a small doublet at 1.16 for minor isomer), 0.85 (d, 3, methyl). Analytical gas-liquid chromatography on the Carbowax 20 M colurrm. indicated the minor bicyclic ketone 14b (9%) exhibited a lower retention time than the major product 14a (91%). Separation by preparative gas-liquid chromatog- raphy and analysis by IR, NMR, and mass spectra confirmed that the two products were diastereoisomers. Exact mass calcd for C10 H1 ~O: both products. 150.105. Found: 150.105 for Stereochemical Studies on the 0:xy-Cope Rearrangement. trans~~ ~~~~ ~~~~ ~~~~~~~~~~~~ ~~~~~~~~~~~~ ~~~~~ ~~~~~~~~~~~~~~~ Dienol A~(6a ) . The rearrangement of 770 mg of~~ (~99% pure by GLC) was carried out as described above for the mixture of trans-dienols 6a,b to yield 680 mg of crude oil. Analytical GLC using the Carbowax 20M collID111 indicated the ratio (St+ 9t): (Sc+ 9c) was 96:4. The crude product was chromatographed at medium pressure over silica gel (Bv1 Laboratories size B Lobar collID111) . Elution with hexane:ethyl acetate (95:5) yielded 52 0 mg of(~!+~!) (found to contain 1% cisenol et he r by GLC) and 16 mg of (Sc+ 9c ) (>99% pure by GLC). Each enol ether was converted to the aldol products 14a,b by the procedure described above . Analytical GLC on the Carbowax 20M collID111 of the product s derived from (~!+~!) indicated the ratio of!~~=!~~ was 98 :2 and on the product derived from(~~+~~) the ratio of !i~:!~~ was 4: 96 . 'When corrected for the presence of the cis-enol ether (1 %), the ratio of 8t: 9t i s calculated to be 99:1. The results indicate a crossover to 9t and Sc of 0.9 and 0.2%, respectively (both less than 1% experimental error). trans-Dienol B~(6b). The stereochemistry of the rearrangement of 6b (containing 1% of 6a by GLC) was analyzed by the procedure describ ed for trans-di enol 6a . 23:7 7. The r at io of (St+ 9t):(8c + 9c) was Aldol condensation on the separated trans-enol ether (found to contain 1% cis-enol ether) gave a ratio of !~~ : ~i~ equal to 10:90. Aldol condensation on the separated (8c + 9c) (>99% pure by GLC) ~~ ~~ gave a product greater than 99% 14a (14b not detected by GLC). After correction for the presence of 6a and cis -enol ether, the ratio -35- of 8t:9t is 2:98. These results indicate a crossover to St of 0.5% (less than experimental error). No crossover to 9c could be detected. The rearrangement of 7a (containing 1% 6a -- by GLC) was carried out as described above. (Be+ 9c) was fotmd to be 98:2. -- The ratio (~! + ~!): Chromatographic separation followed by aldol condensation on the (St+ 9t) mixture (>99% pure by GLC) gave a ratio of!~~=!~~ equal to 2:98. The cis-enol ether could not be recovered after chromatography. After correction for the presence of 2e, the ratio of ~!=g! is 1:99. These results indicate a cross- over to~! of 0.9% (less than experimental error). The maxinrum crossover possible to 9c is 2%. cis-Dienol B (7b). - ------------- The stereochemistry of the rearrangement of 7b (containing 2% 6b by GLC) was analyzed by the procedure -- ,:-,,- described for trans-dienol 6a. fotmd to be 30:70. The ratio (~! + ~!): (~~ + g£) was Chromatographic separation of cis and trans vinyl ethers followed by aldol condensation of the(~!+~!) mixture (>99% pure by GLC) afforded a ratio of!~~=!~~ equal to 96:4. Aldol condensation on the (Sc+ 9c) mixture (>99% pure by GLC) gave ....,_ -a ratio of !~~=!1~ equat to 3:97. After correction for the presence of 6b, the ratio of 8t:9t is 98:2 and 8c:9c is 1:99. -- -- . These results indicate a crossover to 9t and Sc of 0.6 and 0.7%, respectively (both less than 1%). ~~!!?-rL~:l2:ti~!h2~:!:1E~!hr!:CE,z):~:Er2E~I.!r!l:~:~2£r£!2h~~~~= !:~e!:~2~!e!~_{!~l- To a suspension of 0.33 g (13 ITBJlOl) of oil-free -36sodium hydride (from 0.66 g of 50% oil suspension) in 2.8 g (31 mmol) of dimethyl carbonate and 20 mL of tetrahydrofuran at reflux was added dropwise over 45 min a solution containing 1. 2 g (6. 3 mmol) of ketone ~ in 10 mL of tetrahydrofuran. The mixture was maintained at reflux for 2 h after the addition was complete. The deep red solution was added to 20 mL saturated aqueous annnonil.nn chloride and the aqueous phase extracted twice with ether. The combined organic extracts were washed with saturated aqueous sodium bicarbonate and brine, dried (Na2S04), and concentrated in vacuo to yield 1.4 g of orange oil. The crude product was bulb-to-bulb distilled at 135°C (0.08 mm) to yield 1.3 g (88%) of colorless oil: IR (neat) 3030, 2960, 1740, 1705, 1650, 1615, 1450, 1375, 1275, 1200, 1100, 940, 830, 760 an- 1; NMR (CDCl3) 12.00 (b, 0.75, enol hydroxyl), 6.20 (d, 0.6, J = 13, trans - GI= Q-I-OCH3), 5.88 (d, 0.4, J = 6, cis - GI= CH-OCH 3), 4.53 (m, 0.6, trans rn = rn-OCH3), 4.11 (m, 0.4, cis - CH= CH-OCH 3), 3.70 (s, 3, - CO2CH3), 3.51 and 3.47 (twos, 3, cis and trans - rn = CH-OCH3), 3.31 (m, 0.25, keto tautomer methine), 2 .. 77 to 1.11 (m, 8, aliphatic), 0.99 and 0.94 (two d, 3, side chain methyl). Exact mass calcd for C13 H20O4: 240.136. Fotmd: 240.133. Methyl 4-(3-Methoxy-l-methyl-(E,Z)-2-propenyl)-l-cyclohexene-1- ----------------------------- -- ----------------------------I. By Reduction, Esterification, and Elimination. -------------------------------------------------------------------- carboxylate (19). A solution of 780 mg (3.2 mmol) of keto ester~~ and 61 mg (1.6 rrnnol) of sodium borohydride in 15 mL isopropanol at 0°C was stirred for 2 h. The solution was then added to 10 mL brine and extracted three times with ether. The ether extracts were washed with saturated aqueous sodium bicarbonate and brine, dried (K2CO3), and concentrated in -37vacuo to yield 710 mg of crude product. The crude product was chromato- graphed at meditnn pressure over silica gel (EM Laboratories Size B LoBar colunm; eluted with hexane:ethyl acetate, 85:15) to yield 440 mg (56%) of colorless oil: IR (neat) 3500, 3030, 2960, 1730, 1650, 1450, 1375, 1250, 1200, 1100, 940, 760 an- 1; NMR (CDCl3) 6.20 (d, 0.6, J = 13, trans GI= GI-OCH3), 5.88 (d, 0.4, J = 6, cis - GI= Gl-OCH 3), 4.53 (m, 0.6, trans CH= GI-OCH3), 4.11 (m, 0.4, cis - CH= GI-OCI-13), 3.68 (s, 3, - CO 2CH 3), 3.51 and 3.47 (two s, 3, cis and trans - GI = GI-OCH3), 2.87 (b, 1, - OH), 2.55 to 0.90 (m, 12, aliphatics including_side chain methyl doublets at 0.99 and 0.94). Exact -mass calcd for C13H22O~: 242.152. Fotmd: 242.153. To a solution of 720 mg (3.0 mmol) of hydroxy-~ster and 450 mg (4.4 nmol) of triethylamine in 20 mL of methylene chloride at 0°C was slowly added 370 mg (3.3 rrnnol) of methanesulfonyl chloride. The solution was stirred for 30 min at 0°C, added to 20 mL of 50% aqueous brine, and the organic phase washed twice with saturated aqueous soditnn bicarbonate and once with water. After drying (Na2SO~) the organic phase was concentrated in vacuo to yield 910 mg (96%) of crude mesylate: IR (neat) 3030, 2960, 1735, 1650, 1450, 1350, 1250, 1210, 1175, 1100, 940, 760 an- 1 ; NMR (CDCl3) 6.20 (d, 0.6, J = 13, trans - GI= GI-OCI-I3), 5.88 (d, 0.4, J = 6, cis - GI= CH-OCI-I3), 4.53 (m, 1.6,- CHOS02GI3 and trans GI= GI-OCI-I 3), 4.11 (m, 0.4, cis - GI= GI-OCI-I3), 3.67 (s, 3, - CO2GI3), - -- - 3.51 and 3.47 (two d, 3, cis and trans - GI= GI-OCH3), 2.97 and 2.94 (twos, 3, GI 3S0 3-), 1.73 to 1.11 (m, 8, aliphatics), 0.99 and 0.94 (two d, 3, side chain methyl). -38- A solution of 910 mg (2.8 mmol) of crude mesylate and 3.10 mg (5.7 mmol) of sodium methoxide (from 130 mg of sodium metal) in 20 mL of methanol was heated at reflux for 8 h, a white precipitate appeared during the reaction. The solution was added to 20 mL of brine and extracted three times with ether. The combined ether extracts were washed with saturated aqueous sodium bicarbonate and brine, dried (Na2S04), and concentrated in vacuo to yield a crude yellow oil which was bulb-to-bulb distilled at 115°C (0.1 mm) to obtain 490 mg (77%, overall 74% from2) of colorless oil: ir (neat) 3030, 2960, 1710, 1650, 1450, 1375, 1250, 1210, 1100, 940, 760 an- 1 ; nrnr (CDC1 3) 6.94 (m, 1, = CH-), 6.20 (d, 0.6, J = 13, trans CH= CH-OCH3) 5.88 (d, 0.4, J = 6, cis - CH= CH-OCH3), 4.53 (m, 0.6, trans - CH= CH-OCH3), 4.11 (m, 0.4, cis - CH= CH-OCH3), 3.70 (s, 3, C02CH3), 3.51 and 3.47 (twos, 3, cis and trans - CH= CH-OCH3), 2.67 to 1.13 (m, 8, aliphatics), 0.99 and 0.94 (two d, 3, side chain methyl). Exact mass calcd for C1 3H2 003: II. 224.141. Folllld: 224.143. By Formation of the Hydrazone 21 and Elimination. ----------------------------------------------------- To a stirred 0°C solution of 250 mg (1.0 IIIIlol) of B-keto ester!~ in 5 ml of dichloromethane was added 220 mg (1.1 mmol) of 1-amino-2-phenyl29 aziridine acetate. The resulting solution was stirred for 10 h at 0°C, after which it was added to 10 mL of saturated aqueous sodium bicarbonate. The aqueous phase was extracted with dichloromethane and the combined organic solution washed with saturated aqueous sodium bicarbonate and brine, dried (Na2S04), and concentrated in vacuo to yield 379 mg (102%) of crude hydrazone (21): IR (neat) 3060, 3030, 2960, 2880, 1730, 1650, 1630, 1500, 1450, 1210, 750, 700 an- 1 ; NMR (Cix::1 3 ) o 7.28 (m, 5, aromatics), 5.40-6.52 (complex m, 1, -39- -CH=GI-OCH3), 3.81-4.80 (complex m, 2, -CH=CH-OCH 3 and >GI-CO 2CH 3), 3.15-3.71 (m, 6, CO2CH 3 and -CH=CH-OCH 3), 0.62-3.15 (complex m, 14, aliphatics). To a stirred 0°C solution of 280 mg (2.7 rnrnol) of lithitun diisopropylamide in 10 mL of tetrahydrofuran (fonned by the reaction of a solution of 320 mg (3.2 rnrnol) of diisopropylamine in tetrahydrofuran with 1.7 mL (2.7 mmol) of 1.6 M n-butyllithitun in hexane at -78°C followed by wanning to 0°C) tmder an argon atmosphere was dropwise added over 3 min 379 mg (1.1 mmol) of crude hydrazone. deep red solution was stirred at 0°C for 6 h. The resulting After the addition of a solution of 250 mg (4.6 rnmol) of soditun methoxide in 5 mL of methanol, stirring was continued for 3 hat room temperature. The reaction solution was then added to 20 mL of saturated aqueous soditun bicarbonate and the aqueous phase extracted twice with ether. The combined ether extracts .were washed with saturated aqueous soditun bicarbonate and brine, dried (Na 2SO 4), and concentrated in vacuo to yield 249 mg of brown oil which was chromatographed at meditun pressure over silica gel (EM Laboratories size A LoBar coltunn; eluted with hexane:ethyl acetate, 95:5) to yield 114 mg (49%) of product. 3-(Methyl-4-carboxyl-3-cyclohexenyl)butanoic Acid (23a). ------------------------------------------------------- A solu- tion of 490 mg (2.2 mmol) of ester 19 and 10 mL of 8 N sulfuric acid in 15 mL of acetone was stirred at 0°C for 4 h. After addition of 3 mL (8 mmol) of 2.67 M Jones reagent stirring was continued for 30 min at 0°C. The reaction was quenched with isopropanol and the resulting solution extracted three times with ether. The ether solution was washed with -40- brine, dried (Na2SO4), and concentrated in vacuo to yield 440 mg of a pale yellow oil which crystallized on standing at room temperature overnight. Recrystallization from ethyl acetate/hexane gave 210 mg of analytically pure white crystals, melting point 89-91°C. The remaining material, which would not crystallize, was purified by preparative thin-layer chrana.tography on silica gel (eluted with ethyl acetate) and yi~lded 160 mg of product. 370 mg (76%): Total yield of purified acid was IR (CHCl3) -·3400,- 3030, · 2960, 1700, 1650, 1450, 1375, 1250, 1040 cm- 1 ; NMR (CDCl3)0 6.94 (m, 1, =GI-), 5.8 (b, 1, CO 2!:!), 3.70 (s, 3, CO2C!:!3), 2.70-1.11 im, 10, aliphatic), 0.97 (d; 3, side chain methyl); 13 C NMR (CDC1 3 ) o 179.3 (s), 167.9 (s), 139.1 (d), 130.3 (s), 51.6 (q), 39.0 (t), 37.4 (d), 34.2 (d), 28.3 (t), 26.1 (t), 24.9 (t), 16.2 (q). Anal. (C12H1eO4): C, H. (±)-erythro-Juvabione (15a). __________ .....,..__.....___________ _ A solution of 175 mg (0.77 mmol) of crystalline acid 23a and 230 mg (1. 8 nnnol) o.xalyl chloride in 15 mL of """ benzene was stirred at room temperature for 3 h. yielded 180 mg (97%) of crude acid chloride: Concentration in vacuo IR (neat) 3030, 2940, 1800, 1710, 1650, 1450, 1375, 1250, 1090 cm- 1 • To a 0°C solution of approximately 1. 7 mmol of isobutyl Grignard in 10 mL ether, generated by the reaction of 42 mg (1.7 mmol) of magnesium turnings with 240 mg (1. 7 nnnol) of isobutyl bromide, was added 170 mg (0.95 nnnol) of anhydrous cadmium chloride. After stirring 5 min at room temperature the ether was removed by distillation until the reaction was a thick brown slurry, 10 mL of benzene was added, and the solvent again removed by distillation. After the addition of 10 mL benzene the reaction -41- was cooled to 0°C and 180 mg (0.75 rranol) of crude acid chloride was added. The solution was heated at reflux for 1 h, added to 25 g ice and 25 rnL of 10% sulfuric acid, and the aqueous phase extracted twice with benzene. The combined benzene extracts were washed successively with water, saturated aqueous sodil.Dil bicarbonate, water, and brine. After drying (MgS01+), the solution was concentrated in vacuo to yield 200 mg of crude product. The crude product was chrornatographed at medil.Dil pressure over silica gel (EM Laboratories Size B LoBar colt.mm; eluted . . . with hexane:ethyl acetate, 95:5) to yield 120 mg (60% from23a) of juvabione: ""' IR (neat) 3030, 2960, 1705, 1650, 1450, 1375, 1250, 1090 an- 1; NMR (COCl3) 6.90 (m, 1, = GI-), 3.70 (s, 3, - CO 2Gl 3), 2.67 to 1.10 (m, 13, aliphati_c), 0.90 and 0.86 (two d, 9, side chain methyls); 13 C NMR (CDCl3) 210.1, 167.5, 139.0, 130.0, 52.3, 51.4, 47.9, 37.6, 32.8, 29.8 (about 4-5% of the height of the 28.4 signal), 28.4, 26.1, 24.9, 24.5, 22.5, 16.4. 31 et. al. , were used in the analysis. Exact mass calcd for C16H26O3: 266.188. The assignments of Manville, Follll.d: 266.187. -42- References and Notes ~~~~~---~---~~~~~--~ (1) Experiment performed by Alan M. Golob. (2) Evans, D. A. ; Golob, A. M. J. Am. Chem. Soc. 1975, ~, 4765. (3) Evans, D. A. ; Baillargeon, D. J. ; J. Am. Chem. Soc. (4) Seebach, D.; 1978, 100, 2242. ---- - - Geiss, K.-H.; Chem., Int. Ed. Engl. J. Am. Chem. Soc. (5) Evans, !~~~' n.· A.; Nelson, J. V. Pohmakotr, M. 1976, li, 437. Angew. Still, W. C. 1977, 22_, 4186. Baillargeon, D. J. Tetrahedron Lett. 3315, 3319. (6) Prepared from propargyl alcohol by the procedure of L. Brandsma: Elsevier: New York, 1971; (7) Mercier, F.; Chim. Fr. "Preparative Acetylene Chemistry," Epsztein, R.; pp 38 and 172. Holand, S. Bull. Soc. !~Z~, 690. (8) Kaiser, E. M. Synthesis 1972, 391. (9) Magoon, E. F. ; Slaugh, L.H. Tetrahedron 1967, ~' 4509. (10) Corey, E. J. ; Katzenellenbogen, J. A.; J. Am. Chem. Soc. Hauser, K. L. 1967, 89, 4245. ---- - Posner, G. H. Molloy, B. B.; J. Chem. Soc., Chem. Commun. 1968, 1017. (11) Coke, J. L.; Williams, H.J.; Natarajan, S. J. Org. -43- Chem. 1977, ~' 2380. (12) Popov, S.; C. Carlson, R. M. K.; Wegmann, A.; Djerassi, Steroids 1976, 28, 699. ---- - (13) Picini, J.; Touzin, A. M. Tetrahedron Lett. 1972, 2093, 2097. (14) We wish to thank Professor Picini for spectra of both 13a and 13b and a sample of 13a. ~~~ (15) Perrin, C. L. ; Faulkner, D. J. Tetrahedron Lett. 1969, 2783. (16) Doering, W. von E.; .!!., 67. Tetrahedron 1962, 1963, .zi, 27. Angew. Chem. (17) Hansen, H.-J.; 1959. Roth, W. R. Schmid, H. Vittorelli, P.; Tetrahedron 1974, ~' Hansen, H.-J.; Helv. Chim. Acta 1975, 58, 1293. Schmid, H. Jolidon, S.; Hansen, H.-J. Helv. Chim. Acta 1977, §_Q_, 2436. Lythgoe, B.; Metcalfe, D. A. Tetrahedron Lett. !~Z~, 2447. (18) (a) Trost, B. M.; Verhoeven, T. R. Soc. 1978, 100, 3435. D. F.; Alper, J. B. (c) Picini, J.; Chem. Soc. (b) Trost, B. M.; Tetrahedron Lett. d'Angelo, J.; Noire, J. Taber, 1976, 3857. J. Am. !~Z~, ~' 1213. (19) Bowers, W. S.; E. C. J. Am. Chem. Fales, H. M.; Thompson, M. J.; Uebel, Science 1966, 154, 1020. (20) Nakazaki, M.; Isoe, S. Bull Chem. Soc., Jpn. 1961, -44- 34, 741; 1963, ~ ' 1198. (21) Paws on, B. A.; G. Cheung, H. -C.; Gurbaxani, S.; J. Chem. Soc., Chem. Commun. J. F.; Pawson, B. A.; Pawson, B. A.; G. Ibid. 1969, 715. ---- Gurbaxani, S.; Saucy, J. Am. Chem. Soc. 1970, ~, 336. (22) Cerny, V.; K. Blount, 1968, 1057. Saucy, G. Cheung, H.-C.; Saucy, Dolejs, L.; Tetrahedron Lett. Chem. Commun. g, 1 5 7 9 . Slama, Collect. Czech. 1967, 1053. ---- ---- - Manville, J. F.; g, 1192. 1974, Sorm, F.; 1967, 32, 3926. (23) Rogers, I. H.; Chem. Labler, L.; •I b i d . Sahota, T. Manville, J. F. Can. J. Ibid. 1975, 19 7 6 , ~, _2 3 6 5 . !~Z~, 491. (24) Sakai, T.; Hirose, Y. Chem. Lett. (25) Mori, K.; Matsui, M. Tetrahedron!~~~,~, 3127. Ayyar, K. S.; 46, 1467. V. H. Rao, G. S. K. Birch, A. J.; Can. J. Chem. Macdonald, P. L.; J. Chem. Soc. C 1970, 1469. ---- Tsizin, Y~ S. 1968, Powell, Drabkina, A. A.; J. Gen. Chem. USSR (Engl. Transl.) !~Z2, 44, 422, 691. Trost, B. M.; Tamaru, Y. Tetrahedron Lett. 1975, 3797. Negishi, E.; M.; Brown, H. C. Tetrahedron 1976, Katz, J.-J.; Sabanski, ~ ' 925. (26) Bunnel, C. A.; Fuchs, P. L. J. Am. Chem. Soc. 2-2_, 5184. (27) Felix, D.; Muller, R. K.; Horn, U.; Joos, R.; !~ZZ, -45- Schreiber, J.; Eschenmoser, A. Helv. Chim. Acta !~Z~, ~' 1276. (28) Biller, S. A.; Evans, D. A. (29) Muller, R. K.; Joos, R.; Wintner, C.; Unpublished reuslts. Felix, D.; Eschenmoser, A. Schreiber, J4; Org. Synth. 1976, 55 114. (30) Cason, J.; Prout, F. S. J. Am. Chem. Soc. !~ii,~' 46. (31) Manville, J. F.; Bock, K. Org. Magn. Reson. 1977, ~' 596. (32) Purchased from Ventron/Alfa Inorganics. (33) Watson, S. C.; !~ 2z, ~, 165. Eastham, J. F. J. Organomet. Chem. .,-46- CHAPTER II Stereoselective Aldol Condensations Via Dialkylboron Enolates -4 7.,. Introduction The aldol condensation is a reaction of fundamental importance in the biosynthesis of a broad range of biologically significant natural products. The recognition of both the macrolide and ionophore antibiotics as attainable targets for synthesis has been instrumental in focusing renewed interest towards the development of • 3 stereoregulated variants of this process in the laboratory. Ideally, it would be significant to reveal those stereochemical issues which deal with the control of both reaction diastereoselection (~ 1 + ~ 2 vs !i ,+ ! 2 ) and enantioselection (~ 1 vs ~ 2 or !i vs reaction substrates (eq. 1). OH 0 0 ~CH1 R, R~Rz + OH 0 ~ = R1 R, CH, CH, E, T, 0 R2CHO ! 2) for a range of OH (I) OH 0 R 1~ R 1 CH, R,vRt CH 5 ~ ~ -48- In 1957, in conjunction with a stereochemical study of the Ivanov and Reformatsky reactions, Zimmerman and Traxler accounted for the observed aldol diastereoselection by advancing the hypothesis that the reaction proceeded via a preferred chair-like transition state involving co-operative metal ion ligation of both the enolate and 4 carbonyl substrates (c.f. Scheme I). Subsequent investiga5 6 tions by Dubois and more recently by Heathcock on preformed lithium enolates have unambiguously shown that kinetic aldol diastereoselection is, in part, defined by enolate geometry. With regard to the peri~yclic chair transition states illustrated in Scheme I, both "trans" and "cis" lithium enolates (M = Li) exhibit excellent kinetic threo and erythro product selection respectively when the enolate ligand, R , is sterically demanding such 1 as tert-butyl. The observation that the steric bulk of R (!-C H > i-C H > C H > OCH > H) and the attendant 2 5 3 1 4 9 3 7 5 6 aldol diastereoselection ' are directly coupled is con4 sistent with the elaborated Zimmerman model (Scheme I). For example, for trans-enolates transition state Bis destabilized relative tot due to R1 +-+ R2 interactions. Related trends in aldol stereoselection have been noted 9 7 • • . zinc, 8 an d a 1 um1num eno lat es. f or magnesium, At the outset of the present study the decision was made to explore the role of "metal-centered steric effects" Scheme I + 7 l A 0 OH three R1~R2 CH 3 i i + in the kinetic aldol process, 1 Accordingly, large pseudo- 1,3-diaxial R +-+ L interactions in transition states B 2 and C might render the aldol process, from either enolate .,.50 ... geometry, both highly stereoselective and independent of the steric requirements of the enolate ligand R . 1 For the reasons outlined in our earlier communication, 1 b dialkylboron enolates appeared to be excellent candidates for study. A limited number of literature cases indicated that good levels of aldol diastereoselection might be . . d . 10 ant1c1pate This paper reports the full details of our initial investigations into the generation of stereochemically homogeneous boron enolates and their stereoselective aldol condensations with aldehydes. investigations of Masamune 11 . and Muka1yama 12 The parallel are in accord with those made in the present study. Results and Discussion Selective Generation of Boron Enolates. ---------------------------~~-~------- A variety of published methods exist for the generation of dialkylboron enolates; 13 Nonetheless, only two procedures have been developed which involve the direct enolization of carbonyl substrates.lOb,l 4 Koster has reported that ethyl ketones ! (R 1 = c2H5 , ~-C 3H7 , C6H5 , f-C 6H11 ) react at elevated temperatures (85-110°C) with triethylborane under the catalytic influence of 3 to give enolates . . b rating . . (L = Et) under preswne d equ1l1 con d.1t1ons . 10b . ~~'~! -51- . Mukaiyama has recently disclosed that the dibutylboryl trifluoromethane sulfonate (4a), in the presence of either 2,6-lutidine (Lut) or diisopropylethylamine (DPEA), rapidly enolizes ketones in ethereal solvents at low temperature (~ -78°C). Ster~oselective enolate formation 14 was not addressed in this study. In conjunction with the present investigation, the issue of selective enolate generation via the boryl triflate reagents~ was undertaken. Substrate and reaction variables which include the in~luence of carbonyl ligand (R 1 ), boron ligand (L), base, and solvent have been examined. The •bory l triflate 0 R, /BL 2 Ay CH 3 0 + H R, ~ H CH 3 2c 21 --L 2 BOS0 2 CF 3 4 /BL 2 2• L=!}-C4H9 ~.L=~·C5H9 £,L=C2H5 ~. L 1=c - C5H9, L2= CgH 13 (2) -52- reagents ~~-i£ were prepared from the corresponding trialkylborane (L B) and trifluoromethane sulfonic acid 3 in hig h yield as air and moisture sensitive distillable liquids in direct analogy with literature precedent. 14 ' 15 The general procedure for enolate formation involved r e a c tion of equimolar quantities of ketone or thioester ! and boryl triflate 4 in the presence of 1.1 equiv of tertiar)· amine base in anhydrous ether at temperatures ran g in ~ from -78 ➔ 25°C depending upon the particular car bon v l substrate. The precipitation of insoluble ammo n1u~ triflat e in etheral and hydrocarbon solvents accomp anied enolate formation. Attempts to directly transform the resultant boron enolates, 2c,2t, to enol derivatives which could be more conveniently analyzed led to the unanticipated observation that these nucleophiles did not react cleanly with either chlorotri meth y lsilane or acetic anhydride. This problem was circumvented by conversion of the 2c,2t-mixtures to the an al ogous lithium enolates with ~2 equiv of butyl or rnethyllithium 16 followed by derivatization with chlorotrimethylsilane. The derived trimethylsilylenol ethers were compared with independently prepared samples which 6 have been previously characterized. The only ambiguity in enolate stereochemical assignment was that for the enol silane derived from tert~butyl thiopropionate (6) (Table I, Entry N). The enolate stereochemistry in this system was assigned in analogy to that observed for the related propionate esters since the major enolsilane isomer derived from 6 had the same stereochemistry as that derived from enolization with lithium diisopropylamide (-78°C, THF; 10:90). 17 Table I summarizes the variable reaction and substrate parameters which were studied. ~~'~! Boron enolates were found to be con- figurationally stable at 25°C for as long as 2 h in the presence of the DPEA-HOTf and at 0°C (30 min) presence of Lut·HOTf. At elevated temperatures (77°~, CC1 4 ) complete enolate equilibration achieved (Entries C, G). (~~ ~ ~!) could be As anticipated, enolate equilibrium is reached more rapidly in the presence of the stronger acid, Lut·HOTf. With the exception of Entries C, G, and K, all reported enolate ratios are presumed to be kinetically controlled (Table I). The data in Table I reveal a number of significant trends which bear on the enolization mechanism. Entries A and B illustrate the importance of increased amine steric hinderance in maximizing kinetic selection in the deprotonation process. Relative to the influence of the boron ligand (L), a comparison of the enolate ratios derived from the use of triflates ~~ (L = ~-C 4H9 ) and~~ (c-C H ) on 3-pentanone (Entries A, D) and isopropylethyl 5 9 Table I. __ __ DPEA DPEA Lut Lut L = -n-C 4H9 L = £-C5H9 L = -n-C 4H9 L = -n-C 4H9 L = -n-C 4H9 L = £-C 5H9 L = £-C 5H9 L = -n-C 4H9 L = !!_-C 4H9 L = .!!_-C4H9 Et Et MelH Me 2CH MelH Me 2CH Me 2CH Me 3C Me 3C Me 2CHCH 2 D E F G H I J K L DPEA DPEA DPEA DPEA Lut Lut Lut C L = -n-C 4H9 Et DPEA a Base- B L = -n-C 4H9 4 (L) Et ~ 1 (R 1) -78°(, 30 min +35°C, 2 h 0°C, 30 minf 0°C, 30 min 0°C, 30 min +77°C, 30 min~ -78°C, 30 min -78°C, 30 min 0°c, 30 min +77°C, 3 h~ -78°(, 30 min -78°(, 30 min Con d•1·t·ions-b Kinetic Enolate Formation With Triflates 4a and 4b (eq. 2). A Entry ...., .......... >97:3 (>97:3) 25:75 19:81 42:58 (73 :27) 56:44 45:55 82: 18 (86:14) 69:31 >97 :3 Ratio, 2c:2t£,i I I +::- tJ1 L = !!_-C4Hg Me 3CS N 25°c, 1 h 0°C, 30 min DPEA - Conditionsb - ---~ - - -- ··- -·- - DPEA -- - - Ba sea < 5 :95 > 97: 3 Ratio, 2c: 2t ~•.9_ a) OPEA = diisopropylethylamine, Lut = 2,6-lutidine. b) Except where noted, all reactions carried out in ether. c) Enolate ratios determined on trimethylsilylenol ethers (see text) by 1 H NMR and/ or gas chromatog r aphy by comparison with independently prepared samples (c.f. ref. 6). d) Values reported are kinetic ratios; those in parentheses are equilibrium values-. - -e) Reactions carried out in CC14; prolonged reaction times did not change enolate ratio. f) Incomplete enolization of substrate noted . L = !!_-C4H9 4 (L) C6H5 ---- -- - ·- ! (Rl ) Continued M Entry Table I. tn V, I -56- ketone (En t r ies E, I) is informative. With a given base (D PEA) , the more hi nd ere d b ory l triflate 4b exhibits enh anced kin e tic selection for trans-enolate formation. Thes e observations parallel those noted by Masamune and llb co -Ko rkers. As anticipated, the more hindered triflate ( 4b) is l e ss rea c tiv e in th e enolization proce s s than e ith er 4a or 4c, and reactions with this reagent must be c a r r i ed out at 0 ° C (Entr y D). No significant differences in r e a c ti on st e re o selectio n were noted between the dibut y l an d die t hy l b or y l t r ifl a t es 4a a nd 4c, and the p y ro phoric na t u r e o f 4c rend e r s it less attractive as a rea gent. Fi n a ll :·, f or a gi v en amin e base (DPEA ) and triflate (4a ) , ke ton e sub s trat es ! (R 1 = Et, Me 2 CH, Me 3 C) exhibit a qual i tati v e de crea s e in cis-enolate kinetic selection Ki t h incr e a s ed st e ric re quirements of R (Entri e s A, E, 1 J ). In addition to th e studies noted above which were carr ie d out in ether, it was fo und tha t a range of other s ol vents could be employed with equal facility (CC1 4 , CH C1 , CH c1 , c H , c H ) with only minor variations 2 2 6 6 3 5 12 in kinetic enolate selection. However, those solvents which solub ilize the ammonium triflate were gener a l l y employed to effect enolate equilibration at e l ev ated temperatures (Entries, C, G, K). Solvent effects in the aldol condensation of these enolates, however, were found to be significant (cf. Table III) and "'5 7- will be discussed in the following section. In addition to the observations noted above, additional experiments which could have a bearing on the enolization mechanism were carried out. of the An examination 1 H NMR spectra (CDC1 ) of equimolar solutions of 3 boryl triflate 1! and both 2,6-lutidine and diisopropylethylamine (DPEA) revealed 1:1-complexation between the two reagents (eq. 3)~a Complexation was complete within (3) + minutes with lutidine and in 30 minutes with the more hindered base at 25°C. The 1 !\'MR spectrum of the 13 . d.1cat1ve . • 18 complex was 1n o f a tetracoor d.1nate species. Our observations that other less hindered nitrogen bases such as pyridine, DABCO, DBU, and tetramethylguanidine are totally ineffective in the enolization process could be attributed to the irreversible amine-borane complexation. To account for all observations pertaining to kinetic deprotonation, the following mechanistic model is proposed (Scheme II): (A) Trans and cis-enolates 2t and 2c are derived from deprotonation of syn and anti-complexes 19 Scheme II L , - ,.,,L + .,...s, 0 OTf . H R, 0 R, ~Me + ~ Me .,....BL2 0 -78° ' •.Jy" Me :NR 3 7 NR 3 21 ,_, ~----- L 2 BOTf L,_ ,L B''' ...,BL2 o.,... 'o+ Tf R, ~ Me ~ 0 -78° Me R, H~ :NR 3 --\H 2c ,_, Zand~ respectively. (B) Deprotonation is the rate-determining step rather than complexation . (C) All factors being equal (R deprotonation (~ ➔ deprotonation = E t ) ~ ? = 8 anti1 ~£) is preferred over~- CZ+ l!), Assumption (A) is based upon allylic strain argwnents and related observations in hydrazone deprotonation. 20 Assumption (B) is consistent with both the substrate .,. 59 ~ studies (Table I) and the product selection as a function of base structure. Finally, (C) must be proposed to explain the high cis-enolate stereoselection for 3-pentanone and related systems . .The observation that tert-butyl thiopropionate (~) forms predominately the trans-enolate (2t:2c ~ 95:5) is consistent with the expectation that 7 (R 1 = S!-Bu) might be expected to be more stable than 8 (R 1 = S!-Bu) based upon analogous geometrical preferences . . 21 f or re 1 ate d on1um ions. Nonetheless, these conclusions must be tempered by the observation by Masamune that for thioester ! (R = SC 6H5 ) and 9-BBN triflate (Et 2o, 0°C, 1 DPEA) selective cis enolate (2c) • formation was noted. lld One other potentially attractive method was briefly explored for the stereoselective synthesis of boron enolates (eq. 4). It was found that trimethylsilylenol ethers react rapidly with the boryl triflate reagents to give boron enolates in high yield. However, this exchange process is accompanied by a significant loss in enolate stereochemistry as judged by the resultant aldol condensation experiments (vide infra). The reaction of purified (Z)-silyl ether 2e 6 with~~ (Et 20, -25°C, 30 min) either in the presence or absence of DPEA afforded a ratio 1Qg: l.Ql? == 60:40. The analogous (E)-silyl ether;~ ratio 10b:10a c 80:20, 6 afforded a Related observations with other silylenol ethers were also noted, and all attempts to -60- OSiMe 3 - 4o *"' ~~' R2 + (4) R2 .2. - 10 !:!,, R1= Me, R2 = H 2,R 1=H,R 2 =Me improve exchange stereoselection proved fruitless. 23 Nonetheless, this exchange method could prove useful in the synthesis of boron enolates which are inaccessible • 24 via the triflate reagents. Stereoselective Aldol Condensations. ----------------------------------- The initial set of aldol condensation conditions were similar to those reported by Mukaiyama (Et o, -78°C, DPEA) 14 with either 2 dibutyl or dicyclopentyl boryl triflates 4a and 4b. The derived ketol borate complexes!!~,!!! (Scheme III) were oxidized to the erythro and threo-ketols 12E,12T by one of two procedures. For some substrates the reported b u ff ere d h y d rogen perox1. d e proce d ure 14 was f oun d a d equate; however, for more sensitive substrates such as thioesters -61- the oxidant, MoO 5 •py•HMPT (MoOPH), 25 was found to be superior. In order to insure that the aldol diastereoisomer ratios, 1tE,1tT, reflected the kinetic product ratios, sev- eral aldol ate-complex stability studies were carried out. 2 a Treatment of ~~~ (R 1 = Et, R2 = Ph; ~: ! ~ 9 7: 3) , formed from I 2E with triflate 4a, under the conditions of both aldol condensation and subsequent oxidative isolation resulted in recovery of the ketol 12E with no loss in stereochemistry. The ate-complex ~~~ (R 1 = Et, R2 = Ph) exhibits no tendency to isomerize in refluxing ether (3 h) even in the presence of 0.3 equiv of DBU. Some isomerization was noted (llE~llT = 63i37), however, . in refluxing toluene (1.0 h, 0.3 equiv DBU), We surmise that this equilibration is not proceeding via retro-aldolization, but by acid-base deprotonation of the ate-complex. It was found that the above equilibration procedure was not syntheticall y viable for the production of the thermodynamically more stable threo aldol chelates due to the intervention of other side reactions. Related stability studies on the cyclohexanone aldol adducts 14E and 14T also insured that kinetic product ratios were obtained. From . the data in Table II, in which reaction solvent o, -78°C) variables were held con2 stant, there is a consistently good correlation between and temperature (Et enolate geometry and product aldol stereochemistry. For the .-6 2 - Scheme III 0 II R 1 CCH 2 CH 3 + l L 2 BOS0 2 CF 3 I O [OJ OH R,~R2 CH 3 12E [OJ O OH R 1~ R 2 CH 3 12T 3-pentanone cis-enolate (~~, R1 = Et), the ald('.)l diastereoselection ratio, 12E:12~ corresponds to the enolate ratio 2c:2t within experimental error for not only benzaldehyde, but also the aliphatic aldehydes (Entries A, B, C, D, G). Both ~~methacrolein and tigaldehyde (Entries E~ F) were somewhat less stereoselective. Similar trends were also observed with the thioester 6 (Entries S~X), Another L K J H I G F E D C B A Entry 0 ~ ~ 0 ~ ~ 0 R1C-CH 2CHJ II 0 f-C5H9 c H -CHO 6 5 c6H5-CHO c 6H5-CHO c6H5-CHO !!_-C 4H9 !!_-C4H9 !!_-C H 4 9 f-C5H9 !!_-C4H9 !!_-C4H9 !!_-C 4H9 c6H5-CHO c6H5-CHO !!_-C5H9 f-C5H9 !!_-C4H9 e -n-C 4H9- R2C-H c H5-CHO 6 !!_-C 3H7-CHO -i-C 3H7-CHO • • CH 2=C(CH 3}-CHO (E}CH CH=C(CH }-CHO 3 3 cl, 5-cHo L BOTf-a 2 II 0 +35 0 -78 0 -78 0 -78 -78 -78 -78 -78 -78 Enolization T°C >99: l 45:55 19 : 81 -- >99: l >97 :3 69 : 31 >97: 3 >97: 3 >97 :3 >97 :3 82 : 18 ~~ . . . . . .. Rati oil2c:2t >97 :3 44:56 18:82 >97 :3 84 :16 >97 :3. 72 :28 >97:3 >97:3 92:8 93:7 84:16 --- --- Rati of l 2E: 12T Table II. Kinetic Aldol Condensations With Representative Aldehydes at -78°C (Scheme III) . --~ . . . ~--~ 6~ 6s9(87} 029... (85} 779... 769... 65 61 68 65 (86} I 0\ vi ·1 Yield, %Q. R Q p 0 N M Entry 0 0 Me 3 S i N Ts I 0 ~ !-BOC ~ ~ C5H5 ~ 0 RlC-CHlH3 - II 0 Table II. ' Continued -~-----II c6H5-CHO c6H5-CHO -i-C 3H7-CHO j__-C 3HrCHO c6H5-CHO c6H5.-CHO Rl....,.H 0 ~-C5H9 !!_-C 4H9 !!_-C4H9 f ~-C5H9- !!_-C4H9 !!_-C H 4 9 L BoTf~ 2 -78 0 +25 +25 -78 +25 Enolization T°C --- --- -- 99: l -~ ~- --- 19 :81 35:65 90:10 87: 13 >97:3 >97:3 ....., .......... Rati oQ Ratio~ 2c:2t l 2E: 12T 53 (68) 57- h 6oh 70h 82.9.. Yield, %.9.. I t ~ 0\ Table II. -6 !-Bus~ 0 R1C-CH/H 3 !! 0 Con tinued --- - !:!_-C4H9 ~-C5H9 ~--C4H9 ~-C4H9 !!-C4H9 !!-C4H9 0 0 0 0 0 0 Enolizati on a T"C L2BOTf -- - -- - ------- ----- -- - -- -- -- - - • -- - - - · -· - -- - --- -- - - ---- - - - !!-C 3H7-CHO j_-C 3H7-CHO CH =C( CH )-CHO 2 3 (E)CH 3CH=C(CH 3)-CHO c6H5-CHO c6H5-CHO RzC-H 0 II ·- <5:95 <- 5:95 <5: 95 < 5 :95 --<5:95 <- S:95 . ..... . 10:90 5:95 10:90 9:91 12 :88 18:82 Ra ti o9-. Ratio~ 2c:2t l--- 2E: l 2T ......... -- -- ~ --·~ 75 (90) 67 63 65 61 Yi eld, %~- a) In all cases di isopropylethylamine (DPEA) was used as the base and enolization was carried out i n ether for 30 min except for Entries Mand N where a reaction time of 60 min was employed. b) Data derived from Table I. c) Aldol ratios detennined by 1 H NMR or 1 3c NMR. d) Values reported are for isolated yields. Those in parentheses detennined by 1 H NMR. e) Lutidine wa s employed as the base. f) The reaction so lvent was ether-CH2Cl2. g) Ref. 2a. h) Ref. 2b. X w V u T s Entry ~~ ~~~~ ~- • (./1 °' ... 66- significant conclusion can be drawn from the data on the effects of the boron ligand, L, on aldol diastereoselection. For three enolates (R 1 = Et, i~C 3H7 , t-Bu-S), the change in boron ligand from !!_~butyl to cyclopentyl results in only a minor (~5%) enhancement reaction selectivity (Entries A, G; J, K; S, T). On the other hand, it is apparent that, in the majority of cases, boron ligand structure plays a significant role in the enolization process (Table I). Based upon the excellent aldol diastereoselection observed with the acyclic carbonyl substrates, it was surprising to observe that the cyclohexanone enolate (L = !!_-C 4H9 ) condensation (Et 2o, -78°C) with benzaldehyde (eq. 5) exhibited relatively low stereoselection (14E:14T = c5· 1l PhCHO 21 MoOPH if Ph + Ph ( 5) t-BuS~Ph (6) 14T ---- 14E 13 ~ OBL2 0 0 OH ll PhCHO L·BuS~ CH 3 15 ,..._ if L·BuS~Ph 21 MoOPH + OH - CH3 CH 3 16E 16T 33:67)~a Accordingly enolates 13 and 15 were chosen to -- ':""'- study the interplay of both solvent effects and boron ligand structure on reaction steTeoselection (Table III). For a given boron ligand there is a small but consistent improvement in aldol diastereoselection when the less polar solvents are employed. for both enolates !Jandl~. This trend is observed In subsequent studies we have found that aldol diastereoselection in methylene chloride is comparable to that observed in pentane, and 2 the former is frequently the solvent of choice. b Assuming that these reactions proceed via the pericyclic aldol mechanism (Scheme I), the less polar solvents could well result in "transition state compression'' · thereby enhancing those steric parameters which appear to regulate diastereoselection. The solvent effects noted above have also been found to be significant in the • 1·1 ty trans f er, Zb eno 1 ate c h ira . I n an e ff ort to further enhance aldol selection for enolate !~, we prepared the sterically demanding thexylcyclopentylboryl 26 triflate ~~ from the corresponding boron hydride and TfOH!a In view of our earlier results, the high diastereoselection observed with this mixed ligand was gratifying. A significant body of literature has been devoted to an examination of enediolate aldol stereoselection (eq. 7). 4 , 27 Although our earlier attempts to enolize alkyl esters (methyl propionate) had not been successful, it 5:95 < 5 :95 THF pentane~ pentane-e L ::: ~-C H ( ~~) 5 9 L ::: c H -d2 6 13 L , L = !!_-C H (4d) 4 9 2 1 L1, l2 = ~-C5H9 13 15 F G CH/1 2 < 4 :96 84 92 94 ( 73)f (74) 10of a) All reactions employed DPEA as base and were carried out at -78°C. b) Ratios determined by 1 H NMR. c) Values refer to yields determined by 1 H NMR; those in parentheses were isolated. d) 2,3-Dimethyl2-butyl (thexyl). e) For the comparative experiments in ether see Table II, Entries S, T. f) Ref. 2a. 1 L2 = C6Hl 3-- d 6~ 6:94 = ~-C H 5 9 13 E 1 15:85 pentane Ll' L2 = -c-Cr.::Hg J 13 D L sof 32:68 ether L , L = ~-C5H9 1 2 13 17: 83 C pentane L , L = !!_-C4H9 1 2 13 71f_ B 33:67 ether L , L = .!:]_-C H 2 1 4 9 13 E + T A Solvent Enol ate 1 2 Yield, %~ Entry L L BOTf-- a Ratio~ E:T Aldo l Condensation of 13 and 15 With Benzaldehyde (eq. 5, 6) . Solvent and Ligand Effec t s. -- ------- - - -- -- - - - -- - - - - - ---- - - - - ·- - - -- - - · - - -- -- - · - - Table III. I 00 °' I OM + R1~ 0 M ( 7) was found that dialkylboryl propionates (L BOCOEt) are 2 readily enolized by DPEA and triflates 4a and 4b. The addition of propanoic acid to 2 equiv of triflate and DPEA (Et 2o, 0°C) resulted in the formation of enediolates 17a and 17b (R = CH 3 ) respectively. Both enolates were subject to aldol condensation under the usual conditions (Et 2o, -78°C). Ene~iolate 17a (R = CH ) afforded a ratio 3 ~~~:~~~ = 35:65 while 17b (R = CH ) exhibited moderately 3 greater threo-diastereoselection (18a:19a = 20:80). Under similar conditions, the enediolate ~Z~ (R = OCH 2Ph) derived from benzyloxyacetic acid afforded exclusively the aldol stereoisomer 19b in 85% yield. Confirmation of the aldol stereochemistry in both cases was achieved by stereospecific trans-fragmentation with dimethylformamide dimethylacetal to the trans and cis-olefins 20 and 21. 28 , 29 From the propionate aldol mixture (!~~ =!~~ = 20:80), this procedure afforded the ratio 20a:2la = 20t80 while the Scheme IV OH I) PhCHO + O Ph~OH R !1 g, L=!!-C4H9 g, R=CH 3 2,L=~-C5H9 19 ~.R=OCH 2 Ph L L,, I ''a--o +/~ BzO /2O H H Ph~R PhAyH I BL2 E ~ H - 20 R - 21 hydroxy acid!~~ was observed to give exclusively the Since our earlier studies have demonstrated that boron enolate geometry strongly correlates with product stereochemistry, enediolate 17 can be employed to directly compare cis vs trans-boron enolate reactivity (kcis;ktrans =~~:~~)via internal competition. These experiments imply that trans-propionate enolates, and presumably trans-ethyl ketone enolates (c.f. 2t) exhibit somewhat greater reactivity (2-4X) than 3 O Th • • ' • t h e correspon d 1ng c1s-1somers. ese ob serva t ions are -71.,. in marked contrast to those of Dubois 5c who observed that the trans-lithium enolate derived from 3~pentanone reacted 7-8 times more slowly than the corresponding cis-isomer. These differential rate effects could be interpreted in terms of diastereoisomeric transition state steric effects; 6 alternatively, differing levels of aggregation of the two lithium enolates could also account for the observed rate differences. The markedly enhanced aldol stereoselection which was observed for the benzyloxyacetic ~I~ acid enediolate (R = OCH 2Ph) can be rationalized by invoking internal complexation (c.f. ~' Scheme IV) between the (Z)-boron and . 30 b enzy 1 oxy su b st1tuents. Table IV summarizes the results of five kinetic metal enolate condensations with benzaldehyde. The influence of the metal center, M, and enolate ligand, R1, on aldol stereoselection are readily accommodated by the general transition state model (Scheme I). For cis-enolates, when R is large (Entry A) transition state C is strongly 1 destabilized relative to~ by R1 +-+ R2 interactions, and erythro-diastereoselection is uniformly high. As the enolate ligand, R , is decreased in size, the combination 1 of steric effects of both R and the metal center (R 1 +-+ R2 1 and R +-+ L) become important in maintaining erythro2 selectivity (Entries B, C). Related arguments hold for trans-enolates relative to transition state B. Table IV. Entry Influence of Metal Center on Kinetic Aldol Reactions With Benzaldehyde. Enolate OM A Metal (M) B(C4H9)2 C >98:2d >97:3>97:if. Li B(C4H9)2 C 88:12>97:1- Li MgBr Me3C~ OM B Erythro:Threo Ph~ OM C .a L1B(C4H9)2 80:20 >97:i- .b L,B(C4H9)2 60:40 5:95 Li Al(Et) 2 C 48 :5250:5~ 4: 9rf-. Et~ D OM !-Bus~ OM E 6 B(C5H9)C5H13 a) Prepared from the (Z)-silylenol ether and methvllithium (Ref. 5c). b) Prepared from~ and LOA (THF); enolate ratio, 9:91; condensation carried out for 5 sec. c) Ref. 6. d) Ref. 5b. e) Ref. 9b. f) Ref. 2a. Conclusions The results discussed above illustrate the importance of the metal center in controlling aldol diastereoselection. By proper choice of the boron ligands and reaction solvent, we have shown that con~ sistently good car-relation between enolate geometry and aldol product stereochemistry can be obtained. These methods should find numerous applications in the total synthesis of natural p-roducts. Infrared spectra were recorded on a Beckmann 4210 spectrop h otometer. lH magnetic . resonance spectra were recorded on a Varian Associates EM-390 (90 MHz) spectrometer and are reported in ppm from internal tetramethylsilane on the o scale. Data are reported as follows: chemical shift, multiplicity (s t = singlet, d = doublet, = triplet, q = quartet, m = multiplet, b = broad), coupling constant (Hz), integration, and interpretation. 13C magnetic • resonance spectra were recor d e d on a JEOLFX-90Q (22.5 MHz) spectrometer and are reported in ppm from tetramethylsilane on the o scale. Multiplicities are reported using the format given above. Mass spectra were recorded on a Dupont 21-492B spectrometer by the California Institute of Technology Microanalytical Laboratory. Combustion analyses were performed by Spang Microanalytical Laboratory, Eagle Harbor, Michigan. Analytical gas-liquid chromatography was carried out on a Varian Aerograph Model 1400 gas chromatograph, equipped with a flame ionization detector, using a 6 ft x 0.125 in stainless steel column packed with 10% Carbowax 20M on 60-80 mesh Chromosorb W. Preparative gas-liquid chromatography was performed on a Varian Aerograph Model 90-P gas chromatograph using a 6 ft x 0.25 in copper .,. 7 5 .. column packed with 10% SE-30 on 40-60 mesh Chromosorb W support. Medium pressure chromatography . was performed using EM Laboratories LoBar silica gel 60 prepacked columns on a Chromatronix MPLC apparatus equipped with a Fluid Metering Inc. Model RP Lab Pump. Analytical HPLC was performed on a Water's Associates Model ALC 202/ 401 high pressure liquid chromatograph equipped with a Model 6000 pump and ultraviolet and refractive index detectors. Optical rotations were recorded on a Perkin Elmer 141 polarimeter at the sodium D line. When necessary, solvents and reagents were dried prior to use. Diethyl ether and tetrahydrofuran were distilled from benzophenone ketyl. Pentane and chloro- form were filte_,red through activity I alumina. Methylene chloride, diisopropylethylamine, 2,6-lutidine, and 2,4lutidine were distilled from calcium hydride. Benzaldehyde, ~-butyraldehyde, and isobutyraldehyde were distilled and stored at 0°C. Methacrolein and tiglic aldehyde were distilled immediately prior to use. Chlorotrimethylsilane was distilled from quinoline immediately prior to use. Propionyltrimethylsilane was prepared by the procedure of 6 Heathcock and co-workers. The method of Vedejs 31 and coworkers was used for the preparation of MoO 5 ,pyridine•HMPT (MoOPH). g_-Butyllithium was titrated by the procedure of 32 Watson and Eastham. All other reagents were used as received. PI~E~I~!!2~_2f_~!~!t1!~2It1_!I!f1~2I2~~!b~~~~~1f~~~!~~General Considerations on Handling and Storage. The --------------------------~-~~------~-~~~~-~~~ dialkylboryl triflates are extremely air and moisture sensitive reagents which must be transferred and stored under a scrupulously maintained argon atmosphere. With proper handling the reagents can be stored for several months without any significant decomposition. Although the dialkylboryl triflates often become yellow or orange upon storage, this discoloration had no significant effect on the yields of subsequent reactions. The 33 trifluoromethanesulfonic acid used in the procedures below was obtained from a freshly opened bottle and was not purified before use; partially used bottles which have been opened more than a few weeks should be avoided. Diethylboryl trifluoromethanesulfonate (4c)~a To 13.1 ~ 34 (0.133 mol) of triethylboron under argon at 0°C was -------------------------------------- ----- added 20.0 g (0.133 mol) of trifluoromethanesulfonic acid dropwise over 25 min. After the addition, the pale brown solution was stirred for 30 min at room temperature and was then distilled (54-55°C, 24 mm) to yield 26.0 g (90%) of diethylboryl triflate as a colorless, pyrophoric liquid. This reagent offered no advantages in reactivity or selectivity over di-n-butylboryl triflate which is more easily handled due to its greater stability. Di-~-butylboryl trifluoromethanesulfonate (4a). The reagent was prepared by the procedure of Mukaiyama 12 and co-workers and was stored at room temperature. Dicyclopentylboryl trifluoromethanesulfonate (4b). ~~~~~-------------------------------------------35 To 14.9 g (68 mmol) of tricyclopentylboron at room temperature under argon was added 10.2 g (68 mmol) of trifluoromethanesulfonic acid dropwise with intermittent cooling to maintain the reaction temperature at approximately room temperature. The deep orange solution was stirred for 30 min at room temperature and was then distilled (70-72°C, 1 mm) to yield 18.3 g (90%) of the air-sensitive boryl triflate as a colorless liquid. Dicyclopentylboryl triflate was stored at 0°C. Cyclopentylthexylboryl trifluoromethanesulfonate (4d)~a ~~~~~~~------------------------------------~-~~~~~~~~ A solution of 1.25 mL (12 mmol) of 9.6 ~ borane methylsulfide complex and 1.01 g (12 rnmol) of 2,3-dimethyl-2butene was stirred under argon for 2 hat 0°C. After the addition of 10 mL of tetrahydrofuran the solution was cooled to -30°C and 0.82 g (12 mmol) of cyclopentene were rapidly added. The solution was stirred 1 hat -30°C to 25°C, cooled to -78°C, and 1.65 g (11 mmol) of trifluoromethanesulfonic acid added dropwise (hydrogen evolved with foaming). After the addition the solution was stirred at -78°C for 1 fiand at ~60°C for 15 min. The reagent was then ready for use in subsequent reactions, it was not isolated. General Procedures for the Formation of Boron Enolates. -----------------------------------------------------To a stirred -----------------------------------solution of amine (1.1-1.2 equiv) and dialkylboryl Kinetic Generation of Boron Enolates. triflate (1.1 equiv) in the indicated solvents (2-3 mL/ mmol substrate) at the indicated temperatures (~25°C) under an argon atmosphere was added the substrate (1.0 equiv) dropwise. For reactions in ether and pentane, the progress of the reaction could be monitored by the formation of a white precipitate of ammonium triflate. After the indicated time period the dia~kylboron enolate was ready for subsequent reactions. Equilibration of Boron Enolates. -~~~~~------------------------- After kinetic enolization at 0°C for S min the mixture was heated at reflux for 2-3 h. The dialkylboron enolate solution was then ready for subsequent reactions. The choice of amine and solvent is dependent upon the structure of the ketone. While sterically hindered ketones, such as tert- butylethylketone, can be equilibrated by diisopropyl- ethylammonium triflate in ether, simpler ketones, such as diethylketone, require use of the more acidic 2,6-lutidinium triflate in carbon tetrachloride for equilibration (see text for additional details). No precipitate was observed when chlorinated hydrocarbons were used as solvents due to the solubility of ammonium triflates in these solvents. Silylation of Boron Enolates. To a 0.5 M solution of boron enolate in ether at -78°C under an argon atmosphere was added n-butyllithium (3.3 equiv). After 15 min, chlorotrimethylsilane (3.3 equiv) was added and the solution allowed to warm to room temperature where a white precipitate formed. The mixture was partitioned between brine and pentane and the brine extracted once with pentane; the combined pentane extracts were washed successively with saturated aqueous sodium bicarbonate and brine, dried (Na 2so 4 ), and concentrated in vacuo to afford the crude trimethylsilylenol ethers. Yields in this reaction exceeded 100% due to the presence of boron-derived side products. The enol ethers were analyzed by comparison with authentic 1 samples 6 using gas-liquid chromatography or H NMR (although the spectrum was complicated by the side products the olefin region was clean). General Procedures for the Aldol Condensation of Dialkylboron _Enolates. To a solution of the dialkylboron enolate at -78°C under an argon atmosphere was added the aldehyde (nonenolizable: 1.0 equiv, neat; enolizable: 1,2-1.5 equiv, solution in 2-3 mL solvent/mmol aldehyde). The mixture was then stirred for 30 min at -78°C and 1 hat 0°C. by addition to pH 7 phosphate buffer. The mixture was ex- tracted twice with ether and the combined ether extracts were washed with brine and concentrated in vacuo. The crude oil was then dissolved in methanol (3 mL/mmol) at 0°C and 30% hydrogen peroxide (1 mL/mmol) added. After stirring at room temperature for 2 h, water (5-10 mL/ mmol) was added, and the milky mixture concentrated in vacuo to remove most of the methanol. The residue was extracted twice with ether and the combined ether solution was washed with -5% aqueous sodium bicarbonate and brine, dried (Na 2so 4 ), and concentrated in vacuo to afford the crude aldol adducts. MoOPH Workup. ------------ The dialkylboron alkoxides were oxidized by the addition of MoOPH (1.5 equiv) and the yellow slurry was stirred initially at 0°C (30 min) then at room temperature (45 min). The mixture was added to 1 N aqueous sodium hydroxide and extracted with ether. The ether solution was washed with dilute brine and brine, dried (Na 2so 4 ), and concentrated in vacuo to afford the crude aldol adducts. Silylation of the di-~-butylboron enolate of 3pentanone (Table I, Entry B). Kinetic enolization of ----------------------------0.17 g (2.0 mmol) of diethyl ketone with 0.26 g (2.4 nunol) of 2,6-lutidine and 0.60 g (2.2 mmol) of di-n-butylboryl triflate in 5 mL of ether at -78°C for 30 min was followed by silylation to afford 1.1 g (>100%) of unpurified trimethylsilylenol ether. Analytical gas- liquid chromatography indicated the ratio of 2c:2t was 69:31. Assignments were made by comparison to a known 6 • • mixture generate d b y trapping t h e enolates f orme d using lithium diisopropylamide. Silylation of the dicyclopentylboron enolate of ~:~~!~rI:~:P~~!~~~~~-I!~~I~~~Ii~~~!Er_fl· Kinetic enolization of 0.20 g (2.0 mmol) of 2-methyl-3nentanone with 0.31 g (2.4 mmol) of diisopropylethylamine and 0.66 g (2.2 mmol) of dicycl.opentylboryl triflate in 5 mL of ether at 0°C for 30 min was followed by silylation to afford 0.81 g (>100%) of unpurified trimethylsilylenol ether. Analytical gas-liquid chromatography indicated the ratio of 2c:2t was 19:81. Assignments were made by comparison to a known mixture 6 generated by trapping the enolates formed with lithium diisopropylamide. Silylation of the di-n-butylboron enolate of 2,2- --------------------------------- ---------------I, Entry . K). Enolization ---------------------------------------dimethyl-3-pentanone (Table and equilibration of 0. 23 g CZ. o rnmol) of z;z~ dimethyl-3-pentanone with 0.31 g (2.4 mmol) of diisopropylethylamine and 0.60 g ( 2. 2 rnmol) of di-nbutylboryl triflate in 5 mL of refluxing ether for 2 h was followed by silylation to afford 1.4 g (>100%) of unpurified trimethylsilylenol ether. A sharp quartet for the vinyl proton appeared at o 4.47 (lit.6 4.40) in 1 the H NMR spectrum for the cis-enolate, 2c. Assignment was made by comparison to a known sample generated by trapping the enolate formed using lithium diisopropylamide. Silylation of the di-n-butylboron enolate of 4-methyl- -----------------------------------------------------I, Entry L). Kinetic enolization 3-hexanone (Table of 0.23 g (2.0 mmol) of 5-methyl-3-hexanone with 0.31 g (2.4 mmol) of diisopropylethylamine and 0.60 g (2.2 rnmol) of di-~-butylboryl triflate in 5 mL of ether at -78°C for 30 min was followed by silylation to afford 1.2 g (>100%) of unpurified trimethylsilylenol ether. A sharp quartet for the vinyl 1 proton appeared at o 4.43 in the H NMR spectrum for the cis-enolate, ~~- Silylation of the di-n-butylboron enolate of propiophenone (Table I, Entry M). Kinetic enolization of 0.27 g (2.0 mmol) of propiophenone with 0.31 g (2.4 mmol) of diisopropylethylamine and 0.60 g (2.2 mmol) of di-n-butylboryl triflate in 5 mL of ether at room temperature for 1 h was followed by silylation to afford 1~3 ~ (>10Q%} of unpurified trimethylsilylenol ether. Analytical gas-liquid chromatography indicated only cis-enol ether, 2c (<1% trans) was present. Assignment was made by comparison to an authentic sample 6 generated by trapping the enolate formed with lithium diisopropylamide. A sharp quartet for the vinyl proton appeared at o 5.31 1 in the H NMR spectrum Silylation of the di-~-butylboron enolate of S-tertbutyl propanethioate (Table I, Entry N). Kinetic enolization of 0.15 g (1.0 mmol) of S-tert-b11tv1 nronRnethioate with 0.14 g (1.1 mmol) of diisopropylethylamine and 0.30 g (1.1 mmol) of di-n-butylboryl triflate in S mL of ether at 0°C for 30 min was followed by silylation to afford (0.95 g (>100%) of unpurified trimethylsilylenol ether. A shart quartet for the vinyl proton appeared at o 5.25 in the the trans-enolate, 2t. 1 H NMR spectrum for In samples containing cis- enolate, 2c, an additional signal appeared at o 5.21 (q). Assignments were made by comparison to known mixtures generated by trapping the enolates formed using lithium diisopropylamide in analogy to the work of Ireland, 17 - et al. Erythro-1-hydroxy-2-methyl-1-phenyl-3-pentanone ----------------------------------------------- (Table II. Entry A)?a Kinetic enolization of 0.52 g --------~--------(6.0 mmol) of 3-pentanone with 0.85 g (6.6 mmol) of diisopropylethylamine and 1.81 g (6.6 mmol) of di-n-butylboryl triflate in 15 mL ether at -78°C for 30 min was followed by aldol condensation and hydrogen peroxide workup with 0.64 g (6.0 mmol) of benzaldehyde to yield 1.01 g (88%) of colorless oil. adduct,!~~' was detected by product, vide infra. 1 No threo-aldol H NMR of the unpurified The product was chromatographed at medium pressure over silica gel (hexane:ethyl acetate, 8:1) to afford 0.89 g (77%) of erythro aldol adduct 12E as a colorless oil: IR (CC1 4 , 5%) 3605, 1H NMR (CC1 ) o 3500, 2985, 2969, 1705, 1695, 696 cm-l 4 7.17 (s, 5, aromatic), 4.80 (d, J = 3 Hz, 1, _erythro- C!::!_-OH), 3.19 (s, 1, -0!::!_), 2.65 (rn, 1, -CO-C!::!_-), 2.21 (m, 2, -CO-CH -), 0.98 (d, 3, -CH-C!::!_ 3 ), 0.89 (t, 3, 2 6 -CH 2 -c!::!_ 3 ). Authentic threo-adduct gave rise to an additional signal at & 4.48 (d, J = 8 Hz, threo- C!::!_-OH). These spectra are identical with those 6 reported in the literature for this compound. Erythro-5-hydroxy-4-methyl-3-octanone (Table II, Entry C). Kinetic enolization of 0.17 g (2.0 mmol) of 3~pentanone with 0.31 g (2.4 mmol) of diisopropylethylamine and 0.60 g (2.2 mmol) of di-nbutylboryl triflate in 5 mL of ether at -78°C for 30 min was followed by aldol condensation and MoOPH workup with 0.17 g (2.4 mmol) of n-butytaldehyde to yield 0.22 g (69%) of a colorless oil. No threo-aldol adduct, 12T, was <'(~~ detected by 1 H NMR of the unpurified product, vide infra. The product was bulb-to-bulb distilled (130°C, 1 mm) to afford 0.20 g (65%) of erythro-aldol adduct,!~~' as a colorless oil: IR (neat) 3480, 2960, 1700, 1455, 975 cm -1 1 H NMR (CDCl ) 0 3.89 (m' 1, erythro-C!i_-OH), 2.92-2.38 3 (m, 4' -CO-CH 2 -, -CO-CH- -OH), 1.65-0.82 (m' 13, -' aliphatic). Preparative gas-liquid chromatographic separation of a mixture of aldol products generated by lithium enolate condensation provided compounds for which assignments for the 1H NMR spectra were made by a comparison of the carbinol protons: J erythro o 3.89 (m, = 3 Hz) and threo o 3 . 65 (m, J = 7 Hz). The coupling constants were determined by an analysis of the signal of the proton on carbon 4. Exact mass calcd. for c9H18 o2 : 158.131. Found: 158.132. §EY!~E~:~:~r~E~~r=~~~=~!~~!~r!:~=~~~!~~~~~-i!~~!~ll2 ~~!Et_Pl· Kinetic enolization of 0.17 g (2,0 mmol) of 3-pentanone with 0.31 g (2.4 mmol) of diisopropylethylamine and 0.60 g (2.2 mmol) of di~~-butylboryl triflate in 5 mL of ether at ~78°C for 30 min was followed by aldol condensation and MoOPH workup with 0.17 g (2.4 mmol) of isobutyraldehyde to yield 0.21 g (65%) of a color1 • 1 ess 011. Not h reo-a ld o 1 a dd uct, 12T --~ was detected b·y H NMR of the unpurified product, vide infra. The product was bulbto-bulb distilled (130°C, 1 mm) to afford 0.19 g (61%) of erythro-aldol adduct, 12E, as a colorless oil; ' ' IR 1 (neat) 3490, 2970, 1700, 1455, 973 cm-l 8 3.48 (d of d, J = 3 Hz and 8 Hz, 1, erythro-CH-OH), 2.95 (s, 1, -0!:!_), 2. 71 (d of q, J = 3 Hz and 7 Hz, 1, -CO-C!:!_-), 2.50 (q, 2, -CO-CH 2 -), 1.61 [m, 1, -CH(CH 3 ) 2 J, 1.29-0.80 (m, 12, methyls). Threo-aldol adduct, prepared via the lithium enolate, gave rise to an additional signal at 8 3. 41 (t, J = 7 Hz, threo-C!:!_-OH). Exact mass calcd. for c 9H18o2 : 158.131. Found: 158.134. Erythro- and threo-5-hydroxy-4,6-dimethyl-6-hepten- ---------------~----------------------------------3-one (Table II, Entry E). Kinetic enolization of O.17 g --------------~-------~(2.0 mmol) of 3-pentanone with 0.31 g (2.4 mmol) of diisopropylethylamine and 0.60 g (2.2 mmol) of di-~butylboryl triflate in 5 mL of ether at -78°C for 30 min was followed by aldol condensation and MoOPH workup with 0.21 g (3.0 mmol) of methacrolein to yield 0.23 g (72%) of a yellow oil. The ratio of erythro:threo-aldol adducts, 1~~=!?:!'i in the unpurified product was determined by 1 H NMR to be 92:8 . The product was bulb-to-bulb distilled (150°C, 1 mm) to afford 0.21 g (68%) of a colorless oil: IR (neat) 3480, 3100, 2980, 1705, 1650, 1457, 977, 900 cm- 1 ; 1 H NMR (CDC1 ) o 4.98 (m, 2, olefin), 4.36 (d, 3 J = 3 Hz, 0.92, erythro-CH-OH), 4.17 (d, J = 8 Hz, 0.08, threo-C~OH), 2.90 to 2.39 (m, 4, -CO-CH, -CO-C~ 2 -, and -0~), 1.69 (s, 3, =C-CH ), 1.20 to 0.95 (m, 6, methyls). 3 Exact mass calcd. for c9 H16 o2 : 156.115. Found: 156.116. Ervthro- and threo-5-hydroxy-4,6-dimethyl-(E)-6-~'~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 0.17 g (2.0 mmol) of 3-pentanone with 0.31 g (2.4 mmol) of diisopropylethylamine and 0.60 g (2.2 mmol) of di-nbutylboryl triflate in 5 mL of ether at -78°C for 30 min was followed by aldol condensation and MoOPH workup with 0.25 g (3.0 mmol) of tiglic aldehyde to yield 0.24 g (70%) of a yellow oil. The ratio of erythro:threoaldol adducts, 12E;12~ in the unpurified product was deter- ~-- ~-- mined by 1 H NMR to be 93:7. The product was bulb-to-bulb distilled (150°C, 1mm) to afford 0.22 g (65%) of a colorless oil: -1 IR (neat) 3 4 9 0 , 29 7 0 , 170 0 , 16 6 7 , 14 5 0 , 9 7 0 , 8 2 5 cm ; 1H NMR (CDC1 ) cS 5.47 (m, 1, olefin), 4.58 (s, 1, -0~), 3 4.24 (d, J = 5 Hz, 0.93, erythro-CH-OH), 4.11 (d, J = 9 Hz, 0.07, threo-CH-OH), 2.92 to 2.32 (m, 3, -CO-CH- and -CO-C~ -), 1.60 and 1.55 (d ands, 6, =CH-CH and =C-CH 3 ), 3 2 1.22 (m, 6, methyls). Exact mass calcd. for 170.131. c10 H18 o2 : 170.131. Found: ... 33.,.. Erythro-1-hydroxy-5-methyl-1-phenyl-3-hexanone -~ - --~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ I~EI~-~\~~~!Er_~l~a Kinetic enolization of 0.68 g (6.0 mmol) of 2-methyl-4-hexanone with 0.85 g (6.6 mmol) of diisopropylethylamine and 1.81 g (6.6 mmol) of di-~-butylboryl triflate in 15 mL of ether at -78°C for 30 min was followed by aldol condensation and hydrogen peroxide workup with 0.64 g (6.0 mmol) of benzaldehyde to yield 1.44 g (>100%) of a pale yellow oil. No threo-aldol adduct, !~'!:, was detected by 1 H NMR of the unpurified product, vide infra. The product was chromatographed at medium pressure over silica gel (hexane:ethyl acetate, 8:1) to afford 1.09 g (82%) of erythroaldol adduct,!~~' as a colorless oil: IR (CC1 , 5%) 4 3605, 3510, 2958, 1707, 1694, 1098, J078, 698 cm- 1 ; NMR (CC1 4 ) o 7.23 (s, 5, aromatic), 4.88 (d, J = 1H 4 Hz, 1, erythro-C!:!_-OH), 3.0 (s, 1, -OH), 2.64 (m, 1, -CO-C!:!_-), 2.3-1.75 (m, 3, -CO-CH2-C!:!_-), 0.98 (d, 3, -CH-C!:!_3), 0.83 [d, 6, -CH-(C!:!_ ) ]. Threo-aldol adduct, from reactions 3 2 using dicyclopentylboryl triflate, gave rise to an additional signal at o 4. 64 (d, J Exact mass calcd. for = 9 Hz, threo-C!:!_-OH). c14 H20 o2 : 220.146. Found: 220.146. Erythro- and threo-l-hydroxy-2,4-dimethyl-l-phenyl- -------------------------------------------------------------------------------3-pentanone (Table I I, Entry J) ~a Kinetic enoli zation of 0.60 g (6.0 rnmol) of 2-methyl-3-pentanone with 0.31 g (6.6 mmol) of diisopropylethylamine and 1.81 g (6.6 mmol) of di-~-butylboryl triflate in 15 mL of ether at ~78°C for 30 min was followed by aldol condensation and hydrogen peroxide workup with 0.64 g (6.0 mmol) of benzaldehyde to yield 1.10 g (89%) of a pale yellow oil. The ratio of erythro:threo-aldol adducts, l?~=l?I, in the unpurified product was determined by 1H NMR to be 44:56. The product was chromatographed at medium pressure over silica gel (hexane:ethyl acetate, 12:1) to afford 0.80 g (65%) of a. colorless oil: IR (CC1 , 5%) 3480, 3030, 2970, 1707, 1450, 1100, 4 , -1 1 1005, 698 cm ; H NMR (CC1 ) o 7.30 (s, 5, aromatic), 4 4.91 (d, J = 5 Hz, 0.44, erythro-C~-OH), 4.70 (d, J = 8 Hz, 0 . 56, threo-C~-OH), 3.40 (s, 1, -0~), 3.22 to 2.46 [m, 2, -co-CH-CH and -co-c~-(CH ) 2 ], 1.19 to 0.89 (m, 3 9, methyls). These spectra are identical with those 6 reported in the literature for this compound. Erythro-1-hydroxy-2,4,4-trimethyl-1-pheny1 • 3-pentanone (Table II, Entry L)~a Enolization and equilibration of 0 . 68 g (6 . 0 mmol) of 2,2-dimethyl-3-pentanone with 0.85 g (6.6 mmol) of diisopropylethylamine and 1.82 g (6.6 mmol) of di-n-butylboryl triflate in 15 mL of refluxing ether for 2 h was followed by aldol condensation and hydrogen peroxide workup woth O. 64 g (6. 0 mmol) of benzaldehyde to yield 1.01 g (76%) of a yellow 1 oil. No threo-aldol adduct,!~!, was detected by H NMR of the unpurified product, vide infra. The product was chromatographed at medium pressure over silica gel (hexane:ethyl acetate, 8:1) to afford 0.86 g (65%) of erythro-aldol adduct,!~~, as a colorless oil: IR (CC1 4 , 5%) 3620, 3500, 2970, 1695, 1685, 982, 698 cm- 1 ; 1H NMR (CC1 ) o 7.25 (s, 5, aromatic), 4.76 (d, J = 4 Hz, 4 1 , e ry th r o - CH - 0 H) , 3 . 3 2 - 2 . 9 7 ( m, 1 , - CO - C!:!_ - ) , 3 . 18 ( s , 1 , -0!:!_), 1.02 [s, 9, -C-(C!:!_ ) ], 0.99 (s, 3, -CH-C!:!_ ). 3 3 3 6 Authentic three-adduct gave rise to an additional signal at o 4.60 (d, J = 7 Hz, threo-C!:!_-OH). These spectra are identical with those reported in the 6 literature for this compound. Erythro-3-hydroxy-2-methyl-1,3-diphenyl-l-propanone (Table II, Entry M) ?a Kinetic enolization of O. 80 g (6.0 mmol) of propiophenone with 0.85 g (6.6 mmol) of diisopropylethylamine and 1.81 g (6.6 mmol) of di-~butylboryl triflate in 15 mL of ether at room tempera~ ture for 1 h was followed by aldol c0ndensation and hydrogen peroxide workup with 0.64 g (6.0 mmol) of benzaldehyde to yield 1.60 g (>100%) of a yellow oil. 1 No threo-aldol adduct, ~~1- was detected by H NMR of the unpurified product, vide infra. The product was chromatographed at medium pressure over silica gel (hexane:ethyl acetate, 9:1) to afford 1.12 g (78%) of erythro-aldol adduct, ! ~~, as a viscous oil: IR (CC1 , 4 %) 3605, 3520, 1670, 1662, 1211, 970, 698 cm -1 4 lH NMR (CC1 ) 0 7.95-7.75 (m' 2 ' aromatic), 7.55-7.0 (m' 4 8 ' aromatic), 5.05 (d, J = 3 Hz, 1 ' erythro-CH-OH), 3.53 (m, 1, -CO-CH-), 3.4 (s, 1, -0!:!_), 1.1 (d, 3, -CH 3 ). Authentic 6 threo-adduct gave rise to an additional signal at o 4.92 (d, J = 9 Hz, threo-C!:!_-OH). These spectra are identical with those reported in the literature 6 for this compound. §!X!~f9:I:iI:!:~~!YIE~YE~!~9~¥~:!:~~~~¥E~~P~~!~:~i~: dien-2-yl)-3-hydroxy-2-methyl-3-phenyl-1-propanone (Table II, Entry N)?b Kinetic enolization of 0.446 g (2.0 mmol) of l-(l-!-butyloxycarbonyl-l-aza-~yclo36 penta-2,4-dien-2-yl)-l-propanone with 0.310 g (2.4 mmol) of diisopropylethylamine and 0.603 g (2.2 mmol) of di-~-butylboryl triflate in 5 mL ether at -78°C for 45 min was followed by aldol condensation and MoOPH workup with 0.22 g (2.0 mmol) of benzaldehyde to yield 0.723 g (>100%) of a light yellow oil. No threo-aldol adduct 12T 1 was detected by H NMR of the unpurified product, vide infra. The product was chromatographed at medium pressure over silica gel (hexane, ethyl acetate) to give 0.47 g (70%) of erythroaldol adduct 12E as a colorless oil:. IR (CC1 4 ) 3500, 2980, 2940, 1750, 1700, 1650, 1440, 1410, 1370, 1310, 1150, -1 1 H NMR (CDC1 3 ) o 7.30 (broads, 5, phenyl), 7.28-7.15 (m, 1, pyrrole), 6.78-6.70 (m, 1, 945, 845, 695 cm ; pyrrole), 6.15-6.05 (m, 1, I 1, pyrrole), 5.19 (d, J I -CHCHOH), 3.64 (broads, 1, I = 4 Hz, -O!i), 3.40 (d of q, J = I 7 Hz, 4Hz, 1, CH 3 C!iCHOH), 1. 57 (s, 9, !_-butyl CH 3 ' s), I 1.13 (d, J = 7 Hz, 3, CH 3CH-). In the threo-aldol adduct 36 the signal for CH CHC!iOH .(carbinol center proton) 3 appears at o 4.90 (d, J = 8 Hz). These spectra are identical with those reported in the li terature 36 for this compound. Erythro- and threo-3-hydroxy-2-methyl-1-trimethyl~---~~-~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ~ i!Il::. l::.EI~E~~~12:~- £I~1?. !~ _I_I_,_ ~12!!:I _Ql • Kinetic enol i - zation of 0.13 g (1.0 mmol) of propionyltrimethyl~ silane with 0.16 g (1.2 mmol) of diisopropylethylarnine and 0.30 g (1.1 mmol) of di-n-butylboryl triflate in S mL of ether at -78°C for 30 min was followed by aldol condensation and MoOPH workup with 0.11 g (1.0 mmol) of benzaldehyde to yield 0.16 g (66%) of a yellow oil. The ratio of erythro:threo-aldol adducts, 12E:12~ in the unpurified product wa~ determined • I by 1 H NMR to be 19 : 81. The product was bulb-to-bulb distilled (150°C, 1 mm) to afford 0.12 g (53%) of a colorless oil: IR (neat) 3460, 3030, 2960, 1635, 1450, 1250, 843, 755, 699 cm -1 ; 1 H NMR (CDC1 3 ) o 7.31 (s, 5, aromatic), 5.03 (d, J (d, J = = 3 Hz, 0.23, erythro-CH-OH), 4.72 8 Hz, 0.77, threo-CH-OH), 3.31 (m, 1, -CO-C!:!_-), 2.8 (b, 1, -OH), 0.83 (two d, 3, -CH-CH 3 ), 0.19 [s, 9, -Si-(C!:!_ 3 ) 3 ]. Distillation resulted in a slight enrich- ment in the erythro-adduct. These spectra are identical with those reported in the literature 6 for this compound. Erythro- and threo-S-(1,l-dimethylethyl)-3-hydroxy2-methyl-3-phenylpropanethioate (Table II, Entry S). Kinetic enolization of 0.29 g (2.0 mmol) of S-tertbutyl propanethioate with 0.31 g (2.4 mmol) of diisopropylethylamine and 0.60 g (2.2 mmolJ of di-~~butylboryl triflate in 5 mL of ether at 0°C for 30 min was followed by aldol condensation and MoOPH workup with 0.21 g (2.0 rnmol) of benzaldehyde to yield 0.40 g (80%) of a yellow oil. The ratio of- erythro:threo-,-aldol adducts, !~~=!~I, in the unpurified product was determined by 1H NMR be 10:90. The product was bulb-to-bulb distilled (150°C, 0.5 mm) to afford 0.31 g (75%) of a colorless oil: IR ( n e at ) 3 4 5 0 , 3 0 3 0 , 29 6 0 , 1 6 7 5 , 14 5 0 , 1 3 6 5 , 9 6 0 , 7 0 0 cm - 1 1 H NMR (CDC1 ) 8 7.22 (s, 5, aromatic), 5.03 (d, J = 4 Hz, 3 0.10, erythro-C!:!_-OH), 4.74 (d, J = 8 Hz, 0.90, threoC!:!_-OH), 2.85 (m, 1, -CO-C!:!_-), 2.5 (b, 1, -0!:!_-), 1.48 [s, 9, -S-(C!:!_ ) ], 1.03 (two d, 3, -CH ). 3 3 3 Exact mass calcd. for c H20 o2s: 252.118. 14 252.119. Found: Erythro- and threo-S-(1,l-dimethylethyl-3-hydroxy-2- ---------------------------------------------------Kinetic enoli-----------------------------~-------- methylhexanethioate (Table rr, Entry U). zation of 0.29 g (2.0 mmol) of S-tert-butyl propanethioate with 0.31 g (2.4 mmol) of diisopropylethylamine and 0.60 g (2.2 mmol) of di-!!_-butylboryl triflate in 5 mL of ether at 0°C for 30 min was followed by aldol condensation and MoOPH workup with 0.17 g (2.4 mmol) of !!_-butyraldehyde to yield 0.31 g (70%) of a pale yellow oil. The ratio of erythro:threo-aldol adducts, 12E:12T, in the unpurified product was determined by 1H NMR to be 10:90. The product was bulb-to-bulb distilled (150°C,· 1 mm) to afford 0.29 g (67%) of a colorless oil: IR (neat) 3450, 2960, 1675, 1455, 1365, 960 cm- 1 ; 1 H NMR (CDC1 3 ) cS 4.8 (b, 1, -0!::!_), 3.89 (m, 0.10, erythro-C!::!_-OH), 3.64 (m, 0.90, threo-C!::!_-OH), 2.61 (m, 1, -CO-C!::!_-), 1.49 (s, 9, -S-(C!::!_3 ) 3 ), 1.27 to 0.75 (m, 10, aliphatics). Preparative gas-liquid chromatographic separation of a mixture of aldol products generated by lithium enolate condensation provided compounds for which assignments for the 1 H NMR spectra were made by a comparison of the carbinol protons: (m, J erythro 8 3.89 = 3 Hz) and three o 3.64 (m, J = 6Hz). The coupling constants were determined by an analysis of the signal of the proton on carbon 2. Exact mass calcd. for c10 H22 o2s: 218.133. 218.134. Found: Erythro- and threo-S-(l,1-dimethylethyl)-3-hydroxy- ~~~------------------------------------------------ 2,4-dimethylpentanethioate (Table II Entry V). Kinetic ~~~~~~~~~~~~~~~~~-~~~-~~~~~~~-~~~~~-~~-~~~~~~ enolization of 0.29 g (2.0 mmol) of S-tert~butyl propanethioate with 0.31 g (2.4 mmol) of diisopropylethylamine and 0.60 g (2.2 mmol) of di-~-butylboryl triflate in 5 mL of ether at 0°C for 30 min was followed by aldol condensation and MoOPH workup with 0.17 g (2.4 mmol) of isobutyaldehyde to yield 0.29 g (~6%} of a pale yellow oil. The ratio of erythro:threo-aldol adducts, l}E:!~T, in the unpurified product was determined by 1H NMR to be 9:91. The product was bulb-to-bulb distilled (150°C, 1 mm) to afford 0.26 g (63%) of a colorless oil: IR (neat) 3500, 2960, 1650, 1455, 1365, 960 cm- 1 ; 1 H NMR (CDC1 3 ) 8 3.51 (d of d, J = 3 Hz and 8 Hz, 0.09, erythro-C~-OH), 3.30 (t, J = 7 Hz, 0.91, threo-C!::!_-OH), 2.82 (s, 1, -0~), 2.69 (m, J = 7 Hz, -CO-CH-), 1.70 (m, J = 7 Hz, 1, -CH-(CH 3 ) ), 1.48 (s, 9, 2 -S-(C!:!_ 3 ) 3 ), 1.18 (d, 3,- -CH 3 ), 0 . 89 (two d, 6, -CH-(C!:! ) ). 3 3 Exact filass calcd. for c11 H22 o s: 218.134. Found: 2 218.133. Erythro- and threo-S-(1,l-dimethylethyl)-3-hydroxy- ~.t~: ~!~E:!~t!: ~ :)2~~ !~~~!~!~~ !~ _Q~~l?_!~JJ.1_1?_12,!~">.'.: _lf) • Kinetic enolization of 0.29 g (2.0 mmol) of S-tert~butyl propanethioate with 0.31 g (2.4 mmol) of diisopropylethylamine and 0.60 g (2.2 mmol) of di-~-butylboryl triflate in 5 mL of ether at 0°C for 30 min was followed by aldol condensa~ tion and MoOPH workup with 0.21 g (3.0 mmol) of methacrolein to yield 0.29 g (66%) of a yellow oil, The ratio of erythro:threo-aldol adducts, llf!J~T, in the unpurified product was determined by 1 H NMR to be 12:88. The product was bulb-to-bulb distilled (150°C, 1 mm) to afford 0,28 g (65%) of a pale yellow oil: IR (neat) 3460, 3080, 2960, 1675, 1455, 1365, 960, 900, 745 cm -1 ; (CDC1 ) o 4.92 (m, 2, olefins), 4.37 (d, J = 4 Hz, 0.12, 3 erythro-CH-OH), 4.14 (d, J = 9 Hz, 0.88, threo-CH-OH), 2.76 (m, 1, -CO-C!:i_-), 2.49 (s, 1, -OH), 1.73 (s, 3, =C-C!:i_ 3 ), 1.50 (s, 9, -S-(C!:i_ 3 ) 3 ), 1.13 (d, 3, -C!:i_ 3 ) . Exact mass calcd. for c11 H20 o2s: 216.118. Found: 216.119. Erythro ~ and threo-S-(l,1-dimethylethyl)-3-hydroxy- ----------------------------------------------~---- 2-.z ~.: Eli-rrt~!hr!: ~: h~~~!!~!hi-ge!~ _.Ciee! ~_r_r_,_f~! rr _Il • Kinetic enolization of 0.29 g (2.0 mmol) of S-tert-butyl propanetioate with 0.31 g (2.4 mmol) of diisopropylethylamine and 0.60 g (2.2 mmol) of di-~-butylboryl triflate in 5 mL of ether at 0°C for 30 min was followed by aldol condensation and MoOPH workup with 0.25 g (3.0 mmol) of tiglic aldehyde to yield 0.31 g (71%) of a yellow oil, The ratio of erythro:threo-aldol adducts, !3~=!3!, in the unpurified pro1 duct was determined by H NMR to be _18:82. The product was bulb-to-bulb distilled (150°C, 1 mm) to afford 0.28 g (68%) of a colorless oil: IR (neat) 3480, 1680, 1455, 1370, 960, 830, 740 cm- 1 ; 1 H NMR (CDC1 ) 8 5.47 (m, 1, 3 olefin), 5.03 (b, 1, -0!:!_), 4.19 (d, J = S Hz, 0.18, erythro-C~-OH), 4.10 (d, J = 9 Hz, 0.82, threo-C!:!_-OH), 2.72 (m, 1, -CO-CH-), 1.59 and 1.53 (d ands, 6, =CH-CH , 3 =C-C~ 3 ), 1.48 (s, 9, -S-(C!:!_3 ) 3 ), 1.03 (two d, 3, -C!:h)· Exact mass calcd. for c12 H22 o2s: 230.134. Found: 230.134. Threo-2-phenylhydroxymethyl-1-cyclohexanone (Table III, Entry F) ?a Kinetic enolization ~f 0.98 g (10 mmol) of cyclohexanone with 1.42 g (11 mmol) of diisopropylethylamine and 11 mmol of cyclopentylthexylboryl triflate (2c), generated in situ, in 20 mL of tetrahydrofuran at -78°C for 30 min was followed by aldol condensation and hydrogen peroxide workup with 1.06 g (10.0 mmol) of benzaldehyde to yield 1.92 g (94%) of a pale yellow oil. No erythro-aldol adduct, 11~, was detected by 1 H NMR of the unpurified product, vide infra. The product was chromatographed on 40 g of silica gel (hexane:ethyl acetate, 1:1) to afford 1.49 g (73%) of threo-aldol adduct, 14T, as a white crystalline --- solid: mp 73.5-76°C; 1129, 1043, 698 cm -1 • IR (CC1 4 ) 3540, 2943, 1697, 1450, 1H NMR (CDC1 ) 8 7.2 (s, 5, aromatic), 3 4.6 (d, J = 8 Hz, 1, threo-C!:!-OH), 3.6 (b, 1, -OH), 2.6. Authentic 1.0 (m, 9, cyclohexyl). 6 erythro-adduct gave rise to an additional signal at o 5. 31 (d, J 3 Hz, erythro-C!:!-OH). this comp~und are = The melting point and spectra of identical with those reported in the literature. 8 Erythro - and th reo-'3-hydroxy- 2-methyl - 3-phenylpropanoic acid (18,19a). To a stirred solution of 0.57 g (4.4 mmol) of diisopropylethylamine and 1.15 g (4.2 mmol) of di-~-butylboryl triflate in 15 mL of ether at 0°C under an argon atmosphere was added 0.15 g (2.0 mmol) of propanoic acid dropwise. A white precipitate appeared immediately. After 45 min the white slurry was cooled to -78°C and 0.21 g (2.0 mmol) of benzaldehyde was added. The mixture was stirred for 30 min at -78°C and 1 hat 0°C. The reaction mixture was then added to saturated aqueous sodium bicarbonate and ether. After separation of the layers the organic p~ase was extracted with additional saturated aqueous sodium bicarbonate. The combined aqueous solution was successively acidified to pH 2 with 6 ~ hydrochloric acid, saturated with sodium chloride, extracted twice with ether, and dried (Na so ). Concentration of the ether solution 2 4 in vacuo gave 0.31 g (87%) of clear oil: IR (neat) 3420, 2980, 1710, 1450, 1200, 1010, 700 cm -1 ; 1 H NMR (CDC1 3 ) o ..,99,.., 7. 33 (s, 5, aromatic), 5. 42 (s, 2, -OH and -C0 2 !:i), 5 . 16 (d, J = 4 Hz, 0.35, erythro-CH-OH), 4.73 (d, J = 9 Hz, 0.65, threo-C~-OH), 2.79 (m, 1, -CO-CH-), 1.10 and 0.98 (two d, 3, -c~ 3 ). The spectra of this compound are 6 identical with those reported in the literature. T~re~-3-hydroxy -3-phenyl-2-phenylmethoxypropanoic --- ""·~~ ~~~-~~~~-~~~~--~-·~~--·~~ ~~ -- --~ ~-~- - ~- ~~ ~ ~- ~ . . . . . .. . . . . . ~~!~ _!! ~~2- To a stirred solution of 0.32 g (2.4 mmol) of diisopropylethyJamine and 0.60 g (2 . 2 mmol) of di-nbutylboryl triflate in 5 mL of ether at 0°C under an ~rcrnn Rtmnsnhere was R~~e~ n.17 methox yethanoic acid dropwise. appeared immediately. ~ (l mmol) of ~henvl- A white precipitate After 1 h the white slurry was cooled to -78°C and 0.11 g (1.0 mmol) of benzaldehyde was added. The mixture was stirred for 30 min at -78°C and 1 hat 0°C. The reaction mixture was then added to saturated aqueous sodium bicarbonate and ether. After separation of the layers the organic phase was extracted with additional saturated aqueous sodium bicarbonate. The combined aqueous solution was successively acidified to pH 2 with 6 ~ hydrochloric acid, saturated with sodium chloride, extracted twice with ether, and dried (Na 2so 4 ). Concentration of the ether solution in vacuo gave 0.23 g (85%) of a viscous colorless oil: IR (neat) 3400, 3020, 1 H NMR 2860, 1730, 1495, 1455, 1100, 910, 735, 700 cm -l ; (_CDC1 3 ) o 7.27 (sand m, 10, aromatic), 6.77 (s, 2, -0!:!_ and -CO 2!:!_), 4.92 (d, J = 7 Hz, 1, threo-C!:!_-OH), 4.41 (AB q, J = 12 and 28 Hz, 2, -0-C!:!_ ~c H ), 4 . 03 (d, J = 2 6 5 7 Hz, 1, -C!:!_-C0 H). The stereochemistry of this product 2 was confirmed by dehydrative decarboxylation, vide infra. The product was characterized by conversion to a dicyclohexylammonium salt: mp 175-176°C after recrystallization from ethyl acetate. An a 1. (C H g NO ) : 28 3 4 C, H, N. (Z)-2-Phenylmethoxy-l-phenylethene (21b). A solution of 0.25 g (0.92 mmol) of threo-3-hydroxy-3-phenyl-2phenylmethoxypropanoic acid, vide supra, and 0.66 g (5.5 mmol) of dimethylformamide dimethylacetal in 10 mL of chloroform under a nitrogen atmosphere was stirred for 1 hat room temperature and was then heated at reflux for 7 h. The reaction mixture was concentrated in vacuo to afford an oil which was dissolved in hexane. The hexane solution was washed successively with water and brine, dried (Na so ), and concentrated in vacuo to yield 0.18 g 2 4 of a yellow oil. The product was bulb-to-bulb distilled (150°C, 0.1 mm) to afford 0.16 g (81%) of a colorless oil: IR (neat) 3030, 2940, 1645, 1487, 1445, 1365, 1090, 1 H NMR (CDC1 ) o 7.33 (sand m, 10, 775, 690 cm-l 3 aromatic), 6.22 (d, J = 7 Hz, 1, (Z},-CH=C!:!_-0-), 5.23 (d, J = 7 Hz, 1, (Z) -CH=CH~o-), 4. 92 (s,. 2, -0-C!:!_2-C6H5). Exact mass calcd. for 210.105. c15 H14 o, 210.104. Found1, .-102.,. References and Notes (1) Aspects of this work have been previously disclosed: (a) Evans, D. A. 15th Eurochem Conference on Stereo- chemistry, Burgenstock, Switzerland, May 5, 1979. Evans, D. A.; Nelson, J. V. J. Am. Chem. (2) (a) Experiment performed by Ernst Vogel. (b) Experi- Soc. Vogel, E.; (b) !~Z~, 101, 6120-6123. ment performed by Terry R. Taber. (3) For a review of early efforts in this area see : Nielson, A. T. ; Houlihan, w. J. Org. React. !~~~' Traxler, M. D. J. Am. Chem. Soc. !§_, 1- 4 38. (4) Zimmerman, H. E. ; 1957, 79, 1920-1923. ---- - (5) (a) Dubois, _J. E.; Fort, J. F. Tetrahedron l~Z~, 1§.., 1653-1663, 1665-1675 and references cited therein. (b) Dubois, J. E.; Fellman, P. Sci. 1972, 274, 1307-1309. -- ---- - - Fellman, P. C. R. Acad. (c) Dubois, J.E.; Tetrahedron Lett. 1975, 1225~1228. (6) Heathcock, C. H.; Pirrung, M. C.; Buse, C. T.; Sohn, J.E . ; Kleschick, W, A.; Lampe, J. J. Org. Chem. 1980, !.§_, 1066-1081, and citations to earlier work. (7) Fellmann, P.; Dubois, J . E. Tetrahedron 1978 , 34, ,-.103.,, 1349~1357. C8) House, H. 0.; CrUJnrine, D. S.; Olmstead, H. D. J. Am. Chem. Soc. (9) (a) Jeffrey, E. A.; Meisters, A.; (b) Maruoka, K.; !~Z~, ~' 3310-3324. Mole, T, !2Z4, Z!, 365~372, 373-384. J. Organomet. Chem. Yamamoto, H.; Teranishi, A. Y,; Hashimoto, S.; Nozaki, H. Kitagawa, Y.; l2ZZ, J. Am. Chem, Soc. 99, 7705-7707. (10) (a) Mukaiyama, T.; Inomata, K.; Chem. Soc. 1973, ~' 967-968. R. Muraki, M. J. Am. Cb) Fenzl, W.; Koster, Justus Liebigs Ann. Chem, 1975, 1322-1338. . Fenzl, W.; Koster, R.; Zimmerman, H. J. (c) Ibid. 1975, 2201-2210. (11) (a) Masamune, S~ ; D. W. Mori, S.; Tetrahedron Lett. 1979, 1665-1668. Hirama, M,; Masamune, S. (c) Van Horn, D. E.; 2229-2232. D.-L.; Van Horn, D.; Masamune, S, (12) Inoue, T.; (b) Ibid. 1979, 2225-2228. -- ---- Masamune, S. (d) Hirama, M.; Brooks, Ibid. !~~~' Garvey, D. S,; Lu, L. Ibid. 1979, 3937-3940. . . ---- Mukaiyama, T. Bull. Chem. Soc. Jpn. 1980, .?2_, 174-178. (13) (a) Tufariello, J. J,; P. 218. ~~~z, J, Am. Chem. Soc. D. J.; Wojtkowski, P. Cc) Hooz, J,; Lee, L. T. C.; Wojtkowski, ~' 6804,.6805, Tetrahedron Lett, Linke, S. Cb) Pasto, ~~Z~, 215- J, Am, Chem. Soc. 1968, ~, 5936.,-5937. M. M.; (d) Brown, H. C.; Rathke, M. W.; Rogic, Kabalka, G. W. Ibid. !~~~, ~ ' 818-820. (e) Inomata, K. ; Mukaiyama, T. Bull, Chem. Soc. JEn, 1973, ~ ' 1807- Muraki, M. ; 1810. (14) Mukaiyama, T. ; Inoue, T. Chem. Lett. !~Z~, 559-562. (15) Trofimenko, S. J. Am. Chem. Soc. (16) Pasto, D. J.; Wojtkowski, P. W. 1971, ~' 1790-1792. Negishi, E.; !~~~' 91, 2139-2140. J. O!g. Chem. For related studies see: Idacavage, M. J. Tetrahedron Lett, !~Z~, 845-848. (17) Ireland, R. E.; Mueller, R, H.; Willard, A. K. J. Am. Chem. Soc. 1976, ~' 2868-2877. For related studies on the enolization of 6 with lithium diisoMcGee, L. R. propylamide see: Evans, D, A.; Tetrahedron Lett. !g~Q, 0000-0000. (18) Experiments carried out by L. R. McGee. (19) Mukaiyama has noted that triethylamine is a suitable base, Ref. 12. (20) Bergbreiter, D. E.; 1272, 4145-4148. Newcomb, M. Jung, M. E.; R. R. ; Banville, J.; 4152. Davenport, K. G.; D.; Newcomb, M.; Tetrahedron Lett. Shaw, T. J.; Taymaz, K. Ibid. Eichenauer, H.; Bergbreiter; D. E. Fraser, !~Z~, 4149Enders, J, Am, Chem. Soc. 1979, 101, 5654~5659. (21) This conclusion is drawn from the observed stabilities of isomeric dioxolenium ions and protonated thioesters. J. Am. Chem. Soc. 1968, 90, Borch, R. F. ; 5303-5305. ---- Olah, G. A.; Ku, A. T. - J. Org. Chem. 1970, ~ ' 331-335. (22) House, H. 0.; H. D. Czuba, L. J.; Gall, M.; Olmstead, J. Org. Chem. 1969, 34, 2324-2336. (23) Experiments carried out by Dr. M. Wada. Analogous exchange reactions with dialkylbromoboranes were discovered by Dr. Wada. (24) The triflate reagents are ineffective in the formation of both ester and amide enolates. (25) (a) Schmitt, G.; Olbertz, B. !~Z~, 152, 271-279. L.; (26) Sajus, L. (b) Mimoun, M.; Negishi, E, 1972, ~ ' 3567-3572. (27) Ibid. Seree de Roch, Bull. Chim. Soc. Fr. 1969, 1481-1492. (a) Brown, H, C.; D. J. Organomet. Chem. J. Am. Chem. Soc. (b) Brown, H, C.; Pfaffenberger, !~~z, ~, 5475-5477. (a) Mulzer, J.; Segner, J.; Bruntrup, G. Tetrahedron Lett. 1977-, 4651-4654. (b) Mulzer, J.; Finke, J.; J. Am. Chem. Soc. 1979, 101, Zippel, M. Brilntrup, G.; 7723-7725, and references cited therein. (28) (a) Hara, S.; H. Taguchi, H.; Yamamoto, H.; Tetrahed~on Lett. 1975, 1545-1548. ~--- Nozaki, (b) Vogel, E. Ph.D. G. Dissertation, ETH Zurich, 1978, (c) Frtter, Helv. Chim. Acta 1979, ~' 2825-2828. (29) The analogous trans•fragmentations were also carried out with azodicarboxylate, Ph 3P; however, the yields in this reaction were inferior to the alternate method employed, Ref. 28. (30) More detailed studies on boron enediolate condensations are currently in progress and will be reported shortly. (31) Vedejs, E.; Engler, D. A.; Telschow, J. E. J. Org. Chem. 1978, 43, 188-196. (32) Watson, S. L.; Eastham, J. F. J. Organomet. Chem. !~~z, ~, 165-168. (33) Purchased from Aldrich Chemical Company. (34) Purchased from Ventron/Alfa Inorganics. (35) Bro¼~, H. C.; Subba Rao, B. C. J. Am. Chem. Soc. 1959, 81, 6423-6428. ---- - (36) Sacks, C. E. Ph.D. Thesis, California Institute of Technology, 1980, pp. 119-120. APPENDIX I A Brief Review of the Methods for the Generation of Boron Enolates In previous work, 1 we have demonstrated the utility of boron enolates for stereoselective aldol condensation. In that study we concluded that the geometry of the boron enolate could be completely translated into aldol stereochemistry . The ability to generate stereo-defined boron enolates is, therefore, extremely important. This appendix summarizes the literature methods for the generation of boron enolates with particular emphasis on the geometry of the enolates formed. The methods of generating boron enolates can be divided into two classes: those involving the indirect formation of the enolate by the insertion of an enolate precursor into the carbon-boron or heteroatom-boron bond of the organoborane and those involving the direct enolization of the substrate with a dialkylboron enolization reagent . The general applicability of the indirect methods is limited due to the required incorporation of a group from the organoborane into the enolate; however, for some applications this may not be a problem. Indirect Methods. In the late 1960's, methods were developed for the synthesis of alkylated ketones, esters, and amides by the reactions of trialkylboranes with sulfur 4 2 ylids, a-diazo-ketones, and esters; Scheme I. The intermediacy of a boron enolate was not recognized until 1970. 5 The geometry of the boron enolate in the sulfur Scheme I +- (CH3)2SCHCOR R = aryl, OEt, NEt 2 R 'B' 3 BrCH 2COR + !-BuOK R = alkyl, OCH 3 R1 OBR' >=<_ H ~drolysis R 'CHzCOR R N2CHCOR R = alkyl, OEt, H ylid reaction is known in only one case, eq 1, where it is "almost exclusively" (f)-enolate. There have been no studies on the geometry of the enolates generated from a-bromoketones and esters. The generation of boron enolates THF (1) from a-diazoketones and esters has been more extensively 5 investigated. Pasto and Wojtkowski have reported one case of the reaction generating a mixture of (~)- and (f)while Masamune 6 and co- enolates in a 3:1 ratio, eq 2; workers have reported that the reaction produced "nearly exclusively" the (E)-enolate for all three cases studied, eq 3. Masamune suggests that the lower selectivity observed by Pasto is due to trace contamination by moisture THF c6 H5 + R (n-C ~ ) BO 3 7 2 H (2) n-C H7 3 75:25 THF or to isomerization during distillation. The isomeriza- tion of (E)-enolates to (f)-enolates and aldol condensations of both (E)- and (f)-enolates were also discussed by 7 7 Masamune. Mukaiyama a and Daniewski b have also used this reaction to generate boron enolates for aldol condensation; however, these investigators did not determine the enolate geometries. 8 In 1967, Brown reported that trialkylboranes add to a,l?_~unsaturated ketones to afford, after hydrolysis of the intermediate boron enolate, a t-alkylated ketone (eq 4). Koster 9 and co.,.workers have studied the stereo- 0 + 'Y'R• R" - (4) chemistry of the enolates generated from triethylborane and a variety of enones; in Table I. Table I. ------- their results are summarized An analysis of these results does not reveal Stereochemistry of the Boron Enolates Generated by the Addition of Triethylboron to Enones Enolate Ratio Z:E R' R" H CH CH 3 H ::::55: 45 CH 3 CH 3 15:85 C6H5 H 100:0 C6H5 CH 3 3 0:100 50:50 any clear trends. KBster also reported several stereo- selective aldol condensations using these enolates. Mukaiyama 7 a has also used this reaction to generate boron enolates for aldol condensations; however, he did not determine the enolate ratio. The addition of a thioborinate to ketene generates a boron enolate 10 which can be trapped in situ by an aldehyde to afford an aldol adduct in good yield, eq 5. However, the boron enolate must be generated in the RSBR'z + CH =C=O 2 OH 0 RnCHO R"~SR (5) presence of the aldehyde to prevent condensation of the 11 has used methylketene enolate with ketene . Masamune in this reaction for a highly selective synthesis of erythro-aldol adducts, eq 6, presumably via an (~)-enolate. (6) Direct Methods. K5ster 12 has developed two reagents for direct enolization, one for ketones and one for aldehydes. Diethylboron pivalate 12 a has been used to enolize a number of ketones, eq 7 and Table II, and some of these reactions are quite stereoselective. In addition, (CzH5)3B (7) 0 R ><°'oB cc H ) 2 5 2 only a catalytic amount (1-10%) of the reagent is needed since the pivalic acid generated in the reaction reacts with triethylboron to regenerate the pivalate. Table II. -----~-- However, Stereochemistry of the Enolates Generated by the Reaction of Ketones and Diethylboron Pivalate R Enolate Ratio Z:E C2H5 ::::9 0: 10 i-C H 3 7 ::::go: 10 C6Hll >95:5 c6H5CHz 75:25 C6H5 100:0 ... 114.,. the long reaction times and high temperatures required by this reaction limit its utility. KBster has also prepared the boron enolates of aldehydes using 4-dialkylboryloxy-2-isopropyl-6-methylpyrimidines, eq 8 and 9, which are readily prepared as shown below, eq 8. (8) + R" (9) 1 R" Unfortunately, the enolates generated were mixtures of (£)and (f)-isomers. Koster has used the boron enolates generated from both of these methods for aldol condensations. The dialkylboryl triflate reagents, which have been 1 used extensively in this laboratory as well as by Masamune 11 , 14 for aldol condensation, were developed by 13 Mukaiyama and co-workers. These reagents enolize ketones under extremely mild conditions and are highly stereo15 selective in many cases. Sugasawa has reported stereoselective aldol condensations using boryl chlorides to generate . the boron enolates but these reagents are less reactive than boryl triflates. Although a considerable amount of work has been reported in this area, the problem of stereocontrolled boron enolate generation has not been completely solved. Further investigations will hopefully lead to a solution . --116..References and Notes (1) Evans, D. A.; Vogel, E.; Nelson, J. V. Chem. Soc. 1979, 101, 6120-6123. J. Am. Nelson, J. V. Ph.D. Thesis, California Institute of Technology, 1981, Chapter II. (2) Tufariello, J. J.; Lee, L. T. C.; Wojtkowski, P. J. Am. Chem. Soc. 1967, ~ ' 6804-6805. (3) Brown, H. C. ; Rogic, M. M. ; Rathke, M. ~-~~ G. w. H. C. ; w. ; J. Am. Chem. Soc. 1968, Q_Q_, 818-820. ~-:v-Rogic, M. M. ; Rathke, M. W. Kabalka, Brown, Ibid. !~~~' 90, 6218-6219. (4) Hooz, J. ; Linke, s. J. Am. Chem. Soc. 1968, Q_Q_, ':"'-'--':"'-' 5936-5937. Hooz, J. ; Linke, s. Ibid. 1968, Q_Q_, --':"'-'- 6891-6892. Hooz, J. ; Morrison, G. F. Can. J. Chem. 1970, 48, 868-870. -~-- - (5) Pasto, D. J.; Wojtkowski, P. W. Tetrahedron Lett. 1970, 215-218. (6) Masamune, S.; Mori, S.; Tetrahedron Lett. (7) (a) Mukaiyama, T.; Van Horn, D.; Brooks, D. W. !~Z~, 1665-1668. Inomata, K.; Chem. Soc. 1973, ~' 967-968~ Muraki, M. J. Am. (b) Daniewski, A. R. J. Org. Chem. 1975, .!Q_, 3135-3136. (8) Suzuki, A.; Brown, H. C.; Arase, A.; Matsumoto, H.; Rogic, M. M.; Itoh, M.; Rathke, M, W. J. Am. Chern. Soc. 1967, 89, 5708-5709. (9) Fenzl, w. ; Koster, R. ; Zimmerman, H. -J. Justus Liebigs Ann. Chem. 1975, 2201-2210. !""-'!"W- (10) Inornata, K. ; Muraki, M. ; Mukaiyama, T. Bull. Chern. Soc. Japan. 1973, 46, 1807-1810. ----:--(11) Hirarna, M.; Masamune, S. Tetrahedron Lett. 1979, 2225-2228. (12) (a) Fenzl, W.; Koster, R. Chern . . !~Z~, 1322.,.1338, Justus Liebigs Ann. (b) Penzl, W.; Kosfeld, H.; Koster, R. Ibid. 1976, 1370-1379. -(13) Mukaiyarna, T.; Inoue~ T. Chem. Lett. 1976, 559~--":""' 562~ Inoue, T.; Uchirnaru, T.; Mukaiyama, T. Ibid. 1977, 153-154. (14) Van Horn, D. E.; ---- 1979, 2229-2232. L. D.-L.; • Masamune, S. Tetrahedron Lett. Hirarna, M.; Garvey, D. S.; Masamune, S. Lu, Tetrahedron Lett. 1979, 3937-3940. (15) Sugasawa, T.; Toyoda, T. Tetrahedron Lett. 1979, 1423-1426. Sugasawa, T.; Toyoda, T.; Syn. Commun. !~Zg, ~' 515-528, 583-602. Sasakura, K. . . 118 ~ APPENDIX II IR and 1H NMR Spectral Catalog for Chapter I .,.119..,. OMe Page 27 11 neat . • - -":- ... ~- L..!..~ ; t ·~ ~ !;· • - •. . ' -- ----- - . I I • ' 750 I - ,...,' I 3/S i I 150 I ,, I '''' ,--,·,'l ' , I 600 I Ii + I I 1 0 I: - r-·· I:r... I r L~1-··· 1· .-+,.-+- t tNDOF &WEEP I I ,,o I i 1",U I I IS I "° I 30 I --T -1 . i I I I". ., 11> nt> i I -L-1 1-i~;-;···· , 4 !-lO I I ,.. .. I '""1 '. I I 'I I I - -i-·t '::::j I i ! ~:-- .. I tt ~ ~,· -~ I . ; .,, I 9 ~I 8 I· : ' · :·.:7 .·: •·- I ..... l -+._._.u....""-+-"""'-----' 1 - -~ 0 Page 28 HO ~Me 6a ,..._ neat :1 ,I I .i; ~ 1·' It !ill1,,1 I I I - ,. CDC1 3 STAHT OF SWHI-' 1b11 bl)O I I ' :J/t> JOO .! .'', ! I 1'0 ' ~,u 1:,v ! ; i -Ir - 1 .... 1·--- i- .. .I: I I ! I I I I I • I I . . I-· 1 ' I 6 .,..121 ~. Page 28 OMe 6b , I ·r I i I ., ,. 1· •.. I I 600 4~11 jo ;.,n, 1 0 !Kl I I I I l I Page 29 HO OMe ii 7a neat START Of SWHf' I I 900H, I I 1 0 ' I I nOO 37> )OU I I 150 4M ' I 750 I l "lU I . if •· ~ ' ; : I I . r-!-- i i i i ·! I ···! ~l •• • 1··• ···· ! ! : i I Ji '! 'i I 1 i i I I I i I ,,, ' -l..~-1 j. 10 Q u u Page 29 OMe 7b neat ' T" • Httt!+!ttHtt+Htt+Htt+lttitHJH_H • ' :1 I 1 1 } ) : : . ~ ~ HiH.,.+i!41!,1,,11'1!1;~+:1'1;1:~ :tl' I --:!~ p ' s.: - ,..,--noo 1 ---- 900Hz I ·r 160 ' I TSO I 'o00 J7S JOO I I I I 1· 0 ISO - I • • ! I I) I 10 I - - - END 4:,u I :.1!2!> ·,,,o ' .J""t"-:--,~ 1:10 I ,. F IWlEP T ~-~i a1 · rr, · •c,•}!1 •o + - i- ·- •• i---- -1 ·• l:/41 1,™M#ltttllllttll!Htt+H!l · J. ,·: r : , 1-1 : ~ ·1 I iI i t , : ~ . -- .. _._..__U.W.U.W.U.W.UWJ=cUWJ.W.C.W.C.W...U.UW.U.W.U.WU"""wm 1i11D1 IMO, l«IO ,_ 1111 -r - ~! .. ;~ ' 1!1i'1t'tt11tttt1~1lilHi 1 }:ntt•;f·:tj.:itt,:,'i+,,Htt+Htt+Htt+H+!tHtt+ll!H!l - .1·· ·11·> I " I 1 :;i; •:: Jf ,, ' i:' f. ::' -~j\!i :~: +: ST.ART OF SWHP I 1 ;'f+;fjlj;; i • r r· ·1 l i r. t · ; !!. Page 30 OMe 8t,c neat ~ -11 · ► START Of· SWH~ , : ·, ; 1 i 1,0 900ft, i I lb 4 50 i I .i!>O I I 120 : r.> JOO I I vOO 100 ,r- I : l11\I END OF SWEEP ,.,_,,-,., -,-_.. -r do I ,,I 'J;O I JO u, I ' i 1 ; i --.! I I t .,, i '/J . 1- ·-·- ·· - L :, II ! '' I I 1· . - , • . . ---, I 9 I & I · 1· ; , ,I·, I -125.,. Page 31 OMe 9t,c neat CDC1 3 STAIIT OF swe•• i • I I 900H1 750 I 450 Jr, I 1 0 1'0 I i I j I l LL. I •: ! I +--+--,-~-- - -•-•i I' I ! I I I I II ' I "' I i ! ··--r I ,Is 30 -,- ! • ·-+-··- r llll 1:lU 1· .1, I !,----,-- I T J~U I 1:;o 4 ' ,11 11011 I ; I END OF SWEI!~ II > I. II. 10 I 9 I 8 L 1 • -126,, Page 31 neat STARl 0 ► SWU.P . > ttiu hllti ' . ..., 3i:, Jt)1 1 , ... I \K.IOH.t ! 4SO I i 180 I ,-···, -· iI 1· I 150 ENO Uf, SWf[P I I 120 I I I I I ; __ ,, ,. i iI I 1- •-+- · ,_j . I ! ' 1 71 I : ~-L : i I I I -· -i I I I I · · -T--~ :· ! ·i ··i 10 Page 32 13 neat • START Of- SWU:., .. I I ,~o 1:WOH, I I I ••o 37!> I I ldO l !iO I , 1 ,, , I I' I I t>O O EHDOF IWUP ~r r · •: ! .jCJU I 1.lO I I I I f--i--- 1 I I I . i I j I ·,o ! 9 i ·4--- -1 I Page 33 14 neat uoo , - .. - ·· ~ ,. ·- CDC1 3 START OF SWHP • I! . EHO OF SWEEP I : ·1 I / Ml !:NlO Hz ' o Ol l I I • ~o ,,I I ' I I ISO J 7t> :11 HJ I ,~u I I 120 30 . . -1····---+ I . ,- ,·-1-·- . I I . I I I .-:/--A . - ----1 -7 · -! -· - -1 I :I I I ·r- 1-; ·I I I I i .; .... ·1 I 'i i ;I I 9 I 8 b -~: L _L . _ _..,L__j I 0 1/ I -129Page 35 18 OMe neat If .. ~I I , ' Hl 'i , ,:, . I. ';. ,I, •, ~;· 1t :!I' i]; ·-,_,_,..._ . CDC1 3 START Of SWHP • ,r ~~~:-, •••. I . . > £110 Of' SWIEP 900Hz I ·•fu .so 300 I I I 4' ,u no i I I f- i ·! I j I Ii ! I i-. -,- - · l ! I I I .. t . i I ..' . ' ! ' ' I 10 ..I 9 I. 7 I. 6 t, - - - .. - .. ,-,-,-,-,,- I I I 0 11 II It .• .,. 130-:- Page 36 OMe neat I) . :, 11,:. -r4-4-l-,.I- 'I :.. !• CDC1 I I ., ... -- 3 . ,, ► STAHT Ot- SWHV ' uOO I 300 4•,t1 END OF IWEEP •, . I I 150 ' J~ ., 1- , - :-r-i' ....-r-..-,...... i I ! 120 30 ..--,-- . I .!--+-' I I j I 10 8 .~-.::~.:~L·--'--'L---+---'--2 i: i . r 0 Page 37 OMe neat ', : , j , ,ij tr: .. ,1: ,1 , · I - - - I. - I ,.. i START OF SWHP tNO OF S.WEEP ! I ' 900Hz /50 I I 180 375 i 450 i ISO I 600 I jo I 0 i -I ' ~ I l- :r-·- • ····"': - · • T- . I . 1--- I ., i I ; I ·- · ... -•· 1 ·,o I 9 0 .,._13z.,._ Page 38 OMe 19 neat ·1 • '! rrf,j" . II -- j~ I i I i I I ! I I II CDC1 I I i 3 START OF SWUP • · 1> I / ",l} I :1/!> IHO l:"10 : oOO END Of SWEEP · ,,. l ~ I·: , r I lI :Jho I fI I •~o ! i .so i ·1 I iKlUIIJ i 120 ,I 30 I i •! •. I .•: 1· 11 · I• I I --r •· •· I i ! 1 ' +- t•l 10 ;_ 6 ... 133.,. Page 38 OMe 21 neat • " ,, I 1, 1, . ,I ....: I ~ !Ii i 1,1 ·, '.j; '! I ·' ' CDC1 3 START OF SWEEP , . -, . : .. ! 'I' '' I I I IIIO I I WO I~ r' I! ·i 4 ")1 1 i ~•:•:, ! I ,· o 1>0 I -· 1 \ ' - 40 I _,_ _.. ,i I i I l ' I --t i-~- I i 10 9 8 I· I I I ·····- ! , , . - r - .,,T : EIIOOFSWIEP r -:--t. .,- T"TT"TT ... I , ,I Jo J7S I I :1 ' I 1· I i 450 i r- ···• .I: 1', j1 !;ii 11 ► I IIOOHz UI II - - ·- - " I -- · •·· -·· - ;' I I I 1''! ~:: ,, Page 39 23a CHC1 3 STAHT 01- SWU:P I i I 1 0 : .., · :- ; I I 120 i 31!> 450 I ! t,00 7>0 ~OH, END OF SWEEP ! ' ', ' I JOO I 150 I · ·-T· · I 11 _.J...-_ :._...._,;.;.....+---------..,.., , - I 10 9 I. 8 'I .....J~- ___ .........i..., 6 0 ' Page 40 15a neat , I 'I ' I I) T Ill" ~ .,. ' I I 1J If ' ' •, • .• CDC1 3 =...,.~ I ·- r ..,. -,-,- I START OF SWEEP • ' 900H1 1 I 150 I I 180 l 7S • I I 150 ◄ 50 ' ·, ' 600 I 11- ► I • ·r I .I' ,Jo ), 300 I I 0 I , . .·---1· -+- ( Ii ; • +· I • • ... j ···- •• - I I ! 30 ,_i • "' .:,i • r· ·7-+ I ' iI •' !' i I' I : I( .. :::'. :. !'A°, , • 7 .J., .',J "'·' '. ~r __ j _ m _ . - 10 •• . -. =~::.:l· . J. r·i : __ ;___ .. _: __; _ 8 7 6 "• :t IS • APPENDIX III IR and 1 H NMR Spectral Catalog for Chapter II Page 83 Ph Table II, Entry A L... I - : _j START OF SWt.tJt ,. . I , 1 I • 11 • . 11 n 1 ,so . 90011, + i 4/,o I 1 150 r11. 1 ,11 r 1 : • • , 11 1·1 1 1 1 . Jo ! ; I ' • 300 • I 1 0 i I I I I , ·r·-- -+·-f--· i -·r·; '" i. ! I ·r ··· I i ;i I t; I I~. - ··rI - •' i I I , I ! H j i i r - ·t I I I, I I ;I ... i 1I ' I I I ' ! 1 -:::,-"""'r,.. --1-·- - ·, · ' ' 'I' • I. ill ! , ,, ·, ,,, 2 - • ....,/ I"' - ~~ dK.-.w..1..J •.01...-.~...L // ... 13s.., Page 84 Table II, Entry C neat START OF SWEEP :r-: - ·:' I , I IIOOHr I I I .. 50 I I I 0 I ;_· ,-,-- I 7i° [ T : I I ISO I I 600 I 300 I 1 0 --, ! ,.-- ' I! -- ,- ····i-·- +--·•-· ...._ i I ~ ' -- --t-- i I : r1. , · 1,1 10 i- _: I 9 b 6 : ----_fr-A _r_Ll __i ______, -.-·. .--• 3 2 1 . i __j_J .. 139 ... Page 85 Table II, Entry D neat . I ' ' ' :' I I -r -~ 1- !-'-!-;;!·-"'....i:; -+_-'1'11 : !11!14-·-+-+--+-+--1-lJL!t'-l~J.;..#;j --r·-· . -T T .. ····1 . - - -·--··· . I -00 1,UO START OF SWEEP ''I , I g()()Hz 1>0 I I t .I I I IO I 31) 450 I ' ' + 600 1)0 1.00 . r : ·:: •• • I l ~~-7"• 1 ,. ...., 300 300 I ' -- 1,00 1J0 I ' '' II Ji 1 ' I· 1!· I . ' i 1 !, II ~T I ····· ··! • " ··· 1 ·· I !- I • I I ' ½:!' j I "- ; 'j I I I !. 1. ·1 ' i . L --- l i , 1··· I j ··-.,....,,.....,-t- I i I ! i ••• i 1 I I I I I I I I ' i i ·,o 1•·. :· 'jo 1 7~ ·I I 30 I I 1100 I ._ I QW r: I 1· rn, -;I .-·•' 1·· i- ·1,· ~t+1- -i~•I • I ,_ I. 6 -·_' i. _·, ····· • : 1 Page 86 Table II, Entry E neat " klO , , ,. WAYllfNC ; III 1•• I •• · ,- -~ ,- ·u1•:; •~ : '. " ' ' ·:· . • ' '! I ...; " 11 " I l !I I •• l1 ••I - I I ·••• START OF SWEEP - 1000 MOO llfXI >-11 ➔ I I I 600 900H1 I ! 1 0 l()nO 1,00 I -~ . l«IO , 1:1110 It. ! ... :;.. \JOO UOO I 300 I 150 I 60 ' I 150 ,,I ,. I I I 30 rr l Ii- t - 'f1 I • I, I I I I I' --H-- · I • I i I, f-'t I i ! r--i- If 1 iol 10 I. 9 - ... . , I ,·,· I >25 I 90 I 0 I i IIOI 450 I 300 450 -T T _...................... ' .L-. , .~. 0~ 1 Page 87 Table II, Entry F neat ,, J . * ·· , · ,r T WA'llllllt, 111 ••" I I ' ' , -, I ' . ,. . . . -· •. i: " . 1.. ,, _, . -·- -· -- -- ~ . r i I I I ' r·- --- IMI W'II .w•vt ..... u• r I MIO ra.-t _!!_ - 1.00 t• - END 300 1!>0 I ), I 60 I ISO i i , - --,- F SWEEP ,-: TT r r I I I - j I ' I -I I I . r-,-+----+--+-- •-:-- -!-· ·1 i •• --Ll ! i I i I ~--r- I Ill ·,o r: 9 ~t : "'~ ---~ 1 0 - 142.,. Page 88 Table II, Entry H • ~ ~;: •• \ ·1 ' , 1 1ii;1, 'T ' I '#"Vlllll(jlll 1,M ·:- ' 1 , - - :--- - · • • • "r · ;-... T .. -· ...... . J' .. 10 " ' i''" ,. I rn . . -~.. - goo --- :. • ) ,,~• ---:,:~ .. , i ·;,·I·· I I: :~:-~-: ..,.. ~ .. -r - ··1. -- --l - --- ---r -- -·-- - -·r ., ,. ___ I,_ _... jI r START OF SWEEP ..... -rT""l'·r r r ,..., . r, r r 11· r r 1·1 1 + T' Jo ; ··; ; '. 1· jH• I • I l ·r i , o I i 31° ! 1 0 ! i ! ·- ,- .. -,--7 ' I I I ---·t-· r .. , I I ! --i- i r IJ J. ... , ;-·· -r · · I -r I I 8 6 I. .,.; 0000 - .... _J - .. - Page 88 Ph Table II, Entry J CCI _!' 5% I I••· ' I ' ' , -, I I !. i i 1 " 'I ''I I ' l•·· l ' 1' I I J I. . . i ; I I r I ."· l I ! I I • I 11--- I I ltoO • •• t,m lt(ICI 1,00 wav-..---• rw-t •• 1· IJOCI I 1)00 ··1 •• 900H, : ! <SO -r ,-,' ' I i I ! i I ····•,.-- ···1·-· I i . •• " ! \ · i- ;• I !· !i :} ,;:. ~ ':='· .:: I 1-;(ol 10 1· I I . 8 I . 7 I. • '. c_:r, J u I I I i .. . I . -1 ··11 1 L__ .... !L~ ·~ 2 I IOOOtoOaJ)l'ODQ STAHT Ot- SWEE!' I i I 0 .J -i··-t 1. IL :L, I . .... l«IIO ; I I... . . 10IIO i I - -T ' I •• I. I 0 Page 89 OH Ph Table II, Entry L CC1 4 , 5% " , llfllAVUlfll 1111,M ' ' ' 1 I••; ! , I I r . I 1 1 tr . I I .. I i ~t ~ •• • lt-"tt--t-"111'11 -·---- r --~-- "i - i - - , -- ~ ... -r · •----- --i -~ --=~ J~ J1'GD _..,., 1,00 WA""""""'NI CM-t l,00 I- tJ10 IIOO START OF SWtEP :·· 1 - ... - ....... END OF IWHP , :-- 1 ·1 . r t r,- ~ 900Hl I •5o I I 0 I ~---i-- 1 150 T : •! ·-· .,I .. - !r· .I I i 1,1 I 10 ·.,' ..! 8 . '' ~.ZS 1 . . 1. 6 L . , . - _'If I • ' -,i-..J I -.1,12 :l,,'1 .I 2 Page 90 O Ph OH Y Ph Table II, Entry M I .. I I I . I --1 . . .. . -- ·- - - - STAHT Of ~WLI J> i I I 1~,o 900H1 I I 1 0 "I . I I ,\~() 3()0 77~, I 1>0 I •~o · - - -L-.L- - JOO LNl1 f)I SWEEP I I 300 l ',f) I I ; i._ . ,ao f, 0\) I ii!, ,50 -- 150 I i 60 Q(J J I) I - -,' I ,- -+- i ! .i f- 1 "i i I i- --l~--i~ ·--..,__ _,~ i - I --,: ~a 8 ·1 I ; ~:,__J__-~ ·-'- i- I i ! tl JJ i I • '---· __ _:::;:J.:~~~..:... I,_~ ·-·_ - ;:___ ___ u........_, L..•.w ... 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