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Stereoselection via anionic intermediates: Studies of the Haller-Bauer cleavage and the anionic oxy-Cope rearrangement
Maynard, George Daniel, Ph.D.
The Ohio State University, 1991
UMI 300 N. Zeeb Rd. Ann Aibor, MI 48106 NOTE TO USERS
THE ORIGINAL DOCUMENT RECEIVED BY U.M.I. CONTAINED PAGES WITH POOR PRINT. PAGES WERE FILMED AS RECEIVED.
THIS REPRODUCTION IS THE BEST AVAILABLE COPY. STEREOSELECTION VIA ANIONIC INTERMEDIATES: STUDIES OF THE HALLER-BAUER CLEAVAGE AND THE ANIONIC OXY-COPE REARRANGEMENT
DISSERTATION
Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University
by
George D. Maynard, B.S.
****
The Ohio State University 1991
Dissertation Committee: Approved by Prof. Leo A. Paquette Prof. Anthony W. Czarnik Prof. Harold Shechter
Advisoi Department of Chemistry To my Mother
ii ACKNOWLEDGMENTS
I would like to express my appreciation to Professor
Leo A. Paquette for his guidance, understanding, and
constant support during my graduate studies. His enthusiasm
for chemistry and his productivity have had an especially positive effect on my developement as a chemist.
I am also deeply indebted to fellow members of the
Paquette group, past and present, for their chemical
insights and valuable assistance. My association with
Christophe Philippo, Ho Jung Kang, and John Gilday proved especially fruitful. Dirk Friedrich's assistance with
NMR-structure correlations was critical and is greatly appreciated. I am particularly grateful to Professor
Hans-Georg Gilde for his guidance during my undergraduate studies at Marietta College. VITA
August 8 , 1962...... Born-West Union, Ohio
1980...... Valedictorian, West Union High School
1984...... B.S., summa cum laude, Departmental Honors, Phi Beta Kappa, Marietta College, Marietta, OH
1984-1986...... Chemist, Biomedical Products Department, E. I. Du Pont de Nemours & Co., Inc.
1986-198 7 ...... Graduate Research Fellow
1987-198 8 ...... Graduate Research Associate
1988-198 9 ...... National Need Fellow
1989-199 0 ...... ACS Organic Division Fellow
FIELD OF STUDY
MAJOR FIELD: Chemistry
Studies in Organic Chemistry TABLE OF CONTENTS
DEDICATION...... ii
ACKNOWLEDGEMENTS...... iii
VITA ...... iv
LIST OF TABLES...... vii
LIST OF FIGURES...... viii
LIST OF SCHEMES...... ix
CHAPTER PAGE
I. CARBON-CARBON BOND CLEAVAGE WITH RETENTION OF CONFIGURATION VIA THE HALLER-BAUER REACTION A. Introduction...... 1 1. Background Information...... 1 2. Diastereomeric Retention of Configuration...... 4 B. Preparation of Starting Materials...... 6 1. 3-Methylcyclopentanes...... 6 2. 4-tert-Butylcyclohexanes...... 8 3. 2-Methylcyclopentanes...... 9 C. Haller-Bauer Cleavage Reactions...... — 10 1. 3-Methylcyclopentanes...... 10 2. 4-tert-Butylcyclohexanes...... 13 3. 3 -Methylcyclopentanes...... 17 D. Summary...... 18 Experimental...... 20 References...... 47
II. MECHANISTIC INVESTIGATION OF THE HALLER-BAUER REACTION AND THE CRAM CLEAVAGE A. Introduction...... 50 1. Overview of the Mechanistic Investigation...... :.... 50 2. Historical Backdrop...... 52
v B. Substrate Preparation...... 56 1. Cycloalkylphenyl Ketones...... 56 2. 2-Oxa-4-pentenyl Derivatives...... 57 C. Haller-Bauer Cleavages...... 58 1. a-Cyclopropyl Ketone...... 58 2. a-Cyclobutyl Ketone...... 61 3. 2-Oxa-4-pentenyl Derivative...... 62 D. Cram Fragmentation Studies...... 63 1. p-Cyclopropyl Alcohol...... 63 2. p-Cyclobutyl Alcohol...... 65 3. p-2-Oxa-4-pentenyl Alcohol...... 6 6 E. Anionic Decarboxylations...... 67 F. Discussion...... 6 8 G. Summary...... 74 Experimental...... 76 References...... 110
III. STEREOSELECTION VIA THE ANIONIC OXY-COPE REACTION A. Introduction...... 113 1. Overview of the Anionic Oxy-Cope Reaction...... 113 2. Strategy for the Present Oxy-Cope Study...... 119 B. Synthesis of Oxy-Cope Precursors...... 120 1. (E) and (Z)-1,5-Heptadien-3-ols...... 120 2. tert-Butylcyclohexene Derivatives...... 123 3. Norbornene Derivatives...... 127 4. Camphene Derivatives...... 130 C. Anionic Oxy-Cope Rearrangements...... 132 1. Acyclic Derivatives...... 132 2. tert-Butylcyclohexenes...... 140 3. Norbornene Derivatives...... 144 4. Camphene Derivatives...... 147 D. Conclusions...... 150 Experimental...... 152 References...... 194 APPENDICES A. XH NMR Spectra for Chapter 1 ...... 199 B. 1H NMR Spectra for Chapter II ...... 222 C. 1H NMR Spectra for Chapter III...... 263 D. 19F NMR Resonances for Mosher Esters...... 301 E. X-ray Crystal Structures...... 303 F. Sample Calculation of Oxyanion Orientation from the OpticalPurity...... 310 G. Molecular Mechanics Calculations...... 312
vii LIST OF TABLES
TABLE PAGE
1. Haller-Bauer Cleavage of 1 and 2 ...... 12
2. Haller-Bauer Cleavage of 3 and 4 ...... 14
3. Haller-Bauer Cleavages of 23a...... 60
4. Haller-Bauer Cleavages of 23b...... 62
5. Haller-Bauer Cleavage of p-Allylether Analogue 63
6 . Cram Cleavages of 24a...... 65
7. Cram Cleavages of 24b...... 6 6
8 . Cram Cleavages of 30...... 67
9. Product Stability Studies...... 108
viii LIST OF FIGURES
FIGURE PAGE
1. Cyclic Trimethylsilyl Substituted Derivatives...... 5
2. 1 3C Shifts; Axial vs Equatorial...... 16
3. Models for Carbanion Stabilization by Si ...... 19
4. Diagnostic Proton Shifts at 300 MHz in CDC13...... 57
5. Oxy-Cope Substrates Selected for this Study...... 119
6 . MM Calculations for 10 and 11...... 138
7. Lee's Proposed Orbital Interpretation...... 139
8 . Ireland's Claisen Study...... 142
9. Possible Reaction Pathways for 12 and 13...... 144
10. Possible Reaction Pathways for 14 and 15...... 147
11. Possible Reaction Pathways for 16 and 17...... 149 LIST OF SCHEMES
SCHEME PAGE
1. Pathways for the Haller-Bauer Cleavage...... 2
2. Walborsky' s Investigations...... 2
3. Optically Active Substrates...... 3
4. Mechanism for Retention Pathway...... 4
5. Synthesis of 3-Methylcyclopentanes...... 7
6 . Preparation of tert-Butylcyclohexanes...... 8
7. Preparation of 2-Methylcyclopentane 6 ...... 10
8 . Attempted Haller-Bauer Cleavage of 6 ...... 17
9. C-C Bond Cleavage Reactions...... 51
10. The Stability of p-Carbon-Oxygen Bonds in
Radical Processes...... 54
11. p-Elimination of Oxygen from Carbanionic
Intermediates...... 55
12. Elimination in p-Methylstyrenes...... 55
13. Preparation of a-Cycloalkyl Derivatives...... 56
14. Preparation of 2-Oxa-4-pentenyl Analogues...... 58
15. Haller-Bauer Reaction of a-Cyclopropylphenyl
Ketone...... 59
x 16. Haller-Bauer Reaction of a-Cyclobutylphenyl
Ketone...... 61
17. Haller-Bauer Cleavage of p-Allylether Analogue....63
18. Cram Cleavage of the Cyclopropyl Derivative...... 64
19. Cram Cleavage of the Cyclobutyl Derivative...... 6 6
20. Cram Cleavage of the 2-Oxa-4-pentenyl Analogue....67
21. Pathways for the Cram Cleavage...... 70
22. Mechanisms for Radical Production...... 72
23. Alternate Mechanisms for 3-Elimination...... 74
24. Rearrangements with an Axial Oxyanion...... 114
25. Rearrangements with an Equatorial Oxyanion...... 115
26. Le Noble's Study of Facial Selectivity...... 116
27. Nakai's Oxy-Cope Study...... 118
28. Preparation of (3R,5E)-1,5-Heptadien-3-ol...... 121
29. Preparation of (3R,5Z)-1,5-Heptadien-3-ol...... 122
30. Preparation of tert-Butylcyclohexene Derivatives.124
31. Bromoetherification Reaction...... 126
32. Bromoether Reduction...... 127
33. Synthesis of Norbornene Derivatives...... 129
34. Synthesis of Camphene Derivatives...... 131
35. Anionic Oxy-Cope Rearrangement of 10 and 11...... 134
36. Preparation of (S) -4-Methyl-5-hexenal...... 135
xi 37. Oxyanion Orientation in Acyclic Derivatives...... 137
38. Oxy-Cope Rearrangement of tert-Butylcyclohexenes.141
39. Oxy-Cope Rearrangement of Norbornenes...... 145
40. Oxy-Cope Rearrangement of Camphene Derivatives...148
xii CHAPTER I
CARBON-CARBON BOND CLEAVAGE WITH RETENTION OF CONFIGURATION
VIA THE HALLER-BAUER REACTION
A. INTRODUCTION
1. Background Information
The Haller-Bauer reaction 1 involves the base-promoted fragmentation of non-enolizable ketones to give a carboxylic acid derivative and a product in which the carbonyl group has been replaced with a proton. In most cases, a phenyl ketone is used as the starting material and sodium amide is the base. Phenyl ketones which do not have a suitably positioned anion stabilizing group at Ca give as products the corresponding quaternary amide and benzene. With an anion stabilizing substituent such as a phenyl2, cyclopropyl3, or silyl 4 attached a to the carbonyl the cleavage proceeds to give exclusively a benzoic acid derivative and the tertiary alkane (Scheme 1).
Because organic chemists are most usually interested in introducing functionality into molecules rather than removing it, the Haller-Bauer reaction originally gained
1 2 prominence as a method of synthesizing amides heavily substituted at carbon. Interest was renewed when Walborsky demonstrated that the cyclopropyl stabilized process proceeds with retention of configuration (Scheme 2)3b,d,h,i.
Unfortunately, since anionic centers on three-membered rings are known to be configurationally stable5, the scope of the retention pathway remained unclear.
Scheme 1: Pathways for the Haller-Bauer Cleavage.
o o NaNH2
R groups are not good anion stabilizers
O NaNH2
Ri is an anion stabilizer
Scheme 2: Walborsky's Investigations
o O NaNH; +
X - CH3, Cl, F, OCH3 Retention of Configuration
Subsequent investigations by Paquette with optically active acyclic and cyclic phenyl and trimethylsilyl 3
substituted derivatives revealed that the retention pathway
is entirely general . 2 d • 4 * 6 Thus, a method evolved for achieving optical purity by use of a carboxylic acid
function, and then proceeding to the corresponding optically active decarboxylated derivative via the Haller-Bauer cleavage (Scheme 3). Because of recent interest in optically active C-centered organosilanes 7 as useful
intermediates 8 and as important mechanistic probes9, a significant proportion of the recent investigations centered upon these derivatives.
Scheme 3: Optically Active Substrates.
O O O II 1.COCI2 II 1-LDA y
Ho A < R 2.R-0H « 2 Mel— R * O ^ X Ph Ph Ma 3. Separation Ph^'Me H R
R* - chiral auxiliary
o
Ph ;•••<• Me Ph
The mechanism presumed to operate during retention of configuration when an amide base is employed is shown in
Scheme 4. The cleavage proceeds to give a carbanion that is coordinated within the solvent shell to counterion and departing benzamide in such a fashion as to allow -proton delivery from benzamide with retention of configuration. 4
Scheme 4: Mechanism for Retention Pathway
NH -C L ..NH2 MNH2 R^Ph *r^ph RS R1 is an anon stabilizer
1 H M+ HN Ph
Despite the success of the process with simple optically active derivatives, serious questions remained regarding its use in preparing derivatives with preservation of various diastereomeric relationships. Specifically, it was observed that the phenyl stabilized cleavage can proceed with undesirable levels of configurational inversion when the system is burdened with heightened steric interactions . 10
2. Diastereomeric Retention of Configuration.
The study of Haller-Bauer methodology encompassed in this dissertation focused on investigating the process as a means of preparing diastereomerically pure organosilanes.
Specifically, we were interested in the course of those reactions having a steric bias present that was expected to favor the formation of one product over another. To this end, the derivatives shown in Figure 1 were selected for
investigation.
(CH3)3Si
(CH3)3Si
Si(CH3)3 (CH3)3C (CH3)3C Si(CH3)3
O CH:CH3 CH.
Ph
(CH3)3SiLV.Si V- Ph 5
Figure Is Cyclic Trimethyisilyl Substituted Derivatives.
In Figure 1, steric interactions increase in proceeding from the 3-raethylcyclopentane derivatives 1 and 2 to the
4-tert-butylcyclohexanes 3 and 4 and reach a maximum in the
2-methylcyclopentane derivatives 5 and 6 . This increasing steric interaction at the newly created diastereomeric center was expected to exert multiple influences on the reaction. First of all, increased steric congestion near the already sterically hindered carbonyl should retard nucleophilic addition and therefore slow reaction. 6
Secondly, those steric interactions present in each of the
derivatives were expected to destabilize coordination of
counterion and departing benzamide in the way described in the previous section (Scheme 4). Because of prevailing 1,3 diaxial interactions, this effect was anticipated to be
especially pronounced in 3. Finally, a thermodynamic preference for formation of trans products exists in each
instance.
B. PREPARATION OF STARTING MATERIALS
1. 3-Methvlcvclopentanes.
Because of the propensity of a-trimethysilyl carbonyl derivatives to undergo various undesired processes such as migration of silicon to oxygen 11 and desilylation, careful selection of reagents and conditions was required. After considerable investigation, the route outlined in Scheme 5 was found to be the most efficient and reliable.
Two-step spiroalkylation of tert-butyl (trimethyisilyl) acetate 12 (7) with 2-methyl-1,4-diiodobutane 1 3 (8 ) in the presence of lithium diisopropylamide provided 9 as a mixture of diastereomers. Reduction with diisobutylaluminum hydride made available the chromatographically separable alcohols 1 0 and 11. Appropriate distinction between the diastereomers was achieved by means of nuclear Overhauser studies.
Whereas 11 is characterized by two key NOE effects, 7
CH 3/Si(CH 3 )3 (2.4%) and methine CH/CH2OH (2.7%), 10 gives evidence of nonbonded steric interaction only between its methine CH and Si(CH 3 ) 3 (2.7%). Evidently, the distance between the CH 3 and the CH2OH groups in the latter falls outside the range capable of giving rise to a detectable effect despite their cis orientation.
Scheme 5: Synthesis of 3-Methylcyclopentanes.
CH, /-BuOOC t- BuOOC,^— ^ > * LDA Dibal-H Me3Si (CH3)3Si
CH. CH, HOCH. separated (CH3)3S i v ^ - Y ^ H by HPLC h o c h / V — —■*
10 1. AgN03, Celite 11 2. PhU, Et20 3. CrQ3*py2 c h 3 (CH3)3S i ^ ^ - ^ H
O o
Subsequently each alcohol was oxidized using Fetizon's reagent 14 to give the corresponding aldehydes, which were directly reacted with phenyllithium and oxidized under
Collins conditions 15 to give ketones 1 and 2. 8
2. 4-tert-Butvlcvclohexanes.
Spiroalkylation of tert-butyl (trimethyisilyl)acetate with diiodide 1 2 as previously described gave a good yield of ester 13 as an isomeric mixture which could be partially separated into its component isomers by chromatography.
Subsequent reduction of these isomerically enriched samples to the alcohols with diisobutylaluminum hydride permitted separation of 14 and 15 by recycling on a Prep 500 HPLC.
Whereas the carbinol protons of the axial CH2OH isomer (the trans series) appear at 3.50 ppm, those of the equatorial stereoisomer are considerably more shielded (3.17 ppm), in line with a well-established trend . 16
Scheme 6 : Preparation of tert-Butylcyclohexanes.
f-BuOOC Si(CH3)3 LDA (CH3)3C > * THF coor-Bu Me3Si 7 12 13
CH2OH . . I *= separated Si(CH3)3 Dibal-H (CH3)3C by HPLC (CH3)3C Si(CH3)3 CH2OH 14 15
1. Cr03-py2 2. PhLi, Et20 3. Cr03*py2
Ph Si(CH3)3 (CH3)3C Ph (CH3)3C ^ / ^V ^ { Si(CH3)3 4 O 9
The alcohols 14 and 15 were then separately elaborated
as shown in Scheme 6 . In this instance, Fetizon's reagent
was not reactive enough to effect oxidation to the aldehyde
of either isomer. Although it was slightly less efficient
than is usually the case with Fetizon's reagent, Collins
oxidation provided the desired aldehydes in good yield.
Subsequent treatment with phenyllithium followed by
immediate oxidation with Collins reagent gave isomerically
pure samples of ketones 3 and 4.
3. 2-Methylcvc1opentanes.
The considerable steric interaction present in the
2 -substituted derivatives was reflected by the high level of diastereoselection observed in the spiroalkylation reaction.
Specifically, treatment of methyl (trimethyisilyl)acetate with 1 ,4-diiodopentane (16) in the presence of lithium diisopropylamide gave exclusively 17. Ester 17 was elaborated as previously described to give the desired phenyl ketone 6. Due to the stereochemical integrity of the spiroalkylation product 17, extensive chromatography was avoided in this instance.
The cis diastereomer was also sought. In the hopes that a differing carbanion intermediate might change the product ratio, (trimethyisilyl)acetonitrile was spiroalkylated. Once again, the trans product predominated
(45:1). Use of tert-butyl (trimethyisilyl)acetate also 10
failed to provide synthetically useful quantities of the desired cis product. Eventually, because of results
obtained in the Haller-Bauer cleavage of 5, synthetic
efforts to obtain 6 were abandoned.
Scheme 7: Preparation of 2-Methylcyclopentane 6 ,
CH3 c h 3o 2c LDA CH; * > ° 2° X j D Me3Si (CH3)3Si 16 1 7
OCH;OCH3 1. Dibal-H 2. CrC>3*py2 Ph 3. PhLi, Et20 (CH3)3Si-V.Ri-Sda V* 4. Cr03*py2
C. HALLER-BAUER CLEAVAGE REACTIONS
1. 3-Methvlcvclopentanes.
Although the Haller-Bauer reaction can be efficiently carried out using oxygen bases such as potassium
tert-butoxide as well as the traditional amide bases, the sensitivity of silyl funtionality precludes the use of oxygen bases in this instance. Additionally, the low reactivity of lithium amide resulted in extended reaction times and low overall conversion to products. Thus, the reaction conditions employed for the cleavage of trimethyisilyl substituted derivatives are limited to the 11 use of reactive amide bases such as sodium amide and potassium amide.
Due to the volatility of the resulting organosilane products, isolation provided some technical difficulties.
The most efficient means of obtaining solvent-free material from the milligram scale reactions involved concentration at atmospheric pressure followed by separation of the organosilane products by preparative gas chromatography.
Thus, although the cleavage reactions proceed cleanly with high GC yields, isolated yields range from 35 to 60%.
Isolated yields are enhanced for the Haller-Bauer cleavage when products of low volatility result.
The results obtained from the cleavage of 1 and 2 are summarized in Table 1. With NaNH 2, the cleavage of 1 was complete in 2 h. The product distribution was determined by capillary GC to be 98:2. The major product was subsequently isolated and shown to be 18. This silane exhibited a pair of intense NOE effects: CH 3/a-silyl CH (11.2%) and a-methyl
CH/Si(CH 3 ) 3 (19.4%). With KNH 2 as the coreagent, the cleavage required somewhat longer (5 h) and the product composition fell reproducibly to 96:4. However, 18 remained the dominant component of the product mixture.
Presumably because of prevailing 1,3 steric effects, the Haller-Bauer cleavages of 2 proceeded somewhat more slowly than those involving 1. The respective reaction times required to realize complete consumption of ketone 12
were 3.5 h (NaNH2) and 10 h (KNH2) • Both processes gave
rise to an identical 95:5 product distribution. That cis
silane 19 had now been produced predominantly was evident
from the a-silyl CH/a-methyl CH NOE effect generated within
the molecule (1.4%) and the anticipated (in light of the
behavior of 10) undetectability of a related CH 3/Si(CH 3 )3
contribution.
Table 1: Haller-Bauer Cleavage of 1 and 2.
Major Reactant Base Time, h * product Ratio
O V CH3 NaNHo c h 3 98:2 Ph H H (CH3)3SiAJSaf'H .S I V - KNH2 (CH3)3Si 96:4 1 8
CH3 c h 3 NaNHo 3.5 95:5 (CH3)3Si (CH3)3Si H Phx /-h H KNH2 10 95:5 O 2 19
* In rerluxing benzene under inert atmosphere.
The differing reflux times required to effect complete
consumption of starting materials coupled with observed NOE
interactions in both alcohols 1 0 and 1 1 and cleavage
products 18 and 19 give an indication of the differing
steric interactions present in 1 and 2. Specifically, the
cis relationship between the trimethylsilyl group and the 13
methyl group in 2 forces the phenyl ketone function and the a-methyl proton into close proximity. This expectation is supported by examination of models and by molecular mechanics calculations. Despite the potential for steric destabilization of the coordination complex that leads to retention, 2 cleaves with minimal loss of stereochemistry.
2. 4-tert-Butvlcvclohexanes.
As in the previous examples, the cleavages of 3 and 4 were carried out in refluxing anhydrous benzene under an argon atmosphere with sodium amide or potassium amide as base. Cis ketone 3 underwent Haller-Bauer cleavage with considerable difficulty when heated with either amide base.
In the runs involving NaNH2, reaction times of approximately
135 h were necessary to consume the starting material.
According to capillary GC analysis, these reactions resulted uniquely in loss of the benzoyl group. However, the relative levels of silanes 2 0 and 2 1 could not be established by this analytical technique since the isomers were shown not to be separable under a wide variety of flow-rate and temperature conditions. When recourse was made to XH NMR (300 MHz) , only trans isomer 20 could be detected within confidence limits of ±5%. Accordingly, cleavage occurs in this instance with at least 95% retention of configuration. 14
With KNH 2 as base, reaction was complete in 100 h.
However, only a trace of 20 was formed, the major product being 4-tert-butylcyclohexanone (22) . In our view, ketone formation originates by initial desilylation with generation of the potassium enolate. As a consequence of the long reaction time, the latter intermediate finds it possible to react with adventitious oxygen present in the reaction vessel . 17 To test this premise, 3 was purposefully desilylated with tetra-n-butylammonium fluoride in tetrahydrofuran and the unpurified 4-tert-butylcyclohexyl phenyl ketone was heated with KNH 2 in benzene. After 36 h, conversion to 2 2 had materialized to a substantial extent, although some minor unidentified compounds were produced concomitantly.
Table 2 Haller-Bauer Cleavage of 3 and 4.
Reactant Base Time, h * Products Ratio
20:21 >95:5
(CH3)3C Si(CH3)3 KNH2 100 22 trace of 20 3
Si(CH3)3 NaNH2 3 21:20 >95:5 (CH3)3C 16 21:22 14:86 O 4 Si(CH3)3
(CH3)3C (CH3)3c - (cH3)3C-~ Si(CH3)3
20 21 22 * In refluxing benzene under inter! atmosphere. 15
The unreactivity of 3 can be attributed to massive
steric screening. Its benzoyl carbonyl center not only
resides in an axial environment but is also flanked by a
geminal trimethylsilyl group. When the location of the two
substituents is reversed as in 4, the congestion is somewhat
alleviated because the benzoyl is now situated equatorially.
As a consequence, 4 was expected to be more reactive than 3,
and it is. Heating 4 with NaNH 2 in benzene for only 3 h
resulted in smooth conversion to 21. Stereochemical purity
within ±5% limits was established by XH NMR (300 MHz)
analysis (Table 2) .
Recourse to KNH 2 required 16 h to consume all of 4.
The resulting two-component product mixture consisted of 21
(14%) and 22 (8 6 %). Thus desilylation remains kinetically
important when KNH 2 is used. The loss of trimethylsilyl in
4 may stem from its axial disposition, the steric
acceleration attending its departure from the molecule
likely being substantial. Notwithstanding, 4 also responds
to the desired cleavage by experiencing protonation predominantly, if not exclusively, with retention.
The structural assignments to 20 and 21 follow convincingly from comparison of select XH and 13C NMR shifts with those established by others for closely related molecules . 18 As seen in Figure 2, the equatorial trimethylsilyl group in 2 0 is more shielded than its axial counterpart in 21 (A8 = 2.96). This relative ordering has 16
been recognized before. The 23/24 (A8 = 1.56) and 25/26 stereoisomeric pairs (A5 = 2.63) are exemplary of the trend.
Additionally, the relative configuration of 20 is indicated by the appearance of its cyclohexyl a-silyl proton as a clean triplet of triplets with coupling constants of 12.3 and 3.0 Hz, as would be predicted from the torsional angles this C-H bond defines with the adjacent methylene protons.
- 0.80 ppm -2.36 ppm H / Si(CH3)3 (CH3, 3 0 ^ i ^ z k s / 3)3 ( C H A C ^ ^ k n
23 OH 24 OH - 9.41 ppm H -,2;°4PPm ?n(CH3)3 (CH3)3C - ^ 7 k s ^ H3)3 (CHAC. ^ ,H
2 5 2 6
Figure 2: 13C NMR Shifts; Axial vs Equatorial.
Finally, the stability of 20 and 21 to the reaction conditions under which they are formed was ascertained by heating each with KNH 2 in benzene at reflux for 100 h. No significant decomposition of either silane was detected by capillary GC. Because of the volatility of these compounds, losses were incurred during such treatment. This factor almost certainly contributes in a major way to the modest isolated yields realized for the Haller-Bauer cleavages of all of the a-trimethylsilyl ketones examined. 17
3. 2-Methvlcvclopentanes.
Based on the high levels of diastereoselection observed
in the spiroalkylation process used to obtain 6 , there is a
large amount of steric interaction between the reaction
center and the 2-methyl substituent. This strong
interaction was expected to manifest a pronounced effect on the course of Haller-Bauer cleavage.
Under conditions identical to those described in previous sections, no Haller-Bauer cleavage could be induced
for 6 . Rather, 6 preferentially underwent desilylation to give 27. That this reaction course had been followed was confirmed by independent desilylation of 6 using tetra-n-butylammonium fluoride in tetrahydrofuran.
Scheme 8 : Attempted Haller-Bauer Cleavage of 6 .
o c h , o CH3
S' 'lJSCi a \ f „ M -Na‘-K* \ TBAF 0° C, 5 min, THF
In this instance, steric compression impedes nucleophilic addition sufficiently that preferential removal of silicon is the exclusive result with both NaNH 2 and KNH2.
Efforts to change the course of reaction by using such 18
techniques as sonication failed to improve the situation.
Thus, a-silyl derivatives with substitution at the 2-postion
should be considered as potentially poor candidates for the
Haller-Bauer cleavage.
C. SUMMARY
The results obtained in this study demonstrate the
utility of the Haller-Bauer reaction in obtaining
unfunctionalized organosilanes of high diastereomeric
purity. Furthermore, unlike previous phenyl stabilized
cleavages, the stereochemical course of the cleavage is
relatively insensitive to steric interactions within the molecule which might tend to favor the formation of one
product isomer over the other. One possible explanation is
the relatively long Si-C bond which would tend to alleviate
some of the steric destabilization of benzamide coordination
and subsequent proton delivery with retention. Another
possible explanation for the enhanced stereoretention with
organosilicon substrates could arise from the nature of
carbanion stabilization by silicon . 19
As shown in Figure 3, two potential explanations have
been proposed for carbanion stabilization by silicon. Early
rationalization of this phenomenon favored the dn-pn model A
as the source of the stabilizing influence . 2 0 More
recently, the relative importance of d orbitals has been 19 discounted in favor of stabilization by means of the high polarizability of Si and the presence of an empty o* orbital on the heteroatom which can overlap with the filled p-orbital of the carbanion (B) . 21
M
Figure 3s Models for Carbanion Stabilization by Si.
Although the possibility has not been sufficiently addressed by theoreticians, this overlap with the o" orbital on silicon could lead to some slight deviation from planarity in the carbanion. If such is the case, coordination of counterion and benzamide with the newly formed carbanionic center should be stabilized relative to a completely planar intermediate.
Finally, the limitations of the a-silyl stabilized
Haller-Bauer process have been more clearly defined.
Molecules with increased steric compression at the reaction center tend to favor desilylation rather than the cleavage reaction. This problem is especially severe with
2 -substituted derivatives. 20
EXPERIMENTAL
General Methods
Melting points were measured using a Thomas Hoover
(Uni-Melt) capillary melting point apparatus and are uncorrected. Optical rotations were measured using a
Perkin-Elmer Model 241 polarimeter and concentrations are given in grams/100 ml. Infrared (IR) spectra were recorded with a Perkin-Elmer 1320 spectrometer and are expressed in reciprocal centimeters (cm-1). Proton nuclear magnetic resonance spectra (XH NMR) were measured at 300 MHz (Bruker
WP 300 and Bruker AC 300 FT NMR spectrometers) and the splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet, q, quartet and m, multiplet.
Carbon-13 NMR were recorded at 75 MHz (Bruker WP 300 and
Bruker AC 300 FT NMR spectrometers) and fluorine-19 NMR spectra were recorded at 235 MHz (Bruker AM 250 FT NMR) .
The chemical shifts are given in parts per million (8 ) and the coupling constants are expressed in hertz (Hz) .
Combustion analyses were performed by the Scandinavian
Microanalytical Laboratory, Herlev, Denmark. Exact mass measurements were determined at the Ohio State University 21
Chemical Instrument Center with a Kratos MS-30 mass spectrometer. Gas chromatography/mass spectrum (GC/MS) analyses were performed using a Hewlett Packard 5970 series mass selective detector GC/MS fitted with a 12 m x 0.20 mm methyl silicone gum column and set at a flow rate of 0 . 2 ml/min. Capillary gas chromatography (GC) analyses were performed using a Carlo Erba Strumentazione Fractovap 4130
GC fitted with a 30 m x 0.25 mm Durabond 5 column set for a flow rate of 2 ml/min at 100 °C and with a split ratio of
30:1. Preparative GC separations were carried out using a
Perkin-Elmer Model 960 GC fitted with a thermal conductivity detector. Columns used were: (A) 1.1 m x 6 mm (5% SE 30 on
Chromosorb W) and (B) 2.4 m x 6 mm (5% SE 30 on Chromosorb
W) with a flow rate of 12-20 ml/min.
All solvents used were reagent grade and were pre-dried where appropriate. Reactions involving non-aqueous media were carried out under inert atmosphere.
Preparation of 2-Methyl-l,4-diiodobutane (8 ).
CH3
Dimethyl itaconate (121.7 g, 0.77 mol) was placed in a
500 ml medium pressure hydrogenation bottle along with ethyl acetate (150 ml) and argon was bubbled through the solution 22
for 1 0 min before platinum oxide ( 1 2 1 mg) was added under a stream of argon. The flask was capped and alternately evacuated and charged with hydrogen several times. The mixture was stirred under hydrogen (40 psi) for 5.5 h before being eluted through silica gel with several portions of diethyl ether. Evaporation of the solution at reduced pressure gave 119.5 g (97%) of colorless liquid; IR (neat, c m -1) 2960, 1740, 1440, 1170, 1063, 1013, 842; XH NMR (80
MHz, CDC13) 6 3.65 (s, 3H), 3.63 (s, 3H), 3.10-2.20 (m, 3H),
1.18 (d, J = 6.9 Hz, 3H) . The hydrogenated material was added dropwise over 3 h as a solution in diethyl ether (150 ml) to a slurry of lithium aluminum hydride (51.0 g, 1.34 mol) in anhydrous diethyl ether (300 ml) at -78 °C with mechanical stirring. The reaction was extremely exothermic and tended to form a crust over the surface. The reaction mixture was allowed to reach room temperature overnight.
The mixture was cooled to -78 °C and quenched by slow addition of ethyl acetate (40 ml) over 2 h followed by water
(51 ml) , 15% sodium hydroxide (51 ml) , and finally water
(168 ml). The mixture was thoroughly stirred with cooling to give a white precipitate. Magnesium sulfate was added to the white mixture to remove excess water. The material was filtered and the filter cake was washed with diethyl ether
(100 ml X 5). Evaporation of the ether solution followed by bulb-to-bulb distillation to gave 60.5 g (78%) of colorless oil; IR (neat, cm-1) 3350, 2940, 1455, 1380, 1050, 850; XH 23
NMR (80 MHz, CDCI 3 ) 6 4.00-3.20 (m, 4H) , 2.95 (s, 2H) ,
2.00-1.70 (m, 3H), 0.95 (d, J = 6.95 Hz, 3H). A solution of the above compound (10.4 g, 0.10 mol), dihydropyran (25.2 g,
27.4 ml, 0.30 mol), and pyridinium p-toluenesulfonate (2.51 g, 0.01 mol) in dry dichloromethane (250 ml) was stirred under nitrogen at room temperature for 18 h. The solution was extracted with water (2 x 1 0 0 ml) and the combined aqueous layers were extracted with dichloromethane (2 x 50 ml) . The combined organic parts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the bis(tetrahydropyranyl) ether as 25.6 g (94%) of light yellow oil; XH NMR (80 MHz, CDC1 3 ) 6 4.65-4.40 (m,
2H) , 4.05-3.00 (m, 8 H) , 2.10-1.15 (m, 15H) , 0.95 (d, J =
6.95 Hz, 3H). A magnetically stirred solution of triphenylphosphine (38.5 g, 147 mmol) in dry dichloromethane
(500 ml) at 0 °C was treated dropwise under argon with bromine (7.60 ml, 147 mmol) during 40 min. The solution was stirred at 0 °C for 20 min during dropwise addition of a dichloromethane solution of the bis(tetrahydropyranyl) ether
(10.0 g, 36.7 mmol) from above. The solution was allowed to warm to room temperature and stirred for 18 h before being washed with water (2 x 200 ml) . The aqueous washings were extracted with dichloromethane ( 1 0 0 ml) and the combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a dark oil. The oil was mixed with petroleum ether and the 24
resulting dark solid was removed by filtration. The petroleum ether solution was concentrated and eluted through
silica gel with petroleum ether using suction. Evaporation of the eluent to gave 7.00 g (83%) of
2-methyl-l,4-dibromobutane as a colorless liquid. A mixture of the dibromide (7.00 g, 30.0 mmol), sodium iodide (18.0 g,
120 mmol) and dry acetone (40 ml), was stirred overnight at room temperature under argon. The mixture was filtered, concentrated under reduced pressure, diluted with pentane, and filtered through Celite. Concentration of the resulting solution under reduced pressure provided 9.28 g (99%) of
2-methyl-l,4-diiodobutane (8) as a light yellow liquid; IR
(neat, cm-1) 2960, 2925, 1455, 1427, 1380, 1247, 1200, 737;
1H NMR (80 MHZ, CDC13) 8 3.40-3.00 (m, 4H), 2.05-1.35 (m,
3H), 0.98 (d, J = 6.04 Hz, 3H).
tert-Butyl 1-(trimethylsilyl)-3-methylcyclopentane carboxylate (9).
/-BuOOC,
(^^3)3^1
To a solution of lithium diisopropylamide (70.1 mmol)
(from 53.9 ml of 1.30 M n-butyllithium and diisopropylamine
(1 1 . 2 ml, 80.0 mmol)) in anhydrous tetrahydrofuran ( 2 0 0 ml) at -78 °C was added dropwise tert-butyl (trimethylsilyl) 25 acetate (11.0 g, 58.4 mmol). The solution was stirred for
15 min at -78 °C and warmed to -30 °C before 13 (20.8 g,
64.2 mmol) was added in one portion. After 3 h of stirring at -30 °C, another 70.1 mmol of lithium diisopropylamide was added dropiwise to the solution, which was cooled to -78 °C and allowed to warm to room temperature overnight. The reaction mixture was quenched with saturated ammonium chloride solution ( 1 0 0 ml), diluted with diethyl ether ( 2 0 0 ml), washed with saturated sodium bicarbonate and saturated sodium chloride solutions, dried over magnesium sulfate, filtered, and concentrated to obtain 14.9 g of yellow liquid. Flash chromatography on silica gel provided 10.78 g
(72%) of a light yellow liquid which was a 60:40 mixture of diastereomers based on analytical gas chromatography; IR
(neat, cm"1) 2950, 2860, 1700, 1363, 1245, 1150, 840? XH NMR
(300 MHz, C 6 D6) 5 2.70-2.40 (m, 1H), 2.20-1.45 (m, 4H), 1.37
(2s, 9H) , 1.30-0.95 (m, 2H) , 0.98, 0.92 (2d, J = 6.48, 6.45
Hz, 3H) , 0.07 (s, 9H) ; 13C NMR (75 MHz, C 6 D6) ppm 177.55,
177.11, 79.27, 46.00, 44.77, 41.07, 39.57, 35.46, 35.38,
34.51, 31.97, 30.78, 28.25, 20.25, 19.82, -3.18, -3.25; MS: the molecular ion peak was too transient for high resolution measurement.
Anal. Calcd for Ci 4H 2 8 0 2Si: C, 65.57; H, 11.00.
Found. C, 65.51; H, 11.14. 26 cis- and trans-l-(Trimethylsilyl)-3- methylcyclopentane- methanol ( 1 0 and 1 1 ).
h o c h 2 . (CH3)3Si (CH3)3Si HOCH.
To a magnetically stirred solution of 9 (10.78 g , 42.0 mmol) in anhydrous methylene chloride (500 ml) at -10 °C under argon was added diisobutylaluminum hydride (127 ml of
1.0 M in hexane, 127 mmol) dropwise over 40 min. The solution was stirred at -10 to 0 °C for 4 h and cautiously quenched with methanol (50 ml). The resulting cloudy solution was diluted with diethyl ether ( 1 1 ) and stirred with saturated Rochelle salt solution during 1 hour. The organic layer was separated and extracted with saturated sodium chloride solution, dried over sodium sulfate, filtered, evaporated, and distilled bulb-to-bulb to provide
7.62 g (97%) of colorless liquid. The mixture of diastereomers was separated using high pressure liquid chromatography on silica gel to obtain 1.40 g of alcohol with silicon trans to the methyl group (10), 1.29 g of alcohol with silicon cis to the methyl group (11), and 1.58 g of diastereomeric mixture. The diastereomerically pure materials were separately characterized. Trans diastereomer
10: IR (neat, c m -1) 3340, 2940, 1245, 1040, 835; lH NMR (300
MHz, C 6 D 6) 6 3.27 (s, 2H) , 1.80-1.35 (m, 4H) , 1.20-1.00 (m, 27
1H), 0.98 (d, J = 5.88 HZ, 3H), 0.90-0.70 (m, 3H), 0.04 (s,
9H); 13C NMR (75 MHz, C 6 D6) ppm 70.02, 40.25, 36.68, 35.42,
34.99, 31.67, 20.26, -2.96.
Anal. Calcd for C 1 0 H 2 2 OSi: C, 64.45; H, 11.90. Found:
C, 64.24; H, 11.91.
Cis diastereomer 11: IR (neat, cm"1) 3340, 2940, 1245,
1040, 835; JH NMR (300 MHz, C 6 D6) S 3.27 (s, 2H), 1.95-1.80
(m, 1H), 1.80-1.66 (m, 1H), 1.66-1.57 (m, 2H), 1.35-1.20 (m,
1H), 1.05-0.80 (m, 3H), 0.96 (d, J = 6.33 Hz, 3H), 0.05 (s,
9H); 13C NMR (75 MHz, C 6 D6) ppm 69.52, 40.39, 36.19, 35.26,
34.57, 31.05, 19.99, -2.97; MS: The molecular ion peak was too transient for high resolution measurement, m/z (M+
-TMSOH) calcd 96.0813, obsd 96.0953.
Anal. Calcd for C 1 0 H 2 2 OSi: C, 64.45; H, 11.90. Found:
C, 64.13; H, 11.81.
trans-l-Benzoyl-1-(trimethylsilyl)-3-methylcyclopentane
(1)
(^H3)3si
To a solution of the trans diastereomer 10 (1.52 g,
8.16 mmol) in benzene (100 ml) contained in a 250 ml round-bottomed flask equipped with a reflux condenser and a
Dean-Stark trap was added Fetizon's reagent (25 g, -5.4 28 eq.). The mixture was heated at reflux with vigorous stirring for 7 h and allowed to cool to ambient temperature.
The mixture was filtered through a Celite pad which was rinsed with diethyl ether (50 ml) . Removal of solvent provided 1.28 g (85%) of aldehyde as a colorless liquid; IR
(neat, cm-1) 2960, 2870, 2810, 2690, 1745, 1695, 1455, 1255,
1160, 1120, 845,755; *H NMR (300 MHz, C 6D 6) 5 9.52 (s, 1H) ,
2.29-2.21 (m, 1H) , 1.79-1.28 (m, 6 H) , 0.82 (d, J = 6.14 Hz,
3H) , -0.11 (s, 9H) ; 13C NMR (75 MHz, C 6 D6) ppm 204.71,
54.48, 36.83, 35.68, 35.54, 29.70, 19.88, -3.81; MS m/z (M+) calcd 184.1283, obsd 184.1299.
To a solution of the aldehyde in diethyl ether (125 ml) under argon at -78 °C was added phenyllithium (14.9 ml of
-3.0 M, -20.8 mmol) dropwise over 10 min. The solution was stirred at -78 °C for 20 min and quenched with water. After being warmed to room temperature, the solution was washed with water ( 1 0 0 ml x 2 ), brine ( 1 0 0 ml), dried over sodium sulfate, filtered, and concentrated to provide 2 . 1 0 g of yellow liquid that was directly oxidized.
To a mechanically stirred suspension of dry chromium trioxide (6.90 g, 6.90 mmol) in dichloromethane (150 ml) at
0 °C under argon was added pyridine (11.05 g, 14.0 mmol) dropwise via syringe. After 20 min, the crude secondary alcohol from above was added dropwise as a solution in dichloromethane (5 ml) . After an additional 40 min, the mixture was filtered through Celite followed by silica gel 29
to remove the chromium salts. The filter pads were rinsed with diethyl ether and the combined filtrates were
concentrated to provide 2.39 g of yellow liquid. MPLC
(silica gel, elution with 0.4% ethyl acetate/petroleum
ether) provided 1.40 g (78% from the aldehyde) of 1 as a white solid. Recrystallization from pentane provided an
analytical sample, mp 45-47°C; IR (KBr , cm-1) 3070, 2970,
2895, 1645, 1595, 1575, 1445, 1365, 1255, 1230, 1050, 1025,
845, 750, 700; XH NMR (300 MHz, C 6 D 6) 67.89-7.86 (m, 2H) ,
7.11-7.08 (m, 3H) , 2.94-2.86 (m, 1H) , 2.18-2.15 (m, 2H) ,
1.83-1.73 (m, 2H) , 1.50-1.46 (m, 1H) , 0.98-0.78 (m, 1H) ,
0.77 (d, J = 6.53 Hz, 3H) , 0.01 (s, 9H) ; 13C NMR (75 MHz,
C 6 D6) ppm 205.18, 138.96, 131.10, 129.73, 128.31, 53.35,
42.72, 36.25, 35.59, 33.94, 19.74, -2.17; MS a/z (M+) calcd
260.1597, obsd 260.1587.
Anal. Calcd for C 1 6 H 2 4 0 Si; C, 73.79; H, 9.29. Found; C,
73.87; H, 9.28.
cis-l-benzoyl-1-(trimethylsilyl)-3-methylcyclopentane (2).
(CH3)3Si
O
To a solution of the cis diastereomer 11 (1.40 g, 7.51 mmol) in benzene (100 ml) contained in a 250 ml round-bottomed flask equipped with a reflux condenser and a 30
Dean-Stark trap was added Fetizon's reagent (25 g, -6.0 eq.). Themixture was heated at reflux with vigorous stirring for 5 h and allowed to cool to ambient temperature.
The mixture was filtered through a Celite pad and the pad was rinsed with diethyl ether (50 ml) . Removal of solvent provided 1.15 g (83%) of aldehyde as a colorless liquid; IR
(neat, cm-1) 2960, 2870, 2690, 1745, 1695, 1455, 1255, 1160,
1120, 845,755; XH NMR (300 MHz, C 6 D 6) 8 9.46 (s, 1H) ,
2.61-2.35 (m, 1H) , 1.85-1.15 (m, 6 H) , 0.84 (d, J = 6.35 Hz,
3H), 0.04 (s, 9H); 13C NMR (75 MHz, C 6 D6) ppm 204.65, 55.18,
38.41, 35.32, 34.99, 28.07, 19.58, -3.73; MS m/z (M+) calcd
184.1283, obsd 184.1289.
To a solution of aldehyde in diethyl ether (125 ml) under argon at -78 °C was added phenyllithium (14.9 ml of
-3.0 M, -20.8 mmol) dropwise over 10 min. The solution was stirred at -78 °C for 20 min and quenched with water. After being warmed to room temperature, the solution was washed with water ( 1 0 0 ml x 2 ) and saturated sodium chloride solution ( 1 0 0 ml), dried over sodium sulfate, filtered, and concentrated to provide 1.89 g of yellow liquid that was used without further purification.
The crude alcohol was treated with Collins reagent as described for the preparation of 1 to obtain after MPLC on silica gel 2 as 1.07 g (6 6 % from the aldehyde) of- white solid. Recrystallization from pentane provided an analytical sample mp 65-67 °C; IR (KBr , cm" 1) 3060, 2950, 2880, 1630, 31
1595, 1575, 1445, 1250, 1060, 845, 750, 700; XH NMR (300
MHZ, C 6 D 6) 6 7.83-7.79 (in, 2H), 7.11-7.07 (m, 3H), 3.11-3.04
(m, 1H), 2.49-2.39 (m, 1H), 2.01-1.93 (m, 1H), 1.63-1.49 (m,
2H), 1.30-1.22 (m, 1H), 0.95-0.83 (m, 1H), 0.86 (d, J = 6.11
Hz, 3H) , 0.02 (s, 9H) ; 13C NMR (75 MHz, C 6 D 6) ppm 205.41,
139.28, 130.96, 129.43, 128.33, 54.15, 43.03, 36.30, 35.24,
33.79, 19.46, -2.08. Anal. Calcd for Ci 6H 2 4 0 Si: C,
73.79; H, 9.29. Found; C, 73.81; H, 9.29.
tert-Butyl-1-(trimethylsilyl)-4-tert-butylcyclohexane
Carboxylate (13).
Si(CH3)3
(CH3)3C - / ^ ^ ^ c O O f - B u
To a solution of lithium diisopropylamide (87.5 ml of
0.80 M, 70 mmol) in dry tetrahydrofuran (350 ml) at -78 °C under argon was added dropwise tert-butyl (trimethylsilyl) acetate (11.30 g, 60.0 mmol) as a solution in tetrahydrofuran (30 ml). The solution was stirred at -78 °C for 10 min after the addition was complete and warmed to -30
°C before adding 3-tert-butyl-l,5-diiodopentane (22.80 g,
60.0 mmol) rapidly dropwise as a solution in tetrahydrofuran
(30 ml). After 3 h at -30 °C, the solution was cooled to
-78 °C and lithium diisopropylamide (87.5 ml of 0.80 M, 70 mmol) was introduced in rapid dropwise fashion with a 32 cannula. The light yellow solution was allowed to reach ambient temperature slowly over 3 h. The reaction mixture was quenched with saturated ammonium chloride solution, diluted with diethyl ether, washed with water (500 ml x 2) and saturated sodium chloride solution (250 ml), dried over magnesium sulfate, filtered, and concentrated to provide
21.72 g of dark oil. Analytical gas chromatography indicated the material consisted mostly of two closely spaced peaks in a ratio of 60:40, with the first to elute comprising the bulk of the mixture. Chromatography on silica (elution with 0.5% ethyl acetate/ petroleum ether) provided 12.78 g of 13 (71%) as a light yellow liquid.
Attempted separation of the isomeric mixture using high pressure liquid chromatography on silica gel was only partially successful. Preparative gas chromatography was used to obtain an analytical sample of each isomer. For trans-13: IR (neat, cm-1) 2950, 2855, 1705, 1480, 1445,
1390, 1365, 1250, 1165, 1140, 1040, 905, 850, 755; XH NMR
(300 MHZ, CDCl3) 6 2.22-2.18 (m, 2H) , 1.63-1.59 (m, 2H) ,
1.44 (s, 9H), 1.24-0.82 (m, 5H), 0.80 (s, 9H), 0.01 (s, 9H) ;
13C NMR (75 MHZ, CDCl3) ppm 175.29, 79.17, 47.80, 39.69,
32.53, 29.59, 28.29, 27.36, 24.70, -3.97; MS: the molecular ion peak was too transient for high resolution measurement.
Anal. Calcd for C 1 8 H 3 60 2Si: C, 69.17; H, 11.61. -Found:
C, 69.05; H, 11.61. 33
For cis-13: IR (neat, cm "1) 2950, 2855, 1705, 1475,
1445, 1390, 1365, 1250, 1155, 840, 755; XH NMR (300 MHZ,
CDCl3) 6 2.06-1.99 (m, 2H), 1.71-1.61 (m, 4H), 1.42 (s, 9H),
1.21-0.80 (m, 3H) , 0.82 (s, 9H) , 0.10 (s, 9H) ; 13C NMR (75
MHz, CDCl 3 ) ppm 177.32, 79.32, 46.29, 38.07, 32.58, 29.90,
28.25, 27.54, 24.09, -1.32; MS: the molecular ion peak was too transient for high resolution measurement.
Anal. Calcd for Ci 8H 3 60 2Si: C, 69.17; H, 11.61. Found:
C, 69.41; H, 11.49.
trans- and cis-1-(Trimethylsilyl)-4-tert-butylcyclohexane- methanol
CH2OH Si(CH3)3
(0H°)3C'^-7SI(Ch 3,3 (CH3)3°---- ^ 'CH^H
Partially enriched fractions from the high pressure liquid chromatography of 13 were reduced separately according to the procedure outlined for the preparation of
10 and 11. A total of 7.66 g (25.5 mmol) of ester was reduced and purified using high pressure liquid chromatography (silica gel, elution with 3% ethyl acetate/ petroleum ether) to provide 1.23 g of pure trans isomer 14,
1.50 g of pure cis isomer 15, 1.06 g of trans enriched mixture, and 1.40 g of cis enriched mixture. The combined yield of purified materials was 5.19 g (84%). For trans 34
isomer 14: IR (neat, cm"1) 3380, 2950, 2865, 1480, 1450,
1395, 1370, 1250, 1030, 860, 840, 755; XH NMR (300 MHz,
C 6 D 6) 6 3.51 (s, 2H), 1.64-1.59 (m, 2H), 1.41-1.37 (m, 2H),
1.30-1.20 (m, 2H), 1.13-0.85 (m, 4H), 0.86 (s, 9H) , 0.10 (s,
9H) ; 13C NMR (75 MHz, C 6 D 6) ppm 64.80, 48.67, 32.61, 28.59,
27.61, 26.44, 21.79, -2.98.
For the cis alcohol 15: colorless crystals, mp 89-90 °C
(from pentane): IR (KBr, cm-1) 3370, 2960, 2860, 1480,
1450, 1390, 1370, 1255, 1030, 860, 840, 755; 13C NMR (75
MHz, C 6 D 6) ppm 3.17 (s, 2H) , 1.87-1.81 (m, 2H) , 1.61-1.55
(m, 2H), 1.20-0.80 (m, 6 H), 0.85 (s, 9H), 0.15 (s, 9H); 13C
NMR (75 MHz, C 6 D6) ppm 73.78, 48.48, 33.63, 32.58, 31.97,
29.29, 27.70, 24.68, 22.96, -0.08; MS: The molecular ion was too transient for high resolution measurement.
Anal. Calcd for Ci 4H 3 0 OSi: C, 69.35; H, 12.47. Found:
C, 69.38; H, 12.39.
trans-1-benzoyl-1-(trimethylsilyl)-4-tert-butylcyclohexane
(3)
(CH3)3c Si(CH3)3
A mechanically stirred suspension of anhydrous chromium trioxide (4.12 g, 41.2 mmol) in dichloromethane (100 ml) at
-10 °C was treated dropwise via syringe with pyridine (6.52 35 g, 82.4 nunol). After 30 min, the cis isomer of 18 (960 mg,
3.96 mmol) was introduced dropwise as a solution in dichloromethane (5 ml) . The resulting mixture was stirred for 30 min and filtered through Celite followed by silica
(elution with diethyl ether). Concentration of the combined filtrates provided 890 mg of aldehyde as a light brown solid which was used immediately without further manipulation; IR
(melt, cm-1) 2960, 2860, 1710, 1455, 1365, 1250, 1175, 1145,
1095, 850, 760, 695; XH NMR (300 MHz, C 6 D 6) 6 9.49 (s, 1H),
2.45-1.95 (m, 2H) , 1.90-1.05 (series of m, 4H) , 1.00-0.60
(m, 3H) , 0.77 (s, 9H) , 0.06 (s, 9H) .
Phenyllithium (7.4 ml of 2.0 M in ether, -14.8 mmol) was introduced dropwise into a solution of the above aldehyde (890 mg, -3.7 mmol) in diethyl ether (80 ml) at -78
°C. The solution was stirred for 15 min and quenched with water. After being warmed to room temperature, the solution was washed with water ( 1 0 0 ml x 2 ) and saturated sodium chloride solution ( 1 0 0 ml), dried over sodium sulfate, filtered, and concentrated to provide 1.40 g of light brown solid that was used without further purification.
A solution of the above alcohol in dichloromethane (5 ml) was added to 41.2 mmol of Collins reagent (prepared as above) in dichloromethane (100 ml). The solution was stirred for 20 min at -10 °C and filtered through -Celite followed by silica gel (elution with diethyl ether).
Concentration of the combined filtrates provided 1.35 g of 36 tan solid. MPLC (silica gel, elution with 0.5% ethyl acetate/petroleum ether) of the solid provided 780 mg of 3
(62% overall) as a white solid. Recrystallization from pentane provided an analytical sample, mp 109.5-110.5 °C; IR
(KBr, cm "1) 3050, 2950, 2870, 1635, 1385, 1370, 1260, 980,
870, 850, 770, 750, 705; *H NMR (300 MHz, C 6 D 6) 6 7.69-7.65
(m, 2H), 7.11-7.05 (m, 3H), 2.79-2.73 (m, 2H), 1.57-1.52 (m,
2H) , 1.35-1.07 (m, 4H) , 0.98-0.89 (m, 1H) , 0.75 (s, 9H) ,
0.00 (s, 9H) ? 13C NMR (75 MHz, C 6D6) ppm 206.67, 142.85,
130.20, 128.32, 49.57, 48.49, 32.52, 31.43, 27.45, 25.64,
-2.74? MS m/z (M+) calcd 316.2222, obsd 316.2205.
Anal. Calcd for C 2 oH 3 2OSi; C, 75.89? H, 10.19. Found:
C, 75.83? H, 10.16.
cis-l-Benzoyl-1-(trimethylsilyl)-4-tert-butylcyclohexane
(4). Si(CH3)3 (CH3)3C O
The trans isomer of 18 (l.OOg, 4.12 mmol) was introduced dropwise as a solution in dichloromethane (5 ml) to a solution of Collins (41.2 mmol) reagent (prepared as previously described) in dichloromethane (100 ml). After 30 min at -10 °C, the mixture was filtered through -Celite followed by silica (elution with diethyl ether).
Concentration of the combined filtrates provided 920 mg of 37 cis aldehyde as a light brown solid which was used immediately without further manipulation; IR (neat, cm-1)
2960, 2865, 1670, 1450, 1365, 1255, 845, 760, 690; XH NMR
(300 MHz, C 6H 6) 8 9.47 (s, 1H), 2.30-1.70 (m, 2H), 1.60-1.45
(m, 4H), 1.10-0.70 (m, 3H), 0.77 (s, 9H), -0.04 (s, 9H).
To a solution of the cis aldehyde (920 mg, -3.8 mmol) in diethyl ether (80 ml ) at -78 °C under argon was added dropwise phenyllithium solution (7.4 ml of 2.0 M in ether,
-14.8 mmol). The solution was stirred for 15 min and quenched with water. After being warmed to room temperature, the solution was washed with water ( 1 0 0 ml x 2 ) and saturated sodium chloride solution ( 1 0 0 ml), dried over sodium sulfate, filtered, and concentrated to provide 1.51 g of brown solid which was used without further purification.
The procedure used in preparation of 3 was repeated using the above product to obtain after chromatography on silica gel 785 mg (60% yield from cis alcohol 15) of 4 as white solid. Recrystallization from pentane provided an analytical sample, mp 89-90 °C; IR (KBr, cm-1) 3060, 2970,
2860, 1645, 1450, 1365, 1255, 1230, 1070, 990, 860, 845,
705; XH NMR (300 MHz, C 6D 6) 8 7.61-7.58 (m, 2H), 7.11-7.07
(m, 3H), 2.38-2.31 (m, 2H), 1.85-1.75 (m, 2H), 1.55-1.48 (m,
2H) , 1.18-1.06 (m, 2H) , 0.90-0.70 (m, 1H) , 0.78 (s, 9H) ,
0.14 (s, 9H) ; 13C NMR (75 MHz, C 6 D6) ppm 209.09, 141.76,
130.09, 127.91, 46.59, 46.30, 32.56, 32.20, 27.50, 24.76,
-0.26; MS m/z (M+) calcd 316.2222, Found 316.2216. 38
Anal. Calcd for C 2 oH 3 2 OSi: C, 75.89; H, 10.19. Found:
C, 75.67; H 10.16.
Methyl trims-l-(trimethylsilyl)-2-methylcyclopentane- carboxylate (17).
c h 3
(CH3)3Si
To a magnetically stirred solution of lithium diisopropylamide (26.3 mmol) (from 36.5 ml of 0.721 M) in anhydrous tetrahydrofuran (150 ml) at -78 °C under nitrogen was added dropwise methyl (trimethylsilyl)acetate (3.60 ml,
3.21 g, 21.9 mmol). The resulting light yellow colored solution was stirred for 30 min at -78 °C and warmed to -30
°C before being treated with 1,4-diiodopentane (7.45 g,
23.0 mmol) in one portion. The solution was stirred for 3 h at -30 °C before dropwise addition of another 26.3 mmol of
0.721 M lithium diisopropylamide. The reaction mixture was cooled to -78 °C and allowed to reach -10 °C over 3 h before being quenched with saturated ammonium chloride solution (50 ml) . The resulting mixture was diluted with diethyl ether
( 1 0 0 ml) and the organic phase was separated, washed with saturated sodium bicarbonate and saturated sodium chloride solutions, dried over magnesium sulfate, filtered, and concentrated to obtain 6.21 g of yellow liquid. Flash 39
chromatography on silica gel provided 2.10 g (45%) of 17 as
a pale yellow liquid; IR (neat, cm"1) 2950, 2875, 1715,
1450, 1252, 1220, 842, 760 ; XH NMR (300 MHz, CDC13) 6 3.37
(S, 3H) ? 2.58-2.56 (m, 1H) ; 2.20-2.05 (m, 1H) ,* 1.95-1.75 (m,
1H) ; 1,74-1.61 (m, 2H) ; 1.45-1.38 (m, 2H) ; 1.13 (d, J = 6 . 8
Hz, 3H)? 0.11 (s, 9H); 13C NMR (75 MHz, CDC13) ppm 176.30,
50.47, 47.25, 40.67, 35.40, 31.59, 24.28, 17.76, -2.52; MS
m/z (M+) calcd 214.1389, obsd 214.1368.
Anal. Calcd for C 1 1 H 2 2 0 2 Si: C, 61.63; H, 10.34. .Found:
C, 61.81; H, 10.41.
trans-l-Benzoyl-l-(trimethylsilyl)-2-methylcyclopentane
(6)
To a magnetically stirred solution of 17 (2.93 g, 13.7 mmol) in anhydrous methylene chloride (250 ml) at -10 °C under nitrogen was added diisobutylaluminum hydride (41.0 ml of 1.0 M in hexane, 41.0 mmol) dropwise over 20 min. The solution was maintained at -10 to 0 °C for 4 h and cautiously quenched with methanol (10 ml) . The resulting cloudy solution was diluted with diethyl ether (1 i) and stirred with saturated Rochelle salt solution for 1 hour.
The organic layer was separated and washed with saturated 40
sodium chloride solution, dried over sodium sulfate,
filtered, evaporated, and distilled bulb-to-bulb to provide
2.52 g (82%) of alcohol as a colorless liquid; IR (neat, cm-1) 3400, 2950, 1450, 1248, 1025, 835, 6 8 ? XH NMR (300
MHz, C 6 D 6) 6 3.36 (q, J = 5.61 Hz, 2H) , 1.90 - 1.75 (m,
1H) , 1.75 - 1.60 (m, 2H), 1.60 - 1.50 (m, 2H), 1.45 - 1.20
(m, 3H), 1.01 (d, J = 6.93 Hz, 3H), 0.06 (s, 9H) ; MS; The molecular ion peak was too transient for high resolution measurement, m/z (M+-TMSOH) calcd 96.0839, obsd 96.0953.
To a suspension of anhydrous chromium trioxide (4.29 g,
42.9 mmol) in methylene chloride (100 ml) at 0 °C was added pyridine (6.79 g, 6.94 ml, 85.8 mmol) dropwise. After 20 min, a portion of the alcohol from above (800 mg, 4.29 mmol) was added dropwise to the mixture as a solution in dichloromethane (5 ml) . The solution was held at 0 °C for
1.5 h and filtered through silica which had first been washed several times with diethyl ether (elution with 2 0 % ethyl acetate/petroleum ether). Cautious evaporation provided 720 mg of aldehyde as a colorless liquid which was used immediately without further purification.
To a magnetically stirred solution of the aldehyde (720 mg, 1.95 mmol) in anhydrous diethyl ether (100ml) at -78 °C under nitrogen was added phenyllithium (5.90 ml of 2.0 M, 12 mmol) dropwise over 10 min. The solution was stirred-for 30 min at -78 °C and quenched with water (10 ml). After being warmed to room temperature, the solution was washed with 41
water ( 1 0 0 ml x 2 ) and brine ( 1 0 0 ml), dried over magnesium sulfate, filtered, and evaporated to provide 1.60 g of yellow liquid.
Oxidation of this material as a solution dichloromethane (5 ml) with Collins reagent in a manner paralleling that detailed for preparation of the aldehyde above followed by purification by MPLC on silica gel
(elution with 1.5% ethyl acetate/petroleum ether) provided
395 mg (35% overall) of 6 as a colorless oil; IR (neat, cm-1) 2940, 1640, 1250, 1235, 840, 750, 700? XH NMR (300
MHz, C 6 D 6) 6 7.85-7.75 (m, 2H), 7.12-7.05 (m, 3H), 2.90-2.65
(m, 1H) , 2.50-2.30 (m, 2H) , 2.05-0.80 (series of m, 4H) ,
1.02 (d, J= 6 .7 Hz, 3H), 0.10 (s, 9H)? 13C NMR (75 MHz, C 6 D 6) ppm 206.40, 141.29, 130.81, 128.45, 127.80, 57.41, 41.26,
35.00, 30.73, 22.57, 18.44, -1.52; MS m/z (M+) calcd
260.1594, obsd 260.1620.
Anal. Calcd for Ci 6H 2 4 0 Si: C, 73.79; H, 9.29. Found;
C, 73.77 ; H, 9.35.
Haller-Bauer Cleavage Reactions. For runs with sodium amide as base, 60 mg of ketone was combined with 390 rag of sodium amide in 4 ml of benzene and heated at reflux. For runs with potassium amide, 80 mg of ketone was combined with 600 mg of potassium amide in 4 ml of benzene and heated at reflux. After complete consumption of starting material the reaction mixture was allowed to cool to room temperature, 42 quenched with saturated ammonium chloride solution, and diluted with pentane (10 ml) . The separated organic phase was washed with brine (5 ml), dried over sodium sulfate, and filtered. Capillary GC analysis was conducted prior to any further manipulation. Excess solvent was removed by distillation through a Vigereaux column to leave 0.6 ml of residue. Product was separated from the concentrate by preparative gas chromatography (Column B).
Spectral Data for trans-1-(trimethylsilyl)-3-methyl- cyclopentane (18).
(CHafeSi
Obtained as a colorless liquid: IR (neat, cm"1) 2955,
2870, 1450, 1250, 900, 838, 750; XH NMR (300 MHz, C 6 D 6) 6
1.90-1.86 (m, 1H) , 1.85-1.68 (m, 2H) , 1.58-1.48 (m, 1H) ,
1.32-1.19 (m, 2H) , 1.14-0.60 (m, 2H) , 0.97 (d, J = 6.7 Hz,
3H), -0.01 (S, 9H); 13C NMR (75 MHz, C 6 D 6) ppm 35.88, 34.93,
34.26, 27.43, 23.57, 20.12, -3.92; MS m/z (M+) calcd
156.1334, obsd 156.1348. 43
Spectral Data for cis-l-(trimethylsilyl)-3-methyl cyclopentane (19).
CH. (CH3)3Si H
Obtained as a colorless liquid: IR (neat, cm-1) 2960,
2870, 1455, 1252, 900, 840, 750; XH NMR (300 MHz, CDCl 3 ) 5
1.80-1.56 (m, 4H) , 1.35-1.25 (m, 1H) , 1.05-0.78 (m, 2H) ,
0.88 (d, J = 6.2 Hz, 3H) , 0.76-0.63 (m, 1H) , -0.15 (s, 9H) ;
13C NMR (75 MHz, CDCl 3 ) ppm 37.62, 36.46, 35.52, 26.85,
26.73, 20.36, 12.13.
Spectral Data for trans-4-tert-butyl-l-(trimethylsilyl)- cyclohexane (20).
H
(CH3)3C Si(CH3)3
Obtained as a colorless liquid: IR (neat, c m -1) 2960,
2848, 1477, 1450, 1364, 1250, 883, 834, 750, 6 8 6 ; XH NMR
(300 MHz, CDCl3) 5 1.85-1.70 (m, 4H) , 1.15-0.70 (series of m, 5H), 0.83 (s, 9H), 0.44 (tt, J = 12.3, 3.0 Hz, 1H), -0.07
(S, 9H) ; 13C NMR (75 MHz, CDCl 3 ) ppm 48.45, 32.52, -28.88,
27.89, 27.49, 25.99, -3.52; MS m/z (M+) calcd 212.1961, obsd
212.1950. 44
Spectral Data for cis-4-tert-butyl-1-(trimethylsilyl) cyclohexane (2 1 ).
Si(CH3)3
(CH3)3C
Obtained as a colorless liquid: IR (neat, cm-1) 2960,
2845, 1477, 1450, 1364, 1250, 883, 834, 750, 6 8 6 ; XH NMR
(300 MHz, CDCl3) 6 1.95-1.83 (m, 2H) , 1.65-1.44 (m, 4H) ,
1.1-0.90 (m, 3H) , 0.90-0.75 (m, 1H) , 0.86 (s, 9H) , 0.06 (s,
9H); 13C NMR (75 MHz, CDC13) ppm 48.22, 32.64, 27.70, 27.56,
25.42, 23.69, -0.56; MS m/z (M+) calcd 212.1961, obsd
212.1968.
Anal. Calcd for Ci 3 H 2 8 Si: C, 73.50; H, 13.28. Found:
C, 73.92; H, 13.29.
Desilylation-Oxidation of 3: Ketone 3 (173 mg, 0.55 mmol) was dissolved in tetrahydrofuran (5 ml) . To this solution was added tetra-n-butylammonium fluoride (1.00 ml of 1.0 M in THF, 1.0 mmol) dropwise with stirring. After 1 hour at room temperature, the reaction mixture was diluted with water (10 ml), extracted with diethyl ether (15 ml), -washed with water ( 1 0 ml x 2 ), dried over magnesium sulfate, filtered, evaporated, and placed under high vacuum (0.3 45 mmHg) overnight to obtain 167 mg of yellow solid. A mixture of the desilylated ketone (167 mg), potassium amide (0.80 g), and benzene (5 ml) was heated at reflux under argon for
36 h. The reaction mixture was quenched with saturated ammonium chloride solution ( 1 0 ml) and diluted with pentane
(10 ml). The organic phase was washed with water (2 x 10 ml) and dried over sodium sulfate. Solvent was carefully removed and the residue was distilled in a Kugelrohr apparatus (35 °C/0.3 Torr) to provide 5.1 mg of colorless liquid shown by capillary GC and XH NMR to contain >80%
A-tert-butylcyclohexanone.
Attempted Haller-Bauer Cleavage of 6. Heating of 6 (60 mg,
0.23 mmol) with either sodium amide (390 mg) or potassium amide (600 mg) in dry benzene (4 ml) under nitrogen was continued until starting material was consumed. The cooled reaction mixture was quenched with saturated ammonium chloride solution and diluted with pentane (10 ml) . The separated organic phase was washed with brine, dried, and concentrated to leave 27 as a pale yellow oil. For the major diastereomer which was purified by preparative gas chromatography: IR (neat, c m -1) 3070, 2965, 2880, 1677,
1597, 1582, 1450, 1375, 1220, 700; XH NMR (300 MHz, CDC13) 6
7.97-7.93 (m, 2H) , 7.56-7.25 (m, 3H) , 3.33-3.24 (m-, 1H) ,
2.45-2.34 (m, 1H), 2.10-1.40 (series of m, 5H), 1.37-1.23
(m, 1H), 1.03 (d, J= 6 .7 Hz, 3H); 13C NMR (75 M H z , CDCl 3 ) ppm 46
203.04, 137.46, 132.66, 128.44, 128.30, 54.23, 38.08, 34.88,
31.21, 24.83, 19.77; MS m/z (M+) calcd 188.1201, obsd
188.1192. 47
REFERENCES
1. (a) Hamlin, K. E.; Weston, A. W. Org. React. 1957, 9, 1. (b) Kaiser, E. M . ; Warner, C. D. Synthesis 1975, 395.
2. (a) Cram, D. J. ; Langemann, A.; Allinger, J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81, 5740. (b) Calas, M. ; Calas, B.? Giral, L. Bull. Soc. Chim. France 1976, 857. (c) Alexander, E. C. ; Tom, T. Tetrahedron Lett. 1978, 1741. (d) Paquette, L. A.? Gilday, J. P.; Ra, C. S. J. Am. Chem. Soc. 1987, 109, 6858.
3. (a) Walborsky, H. M.; Impastato, F. J. Chem. Ind. (London) 1958, 1690. (b) Walborsky, H. M. Rec. Chem. Prog. 1962, 23, 75. (c) Impastato, F. J.; Walborsky, H. M. J. Am. Chem. Soc. 1962, 84, 4838. (d) Walborsky, H. M.; Allen, L. E. ? Traenckner, H.-J.; Powers, E. J. J. Org. Chem. 1971, 36, 2937. (e) Piehl, F. J. ; Brown, W. G. J. Am. Chem. Soc. 1953, 75, 5023. (f) Hamlin, K. E. ; Biermacher, U. J. Am. Chem. Soc. 1955, 77, 6376. (g) Gassman, P. G.; Lumb, J. T.; Zalar, F. V. J. Am. Chem. Soc. 1967, 89, 946. (h) Paquette, L. A.; Uchida, T. ; Gallucci, J. C. J. Am. Chem. Soc. 1984, 106, 335. (i) Walborsky, H. M. ; Impastato, F. J. Chem. Ind. (London) 1988, 1960.
4. Paquette, L. A.; Gilday, J. P.; Ra, C. S.; Hoppe, M. J. Org. Chem. 1988, 53, 704.
5. (a) Walborsky, H. M.; Impastato, F. J. J. Am. Chem. Soc. 1959, 81, 5835. (b) Walborsky, H. M.; Young, A. E. J. Am. Chem. Soc. 1961, 83, 2595. (c) Ibid. 1964, 86, 328. (d) Walborsky, H. M. ; Aronoff, J. Organometal. Chem. 1973, 52, 31. (e) Walborsky, H. M . ; Pierce, J. B. J. Org. Chem. 1968, 33, 1962. (f) Walborsky, H. M. ; Johnson, F. P.; Pierce, J. B. J. Am. Chem. Soc. 1968, 90, 5222. (g) Walborsky, H. M. ; Impastato, F. J. ; Young, A. E. J. Am. Chem. Soc. 1964, 86, 3283. (h) Walborsky, H. M.; Periasamy, M. P. J. Am. Chem. Soc. 1974, 96, 3711. (i) Walborsky, H. M . ; Periasamy,- M. P. Org. Prep, and Proc. Int. 1979, 22, 293. (j) Hoell, D . ; 48
Schneiders, C.; Mullen, K. Angev. Chem., Int. Ed. Engl. 1983, 22, 243.
6. For a review: Paquette, L. A.; Gilday, J. P. Org. Prep, and Proc. Int. 1990, 22, 169.
7. Hathaway, S. J.; Paquette, L. A. J. Org. Chem. 1983, 48, 3351.
8. (a) Hayashi, T. ; Konishi, M. ; Ito, H.; Kumada, M. J. Am. Chem. Soc. 1982, 104, 4962. (b) Hayashi, T.; Kabeta, K.; Yamamoto, T.; Tameo, K.; Kumada, M. Tetrahedron Lett. 1983, 5661. (c) Hayashi, T.? Konishi, M.; Okamoto, Y. ; Kabeta, K. ? Kumada, M. J. Org. Chem. 1986, 52, 3772. (d) Hayashi, T. ? Yamamoto, A.; Iwata, T. ; Ito, Y. J. Chem. Soc., Chem. Commun. 1987, 965.
9. (a) Hayashi, T . ; Ito, H . ; Kumada, M. Tetrahedron Lett. 1982, 4605. (b) Hayashi, T.; Konishi, M.; Kumada, M. J. Am. Chem. Soc. 1982, 104, 4963. (c) Wetter, H. ,* Scherer, P. Helv. Chtm. Acta 1983, 66, 118. (d) Hayashi, T.; Okamoto, Y.; Kabeta, K.; Hagihara, T. ; Kumada, M. J. Org. Chem. 1984, 49, 4224. (e) Coppi, L.; Mordini, A.; Taddei, M. Tetrahedron Lett. 1987, 969. (f) Hayashi, T.; Matsumoto, Y.; Ito, Y. Organometallics 1987, 6, 884. (g) Russell, A. T . ; Procter, G. Tetrahedron Lett. 1987, 2041, 2045.
10. Paquette, L. A.; Ra, C. S. J. Org. Chem. 1988, 53, 4978.
11. (a) Brook, A. G. Acc. Chem. Res. 1974, 7, 77. (b) Brook, A. G. Pure Appl. Chem. 1966, 13, 215. (c) Brook, A. G.; MacRae, D. M.; Limburg, W. W.; J. Am. Chem. Soc. 1967, 89, 5493.
12. Rathke, M. W.; Sullivan, D. F. Synth. Commun. 1973, 3, 67.
13. (a) Riddell, F. G. ; Williams, D. A. R. Tetrahedron 1974, 30, 1083. (b) Volynskii, N. P.; Schherbakova, L. P. Izv. Akad. Rauk. SSSR, Ser. Khim. 1979, 1080.
14. (a) Baloph, V.; Fetizon, M.; Golfier, M. J. Org. Chem. 1971, 36, 1339. (b) Fetizon, M.; Golfier, M. C. R. Seances Acad. Sci., Ser. C 1968, 267, 900. (c) McKillop, A.; Young, D. W. Synthesis 1979, 401.
15. Collins, J. C. ; Hess, W. W. ; Frank, F. J. Tetrahedron Lett. 1968, 3363. 49
16. Watson, J. C. ; Ingold, K. U. J. Chem. Soc., Perkin Trans. 2 1986, 1337.
17. For example: (a) Bailey, E. J.; Barton, D. H. R.; Elks, J. ? Templeton, J. F. J. Chem. Soc. 1962, 1578. (b) Gardner, J. N.; Carlon, F. E. ? Gnoj, 0. J. Org. chem. 1968, 33, 3294. (c) Gardner, J. N.; Poppen, T. L.; Carlon, F. E. ? Gno j, 0.; Herzog, H. L. J. Org. Chem. 1968, 33, 3695.
18. (a) Lambert, J. B.; Wang, G.; Finzel, R. B.; Teramura, D. H. J. Am. Chem. Soc. 1987, 109, 7838. (b) Kitching, W.; Adcock, W.; Doddrell, D.; Wiseman, P. A. J. Org. Chem. 1976, 41, 3036. (c) Kitching, W . ; Olszowy, H . ; Waugh, J. J. Org. Chem. 1978, 43, 898.
19. Paquette, L. A.; Gilday, J. P.; Gallucci, J. C. J. Org. Chem. 1989, 54, 1399.
20. (a) Pitt, C. G. J. Organometal. Chem. 1973, 61, 49. (b) Ensslin, W.; Bock, H.; Becker, G. J. Am. Chem. Soc. 1974, 96, 2757. (c) Jung, I. N.; Jones, P. R. J. Organometal. Chem. 1975, 101, 27, 35. (d) Ponec, R. ; Chernyshev, E. A.; Tolstikova, N. G. Chvalovsky, V. Collect. Czech. Chem. Commun. 1976, 41, 2714. (e) Reynolds, W. F.; Hamer, G. K.; Bassindale, A. R. J. Chem. Soc., Perkin Trans. 2 1977, 971. (f) Ramsey, B. G. J. Organometal. Chem. 1977, 135, 307. (g) Adcock, W.; Aldous, G. L.; Kitching, W. Tetrahedron Lett. 1978, 3387. (h) Fleming, I. In distilled Comprehensive Organic Chemistry, Barton, D. H. R. ? Ollis, W. D. , Eds.; Pergamon Press: Oxford, 1979, Vol. 3, Chapter 13. (i) Hopkinson, A. C . ; Lien, M. H. J. Org. Chem. 1981, 46, 998. (j) Larson, J. R . ; Epiotis, N. D. J. Am. Chem. Soc. 1981, 103, 410. (k) Durmaz, S. J. Organometal. Chem. 1975, 96, 331.
21. Schleyer, P. von R.; Clark, T.; Kos, A. J.; Spitznagel, G. W.; Rohde, C.; Arad, D. ; Houk, K. N.; Rondan, N. G. J. Am. Chem. Soc. 1984, 106, 6467 and references cited therein. CHAPTER II
MECHANISTIC INVESTIGATION OF THE HALLER-BAUER REACTION
AND CRAM CLEAVAGE
A. INTRODUCTION
1. Overview of the Mechanistic Investigation.
Comparison of the results obtained for the silyl stabilized Haller-Bauer cleavage from the previous chapter and from other studies with the analogous phenyl stabilized process revealed that, under identical conditions, the silyl stabilized examples proceed with significantly higher levels of stereoretention.1 One possible explanation for this effect, described in the previous section, arises from the nature of the carbanion. A second possibility is the appearance of variable levels of radical mediators in the phenyl stabilized process.
Questions regarding the nature of the intermediates involved in the phenyl stabilized cleavages were also raised by studies from the Paquette group involving cyclization of the resulting intermediates onto unfunctionalized double bonds.2 Specifically, the three base-catalyzed cl-eavage
50 51 reactions illustrated in Scheme 9 were examined for their intrinsic ability to generate anionic intermediates capable of intramolecular cyclization, viz., R = -(CH2)3CH=CH2 and
-(CH2)4CH=CH2. As expected, the most efficient method of forming both cyclopentanes and cyclohexanes involved decarboxylation to form a reactive carbanion in the absence of a good proton source.3 Significant amounts (33%) of cyclopentanes were also formed in the Haller-Bauer cleavage despite the concurrent generation of a good proton source
(benzamide) in the reaction. Although this cyclization was thought to be primarily anionic in nature, a modest level of radical participation was also feasible. The conceptually related Cram cleavage4 provided only small amounts of cyclized materials.
Scheme 9: C-C Bond Cleavage Reactions
o
Y + (Haller-Bauer)
CH3Li (xcs); HMPA Ph
O
(Cram) (Gilday) 52
In order to ascertain the relative importance of radical intermediates in the phenyl stabilized Haller-Bauer cleavage and thereby provide insight into the above observations, a series of mechanistic investigations were undertaken. Specifically, an assessment has been made of the effects of changes in the chemical nature of the intermediates generated during the course of the
Haller-Bauer, Cram, and Gilday2 cleavage reactions upon possible subsequent ring cleavage [i.e., when R =
-C(CH 3 ,C6H 5)-c-C3H 5 and -C(CH3,C6H5)-c-C4H7] and bond fragmentation (R = CH2OCH2CH=CH2) events. As will become evident, the structural features of the starting materials have been selected to allow as well for additional mechanistic insight to be gained as alterations in the character of the metal cation and solvation environment are implemented.
2. Historical Backdrop.
Conversion of the cyclopropylcarbinyl radical to the
3-butenyl radical is a very fast reaction (k = 1.0 x 108 s"1 at 25 °C) 5 that qualifies it as a distinctfully useful
"radical clock" mechanistic probe.6 The cyclobutylcarbinyl radical is a less strained system7 that exhibits a much slower ring cleavage rate (k = 5.6 x 102 s-1 at 2& °C)8, but continues to play a utilitarian role in assessing relative reaction rates in trapping reactions.9 Expectedly, 53 cyclopropylcarbinyl Grignard10 and lithium reagents11 are also very labile compounds that rearrange to the corresponding allylcarbinyl derivatives at temperatures as low as -40 °C.12 Cyclobutylcarbinylmagnesium bromide experiences ring cleavage at a somewhat slower rate (k =
0.88 x 105 s-1 at 78 °C).13 Both rearrangements are reversible and the extent to which this equilibrium is manifested is dependent upon the degree and nature of the substitution pattern.12,14 Thus, rupture of a cyclopropane or cyclobutane ring is not an exclusive characteristic of a free radical or a carbanionic process, but is common to the two. As a consequence, such reactions cannot per se serve as a distinguishing diagnostic tool. Other associated chemical events are required if the operation of a particular process is to be recognized. This complication does not surface when the probe involves cleavage of a carbon-oxygen bond. In their study of S'H reactions of substituted allyl compounds, Migita and co-workers demonstrated that ethers such as la and lb were unique in their ability to undergo addition of a phenyl radical on the terminal unsaturated carbon to give an adduct (2) that totally resists C-0 bond fragmentation.15 Similarly, Ono et al., have demonstrated that while nitro acetate 3 experiences smooth free radical denitrogenation to 4,- other groups such as N02, SPh, and S02Ph are rapidly lost to give stilbene.16 The ability of 5 to cyclize efficiently to 6 54
(74% isolated yield) is a further reflection of the non-frangibility of C-0 bonds when positioned p to a free radical site.16
Scheme 10: The Stability of p-Carbon-Oxygen Bonds in
Radical Processes.
CH2=CH CHjPR + Ph* PhCH2CHCH20R
1a, R - Et 2 b, R ■ Ph
OAc OAc I AIBN I Ph—CH-CH-Ph Bu3SnH PhCH2—CHPh I CeHe NOz A
AcO, AcO CH.
AIBN CeHe A H
In contrast, the ready conversion of 7 to 5-hexyn-l-ol
(8) in the presence of sodium amide17, and the cathodic reduction of 918 exemplify the ease with which p-alkoxy anions (e.g., 10) eject alkoxide and generate olefinic centers. The intramolecular variant 12/13 (cis/trans =
10:1) represents a clever application of this phenomenon in a synthetic context.19 The intramolecular S'N cleavage of allylic ethers by enolate anions has also recently been discovered to proceed readily.20 55
Scheme 11: 3-Elimination of Oxygen from Carbanionic
Intermediates.
NaNH2 HC=C(CH2)4OH NH3 " a' O ' ' c h 2ci 7
2 e o s o 2c h 3 O 11 9 10
OCH. H-BuLi
•v 12 13
As far as we are aware, this dichotomy of behavior has rarely been utilized to fingerprint the heterolytic/ homolytic course of reactions where both processes can be operative. In fact, the only examples known to us involve
Scheme 12: Elimination in p-Methylstyrenes.
o Ph
Ph
p-methylstyrene oxides related to 14.21 Whereas conversion to radical 15 (from 14-C1, etc) triggers C-C bond homolysis 56 exclusively, deprotonation of 14 (R = H) with lithium diisopropylamide induces unidirectional heterolysis of the
C-0 bond.2 2
B. SUBSTRATE PREPARATION
1.Cycloalkvlphenvl Ketones.
The requisite a-cyclopropyl and a-cyclobutyl starting materials were prepared as shown in Scheme 13. Application
Scheme 13s Preparation of a-Cycloalkyl Derivatives.
1.KOH CICHsjCCfeEt Ph ,C02Et aq. EtOH Ph
1 8 1 9 a, n = 1; b, n « 2
1. Dibal - H 1.LDA Ph OCH. OR CH. CH.
22 21 20 1. PhLi KOH, 2. C r03 • 2 py aq. MeOH OH
PhLi Ph EtaO OH CH. CH. CH.
23 24 25 of the Darzens glycidic ester synthesis23 to cycloalkylphenyl ketones 17a and 17b made available the homologated aldehydes 19. Intermediates 18a and 18b were both obtained as an 8:1 mixture of isomers, the stereochemical features of which were assigned on the basis of their diagnostic NMR spectra (Figure 4). Oxidation to the carboxylic acid level was best realized with alkaline silver nitrate in aqueous ethanol solution. Once esterification was accomplished, the requisite quaternary center was generated by methylation of the respective enolates. The ensuing steps to arrive at 23, 24, and 25 were performed according to precedent.1
8 4.40 - 4.23 83.61
8 3 .9 5 - 3.82 80.88 83.53
8 4 .3 2 -4 .2 0
83.54
8 3.97 - 3.80 8 0.87 83.42
Figure 4: Diagnostic Proton Shifts at 300 MHz in CDC13.
2. 2-Oxa-4-pentenvl Derivatives
Acquisition of the non-cyclic 2-oxapentenyl analogues 58 began by suitable base-promoted condensation of 2624 with formaldehyde to give 27a and allylation of this hydroxy ester. The remaining steps parallel those utilized earlier.
Scheme 14: Preparation of 2-Oxa-4-pentenyl Analogues.
Ph 1.Dbal-H Ph. OCH OCHa 2.Cc02-2py CH CH. C H / CHoOR 2 8 26 27a, R - H b,R-CH2CH=CH2
1. PhLi ' KOH. 2. C K V 2 py MeOH
OH Ph PhPhU Ph OH CH. CH. 29 31 30
C. HALLER-BAUER CLEAVAGES
1. a-Cvclopropvl Ketone
The first cleavage studies involving 23a were carried out with potassium tert-butoxide in refluxing benzene and tert-butyl alcohol as solvents. Although the first of these reactions was heterogeneous, both delivered essentially pure unrearranged hydrocarbon 32 very efficiently (Table 3) . A second series of reactions examined the consequences of 59 utilizing three different amide bases in various solvents to effect the debenzoylation. The changes in product distribution realized as a function of counterion and medium proved to be substantive. For instance, the relative proportion of ring-cleaved product 3325 formed in refluxing benzene was seen to decrease in the order Na+ > Li+ > K+.
The use of sodium or lithium amide in tetrahydrofuran makes possible a dramatic reduction in reaction time with a concomitant decrease in the relative amounts of 33. Rather unexpectedly, the use of sodium amide in n-heptane also resulted in acceleration of the cleavage and decreased production of 33.
Scheme 15: Haller-Bauer Reaction of a-Cyclopropylphenyl
Ketone.
solvent
23a 3 2 3 3
+
CH3 ch3 34 35 60
In line with precedent1,2, arrival at major products 32 and 33 can be concisely interpreted in terms of passage through anionic intermediates. In most of the amide-promoted reactions, 34 and 35 are also formed.
Molecules of this type have long been recognized to stem
from T”Phenylallylcarbinyl free radicals14,26, and we believe that their formation in the present context reflects the minimum percentage of the cleavage process that proceeds by initial C-C bond homolysis (see Discussion).
Table 3: Haller-Bauer Cleavages of 23a.
products, % a reflux base solvent time, h 32 33 34 35 yiel<
KOtBu c 6h 6 20 99 tr 97 KOtBu t-BuOH 20 99 tr 98 k n h 2 c 6h 6 6 90 8 2 41 NaNH2 c 6h 6 12 50 41 7 2 40 NaNH2 THF 3 83 15 1 1 95 NaNH2 heptane 5 63 32 3 2 95 LiNH2 c 6h 6 90 73 19 8 tr 38 LiNH2 THF 1.5 97 3 tr tr 94 LiNH2 THF-C6H6 6 92 6 2 91
“Relative percent based on GC analysis. bYields based on capillary gas chromatography integration areas relative to internal standard. cIsolated yields following preparative gas chromatography.
Samples of 32 and 33 were isolated and identified by comparison of their spectral characteristics with literature values27. The nature of 35 was confirmed by direct GC/MS 61 comparison with a commercial sample. Purified 34 exhibited
1H NMR features identical to those reported earlier.28
2. a-Cvclobutvl Ketone
The product distributions realized upon submission of
23b to similar Haller-Bauer conditions are compiled in Table
4. Each result closely parallels the trends noted earlier for 23a, with the exception that the levels of 37 are significantly reduced. Products related to 34 and 35 were not seen. If the cyclobutylcarbinyl radical was generated, its kinetic stability (due to formation of a seven-membered ring) would preclude intramolecular capture by the phenyl ring. The necessary seven-membered cyclic transition state would also act as a deterrent to the process.
Scheme 16s Haller-Bauer Reaction of a-Cyclobutylphenyl
Ketone.
solvent
23b 3 6 37
The structural assignments to 36 and 37 were arrived at spectroscopically after preparative GC separation. The
E-isomer of 3729 predominated heavily. 62
Table 4: Haller-Bauer Cleavages of 23b.
products, %a
base solvent time, h 36 37 yield, %
KOtBu c 6h 6 20 99 98b KOtBu t-BuOH 20 99 92 b k n h 2 C 6H 6 8 99 1 37 c NaNH2 C 6H 6 14 91 9 46° LiNH2 C 6H 6 114 96 4 35°
See footnotes below Table 3.
3. 2-Oxa-4-pentene Derivative
When 29 was subjected to cleavage conditions, the major product proved to be a-methylstyrene (38), the end result of anticipated rapid 0-elimination within the intermediate anion. Interestingly, the importance of this process is significantly reduced when potassium tert-butoxide in tert—butyl alcohol was employed to promote the cleavage.
Since 39 proved isolable to the extent of 29% (37% GC yield,
Table 5) , these conditions appear to be particularly well suited to efficient proton transfer in advance of competing
C-0 bond heterolysis. Tetrahydrofuran 40 is believed to be the end result of a free radical cyclization. The role of a more acidic solvent in these reactions is thereby highlighted. Although 39 and 40 were not independently synthesized, their spectral properties are fully consistent with the assignments. 63
Scheme 17s Haller-Bauer Cleavage of p-Allylether Analogue.
base solvent CH CH.
3 8
4 0
Table 5: Haller-Bauer Cleavages of 29.
products, % a
base solvent time, h 38 39 40 yield, % b
KOtBu c 6h 6 12 94 4 2 60 KOtBu t-BuOH 12 61 37 2 87 k n h 2 c 6h 6 5 96 4 tr 91 NaNH6 c 6h 6 12 89 8 2 82 LiNH6 c 6h 6 12 99 tr tr 96
See footnotes below Table 3.
D. CRAM FRAGMENTATION STUDIES
1^ B-Cvclooropvl Alcohol
A series of cleavage reactions involving alcohol 24a were carried out in hot benzene or tert-butyl alcohol as solvent with all three alkali metal counterions. The 64 product compositions, compiled in Table 6, are seen to vary appreciably as a function of the reaction conditions.
1-Phenethylcyclopropane (32) was obtained in reasonable amounts (17-41%) when starting from the potassium alkoxide.
A precipitous dropoff to only 4% was realized when the sodium and lithium salts were the starting materials. The cyclopropane cleavage reaction that leads ultimately to 33 is universally unimportant. In contrast, the relative proportions of 34 and 35 in all cases but one (viz.,
KNH2/C6H6) provide indication that the free radical process leading to these naphthalene derivatives does compete.
Scheme 18: Cram Cleavage of the Cyclopropyl Derivative.
OH
+ solvent
24a 41
4 2
When the cleavage of 24a was promoted by potassium amide in benzene, the major product (62%) was determined to be (1,1-diphenylethyl)cyclopropane (41). Evidently, the 65
cyclopropylcarbinyl free radical intermediate is capable of
capturing solvent remarkably well in this instance.
Although phenylation of the homoallylic radical partner does
operate, the proportion of 42 is very low. This alkene
emerged as a principal constituent only when sodium amide in
benzene served as the base/solvent combination. A small
amount of dimer was also isolated by preparative GC as a
dl-/ meso mixture of diastereomers; use of LiNH2 was notably
effective in providing this product (24% isolated).
Table 6: Cram Cleavages of 24a.
products, % yield by GC
base solvent time, h 32 33 34 35 41 42
k n h 2 c 6h 6 11 28 5 62 tr KOtBu c 6h 6 11 17 tr 30 tr 2 tr KOtBu t-BuOH 12 41 tr 9 tr NaNH2 c 6h 6 12 4 3 29 16 tr 15 LiNH2 C6H6 11 4 2 42 tr tr
2. B-Cvclobutvl Alcohol
Behavior similar to that of the cyclopropyl derivative was observed for 24b (Table 7) . Of course, only trace levels of 37 are in evidence because of the diminution in driving force to undergo cleavage of the cyclobutane ring.
This facet of intrinsic reactivity also reduces the -extent to which 44 can be expected to be produced. The smooth conversion to 43 in two runs is as telltale of free radical 66
involvement as it is in the preceding example. Once again,
LiNH2 proved most conducive to dimer formation (37%
isolated).
Scheme 19: Cram Cleavage of the Cyclobutyl Derivative.
solvent
Table 7: Cram Cleavages of 24b.
products, % yield by GC
base solvent time, h 36 37 43 44
k n h 2 c 6h 6 5 29 tr 59 tr KOtBu c 6h 6 12 23 tr 2 tr KOtBu t-BuOH 12 44 tr tr NaNH2 c 6h 6 16 24 22 3 LiNH2 c 6h 6 48 6 7 2 1
3. B-2-Oxa-4-pentenvlalcohol
The results of Cram-type cleavage of 30 are given in
Table 8. Noteworthy here is the significant amount of 67 elimination product observed in each run. Since radical processes are known not to be conducive to the p-elimination of alkoxide at an appreciable rate15,16, an anionic process is most logically implicated here. On the other hand, the isolation of 45 in the LiNH2 experiment provides indication that free radical disprcportdonation is capable of concurrent operation.
Scheme 20: Cram Cleavage of the 2-Oxa-4-Pentenyl Analogue.
OH CH2 Ph base Ph 38 - 40 + solvent CH.
3 0 45
Table 8: Cram Cleavages Of 30.
products, % yield by GC
base solvent time, h 38 39 40 45
k n h 2 c 6h 6 15 98 KOtBu c 6h 6 15 91 3 2 KOtBu t-BuOH 15 93 tr tr NaNH2 c 6h 6 15 89 tr LiNH2 CeHe 42 42 19
E. ANIONIC DECARBOXYLATIONS
The attachment of a small carbocyclic substituent to the a carbon of carboxylic acids as in 25a and 25b has been found 68 to have a deleterious effect on the efficiency of the dissociated ion-pair decarboxylation. For example, treatment of 25a with a large excess of ethereal methyllithium in ether followed by the addition of HMPA delivered 17% of 32 and 1% of 33 as the only identifiable products. The several other components that were present in very minor amounts were not characterized. Comparably extensive degradation was seen during attempts to transform
25a to its methyl ketone (no HMPA added). As concerns 25b, treatment under the standard Gilday conditions afforded 36 in 42% yield.
The decarboxylation of 31 gave a-methylstyrene (38) in
19% yield. Because this alkene experiences extensive decomposition in the presence of methyllithium, our inability to isolate 38 in more robust quantities can be traced directly to this post-decarboxylative side reaction.
F. DISCUSSION
One of the major features of the Haller-Bauer cleavage is its ability to deliver a debenzoylated product, viz., 32 or 36, that has not undergone cyclopropane or cyclobutane ring cleavage. This mechanistically revealing feature is ascribed to the intrinsic preference of adducts 46 (and the corresponding covalent tert-butoxide adducts) to experience heterolysis of the central bond (Scheme 21, path a) with 69 formation of 47 (or the tert-butyl ester) within a solvent shell. The high basicity of the carbanion species in 47 evidently favors proton transfer from the benzamide by-product prior to release from its encased environment.
This interpretation is consistent with earlier stereochemical probing of the Haller-Bauer process (high retention of configuration)1 and the inability of the highly coordinated 47 to undergo cyclization into a suitably tethered double bond.2 The fate of the tert-butyl ester/carbanion pair has been discussed elsewhere1e.
As revealed in Table 3, the role of the metal counterion (M+) and solvent is a significant one. When potassium ions are involved, thecarbanion in 47 is maximally reactive and proton transfer from benzamide is quite effective, particularly in benzene solvent.1,2 When tert-butyl alcohol is the medium, the acidity of the solvent may also play a role contributory to the near-exclusive formation of 32 and 36. The relative amounts of these cyclic hydrocarbons drop off somewhat when Na+ and
Li+ are involved, presumably because the ion pairs are now tighter, the carbanions are longer lived, and the possibility for structural isomerization is enhanced. In these examples, the replacement of benzene by tetrahydrofuran has the effect of providing a more -highly coordinated environment, a situation that is clearly conducive to the enhanced direct capture of 47. 70
Scheme 21: Pathways for the Cram Cleavage.
M M + Ph Ph NH O ^ N H 2 CH CH3 Vx \ 'n Ph
46 4 7 32, 36
n - 1 ,2
M Ph
O Nh 2 ch3 v \ T X:- ' n Ph 4 9
48
To the extent that 33 or 37 is produced, the involvement of free radicals 48 is implicated. Once such reactive intermediates are generated, precedence suggests that conversion to 49 occurs very rapidly.6-9 There remains the question of precisely how 48 materializes. It would not be unreasonable to invoke initial progression along path a
(Scheme 21) to arrive at 47, at which point electron transfer would compete with protonation. This rationalization avoids any mechanistic discontinuity in the early stages, but is dependent on the capacity of benzamide to respond to the proximal carbanion center in two -widely divergent ways (see below). Perhaps more logical is the proposition that bond homolysis within 46 (Scheme 21, path 71
b) is capable of operating alongside the more favored
heterolysis process. The extent to which either process is
involved is strongly dependent on the nature of M+, the
solvent dielectric, and the inherent structural features of
the substrate.
Another approach to the assessment of commonality of
intermediates is reflected in the behavior of 29. The
overwhelming propensity of this heteroatomic system for
elimination to a-methylstyrene is striking. By insisting
that loss of allyloxide can occur only from a carbanion precursor, one simply defines the possible involvement of a
free radical intermediate out of existence. The elevated amounts (37%) of 39 produced in the presence of KOtBu/t-BuOH
stem from effective competitive protonation of the carbanion by solvent.
The Cram fragmentations show a very different product distribution profile. The high efficiency (62%) with which
41 is formed from 24a and KNH2 in C6H 6 constitutes a major diagnostic of the preferred reaction pathway. Advocacy of a carbanion mechanism to explain the covalent incorporation of benzene solvent has no substantive basis of any kind. For this reason, it is argued that 41 is the result of rapid capture of the cyclopropylcarbinyl free radical that is generated as reaction proceeds. As noted above, there are two possible sources of the free radical intermediate 50.
Direct homolytic fission of the central bond in the alkoxide 72 derived from 24a is one of these (Scheme 22) .
Alternatively, heterolytic fission could give rise initially to a solvated complex of the carbanion and
Scheme 22: Mechanisms for Radical Production.
Ph K + k n h 2 2 4 a CeH6 A Ph
50 KNH2> C6H6 A CeHei-H
K
O ^ P h
Ph 51 benzophenone, viz. 51. Arrival at 50 would then transpire by electron transfer back to benzophenone (E vs see = -1.44
V).30 While a distinction between these mechanistic options is not possible at this time, two important points need to be made here. First, electron transfer to benzophenone should occur with considerably greater ease than with either benzamide (E vs Ag/AgCl = 15 V ) 31 or a benzoate ester (e.g., isopropyl benzoate, E vs Hg = -1.76 V).32 The results of the KOtBu/C6H6 or t-BuOH experiments nicely parallel this line of thinking. Furthermore, whatever the actual sequence of events, tight solvation by benzene must be operative 73 since 50 is trapped effectively prior to cyclopropyl ring cleavage in virtually all of the reactions studied. Use of the KOtBu/C 6H 6 combination has the effect of reducing drastically the level of 41 produced (now only 2 %) in favor of the product of intramolecular radical cyclization (34).
The production of naphthalene derivatives predominates in benzene solution when NaNH 2 and LiNH 2 serve as base (Table
6 ) . A closely comparable pattern of behavior is seen for
24b (Table 7).
Remarkably, 30 undergoes Cram cleavage to afford major amounts of a-methylstyrene in most cases (Table 8 ) . Since the conversion to 38 is viewed as a direct consequence of carbanion collapse, one might choose to argue that elimination within 52 is perhaps more rapid than electron transfer to give 53, or that the electron transfer process
52/53 is easily reversible. While this explanation may be a satisfactory one, it is entirely possible that 30 differs totally in its mode of reaction relative to its carbocyclic congeners. As shown in 54, the alkoxide in this particular instance is capable of adopting an antiplanar alignment of sigma bonds that could be especially conducive to synchronous central bond heterolysis with ejection of allyloxide ion. Clearly, mechanistic details are most elusive in this reaction. 74
Scheme 23: Alternate Mechanisms for p-Elimination.
M + Ph Ph
Ph Ph Ph
Ch
54
In the Gilday process, the reaction conditions are too harsh for these systems. The lack of an available proton source constitutes a notable complication in this case because the carbanion intermediates are not capable of surviving for long periods of time. Independent studies have shown that the styrenesformed either by ring cleavage or allyloxide ion loss to be rapidly degraded in the presence of methyllithium.
G. SUMMARY
Present and past observations provide a sound backdrop for the rational application of these three fragmentation reactions in synthesis. Haller-Bauer cleavages proceed 75 predominantly along a carbanion course and enjoy the capacity for capture of the carbanion with almost complete retention of stereogenicity . 1 This property is virtually unrivaled in carbanion chemistry . 33
In contrast, the Cram process favors the transient generation of free radical intermediates. Weakening of the
C-C bond flanking the alkoxide unit of the tertiary carbinol arises for much the same reasons as it does in the oxyanionic Cope rearrangement. Theoretical studies of the latter sigmatropic transformation abound . 34 The free radical bias can be serviceable as a means of degrading carboxylic acids or their benzoyl analogues in a fashion that is complementary to the Haller-Bauer and Gilday schemes.
Finally, the decarboxylation process developed by
Gilday is the most effective known method for degrading carboxylic acids directly and in one laboratory operation into discrete carbanions . 3 Intramolecular cyclization, where feasible, is achieved most efficiently by this protocol . 1 EXPERIMENTAL
Glycidic Ester Condensation with 17a.
>2Et
Potassium metal (4.44 g, 0.113 mol) was dissolved in
dry tert-butyl alcohol (105 ml) and the resulting solution was added slowly with stirring to a solution of ethyl
chloroacetate (13.1 g, 0.107 mol) and cyclopropyl phenyl
ketone (9.76 g, 6 6 . 8 mmol) in dry benzene (35 ml) and
tert-butyl alcohol (15 ml) cooled to °C under argon. The
reaction mixture was allowed to warm slowly to room temperature where stirring was continued for 2 1 h.
Following dilution with water (200 ml), the product was
extracted into pentane (3 x 80 ml) , and the combined
organic phases were washed with water ( 2 x 80 ml) and brine
(80 ml) prior to drying. The solvent was removed in vacuo and the residual oil was chromatographed on silica gel
(elution with 4% ethyl acetate in petroleum ether) to provide 18a as a pale yellow oil (11.3 g, 73%); IR (neat, 77 cm-1) 3080, 3055, 3000, 2980, 1750, 1720, 1445, 1300, 1235,
1195, 1025, 760, 700? XH NMR (300 MHz, CDC1 3 ) (major isomer)
6 7.40-7.24 (m, 5H) , 3.95-3.82 (m, 2H) , 3.61 (s, 1H) ,
1.50-1.41 (m, 1H) , 0.88 (t, J « 7.1 Hz, 3H) , 0.56-0.41 (m,
4H); (minor isomer) 6 7.40-7.24 (m, 5H), 4.40-4.23 (m, 2H),
3.53 (s, 1H) , 1.50-1.41 (m, 1H) , 1.34 (t, J = 7.1 Hz, 3H) ,
0.56-0.41 (m, 4H) ; 13C NMR (75 MHz, CDC1 3 ) ppm (major isomer) ppm 167.12, 136.35, 127.88, 126.86, 65.89, 60.88,
59.08, 16.57, 13.67, 2.50, 1.74; MS m/z (M+) calcd
232.1099, obsd 232.1068.
Anal. Calcd for Ci4Hi603: C, 72.39; H, 6.94. Found:
C, 72.50; H, 7.17.
2-Cyclopropylphenylacetaldehyde (19a).
o
A 11.20 g (48.2 mmol) sample of 18a was added to a solution of potassium hydroxide (15.7 g, 280 mmol) in ethanol (150 ml) and water (0.75 ml). The resulting yellow solution was stirred at room temperature for 2 0 h, acidified with 1 N hydrochloric acid, and stirred until the evolution of carbon dioxide ceased. The product was extracted into pentane (3 x 80 ml) and the combined organic phases were washed with sodium bicarbonate solution (80 ml) and brine 78
(80 ml) prior to drying. Solvent evaporation provided 19a as a pale yellow liquid (5.59 g, 72%) after MPLC on silica gel (elution with 4% ethyl acetate in petroleum ether); IR
(neat, cm-1) 3080, 3020, 2810, 2710, 1718, 1598, 1490, 1450,
1385, 1225, 1025, 825, 760, 702; XH NMR (300 MHz, CDC13) 6
9.74 (d, J = 2.5 Hz, 1H) , 7.56-7.14 (m, 5H) , 2.80 (dd, J =
9.6, 2.3 HZ, 1H) , 1.36-1.23 (m, 1H) , 0.75 (m, 1H) , 0.61 (m,
1H) , 0.37 (m, 1H) , 0.23 (m, 1H) ; 13C NMR (75 MHz, CDC13) ppm 200.31, 136.28, 128.86, 128.59, 127.50, 63.24, 10.92,
4.46, 3.25; MS m/z (M+) calcd 160.0888, obsd 160.0898.
2-Cyclopropylphenylacetic Acid (20a, R = H).
o
A solution of 19a (8.99 g, 56.1 mmol) in ethanol (2 ml) was added to a previously prepared solution of silver nitrate (10.8 g, 63.6 mmol) and sodium hydroxide (6.40 g,
160 mmol) in water ( 6 8 ml) . The resulting mixture was stirred at room temperature for 24 h, filtered through
Celite, and washed with 1 N sodium hydroxide solution. The filtrate and washings were acidified with 2 N hydrochloric acid and extracted with ether (3 x 100 ml) . The combined ethereal phases were washed with brine, dried, filtered, and evaporated to leave the acid as a white solid (5.25 g) . 79
Recrystallization from hexane provided pure 20a (R = H) as colorless crystals, mp 89.5-91.0 °C (11.96 g, 50%); IR (KBr pellet, cm-1) 3100, 1690, 1456, 1418, 1315, 1246, 1232,
1190, 1020, 950, 828, 730, 700; XH NMR (300 MHz, CDC13) 6
9.94 (br s, 1H) , 7.38-7.22 (m, 5H) , 2.80 (d, J = 9.9 Hz,
1H), 1.52-1.39 (m, 1H), 0.69 (m, 1H), 0.56 (m, 1H), 0.39 (m,
1H) , 0.18 (m, 1H) ; 13C NMR (75 MHz, CDC13) ppm 180.09,
138.29, 128.55, 127.98, 127.43, 56.38, 13.88, 4.93, 4.18; MS m/z (M+) calcd 176.0837, obsd 176.0859.
Anal. Calcd for CnHi 202: C, 74.98; H, 6 .8 6 . Found;
C, 74.95; H, 7.04.
Methyl 2-Cyclopropylphenylacetate (20a, R = CH3).
o Ph OCH.
A solution of the preceding carboxylic acid (3.06 g,
17.4 mmol) in dry benzene (100 ml) was treated dropwise with oxalyl chloride (4.55 ml, 6.62 g, 52.2 mmol, 3 eg) via syringe with ice bath cooling and under a dry nitrogen atmosphere. The reaction mixture was stirred with gradual warming to room temperature, maintained at this temperature for 3 h, and evaporated to half-volume on a -rotary evaporator. The residual solution was cooled to 0 °C under a drying tube, whereupon a solution of methanol (5 ml) and 80 pyridine (4.13 g, 4.22 ml, 52.2 mmol) was added dropwise and the temperature was allowed to reach 20 °C. After an additional 3 h, the solution was washed with water (3 x 50 ml) and brine (50 ml). Solvent evaporation provided a yellow liquid, bulb-to-bulb distillation (100-110 °C/0.1
Torr) of which gave 20a as a clear liquid (2.86 g, 8 6 %); IR
(neat, cm-1) 3085, 3040, 3015, 2955, 1737, 1600, 1456, 1436,
1242, 1210, 1160, 1028, 705; XH NMR (300 MHz, CDC13) 6
7.50-7.20 (m, 5H) , 3.68 (s, 3H) , 2.82 (d, J = 10.0 Hz, 1H) ,
1.55-1.38 (m, 1H), 0.75-0.13 (series of m, 4H); 13C NMR (75
MHz, CDC13) ppm 174.19, 138.92, 128.47, 127.81, 127.17,
56.40, 51.92, 14.19, 4.83, 4.11; MS m/z (M+) calcd 190.0994, obsd 190.0982.
Methyl 2-Cyclopropyl-2-phenylpropionate (21a).
o Ph OCH. CH.
To a cold (-78 °C) , magnetically stirred solution of n-butyllithium (3.41 ml of 1.5 M, 5.12 mmol) in dry tetrahydrofuran was added diisopropylamine (570 mg, 5.63 mmol) dropwise, followed 15 min later by 20a (R = CH3) (885 mg, 4.65 mmol) via syringe. The reaction mixture was stirred for 15 min, warmed to °C, treated in one portion with methyl iodide (990 mg, 6.97 mmol), and allowed to reach 81
0 °C slowly. Saturated ammonium chloride solution (10 ml) was introduced and ether (20 ml) was added as a diluent. The organic phase was washed with water (2 x 15 ml) and brine
(15 ml) , dried, and evaporated. Bulb-to-bulb distillation of the residue (100-125 °C at 0.1 Torr) afforded 21a as a clear, colorless oil (931 mg, 98%); IR (neat, cm -1) 3085,
3050, 3000, 2948, 1730, 1600, 1497, 1450, 1384, 1250, 1170,
1120, 1028, 836, 705; *H NMR (300 MHz, CDCI 3 ) 6 7.45-7.17
(m, 5H), 3.67 (s, 3H) , 1.60-1.46 (m, 1H) , 1.25 (s, 3H) ,
0.70-0.27 (series of m, 4H) ; 13C NMR (75 MHz, CDCI 3 ) ppm
176.64, 144.58, 128.18, 126.59, 126.34, 52.01, 50.30, 21.20,
18.12, 2.05, 0.80; MS m/z (M+) calcd 204.1150, obsd
204.1182.
2-Cyclopropyl-2-phenylpropionaldehyde (22a).
o
A cold (-10 °C) , magnetically stirred solution of 21a
(9.27 mg, 4.54 mmol) in dry dichloromethane (50 ml) was treated dropwise under argon with diisobutylaluminum hydride
(13.6 ml of 1.0 M in hexane, 13.6 mmol). After 1 h, methanol ( 1 0 ml) was cautiously added to the mixture, followed by 50 ml of saturated Rochelle salt solution, and stirring was maintained for 1.5 h with warming to room 82 temperature. Following dilution with ether (100 ml), washing of the organic phase with water (2 x 50 ml) and brine (50 ml) , and drying, the solvent was evaporated to leave the alcohol as a clear oil that was purified by
Kugelrohr distillation at 130-160 °C/0.1 Torr. There was isolated 796 mg (99%) of colorless liquid; IR (neat, cm-1)
3390, 3085, 3060, 3010, 2965, 2935, 2880, 1600, 1497, 1445,
1025, 832, 765, 705; XH NMR (300 MHz, CDC13) 6 7.60-7.15 (m,
5H) , 3.87-3.66 (m, 2H), 1.41 (br s, 1H), 1.20-1.05 (m, 1H),
1.06 (s, 3H), 0.60-0.20 (m, 4H); 13C NMR (75 MHz, CDC13) ppm
145.42, 128.28, 126.22, 71.65, 42.39, 10.51, 18.12, 2.22,
0.77; MS m/z (M+) calcd 176.1201, obsd 176.1226. A stock solution of the Collins reagent was prepared by adding pyridine (13.6 g, 172 mmol) dropwise to a mechanically stirred suspension of chromium trioxide (8.58 g, 85.8 mmol) in dry dichloromethane (160 ml). After 20 min, an appropriate portion of this reagent (ca 50 ml) was transferred via cannula into a cold (0 °C), vigorously stirred solution of the alcohol (766 mg, 4.40 mmol) in dichloromethane (5 ml) . After 1 h, the reaction mixture was poured into ether ( 1 0 0 ml), the resulting suspension was filtered through silica gel (ether elution), and the filtrate was evaporated. Kugelrohr distillation (100-125 °C
/0.1 Torr) of the residue provided 677 mg (89%) of 22a as a colorless liquid; IR (neat, cm-1) 3085, 3055, 3010, 2980,
2938, 2870, 2804, 2704, 1720, 1600, 1492, 1445, 1384, 1225, 1077, 1030, 834, 764, 705; XH NMR (300 MHz, CDC13) 6 9.57
(s, 1H), 7.46-7.19 (m, 5H), 1.40-1.28 (m, 1H), 1.15 (s, 3H),
0.75-0.24 (series of m, 4H) ; 13C NMR (75 MHz, CDC13) ppm
201.47, 141.36, 128.68, 127.37, 127.19, 53.21, 17.59,
15.31, 1.17, 0.41; MS m/z (M+-CH0) calcd 145.1008, obsd
145.1017.
2-Cyclopropyl-2-phenylpropiophenone (23a).
o
Ph
A cold (-78°C), magnetically stirred solution of 22a
(645 mg, 3.70 mmol) in dry ether (60 ml) was blanketed with argon and treated dropwise with phenyllithium (5.6 ml of 2
M, 11 mmol). After 30 min, water (10 ml) was introduced and the mixture was allowed to warm to room temperature. The organic phase was washed with water (2 x 30 ml) and brine
(30 ml) , dried, and concentrated. The resulting viscous yellow oil (1 . 0 2 g) was used without further purification.
A cold (0 °C), magnetically stirred solution of the preceding carbinol in dichloromethane (5 ml) was treated with Collins reagent prepared as described above. After 3 h, the usual workup was followed and the product ketone was purified by MPLC on silica gel (elution with 2% ethyl acetate in petroleum ether). There was isolated 750 mg 84
(81%) of 23a as a white solid, mp 61.5-62.5 °C; IR (KBr, cm-1) 3070, 3015, 2985, 2935, 1674, 1595, 1490, 1445, 1384,
1245, 1170, 1023, 964, 914, 842, 770, 705; XH NMR (300 MHz,
CDC13) 6 7.60-7.15 (series of m, 10H), 1.63-1.50 (m, 1H),
1.20 (s, 3H), 0.76-0.10 (series of m, 1H); 13C NMR (75 MHz,
CDC1 3 ) ppm 202.60, 145.11, 136.86, 131.41, 129.69, 128.77,
127.63, 126.27, 126.64, 54.48, 22.12, 18.14, 2.74, 0.17; MS m/z (M+-C 7 H 50) calcd 145.1018, obsd 145.1036.
Anal. Calcd for Ci 8H i 80: C, 86.36; H, 7.25. Found: C,
86.19; H, 7.28.
2-Cyclopropyl-l,l,2-triphenylpropanol (24a).
OH
A cold (-78°C), magnetically stirred solution of 23a
(290 mg, 1.16 mmol) in dry ether (20 ml) was treated dropwise with phenyllithium (1.5 ml of 2.0 M, 3.0 mmol), stirred for 1 h at this temperature, quenched with saturated ammonium chloride solution, and allowed to warm to 20 °C.
The separated organic layer was washed with water (2 x 10 ml) and brine (10 ml) , dried, and evaporated. The clear, glassy 24a solidified on standing (310 mg, 81%) , mp- 78-81
°C; IR (KBr, cm-1) 3540, 3440, 3060, 3030, 1595, 1493, 1442,
1382, 1157, 1030, 1007, 763, 730, 705; XH NMR (300 MHz, 85
CDC13) 6 7.52-7.02 (series of m, 15H) , 3.32 (s, 1H) ,
1.57-1.42 (m, 1H) , 1.12 (s, 3H) , 0.74-0.43 (series of m,
3H) , 0.19-0.05 (m, 1H) ; 13C NMR (75 MHz, CDC13) ppm 145.54,
145.09, 143.95, 129.88, 128.88, 128.26, 127.18, 126.81,
126.29, 83.65, 50.34, 18.06, 17.64, 4.50, 2.14; MS m/z
(M+-Ci 3Hi 0 O) calcd 145.1017, obsd 145.1046.
2-Cyclopropyl-2-phenylpropionic Acid (25a).
o Ph OH CH.
To a solution of 21a (1.50 g, 7.34 mmol) in methanol
(20 ml) was added potassium hydroxide pellets (4.12 g, 73.4 mmol). The solution was heated at reflux for 4 h. Methanol was removed using a rotary evaporator and the resulting off-white solid was dissolved in water (35 ml). The aqueous solution was extracted with ether (15 ml), acidified with 1 N hydrochloric acid and extracted with dichloromethane (3 x 40 ml). The combined dichloromethane extracts were dried and evaporated to give the acid as a white solid (1.40 g) . Recrystallization from hexane provided pure 25a as clear, rhomb-shaped crystals (1.26 g,
90%); mp 90.55 °C; IR (KBr, c m -1) 3000 (br) , 1685,- 1600,
1575, 1492, 1440, 1395, 1290, 1280, 1124, 1085, 1014, 932,
819, 763, 725, 700; XH NMR (300 MHz, CDC13) 6 11.05 (br S, 86
1H) , 7.52-7.20 (series of m, 5H) , 1.66-1.52 (m, 1H) , 1.27
(s, 3H) , 0.75-0.30 (series of m, 4H) ; 13C NMR (75 MHz,
CDCI 3 ) ppm 182.64, 143.77, 128.26, 126.80, 126.56, 50.10,
20.67, 18.11, 2.08, 1.09; MS m/z (M+) calcd 190.0994, obsd
190.1012.
Anal. Calcd for C 1 2 H 1 4 O 2 : C, 75.76; H, 7.42. Found:
C, 75.89; H, 7.46.
Glycidic Ester Condensation with 17b.
Reaction of cyclobutyl phenyl ketone (12.00 g, 74.9 mmol) with ethyl chloroacetate (14.69 g, 120 mmol) in the presence of potassium tert-butoxide (127 mmol) as described above gave an orange oil (20.6 g) . Purification by distillation furnished 18b as a clear, colorless oil, bp
117-119 °C/0.1 Torr (12.67 g, 69%); *H NMR (300 MHz, CDC13)
(major isomer) 8 7.35-7.20 (m, 5H), 3.97-3.80 (m, 2H), 3.59
(s, 1H) , 3.17-3.05 (m, 1H) , 1.99-1.48 (m, 6 H) , 0.87 (t, J =
7.2 Hz, 3H) ; (minor isomer) 6 7.38-7.25 (m, 5H) , 4.32-4.20
(m, 2H), 3.42 (s, 1H), 3.10-3.03 (m, 1H), 2.07-1.54 (m, 6 H ) ,
1.34 (t, J = 7.2 Hz, 3H) ; 13C NMR (75 MHz, CDCl3) (major isomer) ppm 167.63, 135.48, 127.81, 127.74, 126.81, 67.04,
60.84, 57.04, 39.54, 23.99, 21.75, 16.94, 13.67; (minor 87
isomer) ppm 167.42, 137.99, 128.15, 127.83, 126.60, 6 6 .8 6 ,
61.37, 60.42, 36.80, 25.38, 23.58, 18.25, 14.15; MS m/z (M+) calcd 246.1256, obsd 246.1249.
Anal. Calcd for Ci 5H i 803: C, 73.15; H, 7.36. Found:
C, 73.01; H, 7.43.
2-Cyclobutylphenylacetaldehyde (19b).
O
A solution of 18b (17.75 g, 72.06 mmol) in ethanol (210 ml) containing water (1 ml) and potassium hydroxide (24.26 g, 0.432 mol) was stirred at room temperature under argon for 20 h. The major portion of the ethanol was removed at 50
°C and 20 Torr on a rotary evaporator, and the residual material was dissolved in water and acidified with concentrated hydrochloric acid. The product was extracted into pentane (2 x 1 0 0 ml) and the combined pentane layers were shaken with 10% potassium hydroxide solution (2 x 75 ml) . The combined alkaline washings were reacidified as before, heated at reflux for 3 h, and extracted with pentane (2 x 100 ml). The combined pentane layers were washed with 10% potassium hydroxide solution (2 x 75 ml) and all pentane extracts (ca 400 ml) were washed with brine
(100 ml), dried, and evaporated. Purification of the 88 aldehyde was achieved by column chromatography (silica gel, elution with 3% ethyl acetate in petroleum ether): 6.53 g
(52%) of clear, colorless 19b was isolated; IR (neat, cm-1)
3070, 3035, 2980, 2870, 2820, 2715, 1720, 1600, 1495, 1455,
1353, 1250, 1030, 760, 703; XH NMR (300 MHz, CDC13) 6 9.62
(d, J = 2.5 Hz, 1H) , 7.55-7.14 (m, 5H) , 3.52 (dd, J = 10.5,
2.5 Hz, 1H) , 3.04-2.85 (m, 1H) , 2.26-1.70 (m, 6 H) ; 13C NMR
(75 MHz, CDCl3) ppm 200.33, 135.10, 128.87, 128.82, 127.43,
65.63, 35.59, 27.49, 26.52, 18.58; MS m/z (M+) calcd
174.1045, obsd 174.1098.
2-Cyclobutylphenylacetic Acid (20b, R = H).
O
Oxidation of 19b (2.95 g, 16.9 mmol) with silver nitrate (3.54 g, 20.8 mmol) and sodium hydroxide (2.10 g,
52.4 mmol) in water (22 ml) and ethanol (1 ml) in the manner detailed earlier gave 2.29 g (71%) of 20b (R = H) as a white solid, mp 112.5-113.5 °C (from hexane); IR (KBr, cm-1)
3000, 2980, 2860, 2700, 1700, 1455, 1420, 1310, 1290, 1230,
1200, 940, 728, 703; XH NMR (300 MHz, CDC13) 6 10.15 (br s,
1H), 7.32-7.21 (m, 5H), 3.53 (d, J = 10.8 Hz, 1H), 3.00-2.91
(m, 1H), 2.23-2.17 (m, 1H), 1.91-1.76 (m, 4H), 1.60-1.54 (m,
1H) ; 13C NMR (75 MHZ, CDC13) ppm 179.38, 137.04, 128.52, 89
128.23, 127.37, 58.07, 38.10, 27.53, 26.40, 17.83; MS m/z
(M+) calcd 190.0994, obsd 190.1023.
Anal. Calcd for C 1 2 H 1 4 O 2 : C, 75.76; H, 7.42. Found:
C, 75.85; H, 7.56.
Methyl 2-Cyclobutylphenylacetate (20b, R = C H 3).
o
Ph
A solution of carboxylic acid 20b (R = H) (2.20 g, 11.6 mmol) in benzene (5 ml) was added to a solution of pyridine
(2.01 g, 25.4 mmol) and thionyl chloride (1.65 g, 13.9 mmol) in benzene (15 ml) and stirred at room temperature for 6 h.
Methanol (5 ml) was introduced and after 2 h of stirring the mixture was diluted with ether (50 ml), and washed in turn with 1 N hydrochloric acid (2 x 25 ml) , water (25 ml) , saturated sodium bicarbonate solution (25 ml), and brine prior to drying. Solvent evaporation and Kugelrohr distillation (100-125 °C/0.1 Torr) of the residue gave 20b
(R = C H 3) as a clear, colorless oil (2.10 g, 89%); IR (neat, cm"1) 3070, 3040, 2980, 2870, 1728, 1498, 1455, 1435, 1300,
1160, 1008, 735, 700; XH NMR (300 MHz, CDC13) 6 7.32-7.20
(m, 5H) , 3.63 (s, 3H) , 3.54 (d, J = 10.9 Hz, 1H) , 3.10-2.91
(m, 1H), 2.29-2.14 (m, 1H), 1.94-1.72 (m, 4H), 1.71-1.55 (m,
1H) ; 13C NMR (75 MHz, CDC13) ppm 173.61, 137.61, 128.42, 90
128.03, 127.11, 77.43, 77.00, 76.58, 58.09, 51.71, 38.46
27.46, 26.37, 17.80; MS m/z (M+) calcd 204.1150, obsd
204.1179.
Methyl 2-Cyclobutyl-2-phenylpropionate (21b).
O
CH
Methylation of 20b (R = CH3) (2.10 g, 10.3 mmol) with lithium diisopropylamide (11.3 mmol) and methyl iodide (2.19 g, 15.4 mmol) as before and final bulb-to-bulb distillation
(125-145 °C/0.1 Torr) furnished 2.22 g (99%) of 21b as a clear, colorless oil; IR (neat, cm-1) 3100, 3050, 2990,
2950, 2870, 1725, 1600, 1495, 1445, 1378, 1240, 1130, 1034,
970, 865, 740, 700; XH NMR (300 MHz, CDC13) 6 7.33-7.17 (m,
5H) , 3.64 (s, 3H), 3.18-3.05 (m, 1H) , 2.04-1.60 (series of m, 6 H) , 1.52 (s, 3H) ; 13C NMR (75 MHz, CDC13) ppm 176.25,
143.04, 128.18, 126.51, 126.24, 52.36, 51.81, 42.53, 24.25,
24.12, 20.13, 17.40; MS m/z (M+) calcd 218.1307, obsd
218.1250. 91
2-Cyclobutyl-2-phenylpropionaldehyde (22b).
o PhX^H 1 c h 3
Reduction of 21b (1.20 g, 5.50 mmol) with diisobutylaluminum hydride (16.5 mmol) in the predescribed fashion gave after Kugelrohr distillation (120-140 °C/0.1
Torr) 1.04 g (99%) of the carbinol as a colorless oil? IR
(neat, cm"1) 3395, 3090, 3060, 3030, 2975, 2940, 2865,
1600, 1496, 1445, 1376, 1026, 761, 702; XH NMR (300 MHz,
CDCl 3 ) 6 7.45-7.16 (m, 5H), 3.79 (dd, J = 10.8, 3.0 Hz, 1H),
3.53 (dd, J = 10.8, 6.4 Hz, 1H), 2.80-2.66 (m, 1H),
1.95-1.53 (series of m, 6 H), 1.32 (s, 3H), 1.16 (br s, 1H);
13C NMR (75 MHz, CDCl3) ppm 144.04, 128.29, 126.90, 126.08,
69.63, 44.68, 42.68, 23.71, 23.61, 18.33, 17.70; MS m/z (M+) calcd 190.1358, obsd 190.1370. Collins oxidation of the alcohol (1.03 g,5.57 mmol) in dichloromethane (10 ml) at 0
°C provided 22b as a clear, colorless liquid (945 mg, 93%) after Kugelrohr distillation (100-130 °C/0.1 Torr); IR
(neat, cm"1) 3090, 3060, 3028, 2980, 2945, 2870, 2810,
2710, 1720, 1600, 1495, 1448, 1033, 903, 765, 705; XH NMR
(300 MHz, CDCl 3 ) 69.58 (s, 1H), 7.55-7.12 (m, 5H),
3.16-2.98 (m, 1H) , 2.14-1.65 (series of m, 6 H) , 1.-40 (s,
3H) ; 13C NMR (75 MHz, CDC13) ppm 202.60, 139.86, 128.66,
127.30, 127.06, 55.81, 40.08, 24.03, 23.74, 18.11, 16.70; MS 92
m/z (M+) calcd 188.1201, obsd 188.1249.
2-Cyclobutyl-2-phenylpropiophenone (23b).
o ph^Aph — I c h 3
Exposure of 22b (920 mg, 4.89 mmol) to phenyllithium
(15 mmol) gave 1.51 g of carbinol as a viscous yellow oil that was directly oxidized with Collins reagent. MPLC purification of the crude product (silica gel, elution with
1.5% ethyl acetate in petroleum ether) provided pure 23b as a colorless oil (1.09 g, 85%); IR (neat, cm-1) 3060, 3030,
2980, 2945, 2870, 1674, 1595, 1578, 1495, 1446, 1378, 1245,
968, 704; 1H NMR (300 MHz, CDCl3) 6 7.55-7.13 (series of m,
10H) , 3.34-3.16 (m, 1H) , 2.03-1.52 (series of m, 6 H ) , 1.58
(s, 3H); 13C NMR (75 MHz, CDC13) ppm 203.00, 143.19, 136.89,
131.46, 129.49, 128.66, 127.81, 126.66, 56.52, 42.85, 24.35,
23.93, 20.74, 17.92; MS m/z (M+-C 7H 5 0) calcd 159.1172, obsd
159.1229.
Anal. Calcd for Ci 9H 2 oO: C, 86.32; H, 7.63. Found:
C, 86.36; H, 7.69. 93
2-Cyclobutyl-l,1,2-triphenylpropanol (24b)
OH
Treatment of 23b (300 mg, 1.14 mmol) with phenyl lithium (3.0 mmol) in dry ether (20 ml) according to precedent gave 377 mg (97%) of 24b as a colorless glass following MPLC on silica gel (elution with 2% ethyl acetate in petroleum ether); IR (neat, cm-1) 3620, 3050, 2970, 2850,
1595, 1490, 1444, 1152, 1020, 760, 740, 708; XH NMR (300
MHz, CDCl 3 ) 5 7.45-6.84 (series of m, 15H), 3.43-3.26 (m,
1H) , 2.41 (s, 1H) , 2.14-1.95 (m, 1H) , 1.94-1.20 (series of m, 5H) , 1.46 (s, 3H) ; 13C NMR (75 MHz, CDC13) ppm 145.50,
144.68, 142.86, 129.76, 128.76, 127.82, 127.13, 127.00,
126.80, 126.50, 126.00, 84.18, 51.64, 42.06, 26.36, 25.34,
17.82, 17.62; MS the molecular ion was too transient for high resolution measurement; MS/FAB m/z (M+) calcd 342.2, obsd 342.2.
2-Cyclobutyl-2-phenylpropionic Acid (25b). o
Heating 21b (1.10 g, 5.04 mmol) with potassium hydroxide (2.83 g, 50.4 mmol) in methanol (10 ml) for 14 h, 94 followed by the customary workup provided 25b (937 mg, 91%) as colorless crystals, mp 102-103 °C (from pentane-ether);
IR (KBr, cm-1) 3000 (br), 1683, 1600, 1442, 1400, 1280,
1141, 1030, 933, 731, 703; XH NMR (300 MHz, CDC13) 6 10.75
(br s, 1H), 7.45-7.14 (m, 5H) , 3.24-3.06 (m, 1H), 2.10-1.55
(series of m, 6 H), 1.55 (s, 3H); 13C NMR (75 MHz, CDC13) ppm
182.37, 142.16, 128.22, 126.77, 126.43, 52.11, 42.34, 24.27,
24.03, 19.61, 17.35; MS m/z (M+) calcd 204.1150, obsd
204.1158.
Anal. Calcd for Ci 3 H i 60 2 : C, 76.44; H, 7.90. Found:
C, 76.43; H, 7.88.
Methyl 2-(Hydroxymethyl)-2-phenylpropionate (27a).
o
A solution of 26 (10.00 g, 60.9 mmol) in dry tetrahydrofuran (25 ml) was added dropwise to a solution of lithium diisopropylamide (70 mmol) in the same solvent cooled to °C. While vigorously stirred, the reaction mixture was allowed to warm to -20 °C, at which point gaseous formaldehyde was introduced for 30 min. Following a quench with 70 ml of 1 N hydrochloric acid, the product was extracted into ether (3 x 40 ml) and the combined ethereal phases were washed with 1 N hydrochloric acid (70 ml), water 95
(70 ml), saturated sodium bicarbonate solution (70 ml), and brine (70 ml) before drying. Solvent evaporation left a yellow liquid (13.2 g), Kugelrohr distillation of which
(130-150 °C/0.05 Torr) provided 27a as a colorless oil
(10.85 g, 92%); IR (neat, cm-1) 3480 (br), 2955, 2882, 1723,
1497, 1446, 1240, 1126, 1048, 1030, 702? XH NMR (300 MHz,
CDCl3) 6 7.37-7.26 (m, 5H) , 4.09-4.03 (m, 1H), 3.71 (s, 3H),
3.68-3.59 (m, 1H) , 2.54 (t, J = 6.4 Hz, 1H) , 1.66 (s, 3H) ?
13C NMR (75 MHz, CDC13) ppm 176.46, 140.36, 128.57, 127.29,
126.12, 69.64, 52.64, 52.24, 20.00; MS the molecular ion peak was observed, but was too transient for high resolution measurement.
Methyl 2-Methyl-2-phenyl-4-oxa-6-heptenoate (27b). o
Ph OCH, CH
Sodium hydride (2.28 g, 92.3 mmol) was placed in a dry flask under argon. Dimethylformamide (25 ml) , tetrahydro- furan (50 ml), and allyl bromide (11.2 g, 92.3 mmol) were added and the mixture was cooled to 0 °C. A solution of 27a
(6.00 g, 30.1 mmol) in dry tetrahydrofuran (25 ml) was added dropwise and the mixture was stirred vigorously for 1 h, poured cautiously over ice, and extracted with ether (3 x 80 ml). The combined organic phases were washed with water (2 96 x 80 ml) and brine (80 ml) , dried, and evaporated.
Chromatography of the residue on silica gel (elution with
4% ethyl acetate in petroleum ether) provided 27b (4.81 g,
6 6 %) as a colorless oil; IR (neat, cm"1) 3070, 3030, 2990,
2955, 2855, 1733, 1600, 1498, 1447, 1435, 1240, 1142, 1093,
992, 928, 704; XH NMR (300 MHz, CDC13) 6 7.40-7.20 (m, 5H),
5.95-5.76 (m, 1H) , 5.32-5.10 (m, 2H) , 4.10-3.92 (m, 2H) ,
4.01 (d, J = 8 . 8 Hz, 1H), 3.68 (s, 3H), 3.64 (d, J = 8 . 8 Hz,
1H) , 1.66 (s, 3H) ; 13C NMR (75 MHz, CDC13) ppm 175.04,
141.25, 134.70, 128.42, 127.06, 126.01, 116.69,75.82,
72.43, 52.11, 51.61, 21.18; MS the molecular ion peak was observed, but was too transient for high resolution measurement.
2-Methyl-2-phenyl-4-oxa-6-heptenal (28).
O
A 3.00 g (12.8 mmol) sample of 27b was reduced with diisobutylaluminum hydride (38.4 mmol) in the predescribed manner. The usual workup gave 2.59 g (98%) of the carbinol; IR (neat, c m -1) 3430, 3060, 3030, 2975, 2935,
2865, 1600, 1498, 1446, 1085, 1045, 1030, 925, 765, 702; lH
NMR (300 MHz, CDC13) 6 7.54 (m, 5H) , 5.98 (m, 1H) , 5.46 (m,
2H) , 4.01 (d, J = 5.6 Hz, 2H) , 3.82 (d, J = 9.2 Hz, 1H) , 97
3.60 (d, J = 9.2 HZ, 1H) , 4.00-3.42 (m, 2H) , 2.39 (br S,
1H) , 1.34 (s, 3H) ; 13C NMR (75 MHz, CDC13) ppm 143.58,
134.36, 128.36, 126.47, 126.43, 117.16, 77.57, 72.47, 70.39,
43.86, 21.07; MS the molecular ion peak was observed, but was too transient for high resolution measurement.
Oxidation of this carbinol (2.59 g, 12.6 mmol) with the
Collins reagent (100 mmol) was accomplished as detailed earlier. Kugelrohr distillation (150-180 °C/1 Torr) of the crude product furnished 28 (2.22 g, 86%) as a clear, colorless oil; IR (neat, cm-1) 3085, 3060, 3030, 2980,
2935, 2855, 2710, 1722, 1642, 1600, 1495, 1445, 1265, 1090,
925, 760, 700; XH NMR (300 MHz, CDC13) 8 9.61 (s, 1H), 5.92
(m, 1H) , 5.30 (m, 2H) , 4.10 (m, 3H) , 3.70 (d, J = 9.4 Hz,
1H) , 1.51 (s, 3H) ; 13C NMR (75 MHz, CDC13) ppm 201.43,
138.34, 134.27, 128.68, 127.32, 126.88, 116.89, 73.68,
72.34, 54.78, 18.04; MS m/z (M+-CHO) calcd 175.1123, obsd
175.1097.
2-(2-Oxa-4-pentenyl)-2-phenylpropiophenone (29).
o
Ph Ph CH.
Condensation of 28 (2.12 g, 10.4 mmol)- with phenyllithium (31 mmol) in ether (100 ml) at °C in the predescribed manner gave the carbinol as a viscous yellow 98 oil, which was used without purification. Oxidation of this material with Collins reagent prepared from 8.30 g (83 mmol) of chromium trioxide and 13.14 g (166 mmol) of pyridine in cold (-10 °C) dichloromethane (180 ml) was performed in the usual way. MPLC purification of the crude product on silica gel (elution with 2.5% ethyl acetate in petroleum ether) gave 29 as a colorless oil (2.19 g, 75% overall); IR
(neat, cm-1) 3060, 3030, 2980, 2930, 2865, 1674, 1598,
1447, 1250, 1097, 979, 930, 766, 704; XH NMR (300 MHz,
CDCl 3 ) 6 7.56-7.15 (series of m, 10H), 5.80-5.62 (m, 1H),
5.22-5.00 (m, 2H) , 4.04 (d, J = 9.1 Hz, 1H) , 3.90-3.80 (m,
2H) , 3.75 (d, J = 9.1 Hz, 1H) , 1.71 (s, 3H) ; 13C NMR (75
MHz, CDCl 3 ) ppm 202.57, 141.79, 137.03, 134.67, 131.44,
129.15, 128.89, 127.81, 127.12, 126.35, 116.49, 76.44,
72.39, 55.70, 22.60; MS m/z (M+-C 3H 5 0) calcd 223.1122, obsd
223.1099.
Anal. Calcd for C 1 9 H 2 0 O 2 : C, 81.40; H, 7.19. Found:
C, 80.99; H, 7.22.
2-Methyl-1,l,2-triphenyl-4-oxa-6-hepten-l-ol (30).
OH
Treatment of 29 (500 mg, 1.78 mmol) in cold (-78 °C) anhydrous ether (30 ml) with phenyllithium (5.3 mmol) in 99 the manner previously detailed gave 750 mg of a pale yellow oil. MPLC purification (silica gel, elution with 2.5% ethyl acetate in petroleum ether) provided pure 30 as a colorless, very viscous oil that solidified on standing (595 mg, 93%);
IR (neat, cm"1) 3435, 3070, 3020, 2930, 2860, 1595, 1492,
1445, 1075, 1029, 755, 705; NMR (300 MHz, CDC13) 6
7.57-7.06 (series of m, 13H), 6.84-6.70 (m, 2H) , 5.95-5.73
(m, 1H), 5.76 (S, 1H), 5.35-5.14 (m, 2H), 4.08 (d, J = 9 Hz,
1H) , 3.97-3.84 (m, 2H) , 3.54 (d, J = 9.1 Hz, 1H) , 1.61 (s,
3H) ; 13C NMR (75 MHz, CDCl 3 ) ppm 145.47, 144.17, 143.19,
133.58, 128.86, 128.45, 128.21, 127.13, 127.01, 126.92,
126.60, 126.56, 117.69, 82.95, 78.13, 72.65, 50.44, 22.17;
MS m/z (M+-C 1 3 HhO) calcd 175.1123, obsd 175.1115.
2-Methyl-2-phenyl-4-oxa-6-heptenoic Acid (31). o
OH CH.
A 1.51 g (6.44 mmol) sample of 27b in methanol (20 ml) was heated at reflux with potassium hydroxide (3.62 g, 64.5 mmol) for 14 h. Workup in the predescribed manner and
Kugelrohr distillation (140-160 °C/0.1 Torr) furnished 31 as a colorless viscous oil (1.31 g, 92%); IR (neat, cm'1) 3000
(br), 1700, 1600, 1496, 1445, 1405, 1100, 928, 761, 700; XH
NMR (300 MHZ, CDC13) 6 10.62 (br S, 1H), 7.55-7.20 (m, 5H), 100
5.96-5.77 (m, 1H) , 5.34-5.10 (m, 2H) , 4.15-3.96 (m, 2H) ,
4.02 (d, J = 8.9 Hz, 1H), 3.64 (d, J = 8.9 Hz, 1H), 1.65 (s,
3H) ; 13C NMR (75 MHz, CDCl 3 ) ppm 180.27, 140.40, 134.37,
128.50, 127.34, 126.19, 117.16, 75.37, 72.57, 51.43, 21.05;
MS m/z (M+) calcd 220.1099, obsd 220.1082.
Anal. Calcd for Ci 3H i 603: C, 70.89; H, 7.32. Found;
C, 70.49; H, 7.38.
General Conditions for Haller-Bauer and Cram Cleavages. The substrate (0.042 mmol) was dissolved in the appropriate dry solvent so as to make a 0.04 M solution, and an accurately weighed amount (ca 6 mg) of n-undecane was introduced as the internal standard. The base (ca 15 equiv for potassium salts, 30 equiv for sodium salts, and 45 equiv for lithium salts) was next added and the reaction mixture was heated at reflux under an argon atmosphere. The progress of reaction was monitored by GC or TLC analysis and heating was maintained until the starting material had been completely consumed. At this point, the excess base was quenched by means of saturated ammonium chloride solution. The product(s) was (were) extracted into pentane ( 1 0 ml), and washed with water (3 x 10 ml) and brine (10 ml) prior to drying. Analysis by GC and GC/MS permitted yields to be calculated. Product isolation was accomplished by careful concentration to a volume of approximately 0.5 ml followed by preparative GC purification (11 ft x 0.25 in. 5% SE on 101
Chromosorb P, 165-175 °C for the hydrocarbons of MW < 200);
1.5 m x 0.25 in. 5% SE-30 on Chromosorb W, 135-145 °C for hydrocarbons having MW above 200).
1-Phenethylcyclopropane (32).
IR (neat, cm"1) 3080, 3030, 3005, 2970, 2930, 2875,
1600, 1495, 1453, 1373, 1030, 826; XH NMR (300 MHz, CDC13) 8
7.45-7.10 (m, 5H) , 2.10-1.90 (m, 1H) , 1.33 (d, J = 7.0 Hz,
3H) , 1.02-0.85 (m, 1H) , 0.63-0.50 (m, 1H) , 0.50-0.36 (m,
1H) , 0.28-0.10 (m, 2H) ; 13C NMR (75 MHz, CDC13) ppm 147.33,
128.18, 126.95, 125.83, 44.60, 21.54, 18.51, 4.56, 4.28; MS m/z (M+) calcd 146.1096, obsd 146.1090.
(E)-2-Phenyl—2-pentene (33).
XH NMR (300 MHz, CDC13) 8 7.45-7.15 (series of m, 5H),
5.85-5.74 (m, 1H) , 2.27-2.15 (m, 2H) , 2.03 (d, J = 1.0 Hz,
3H), 1.06 (t, J = 7.5 Hz, 3H); MS m/z (M+) calcd 146. 102 l-Methyl-3,4-dihydronaphthalene (34)
XH NMR (300 MHz, CDC13) 8 7.33-7.08 (series of m, 4H),
5.90-5.80 (in, 1H) , 2.84-2.71 (m, 2H) , 2.32-2.18 (m, 2H) ,
2.05 (S, 3H); GC/MS m/z (M+) 144.
1-Phenethylcyclobutane (36).
XH NMR (300 MHz, CDC13) 8 7.42-7.10 (m, 5H) , 2.68-2.52
(m, 1H) , 2.51-2.36 (m, 1H) , 2.22-2.04 (m, 1H) , 1.90-1.50
(series of m, 5H) , 1.14 (d, J = 6.9 Hz, 3H) ; MS m/z (M+) calcd 160.1252, obsd 160.1252. Anal. Calcd for C i 2H i 6: C,
89.94; H, 10.06. Found; C, 89.91; H, 10.13. 103
(E)-2-Phenyl-2-hexene (37)
CH,
*H NMR (300 MHz, CDC13) 6 7.50-7.10 (series of m, 5H),
5.85-5.74 (m, 1H) , 2.25-2.10 (m, 2H) , 2.03 (d, J = 0.8 Hz,
3H) , 1.60-1.39 (m, 2H) , 0.96 (t, J = 7.3 Hz, 3H) ? GC/MS m/z
(M+) 160.
6-Phenyl-4-oxahept-l-ene (39).
*H NMR (300 MHz, CDC13) 6 7.42-7.08 (m, 5H) , 5.97-5.78
(m, 1H) , 5.27-5.08 (m, 2H) , 4.02-3.95 (m, 2H) , 3.64-3.40 (m,
2H), 3.10-2.94 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H)? GC/MS m/z
(M+) 176. 104
3,4-Dimethyl-3-phenyltetrahydrofuran (40).
CH.
CH.
1H NMR (300 MHz, CDC13) 6 7.46-7.15 (m, 5H) , 3.97 (s,
1H) , 3.95 (s, 1H) , 3.65-3.41 (m, 2H) , 1.65-1.56 (m, 1H) ,
1.44 (S, 3H), 1.30 (d, J = 7.0 Hz, 3H); GC/MS m/z (M+) 176.
(1,1-Dipheriylethyl)cyclopropane (41).
Ph ph A
XH NMR (300 MHz, CDCl3) 8 7.42-7.11 (series of m, 10H),
1.54 (s, 3H), 1.51-1.46 (m, 1H), 0.56-0.45 (m, 2H),
0.20-0.10 (m, 2H) ? 13C NMR (75 MHz, CDC13) ppm 149.27,
128.02, 127.61, 125.67, 26.23, 21.86, 1.81, 0.00; MS m/z
(M+) calcd 222.1408, obsd 222.1432. 105
2,5-Diphenylpent-2-ene (42).
Phw H ^3
XH NMR (300 MHz, CDC13) 6 7.45-7.10 (series of m, 10H),
5.88-5.76 (m, 1H) , 2.77 (t, J = 8.1 Hz, 2H) , 2.59-2.45 (m,
2H) , 1.97 (d, J =0.7 Hz, 3H); GC/MS m/z (M+) 222.
2,3-Dicyclopropyl-2,3-diphenylbutane.
Phw Ph ch,TTCHs
XH NMR (300 MHz, CDC13) 8 7.46-7.05 (series of m, 10H),
1.80-1.31 (series of m, 2H) , 1.04 (s, 3H from one diastereomer), 0.98 (s, 3H from other diastereomer), 0.75 to
-0.20 (series of m, 8H) ; GC/MS m/z (M+/2) calcd 145, obsd
145. 106
(1,1-Diphenylethyl)cyclobutane (43)
Ph Ph
CH.
XH NMR (300 MHz, CDC13) 6 7.28-7.02 (series of m, 10H)f
3.23-3.08 (m, 1H) , 1.92-1.44 (series of m, 6H), 1.60 (s,
3 H ) ; MS m/z (M+) calcd 236.1565, obsd 236.1572.
2,3-Dicyclobutyl-2,3-diphenylbutane.
Ph Ph
XH NMR (300 MHz, CDC13) 6 7.45-^7.05 (series of m, 10H) ,
3.40-3.20 (m, 1H) , 3.02-2.85 (m, 1H) , 2.33-1.85 (series of m, 4H) , 1.83-1.15 (series of m, 8H) , 1.40 (s, 3H from one diastereomer), 1.29 (s, 3H from other diastereomer); 13C NMR
(75 MHz, CDC13) ppm 144.06, 143.64, 129.69, 129.43, 126.23,
125.40, 125.29, 49.83, 41.50, 41.31, 26.63, 26.47, 25.78,
25.34, 17.75, 16.96, 16.74; MS m/z (M+/2) calcd 159.1174, obsd 159.1196. 107
2-Phenyl-4-oxa-l,6-heptadiene (45).
CH,
Ph
XH NMR (300 MHz, CDC13) 8 7.53-7.12 (series of m, 5H),
6.01-5.80 (m, 1H) , 5.52 (d, J = 0.7 Hz, 1H) , 5.35 (d, J =
1.2 Hz, 1H) , 5.33-5.00 (m, 2H) , 4.37 (d, J = 0.8 Hz, 2H) ,
4.04 (dt, J = 5.6, 1.2 Hz, 2H) ; MS m/z (M+) calcd 174.1045, obsd 174.1055.
Product Stability Studies. Purified product (ca 5 mg) and an approximately equal amount of n-undecane in dry benzene
(2 ml) was treated with sodium amide (195 mg) and heated at reflux under argon with magnetic stirring. Aliquots were periodically removed, quenched with saturated ammonium chloride solution, and analyzed by capillary GC. The results are compiled in Table 9. In separate experiments,
32 and 36 also proved to be stable to potassium amide during
12 h of heating. The partial destruction witnessed for 33 and 37 proved to be quite variable and is attributed to the presence of adventitious oxygen. Less stringent conditions were utilized for the other products. This involved simply extending the reflux period for an additional 12 h after complete consumption of starting material. In all cases, the cyclic products were stable and the olefinic products 108 were decomposed to the extent of 5-10% depending upon the base/solvent system employed. In other experiments,
a-methy1styrene was almost completely destroyed by methylllthlum In ether or lithium dlisopropylamide In tetrahydrofuran.
Table 9: Product Stability Studies
Compd Reflux time, h Percent rel to n-undecane
32 0 57.5 10 57.5 24 57.0 36 0 61.2 12 61.0 24 61.1 33 0 31.2 10 25.4 24 21.0 37 0 48.6 10 43.7 24 40.1
General Decarboxylation Conditions. The appropriate carboxylic acid (30 mg) along with n-undecane (internal standard) were dissolved in dry ether (5 ml) under argon in a dry 25 ml round-bottomed flask. The solution was cooled to 0 °C and treated dropwise with methyllithium-lithium bromide complex in ether (2.2 ml of 1.0 J5, ca 14 equiv).
The cooling bath was removed and the reaction mixture was stirred for 30 min at room temperature. The cooling bath was replaced and HMPA (2.0 ml) was introduced. A deep 109 red-brown color appeared immediately. The cooling bath was removed and stirring was continued for 4 h. After returning the solution to 0 °C, 5% citric acid solution was carefully added to be followed by water. The organic phase was washed with water (3 x 10 ml), dried, and analyzed by capillary GC. TLC showed no remaining acid to be present in all cases. 110
REFERENCES
1. (a) Paquette, L. A.; Uchida, T.; Gallucci, J. C. J. Am. Chem. Soc. 1984, 106, 335. (b) Paquette, L. A.; Gilday, J. P.; Ra, C. S. Ibid. 1987, 109, 6858. (c) Paquette, L. A.; Gilday, J. P.; Ra, C. S.; Hoppe, M. J . Org. Chem. 1988, 53, 704. (d) Paquette, L. A.; Gilday, J. P. Ibid. 1988, 53, 4972. (e) Paquette, L. A.; Ra, C. S. Ibid. 1988, 53, 4978. (f) Gilday, J. P.; Gallucci, J. C.; Paquette, L. A. Ibid. 1989, 54, 1399. (g) Gilday, L. A.; Maynard, G. D.; Ra, C. S.; Hoppe, M. Ibid. 1989, 54, 1408. 2. Paquette, L. A.; Gilday, J. P.; Maynard, G. D. J. Org. Chem. 1989, 54, 5044.
3. Gilday, J. P.; Paquette, L. A. Tetrahedron Lett. 1988, 29, 4505.
4. (a) Cram, D. J. ; Langemann, A.;Allinger, J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81, 5740. (b) Cram, D. J . ; Langemann, A.; Hauck, F. Ibid. 1959, 81, 5750. (c) Cram, D. J.; Kopecky, K. R.; Hauck, F.; Langemann, A. Ibid. 1959, 81, 5154. (d) Cram, D. J.; Langemann, A.; Lwowski, W.; Kopecky, K. R. Ibid. 1969, 81, 5760 and later papers in this series.
5. (a) Newcomb, M. ; Glenn, A. G. J. Am. Chem. Soc. 1989, 111, 275. (b) Mathews, L.; Warkentin, J. Ibid. 1986, 108, 7981. (c) Mail lard, B.; Forrest, D.; Ingold, K. U. Ibid. 1976, 98, 7024.
6. (a) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 317. (b) Beckwith, A. L. J. ; Ingold, K. U. In Rearrangements in Ground and Excited States; de Mayo, P., Ed.; Academic: New York, 1980; Vol. 1, Essay 4. (c) Surzur, J. M. In Reactive Intermediates; Abramovitch, R. A.; Ed.; Plenum: New York, 1981; Vol. 2, Chapter 2. (d) Newcomb, M.; Curran D. P. Acc. Chem. Res. 1988, 21, 206.
7. Kaplan, L. J. Org. Chem. 1968, 33, 2531.
8. Moad, G. Ph.D. Thesis, University of Aldelaide, 1976. Ill
(a) Beckwith, A. L. J. Abstc. Colloq. Int. CURS, Radicaux Libres Org. 1977, 7. (b) Hill, E. A.; Thiessen, R. J.; Cannon, C. E.; Miller, R.; Guthrie, R. B. ,* Chen, A. T. J. Org. Chem. 1976, 41, 1191. (c) Hill, E. A.; Harder, C. L . ; Wagner, R . ; Meh, D . ; Bowman, R. F. J. Organometal. Chem. 1986, 302, 5.
10. Patel, D. J.; Hamilton, C. L.; Roberts, J. D. J. Am. Chem. Soc. 1965, 87, 5144.
11. Lansbury, P. T. ? Pattison, V. A.; Clement, W. A.; Sidler, J. D. J. Am. Chem. Soc. 1964, 86, 2247.
1 2 . Review: Hill, E. A. J. Organometal. Chem. 1975, 91, 123.
13. Hill, E. A.; Hallade, M. W. J. Organometal. Chem. 1988, 352, 263.
14. For example: (a) Howden, M. E. H. ; Maercker, A.; Burdon, J . ; Roberts, J. D. J. Am. Chem. Soc. 1966, 88, 1732. (b) Maercker, A.; Roberts, J. D. Ibid. 1966, 88, 1742. (c) Halgren, T. A.; Howden, M. E. H.; Medof, M. E . ; Roberts, J. D. Ibid. 1967, 89, 3051.
15. Migita, T.; Kosugi, M.; Takayama, K. ; Nakagawa, Y. Tetrahedron 1973, 29, 51.
16. Ono, N.; Miyake, H.; Kami-mura, A.; Hamamoto, I.; Tamura, R.? Kaji, A. Tetrahedron 1985, 41, 4013. See also Beckwith, A. L. J . ; Glover, S. A. Austr. J. Chem. 1987, 40, 157.
17. (a) Englington, G.; Jones, E. R. H.; Whiting, M. C. J. Chem. Soc. 1952, 2873. (b) Paquette, L. A.; Begland, R. W. J. Am. Chem. Soc. 1968, 90, 5159.
18. Shono, T. ; Matsumura, Y.; Tsubata, K. ; Sugihara, Y. Tetrahedron Lett. 1979, 2157. See also Walling, C. Tetrahedron 1985, 41, 3887.
19. Broka, C. A.; Lee, W. J.; Shen, T. J. Org. Chem. 1988, 53, 1338.
20. Paquette, L. A.; Reagan, J.; Schreiber, S. L. ; Teleha, C. A. J. Am. Chem. Soc. 1989, 111, 2331.
21. Johns, A.; Murphy, J. A.; Patterson, C. W.; Wooster, N. F. J. Chem. Soc., Chem. Commun. 1987, 1238. 112
22. 8-Cleavage of the C-O bond does operate in other less ideally constructed oxiranecarbinyl radical systems: (a) Davies, A. G.; Muggleton, B. J. Chem. Soc., Perkin Trans. 2 1976, 502. (b) Davies, A. G. ; Tse, M.-W. J. Organometal. Chem. 1978, 155, 25.
23. Elliott, M.; Farnham, A. W.; Janes, N. F.; Johnson,D. M . ; Pulman, D. A. Pestic Sci. 1980, 11, 513.
24. Francalanci, F.; Gardano, A.; Abis, L.; Fiorani, T.; Foa, M. J. Organomet. Chem. 1983, 243, 87.
25. James, B. R. ; Young, C. G. J. Organomet. Chem. 1985, 285, 321.
26. (a) Maercker, R. ? Roberts, J. D. J. Am. Chem. Soc. 1966, 88, 1742. (b) Trahanovsky, W. S.; Ong, C. C. J. Am. Chem. Soc. 1970, 92, 7174. (c) Wilt, J. W. In Free Radicals, Volume 1, Kochi, J. K.; Ed.; Wiley, New York, 1973, pp 433-437.
27. Smith, M. B. ; Hrubiec, R. T. J. Org. Chem. 1984, 49, 385.
28. Adamczyk, M.; Watt, D. S.; Netzel, D. A. J. Org. Chem. 1984, 49, 4226.
29. Mohan, A. G.; Conley, R. T. J. Org. Chem. 1969, 34, 3259.
30. Kalinowski, M. K.; Grabowski, Z. R.; Pakula, B. Trans. Faraday Soc. 1966, 62, 918.
31. Horner, L.; Singer, R. Liebigs Ann. Chem. 1969, 723, 1.
32. Ilyasov, A. V.; Kargin, Y. M.; Levin, Y. A.; Morosova, I. I.? Sotnikova, N. N.; Ivanova, V. K.; Safin, R. T. Izv. Akad. Nauk SSSR, Ser. Khim. 1968, 736.
33. Cram,' D. J. The Fundamentals of Carbanion Chemistry, Academic Press, New York, 1965.
34. (a) Rozeboom, M. D.; Kiplinger, J. P.; Bartmess, J. E. J. Am. Chem. Soc. 1984, 106, 1025. (b) Steigerwald, M. L.; Goddard, W. A., Ill; Evans, D. A, Ibid. 1979, 101, 1994. (c) Evans, D. A.; Baillargeon, D. L. Tetrahedron Lett. 1978, 3315, 3319. (d) Epiotis, N. D. J. Am. Chem. Soc. 1973, 95, 1101, 1200, 1206, 1214. (e) Carpenter, B. K. Tetrahedron 1978, 34, 1877. (f) Ahlgren, G. Tetrahedron Lett. 1979, 915. (g) Bach, R. D.; Coddens, B. A., private communication. CHAPTER III
STEREOSELECTION VIA THE ANIONIC OXY-COPE REACTION
A. INTRODUCTION
1. Overview of the Anionic Oxv-Cope Reaction
Recent numerous publications in the field of natural product synthesis have demonstrated the utility of the oxyanion-accelerated Cope rearrangement.1 The combination of low reaction temperature, customarily favorable thermodynamic driving force, and excellent stereoselectivity generally associated with the process make the anionic oxy-Cope rearrangement ideally suited for the simultaneous elaboration of multiple stereocenters in relatively complex molecules. The value of this methodology is further enhanced by the expanding availability of optically active oxy-Cope precursors.2
In general, [3,3] sigmatropic processes such as the anion-accelerated variants of the Cope and Claisen rearrangement are known to proceed via an early transition state that resembles a cyclohexane chair conformation.3 A boat transition state becomes viable only in instances where
113 some unusual geometric constraint precludes access to a low energy chair-like alignment of the 1,5-hexadiene termini.4
For simple systems, the difference in energy between the chair and boat transition structures has been calculated to be about AAG*=5.8 kcal/mol.5 Thus, for acyclic systems and for cyclic systems devoid of unusual constraints, boat transition states are not usually accessible. Despite extensive application of the oxy-Cope reaction and various theoretical investigations6, little is known about the factors that determine the oxyanion orientation in the transition state.
Several cases are known where rearrangement occurs via a chair-like transition state having a pseudoaxial oxyanion.
For example, alkoxides 1 and 2 follow this pathway.7
Scheme 24: Rearrangements with an Axial Oxyanion.
o KH H 5 H Dioxane 115
On the other hand, anionic oxy-Cope rearrangements proceeding through a chair transition structure with an equatorial bond are also common. Alkoxides 3 and 4 illustrate this option.8
Scheme 25: Rearrangements with an Equatorial Oxyanion.
H OMe
KH Diglyma A 3 OMe
HO H 18-Crown-6 CHO THF.A
Of course, many cases are known where both possible chair-like transition structures contribute to product formation. This situation appears to occur when the
1,5-hexadiene is devoid of steric features that strongly differentiate one possible chair from the other. For this reason, acyclic derivatives often proceed through both possible chair transition structures.
Two recently published studies serve to illustrate some of the factors affecting oxyanion orientation in acyclic derivatives.9 As illustrated in Scheme 26, le Noble employed the oxy-Cope rearrangement as a means of examining the electronic influence of a remote fluorine substituent on 116 the adamantane skeleton with regard to facial selectivity.
In an ancillary finding, that the solvated oxyanion was found to effectively compete for equatorial status with the phenyl substituent attached to the same carbon. The authors calculated that the equatorial preference for a phenyl substituent in the absence of the electronic effect imparted by fluorine would be 73%.
Scheme 26: le Noble's Study of Facial Selectivity.
Ph L * o ~ Ph
F
<*<0"
A simple Boltzman distribution calculation showed the difference in energy between the two possible chairs in the 117
absence of fluorine to be only 0.67 kcal/mol. While this
seems to indicate an exceedingly large steric demand
associated with the oxyanion, this interpretation ignores
any potential electronic contribution from the phenyl
substituent. This analysis would be of greater interest if
additional derivatives with different substituents attached
to the carbon bearing the oxyanion had been studied.
Unfortunately, the corresponding unsubstituted derivative 5 was not successfully rearranged by the authors using
potassium hydride in refluxing tetrahydrofuran.
Nakai and co-workers studied the rearrangement of the
various isomers of 4-hydroxy-3-methyl-1,5-heptadienes and
related the resulting alkene configuration in the aldehyde
product to oxyanion orientation in the transition state as
shown in Scheme 27. Their data clearly illustrate that the
steric bulk associated with the oxyanion is significant but
perhaps not as large as surmised by le Noble. The best
indication of the steric bulk of the oxyanion is given by
the rearrangement of 9. Here, the oxyanion and a methyl
group compete for equatorial position, with the methyl group
assuming the equatorial orientation 65% of the time during
rearrangement. This suggests a significantly larger steric
demand by the oxyanion than that ascribed to a simple
hydroxyl group, although apparently smaller than that
exerted by a methyl group. Scheme 27: Nakai's Oxy-Cope Study.
H H( O ' J 99%
H HO
3, C/ — 7 ^ H 8
O H HO 65% 9
Although the results are somewhat variable, one can correctly deduce from these studies and other examples from the natural product field that the oxyanion imposes significant steric demand. The shortcoming of each of the previously described studies with 1,5-hexadienes is that other factors change in the transition state simultaneously with the orientation of the oxyanion. This creates a situation where the transition states involved are non-equivalent even in the absence of a differing oxyanion orientation. Thus, one is forced to contemplate the effect of oxyanion orientation by mathematically factoring out the estimated contributions of other important influences. 119
2. Strategy for the Present Oxy-Cope Study
H, o h H OH 1 0 . (fl) 11. (fl)
12, (a/?,5S), (aS,5R) 13, (aR,5R), (aS,5S) H OH
(CH3)3C (CH3)3C
,\H 14, (aR.1fl.4S), P H 1S,(a/?,1S,4/7), (aS,1S4fl) (aSi1^4S)
CH. ,CH. CH. •CH.
HO ,OH 16, (a/7,1 S,4fl) CH. CH.
Figure 5: Oxy-Cope Substrates Selected for this Study.
A study usefully complementary to those described in the previous section would embody only changes of stereochemistry at the carbon atom bearing the oxyanion. In systems with only one chiral center and with no features inducing n-face selectivity, the resulting transition structures will differ energetically only by virtue of oxyanion orientation. Provided the starting allyl alcohol is optically and isomerically pure, the oxanion orientation in the transition structure can be inferred from the 120 absolute configuration of the newly created stereocenter in the product. Such is the case for dienes 10 and 11. A second classification of substrates in such a study encompasses derivatives such as 12-17 that possess known preferred modes of bond formation (n-face selectivity) by means of favorable steric or stereoelectronic effects. Here the preferences imparted by the oxyanion will alter the resulting distribution of diastereomeric products.
This line of thought led to selection of the compounds shown in Figure 5 for submission to oxy-Cope rearrangement conditions.
B. SYNTHESIS OF OXY-COPE PRECURSORS
1. (E) and (Z)-1.5-Heptadien-3-ols
Since chirality transfer is to be utilized as a probe of oxyanion orientation in the transition states associated with the rearrangements of 10 and 11, it is imperative that the starting alcohols be both isomerically and optically pure. To this end, double bond forming strategies were chosen which were known to lead almost exclusively to the formation of a single geometric isomer. Optical purity was achieved by Sharpless kinetic resolution and confirmed by
Mosher ester analysis.
As shown in Scheme 28, reaction of racemic 3-buten-2-ol with allyl bromide in the presence of aqueous sodium 121 hydroxide under phase transfer conditions cleanly provided the diallyl ether 18. Treatment of 18 with n-butyllithium in tetrahydrofuran at -85 °C followed by gradual warming to
0 °C gave almost exclusively the (£)-isomer10 of l,5-heptadien-3-ol with typical runs producing only 2-5% of the corresponding (Z)-isomer based on capillary GC analysis.
Subsequent Sharpless kinetic resolution of 19 was achieved using cumene hydroperoxide to oxidize the somewhat unreactive terminal double bond.11 Residual cumene alcohol was removed by chromatography after work-up. After this purification, only a trace of (Z) -isomer contaminant could be detected by capillary GC analysis. The product 10 was determined to be optically pure by preparing its Mosher
Scheme 28: Preparation of (3R,5E)-l,5-heptadien-3-ol.
NaOH O. + ((/7-Bu)4NOH)t n-BuLi, THF H-jo OH -85-0°C 18 T
(+)-DIPT H OH Ti(0-APr)4 H OH PhMe2C-OOH [“ Id 25 ■ +3.4° CH2CI2l 3 A sieves 19 -20 °C 10
ester and comparing it with the Mosher esters12 obtained from racemic material 19. The Mosher esters resulting from
19 could be differentiated by capillary GC, proton NMR, 122 carbon-13 NMR, and fluorine-19 NMR. A table of fluorine-19 resonances are provided in Appendix D.
Of the routes explored for the preparation of
(3R,5Z)-1,5-heptadien-3—ol (11), the one outlined in Scheme
29 proved most efficient.13 Reaction of tri-n-butyltin hydride with 3-(phenylsulfonyl)-1-butene in the presence of
AIBN in refluxing benzene provided after chromatography and distillation tri-n-butylcrotyl tin 20 as an isomeric mixture. Reaction of 20 with an equimolar amount of freshly distilled acrolein and 1.5 equivalents of di-n-butyltin dichloride at room temperature over 24 h gave a 59% yield of
21 which was contaminated by only a trace amount (<1%) of
(E)-isomer. The amount of undesired (E)-isomer obtained varied from run to run and reached a maximum of 4%.
Subsequent Sharpless kinetic resolution as outlined previously gave optically pure 11 which was free from detectable isomeric contamination. This was confirmed by
Mosher ester analysis (Appendix D).
Scheme 29s Preparation of (3R,5Z)-l,5-heptadien-3-ol.
Bu3SnH, Bi^SnC^ AIBN Bu3S n ^ ^ x ^ ^ C H 3 Acrolein t H OH PhSO. 20 21 (+)-DIPT Ti(0-/-Pr)4 PhMe2C-OOH CH2CI2, 3 A sieves -20 °C 11 123
2. Preparation of tert-Butvlcvclohexene Derivatives
The synthesis of 12 and 13 was designed in such a way as to permit the use of the readily available starting material 4-tert-butylcyclohexanone. Thus, Vilsmeier-Haack reaction of 4-tert-butylcyclohexanone produced the corresponding p-chloro-a,p-unsaturated aldehyde which was immediately reduced to alcohol 22 using
Meerwein-Ponndorf-Verley conditions in order to minimize decomposition14. The vinyl chloride functionality was then reduced with metallic sodium in the presence of tert-butyl alcohol to give 23.15
Initially, it appeared from the reports of Cohen et al that the most efficient route to 26 could be achieved by a reductive metalation strategy.16 To this end, 23 was efficiently converted to the thiophenyl derivative 24 by treatment with a 1.1 equivalents of N-(thiophenyl)- succinimide and 1.1 equivalents of tri-n-butylphosphine in dichloromethane.17 Unfortunately, treatment of 24 with lithium N,N-dimethylaminonaphthalenide (LDMAN) gave very inconsistent results. Modification of the reaction conditions as well as the method used in preparing the
LDMAN did not improve the situation. Eventually, this route was abandoned and recourse was made to Grignard chemistry as outlined in Scheme 30. 124
Scheme 30s Preparation of tert-Butylcyclohexene Derivatives.
OH (f-BuOH) Et20
P h S -N 1. M g\THF SPh 1. LDMAN 2. CeCI3, -78 °C 2. CeCI3 3. Acrolein 3. Acrolein (CH3)3C 25a, X=Br 25b, X=CI
1. M g\ THF .OH 2. Acrolein
2 7
Conversion of allylic alcohol 23 to bromide 25a or chloride 25b was readily effected. Subsequent generation of the Grignard reagent, however, was plagued by the formation of dimers. Use of large excesses of magnesium (100-fold) and activation of the magnesium surface by such techniques as reaction with 1,2-dibromoethane proved ineffective.
Recourse to the Barbier reaction was not considered feasible since the initially formed allyl magnesium would be expected to react at the most substituted terminus to form 27.18 125
Greater success was achieved by using 325 mesh
magnesium which had been activated by reversible
complexation with anthracene in tetrahydrofuran with
sonication.19 Using this activated magnesium, Grignard
reaction could be effected without extensive dimer
formation. Results were best when the chloride 25b was
used. As expected, reaction of the resulting allylic
Grignard reagent with acrolein produced a 20:1 mixture of 27
and 26.
Addition via cannula of the initially formed Grignard
reagent to 1.5 equivalents of cerium(III) chloride in
tetrahydrofuran at -78 °C produced the yellow colored
allylcerium reagent.16* Subsequent addition of freshly
distilled acrolein led to exclusive formation of 26 as a 1:1 mixture of racemic diastereomers 12 and 13.
As expected, direct separation of the (aR,5R), (aS,5S)
and (aR,5S), (aS,5R) diastereomeric pairs proved
troublesome. These materials could not be differentiated by
MPLC, HPLC, or capillary GC. Recourse to silver nitrate
impregnated silica gel columns produced no separation.
Likewise, derivatization to various esters did not enhance
separation attempts.
It was reasoned that this difficulty might be overcome by rigidifying the structures involved and bringing the diastereomeric centers into closer proximity. To this end,
26 was treated with N-bromosuccinimide as shown in Scheme 126
31.20 Initially, it was hoped that selective trans diaxial attack on one of the possible bromonium ions would lead to exclusive formation of 28 and 29. Instead, both bromonium ions leading to formation of furans proved reactive and the adducts 30 and 31 were formed in significant amounts.
Subsequent chromatographic separation provided an inseparable mixture of 28 and 29 as well as diastereomerically pure 30 and 31.
Scheme 31: Bromoetherification Reaction
OH H NBS CHaCfe/CCL, (CH3)3C
22 2 8 2 9 NOE
NOE NOE
30
As shown in Scheme 32, separate treatment of 30 and 31 with metallic sodium in ether at reflux provided pure 13 and
12, respectively. The relative configuration of 13 was established by formation of the crystalline derivative 32 and its subsequent x-ray analysis (See Appendix E). This 127 knowledge, in combination with NOE studies of the bromoethers as outlined in Scheme 31, permitted structural assignments to be made. The inseparable mixture of 28 and
29 was also reduced with sodium and the resulting diastereomeric mixture of alcohols was re-subjected to bromoether formation. A small amount of various bromoepoxides was also formed in the bromoetherification reaction. This material was also recycled.
Scheme 32: Bromoether Reduction
H H
4 -0 2NCsH6C0CI C ^Cfe, pyridine H (CH3)3C h" o p n b x-ray crsystal structure determined 3 2 H H (CH3)3C (CH3)3C A 12 (a/7,5 S). (aS.5/7) 31 H 3. Synthesis of Norbornene Derivatives Vilsmeier-Haack reaction of norbornanone under various conditions proceeded in low yield. Consumption of starting 128 material proceeded slowly and the resulting aldehyde was susceptible to rapid decomposition. A review of the literature revealed that a potential alternate route from norbornanone via the Shapiro reaction of the corresponding tosylhydrazone would proceed in low yield.21 Based on these findings, the route outlined in Scheme 33 was developed. Dibromination of norbornene by irradiation in the presence of 1,2-dibromotetrachloroethane produced the dibromide 33 with only a small amount of skeletal rearrangement.22 Subsequent treatment of 33 with freshly prepared potassium tert-butoxide provided pure 34 after simple distillation. Vinyl bromide 34 can be transformed into the vinyllithium reagentby metal-halogen exchange. Its condensation with butadiene monoxide would then deliver 35. A potentially serious drawback to this methodology was the problem of regioselective nucleophilic addition to a molecule having three reactive electrophilic sites. However, literature reports describing success with this type of reaction exist.23 Specifically, it has been reported that cuprates and organomagnesiums add to butadiene monoxide at the 2'-position, simple organolithiums predominantly add at the 2-position, and only "hard" nucleophiles add predominantly at the 1-position. Vinyllithiums fall into the latter category. 129 Scheme 33: Synthesis of Norbornene Derivatives. 275 W sunlamp BrCCfeCCfeBr f-BuLi, THF, -78 °C ecu ' £fsgr A. r .O'C 3 3 Br 3 4 if H nH Chromatography w ' 10%AgNO3on * J h,,~oh silica gel a-Naphthylisocyanate CH2CI2, pyridine HN ' * ’Hard* nucleophiles RMgX RU 2 R CuU 3 6 x-ray crystal structure (a/?,1 R.4S) and (aS,1 S,4fl) In the present context, formation of the vinyllithium from 34 in tetrahydrofuran at -78 °C followed by warming to 0 °C and treatment with butadiene monoxide led to a mixture of adducts. Under these conditions, the desired product 35 accounted for approximately 70% of the observed addition products. The oxy-Cope precursor 35 was susceptible to polymerization during purification and storage. In this case, it was found that 35 could be separated into its component (aR,lR,4S), (aS,15,45) and (aR,l5,4R), (a5,lR,45) racemates by MPLC on a silver nitrate-impregnated column. The level of diastereomeric purity was established 130 by carbon-13 NMR. The relative configuration was assigned by x-ray analysis of the crystalline 1-naphthylurethane 36 (Appendix E). 4. Synthesis of Camphene derivatives In contrast to the reported behavior of norbornanone, Shapiro methodology is known to work well for camphor. Furthermore, the efficiency of the process can be maximized by use of the 2,4,6-triisopropylphenyhydrazone derivative 37 rather than the more commonly used tosylhydrazone.24 As outlined in Scheme 34, combination of this Shapiro methodology with regioselective addition to butadiene monoxide provided particularly rapid access to 38. In this instance, the regioselectivity was lower than previously observed for norbornenyllithium. This may be an artifact of changing from tetrahydrofuran to a hexane/TMEDA solvent system. In this case, no product of addition at the 2-position of butadiene monoxide was isolated. Presumably, the hindered camphenyllithium tends to react exclusively at the 1- and 2'-positions. As described for the norbornane derived alcohols 35, 38 could be separated into its component diastereomers by chromatography using silver nitrate-impregnated silica gel. The weaker interaction of the more hindered 38 with adsorbent made multiple recyclings necessary. 131 Since an optically pure starting material was used in this instance, the resulting product consisted of only the (a£,lR,4S) and (aR,lS,AR) diastereomers. Thus, it proved experimentally more convenient to separate the diastereomers only partially by chromatography and then perform a Sharpless kinetic resolution. Scheme 34: Synthesis of Camphene Derivatives. 1. n-BuLi, TMEDA/hexane ______-50to0°C r HCI/H2O . CH(CH3)2 2 ^ S 9 > ,0 ° C 3 o CH3 NNHS02-4 ^-CH(CH3)2 (1 fl)-(+)-Camphor 37 CH(CH3)2 CH(CH3)2 .CH. ,CH. a: H 2NNHSOz CH(CH3)2 CH. CH CH(CH3)2 + OH CH. CH. 38 3 9 Chromatography 1 0 %AgNC> 3 on silica gel (+)-DIPT Ti(0-f-Pr)4 [alo25 “ +4-3° PhMe2C-OOH J hc\ , h CH2CI2.3 A sieves c h 3 -8°C 16. (afl.1H.4S) Mostly (a/l1/?,4S) ,CH. CH. (-)-DIPT Ti(0-/-Pr)4 [a]D25 - -27.6° //HO. H PhMe2C-OOH CH. CH3 CH2Cl2,3 A sieves -8 °C Mostly (a/?,1S,4fl) 132 The reactivity pattern displayed by both antipodes in the Sharpless epoxidation also permitted assignment of absolute configuration. Specifically, only 16 (aR) remained after Sharpless kinetic resolution employing (+)-diisopropyl tartrate as additive. Conversely, 17 (otS)was obtained from the reaction when (-)-diisopropyl tartrate (Scheme 34). Structural assignments were then made in accordance with well established trends11. It should be noted that the potential for ready conversion of the undesired adduct 39 to 38 exists. A typical procedure might involve vanadium-catalyzed epoxidation of the allylic double bond followed by titanium(III)-induced reductive elimination 2 5 to give 38. Because ample material was available to complete the desired study, this option was not explored. C. ANIONIC OXY-COPE REARRANGEMENTS 1. Acyclic Derivatives As shown in Scheme 35, the anionic oxy-Cope rearrangement of 1 0 and 1 1 could be accomplished in good yield only under rather specific conditions. First of all, it was observed that the use of potassium hexamethyldisilazide as base provided only trace amounts of the desired aldehyde, with extensive decomposition occurring 133 prior to complete consumption of starting material. Presumably, the hexamethyldisilazane present in the reaction mixture is a sufficiently good proton source to lead to decomposition of the sensitive aldehyde formed in the reaction. Potassium tert-butoxide was observed to suffer from the same disadvantage. A related instability led to low yields on thermally activating 10. Heating 10 with decal in in a sealed tube for 10 h at 300 °C was usually sufficient to provide for complete reaction. Unfortunately, the best yield of product obtained under these conditions was 13% and the material thus obtained showed no significant rotation of plane-polarized light. Reaction of 10 with excess potassium hydride in either tetrahydrofuran or dimethoxyethane at room temperature or with heating also produced low yields (3-6% via GC). Use of potassium hydride that had been treated with lithium aluminum hydride via a literature procedure slowly produced an unidentified isomeric material which had not undergone oxy-Cope rearrangement . 26 Likewise, treatment of the potassium hydride with a solution of iodine in tetrahydrofuran produced no tangible advantages in this case . 27 The reaction proceeded in excellent yield, however, when potassium hydride was used as base in the presence of 18-crown-6. Under these conditions, the selection of solvent had only a minor effect on the product distribution and yield. 134 Another important factor in obtaining satisfactory results was the method used to quench the reaction. Many reports in the literature disclose the use of buffer solutions or saturated ammonium chloride solutions to quench the excess base at 0 °C. This protocol produced variable, significant amounts of side products. This loss of material during work-up was totally averted by quenching the anionic oxy-Cope reactions by slow addition of methanol at -78 °C. Scheme 35: Anionic Oxy-Cope Rearrangement of 10 and 11. H. .OH KH, 18-crown-6 CHO “ lv<,",’50°C O H / H 10 40 Solvent GC yield Isolated yield foreo. GC) THF 69% 31% OME 92% 41% KH, 18-crown-6 solvent, 50 °C CH{ H 1 1 40 Solvent GC yield IsolatecLyield (prep. GC) THF 78% 30% DME 98% 39% ^6^6 83% 35% H2, 50 psi CHO LAH CHzOH (Pt02) ch 2o h Et20 CH H CH H CH H 41 42 Based on the initial findings outlined above, the oxy-Cope reactions of 10 and 11 were carried out as outlined 135 in Scheme 35. The absolute rotation of the aldehyde thus obtained remained fairly constant regardless of the solvent used. The GC yields were calculated from an internal standard and the relative response factors for both starting material and product were independently determined. Isolated yields were significantly lower due to the loss of volatile product during distillation of excess solvent and purification by preparative GC. With the optical rotation of the aldehyde products in hand, the amount of equatorial versus axial oxyanion in the rearrangement can be calculated. Unfortunately, although both the pure (R) and (s) antipodes of 40 are known in the literature, their rotations were never reported . 28 Thus, pure (5)-aldehyde 40 was synthesized as shown in Scheme 36 and its rotation was accurately determined. Scheme 36: Preparation of (S) -4-Methyl-5-hexenal< MCPBA _ 1 H5 I06 .CHO CH2CI2 " / Et2Ot 0 °C - R.T. u A P u NaHCOa, 0 °C H C H 3 [a]D25-+14.4° (S)-Citronellen Calculations as outlined in Appendix F yielded the results presented in Scheme 37. Subsequently, a more precise number was sought by Mosher ester analysis. Reduction of 4029 by treatment with lithium aluminum hydride 136 as outlined in Scheme 35 permitted preparation of Mosher esters from alcohol 41. Unfortunately, the Mosher esters of 41 were not readily differentiated. However, the Mosher derivatives of the saturated alcohol 42 were amenable to analysis by fluorine-19 NMR (Appendix D). As summarized in Scheme 37, both the (£) and the (Z)-isomer of 3-hydroxy-1,5-heptadiene show a preference for [3,3] sigmatropic rearrangement through a chair transition state with the oxyanion in a pseudoequatorial orientation. The extent of this preference however is not especially dramatic. One possible explanation for the low selectivity would be that the bulk of the solvated oxyanion is not sufficient to affect the ratio. The results of other researchers outlined in the previous section would tend to discount this possibility. Further insight into the issue of oxyanion steric demand can be gained using molecular mechanics calculations . 31 Molecular mechanics (MM) calculations for this study were carried out using the program MODEL KS 2.95 which relies on an Allinger-like parameter set.31* Included in this program are transition structure atom types that can be used to approximate a Cope transition structure for simple systems. This "Cope template" was modified for the purposes of this study by simply attaching the appropriate substituents and assuming an early transition state. Based 137 on consultations with Professor Gajewski, who has performed secondary deuterium isotope studies 32 to determine the extent of bonding in the transition state for the Cope and oxy-Cope rearrangements, an arbitrary bond order of 0.3 was used for the calculations. Using this protocol, the results in Figure 6 were obtained. Scheme 37s Oxyanion Orientation in Acyclic Derivatives. H (S) (fl) (a) Calculated % equatorial % Equatorial oxyanion Solvent W d 25 oxyanion based on [afo25 from Mosher ester of 42 THF +40° 64 61 DME +3.7° 63 61 CH. H :■ CHO o- CH H 4 0 (S) (a) Calculated % equatorial % Equatorial oxyanion 25 Solvent [«]d oxyanion based on M d 25 from Mosher ester of 42 THF -2 7 ° 5 9 57 DME -2.5° 59 55 C6H6 -2.4° 58 55 (a) Average of two experiments. 138 One shortfall of these calculations became immediately obvious. The oxyanion atom type is not adequately parameterized and underestimates both the electronic and steric effects of this substituent. For instance, one obtains virtually the same numbers using a hydroxyl substituent. However, even the use of this underestimated steric demand for the oxyanion gives rise to a Boltzmann distribution that predicts that 80% of the material should rearrange via a chair-like conformation with the oxyanion in a pseudoequatorial orientation. Assignment of a more realistic value to the steric bulk of the oxyanion leads to the prediction of even greater selectivity for rearrangement via an pseudoequatorial oxyanion. An increase in strain energy of +0.9 to +1.0 was calculated for each conversion. Figure 6 : MM Calculations for 10 and 11. As a second point of reference, the calculations were also carried out using the more traditional approximation of a fully formed cyclohexane chair. Somewhat surprisingly, 139 the differences in energy between the two possible oxyanion orientations was nearly identical to those found using the transition structure model (Figure 6 ). One possible explanation for the higher than expected amount of pseudoaxial oxyanion in the transition state is an unexpected electronic contribution. Lee and co-workers have proposed an orbital interpretation favoring pseudoequatorial oxyanion orientation during [3,3] sigmatropic rearrangement . 8 b As shown in Figure 7, they contend that the equatorial oxyanion bond is better able to donate electron density to destabilize the HOMO of an allyl radical system used to approximate the rearrangement. This destabilization of the HOMO should lead to better overlap with the LUMO' of HOMO LUMO' Figure 7: Lee's Proposed Orbital Interpretation. the second allyl radical and provide for a more stable transition state. The problem with this interpretation is that one can easily envision the same efficiency (albeit configurationally different) of overlap for an axially oriented oxyanion. The higher than expected amounts of 140 pseudoaxial oxyanion orientation observed in this study suggest that new stereoelectronic interpretations may be in order. In this respect, ab initio based calculations may be u s e f u l . 3 4 2. Oxv-Cope Rearrangement of tert-Butvlcvclohexenes Anionic oxy-Cope rearrangements of 12 and 13 (Scheme 38) were carried out at 50 °C in the presence of potassium hydride and 18-crown-6 in a variety of solvents. The ratios of equatorial to axial products 43 and 44 were determined by capillary GC analysis. The isolated yields are also listed. The initially formed aldehyde products proved to be somewhat susceptible to decomposition and were therefore directly reduced to the corresponding alcohols with sodium borohydride prior to work-up. The orientation of the newly formed bond on the conformationally rigid tert-butylcyclohexene ring system was determined by 300 MHz proton NMR analysis. As indicated in Scheme 38, the key observation was the relative chemical shift of Hi in each derivative. Previous studies have established that this allylic proton consistently appears further downfield when it is equatorially disposed . 35 141 Scheme 38: Oxy-Cope Rearrangement of tert-Butylcyclohexenes. .OH 2.24 ppm .OH OH H CH. CH 12 (a/?,5S), (aS,5R) 4 3 4 4 Solvent Isolated yield (prep. GC) 43/44 THF 51% (94% from MPLC) 61:1 DME 40% 48:1 CsHe 34% 48:1 .OH .OH CH CH. 13 (a/?,5fl), (aS,5S) 4 443 (a) Solvent Isolated yield foreo. GC) 43/44 THF 34% (92% from MPLC) 1.08:1 DME 56% 1.05:1 C6 H6 39% 1:1.30 I: 1. KH, 18-crown-e, 50 °C; 2. MeOH, -78 °C; 3. NaBH4 (a) Average of two runs. Axial bond formation is recognized to be stereoelectronically preferred in cyclohexene systems with an endocyclic double bond . 36 Ireland's study of the Claisen rearrangement (Figure 8 ) serves as an experimental reference point for this study . 35 In the absence of the effect of an oxyanion substituent, a ^87:13 axial/equatorial bond formation ratio was observed. Comparison of Ireland's results with those obtained in this study reveals that the 142 oxyanion augments this preference in the rearrangement of 1 2 and detracts from it in the reaction of 13. This phenomenon can be explained by the analysis presented in Scheme 20. H (CH3)3C (CH3)3C —X Axial bond formation: >87% Equatorial bond formation: <13% X-C 2 H5 .OTBS Figure 8 : Ireland's Claisen Study. Inspection of the four possible chair-like transition structures reveals that the most favorable situation arises when the oxyanion is equatorially disposed and axial bond formation occurs. When this pathway is available (rearrangement of 12), it prevails to the extent of 99:1 over the option of placing the oxyanion in an axial orientation in preparation for equatorial C-C bond formation. For 13, stereoelectronically preferred axial bonding can occur only by placing the oxyanion in an axial orientation. That this is unfavorable is evidenced by the appearance of extensive amounts of the product of equatorial bond formation. These results can be interpreted on the basis that the oxyanion carries with it appreciable steric demand. Molecular mechanics calculations were performed for each 143 potential transition structure as previously described. Unfortunately, this type of calculation proved to be problematic when applied to highly substituted derivatives. Recourse was made to ground state calculations. The four possible diastereomeric transition states were approximated by orienting the diene in chair-like conformations with the distance between the double bond termini arbitrarily set at 2.0 angstroms. Subsequent energy minimization provided the steric energies given in Figure 9. A representation of the minimized structure was generated by converting the final MODEL structure to CHEMX for printout (Appendix G). Using the artificially low steric value for the oxyanion from the MODEL program and the fairly loose association imposed on the double bond termini, structure B was slightly lower in steric energy than C. Likewise, D was lower in energy than its axial counterpart A. Perhaps more informative in this instance was a comparison of distances between the oxyanion and potential sources of steric interaction on the cyclohexene ring (Appendix G). In the equatorial position, the oxyanion is removed from any close contacts with the cyclohexene ring. For the axial counterpart, however, the steric problems are visually evident in the CHEMX generated representation and are manifested by a close contact of 3.06 angstroms with the pseudoaxial proton at the 6 -position (Appendix G, p. 315). Equatorial bond formation Axial bond formation Axial oxyanion Equatorial oxyanion A MM E - 40.44 kcal/mol B MM E « 39.11 kcal/mol .0" H (CH3)3C (CH3)3C (ctS\5S*) Axial bond formation Equatorial bond formation Axial oxyanion Equatorial oxyanion C MM E - 39.96 kcal/mol D MM E - 39.52 kcal/mol Figure 9: Possible Reaction Pathways for 12 and 13. 3. Oxv-Cope Rearrangement of Norbornene Derivatives Anionic oxy-Cope rearrangement of 14 and 15 was carried out using potassium hydride as base with heating at 50 °C. In this instance, the rearrangement was sufficiently facile that it could be carried out without 18-crown-6. The data summarized in Scheme 39 was compiled through use of this p r o t o c o l . The major aldehyde product 45 was identified based on its spectral properties. Specifically, as illustrated in Scheme 39, the coupling constant between the allylic proton Hi and the bridgehead proton was determined by 300 MHz proton NMR experiments to be 0 Hz. This indicated Hi to be in an endo orientation. The minor product 46 could not be separated from its isomer. However, analysis of the 300 MHz 145 proton NMR and GC/MS of the mixture confirmed its presence. The ratio of aldehydes formed from the oxy-Cope reactions was determined using capillary GC analysis. Scheme 39: Oxy-Cope Rearrangement of Norbornenes. „ J - 0 Hz .CHO H 1.KH, THF, 50 °C 'CHO 2. MeOH, -78 °C CH CH, 4 5 4 6 Additive 3 eq.18-crown-6 94% 59% >99:1 rh None >99:1 ^ ^ X - s / CHO H 0H 1. KH, THF, 50 °C CHO 2. M eOH,-78 °C X CM 15 4 5 Additive GC yield Isolated yield fprep. GCI 3eq. 18-crow 97% 57% 10:1 !bi None 13:1 (b) (a) Average of two experiments. (b) Single determination. As with the tert-butylcyclohexene derivatives 12 and 13, the product distributions appear to be modulated by the steric demand of the oxyanion. Figure 10 depicts the chair-like conformers leading to each of the four possible transition structures. Structure C represents the most favorable situation. Here the oxyanion is equatorially oriented and sterically favored exo bond formation 37 is able to proceed. In structure A exo bond formation occurs with an axially oriented oxyanion which suffers steric 146 interaction with the methylene bridge proton. This steric destabilization of C leads to significant amounts of material rearranging via D to yield endo product. Unfortunately, the preference for exo bond formation is strong enough that modulation by the oxyanion is less pronounced than would be desired. In thisinstance the reaction was facile enough that it could be carried out in good yield without using 18-crown-6. In the absence of 18-crown-6, one might expect that tighter solvation would lead to increased steric demand by the oxyanion. This expectation was not reflected in the observed product distribution. Instead, a small decrease in the effect of the oxyanion orientation on product distribution was o b s e r v e d . Once again, the observed product distribution is qualitatively predicted by the molecular mechanics energies listed in Figure 10. As expected, B is calculated to be lower in steric energy than the axial option C. Additionally, the relative steric environments available to the oxyanion can be qualitatively assessed using the structures in Appendix G. Structure C is characterized by closer contact between the oxyanion and the bridgehead hydrogen at the 1 -position (3.73 A) as well as the syn bridge hydrogen (4.02 A) (p. 317). o . Exo bond formation Endo bond formation Equatorial oxyanion Axial oxyanion A MM E - 59.53 kcal/mol B MM E -57.14 kcal/mol (aS*.1fl\4S*) H y — o~ H Exo bond formation Axial oxyanion Endo bond formation Equatorial oxyanion C MM E - 57.95 kcal/mol D MM E - 58.64 kcal/mol Figure 10: Possible Reaction Pathways for 14 and 15. 4. Oxv-Cope Rearrangement of Camphene Derivatives In contrast to the norbornenyl derivatives 14 and 15, the camphenyl derivatives 16 and 17 were expected to show a strong preference for endo bond formation . 38 Additionally, because of the increased steric demand of this system, the steric demand of the oxyanion should have a larger effect. This increased steric demand made the camphenyl derivatives especially informative. Anionic oxy-Cope rearrangement of optically pure 16 and 17 was carried out using potassium hydride in the presence of 18-crown-6 at 50 °C. The results summarized in Scheme 40 reflect yields of material isolated after chromatography. 148 Scheme 40: Oxy-Cope Rearrangement of Camphene Derivatives. .11% NOE 1. KH, 18-crown-6 THF, 50 °C 2. MaOH, -78 °C Isolated yield fMPLCl .47/48 /a) 90% 1:1.03 .CH, ,CH. CH. CH. CH. ,CH. 1. KH, 18-crown-6 CHO kOH THF, 50 °C CHO + CH. 2. MeOH,-78 °C CH3 \ h CH 4 7 Isolated yield /MPLC1 47/48 79% 99:1 (a) Average of two experiments. Clearly, oxyanion orientation has once again exerted a dramatic influence on the product distribution. In this instance the most favorable situation, structure D, involves endo bond formation with et^iatorially oriented oxyanion. When endo bond formation is forced to proceed at the expense of having an axially oriented oxyanion a significant portion of 16 rearranges via B to give exo product 48. The molecular mechanics results summarized in Figure 11 support an interpretation based on steric interactions. Especially informative is the potential for interaction between the oxyanion and the endo protons in A (3.87 A and 3.35 A, respectively)(p. 323). The structure of endo product 47 was determined by NOE 149 studies at 300 MHz. As illustrated in Scheme 40, an 11% enhancement in the intensity of the syn bridge methyl group resonance was observed upon irradiation of allylic proton Hi. Because the exo aldehyde 48 could not be cleanly separated from endo aldehyde 47, its spectral properties were deduced from the mixture. (afl.1fl.4S) O. Exo bond formation Endo bond formation Equatorial oxyanion Axial oxyanion B MM Energy - 70.33 kcal/mol A MM Energy - 66.56 kcal/mol (aS,1fl,4S) Cf H Exo bond formation Axial oxyanion Endo bond formation Equatorial oxyanion C MM Energy - 71.20 kcal/mo! D MM Energy - 65.71 kcal/mol Figure 11: Possible Reaction Paths for 16 and 17. 150 C. CONCLUSIONS The synthetic and mechanistic investigations described in this chapter provide some insight into the effect of oxyanion orientation on the stereoselectivity of the anionic oxy-Cope rearrangement. In acyclic systems, unexpectedly high levels of product arising from pseudoaxially oriented oxyanion were observed. Qualitative interpretations based on literature reports and molecular mechanics calculations indicate that the product distribution observed for acyclic derivatives cannot be explained on the basis of steric effects alone. For systems where one of the participating double bonds is part of a cyclic system, the steric demand of the oxyanion is the predominant effect. Incyclic systems, the change in product distribution as a result of the relative configuration at the carbon bearing the oxyanion can be substantial. In cyclic systems, a qualitative prediction of the optimal configuration for clean stereochemical transfer from the chiral center bearing oxygen to the developing chiral center can be made on the basis of steric considerations alone. This can be done with simple hand-held models or with the aid of molecular mechanics calculations. Furthermore, the potential value of using chirality at an oxyanion bearing carbon to create an sp 3 151 center stereoselectively in the oxy-Cope reaction has been demonstrated. A logical follow-up to this study would be an examination of the results obtained for the acyclic series in this study and in other studies at the theoretical level. This could involve an attempt to better delineate the electronic contribution of the oxyanion in a pseudoaxial orientation versus a pseudoequatorial orientation using ab initio calculations. Calculations of this type, however, are beyond the scope of this particular study and will be deferred to future researchers. 152 EXPERIMENTAL General Procedure for Oxy-Cope Reactions. To a magnetically stirred solution of alcohol (0.048 mmol) and n-decane (3.00 mg) in dry tetrahydrofuran (1.5 ml) was added 18-crown-6 (38.1 mg, 0.144 mmol) followed by potassium hydride (15.4 mg, 0.384 mmol). The mixture was heated at 50 °C under inert atmosphere in an oil bath. The reaction was generally complete after 3 to 10 h. The resulting mixture was cooled to -78 °C and quenched by dropwise addition of methanol. In the case of 12 and 13, the solution was warmed to 0 °C and stirred with excess sodium borohydride for 10 minutes. After dilution with ether (10 ml), the solution was washed with cold ammonium chloride solution (10 ml), water (5 ml), and brine (5 ml), dried over magnesium sulfate, filtered, and analyzed by capillary GC. Rotary evaporation followed by MPLC on silica gel or preparative gas chromatography (Column B at 180 °C) provided pure products. Yields are tabulated in Schemes 35, 38, 39, and 40. 153 Typical Procedure for Mosher Ester Preparation. To a magnetically stirred solution of the alcohol (0.175 mmol) in ethyl ether (2 ml) at 0 °c was added (R)-(+)-a-methoxy-a-(trifluoromethyl)phenylacetic acid (61.5 mg, 0.262 mmol) followed by a solution of dicyclohexylcarbodiimide (54.2 mg, 0.262 mmol) in ethyl ether (3 ml). 4-(N,N-dimethylamino)pyridine (3.2 mg, 0.026 mmol) was introduced and the resulting mixture was allowed to warm to ambient temperature over 1 h and stirred for an additional 1 h before being filtered through a tightly pressed cotton plug. The filtrate was diluted with ether (5 ml) , washed with saturated ammonium chloride solution (5 ml), water (5 ml), and brine (5 ml) prior to drying over magnesium sulfate. Evaporation provided a colorless semi-solid. The crude product was analyzed by capillary GC and 19F NMR before purification by MPLC on silica gel. Yields ranged from 94 to 100%. Allyl l-Methylallyl Ether (18)10a. To 3-buten-2-ol (43.0 ml, 36.0 g, 0.500 mol) was added with ice bath cooling tetra-n-butylammonium hydroxide ( 1 0 ml of 0.4 M in water, 4 mmol) followed by crushed sodium 154 hydroxide pellets (40.0 g, 1.00 mol). With continued mechanical stirring for 30 minutes, allyl bromide (47.6 ml, 66.5 g, 0.550 mol) was added dropwise over 20 minutes with ice bath cooling. The mixture was allowed to warm to room temperature over 2.5 h and stirred at ambient temperature for 4 h. The resultant white solid was filtered and washed with pentane (25 ml x 3) . The combined filtrates were washed with water (50 ml x 2), dried over magnesium sulfate, filtered, and distilled. The desired product was obtained as a colorless liquid 38.8 g (69%); bp 100-101 °C/760 Torr; IR (neat, cm-1) 3080, 2985, 2935, 2860, 1640, 1445, 1422, 1373, 1316, 1190, 996, 926; *H NMR (300 MHz, CDC13) 8 5.95-5.78 (m, 1H) , 5.76-5.60 (m, 1H), 5.29-5.02 (series of m, 4H) , 4.04-3.75 (m, 3H) , 1.23 (d, J=9.1Hz, 3H) ; 13C NMR (75 MHz, CDCl 3 ) ppm 140.15, 135.05, 116.21, 115.56, 76.09, 6 8 .8 8 , 21.15. (5E)-1/5-Heptadien-3-ol (19)10. A magnetically stirred solution of 18 (10.00 g, 89.15 mmol) in tetrahydrofuran (80 ml) under argon was cooled to -85 °C using an ethanol/dry ice/liquid nitrogen bath. Butyllithium (84.0 ml of 1.50 M in hexanes, 112 mmol) was 155 added dropwise over 30 minutes, after which stirring at -85 °C was continued for 5 h. The colorless solution was allowed to warm to 0 °C during 4 h. Saturated ammonium chloride solution was added slowly (50 ml). The mixture was diluted with ether (50 ml) and the organic phase was separated, washed with water (50 ml), dried over magnesium sulfate, filtered, and freed of solvent. Distillation at 22 Torr provided 8.90 g (89%) of the desired product as a colorless liquid, bp 91-93 °C; IR (neat, cm"1) 3360, 3085, 3010, 2970, 2903, 2842, 1635, 1420, 1373, 1195, 1122, 1018, 987, 962, 919; XH NMR (300 MHz, CDC13) 6 5.95-5.76 (m, 1H) , 5.63-5.47 (m, 1H) , 5.47-5.33 (m, 1H) , 5.22 (d, J=17.2 Hz, 1H), 5.09 (d, J=10.4 Hz, 1H), 4.09 (dd, Ji=12.3 Hz, J 2=5.8 Hz, 1H), 2.36-2.13 (m, 2H), 1.96 (s, 1H), 1.67 (d, J=6.2 Hz, 3H) ; 13C NMR (75 MHz, CDC13) ppm 140.45, 134.03, 129.02, 126.30, 114.41, 72.00, 40.49, 17.95. Sharpless Kinetic Resolution of 19: (3R,5E)-1,5-Heptadien -3-ol (10). Crushed, activated 3 A molecular sieves (1.8 g) was placed in a dry 250 ml round bottom flask equipped with a magnetic stirring bar and the apparatus was flame dried 156 under an argon flow for 20 minutes. After cooling, 19 (2.10 g, 18.7 mmol), n-decane (0.50 ml), diisopropyl L-(+)-tartrate (657 mg, 2.81 mmol), and dry dichloromethane (100 ml) were introduced. The cooled (-20 °C) reaction mixture was treated with titanium tetraisopropoxide (532 mg, 1.87 mmol) and stirred for 30 minutes prior to the dropwise addition of cumene hydroperoxide (2.49 g of 80% which had been pre-dried over 3 A sieves, 13.1 mmol). Stirring was continued for 12 h at -18 °C and for another 8 h at -11 °C while the progress of reaction was monitored using capillary GC analysis. After more than 55% of the starting material had been consumed, 20 ml of a solution containing 2.2 g of citric acid and 6.6 g of ferrous sulfate was added and the mixture was stirred at 0 °C for 1 h. The organic layer was separated and stirred with 10 ml of 30% sodium hydroxide solution in brine (8 ml) at 0 °C for 1 h. The organic phase was dried over sodium sulfate, filtered, and evaporated under reduced pressure at 0-10 °C to yield 6.1 g of yellow liquid which was purified by MPLC (silica gel, elution with 10 % ethyl acetate/petroleum ether) to yield 564 mg of 10 as a colorless liquid, [o]25d +3.4 (c 3.41, CHC13), optically pure as judged by 19F NMR of the Mosher ester. 157 Preparation of (s)-4-Methyl-5-hexenal (40)28. CHO To a magnetically stirred mixture of m-chloroperoxybenzoic acid (3.74 g of 80%, 17.4 mmol) and sodium bicarbonate (2.43 g, 28.9 mmol) in dichloromethane (75 ml) at 0 °C was added in one portion (S)-(+)-citronellen (2.00 g, 14.5 mmol). The reaction was complete by TLC analysis after 10 minutes and was immediately quenched by addition of 1 N Na2S03 (50 ml) and stirred for 15 minutes. Saturated sodium bicarbonate solution (20 ml) was added, the layers were separated, and the organic phase was washed with water (100 ml x 2) prior to drying over magnesium sulfate, filtration, and careful evaporation of the solvent. The 4.10 g of crude product was taken up in ethyl ether (80 ml) and cooled to 0 °C. Periodic acid (3.97 g, 17.4 mmol) was added and the resulting mixture was stirred magnetically while being allowed to warm to room temperature over 3 h and over an additional 4 h at ambient temperature. The colorless mixture was filtered through Celite, extracted with saturated sodium bicarbonate solution (50 ml), followed by 1 H Na2S03 (50 ml). The two aqueous washes were extracted with ether (20 ml) and the combined ether layers were dried over magnesium sulfate and filtered. The ether 158 was removed by distillation through a 20 cm Vigereaux column and the crude product was distilled bulb-to-bulb at 150 °C/15 Torr to obtain 1.14 g (70%) of 40 as a colorless liquid? [a]25D +14.4° (c 3.60, CHC13); IR (neat, cm-1) 3080, 2965, 2940, 1870, 2710, 1712, 1640, 1457, 1422, 13480, 1353, 1135, 1002, 920, 680? XK NMR (300 MHz, CDC13) 6 9.77 (t, J=1.6 Hz, 1H) , 5.72-5.58 (m, 1H), 5.00 (d, J=5.2 Hz, 1H) , 4.95 (s, 1H) , 2.46 (t, J=1.2 Hz, 2H) , 2.25-2.08 (m, 1H) , 1.78-1.54 (m, 2H) , 1.03 (d, J=6.7 Hz, 3H) ; 13C NMR (75 MHz, CDC13) ppm 202.50, 143.29, 113.77, 41.77, 37.42, 28.48, 20.17. 4-Methyl-5-hexenol (41)29. To a magnetically stirred mixture of lithium aluminum hydride (170 mg, 4.48 mmol) in ethyl ether (5 ml) at 0 °C under nitrogen was added dropwise a solution of 40 (200 mg, 1.78 mmol) in ethyl ether (5 ml). The mixture was allowed to warm to room temperature over 1 h and stirred an additional 2 h before being poured slowly into a 1:1 mixture of ice and 0.1 N HC1 (30 ml) with vigorous stirring. The mixture was extracted with ether (10 ml) and the organic layer was washed with brine (5 ml) , dried over sodium 159 sulfate for 2 h, and concentrated to a volume of 0 . 8 ml. Purification of the concentrate by gas chromatography (Column A at 75 °C) gave 151 mg (74%) of 14 as a colorless liquid; [a]25D +16.7° (c 2.05, CHC13); IR (neat, cm-1) 3340, 3080, 2960, 2940, 2875, 1640, 1453, 1420, 1375, 1060, 997, 913; XH NMR (300 MHz, CDC13) 6 5.67-5.53 (m, 1H), 5.00-4.90 (m, 2H) , 4.39-4.4.22 (m, 2H) , 2.18-2.00 (m, 1H) , 1.75-1.62 (m, 2H), 1.36-1.24 (m, 3H), 0.97 (d, J=6.7 Hz, 3H). 4-Methylhexanol (42)30. To a solution of 41 (200 mg, 1.78 mmol) in 2:1 pentane/CHCl 3 (9 ml) was added platinum oxide (2 mg) . The mixture was placed in a medium pressure bottle and stirred magnetically under 50 psi of hydrogen for 102 h. The mixture was filtered through Celite and concentrated at 10 °C on a rotary evaporator to leave 176 mg (85%) of 42 as a colorless liquid; [a]25D; IR (neat, cm-1) 3350, 2960, 2880, 1463, 1382, 1260, 1185, 1120, 1062, 900, 775; XH NMR (80 MHz, CDC13) 3.63 (t, J=6.3 Hz, 2H) , 1.72 (s, 1H) , 1.70-1.03 (series of m, 7H), 1.00-0.86 (m, 6 H). 160 2-Butenyltributylstannane (20)13b-h. Bu3Sn A magnetically stirred solution of 3-(phenylsulfonyl)-1-butene (9.20 g, 46.9 mmol), tri-n-butyltinhydride (31.4 g, 108 mmol), and AIBN (380 mg) in benzene (135 ml) was heated at reflux for 4.5 h under argon. The resulting cloudy solution was filtered through neutral alumina (60 mm x 1 2 0 mm) with benzene elution, and concentrated under reduced pressure to give 41.1 g of colorless liquid. This liquid was distilled (96-97 °C/0.3 Torr) to provide 14.7 g (91%) of 19 as a colorless liquid (91%)? IR (neat, cm-1) 3060, 2980, 2830, 1633, 1580, 1446, 1307, 1150, 1088, 1000, 936, 730, 692? 1H NMR (80 MHz, CDC13) 8 5.85-5.03 (m, 2H), 1.90-1.11 (series of m, 17H), 1.10-0.77 (m, 15H). Preparation of (5Z)-l,5-Heptadien-3-ol (21)13a. A mixture of tri-n-butylcrotyltin (used as an undetermined E/Z isomeric mixture) (14.7 g, 42.6 mmol), 161 freshly distilled acrolein (2.39 g, 42.6 mmol), and di-n-butyltin dichloride (19.4 g , 63.9 mmol) was stirred at room temperature for 24 h. The mixture was placed under reduced pressure (0.5 Torr) and warmed to 50 °C using an oil bath. A colorless liquid containing the desired product (5.30 g) accumulated in an attached trap which had been cooled to -78 °C. The crude product was distilled at 96-98 °C/20 Torr to obtain 2.89 g (59%) of 21 as a colorless liquid; IR (neat, cm-1) 3360, 3095, 3018, 2980, 2910, 2860, 1640, 1422, 1404, 1370, 1122, 1030, 992, 922? XH NMR (300 MHZ, CDCl3) 6 5.96-5.84 (m, 1H) , 5.70-5.57 (m, 1H) , 5.48-5.34 (m, 1H), 5.30-5.05 (series of m, 2H), 4.19-4.06 (m, 1H) , 2.35-2.33 (m, 2H) , 1.66-1.66 (m, 4H) ; 13C NMR (75 MHz, CDCl 3 ) ppm 140.48, 126.94, 125.33, 114.39, 72.30, 34.60, 12.62. Sharpless Kinetic Resolution of 21: (3K,5Z)-1,5-Heptadien Crushed, activated 3 A molecular sieves (1.8 g) were placed in a dry 250 ml round bottomed flask equipped with a magnetic stirring bar and the apparatus was flame-dried under argon flow for 20 minutes. After cooling 21 (2.10 g, 162 18.7 mmol), n-decane (250 m1)t diisopropyl L-(+)-tartrate (657 mg, 2.81 mmol), and dry dichloromethane (100 ml) were introduced. The mixture was cooled to -18 °C prior to the addition with stirring of titanium tetraisopropoxide (532 mg, 1.87 mmol). After 30 minutes, cumene hydroperoxide (2.49 g of 80% which had been pre-dried over 3 A sieves, 13.1 mmol) was added dropwise and the mixture was held at -18 °C for 12 h and for another 8 h at -11 °C while the reaction progress was monitored with the aid of capillary GC analysis. After more than 55% of the starting material had been consumed, 2 0 ml of solution containing 2 . 2 g of citric acid and 6 . 6 g of ferrous sulfate was added and the mixture was stirred at 0 °C for 1 h. The organic layer was separated and stirred at 0 °C for 1 h with 10 ml of a solution of 30% sodium hydroxide in brine. The organic part was separated, dried over sodium sulfate and carefully concentrated to yield 6 . 1 g of yellow liquid which was further purified by MPLC (silica gel, elution with 10 % ethyl acetate/petroleum ether) to provide 761 mg (81% based on 55% consumption) of 11 as a colorless liquid, [a]25D +2.0 (c 3.41, CHCl3), optically pure as judged by 19F NMR of the Mosher ester. 163 5-tert-Butyl—2-chloro-l-cyclohexene-l-ethanol (22). Cl OH (CH3)3C A magnetically stirred solution of N,N-dimethyl- formamide (16.4 g, 0.225 mol) in 1,2-dichloroethane (300 ml) at 0 to 5 °C under argon was treated dropwise with phosphorus oxychloride (19.2 ml, 31.5 g, 0.205 mol) at a rate so as to maintain the temperature under 10 °C. After completion of the addition, the reaction mixture was allowed to warm to ambient temperature before 4-tert-Butylcyclohexanone (28.75 g, 0.186 mol) was introduced as a solution in 1 ,2 -dichloroethane ( 1 0 0 ml). The resulting mixture was heated at 60 °C for 2 h during which time a deep-orange color developed. The solution was cooled to 5 °C before adding an ice-cold solution of sodium acetate (50 g) in water (100 ml). After 10 minutes, the organic phase was separated, dried over sodium sulfate, filtered, and concentrated. The crude product was immediately dissolved in isopropyl alcohol (250 ml) and aluminum isopropoxide (38.1 g, 0.186 mol) was added with magnetic stirring. The mixture was heated in an oil bath at 120 °C while acetone was slowly distilled through a Vigereaux column during 5 h. The resulting dark-green mixture was cooled and poured into dilute HC1 (100 ml of 1 N 164 HC1 and 100 g of ice), extracted with ether (200 ml), washed with dilute sodium acetate solution ( 1 0 g in 1 0 0 ml), washed with brine ( 1 0 0 ml), dried over magnesium sulfate, filtered, and evaporated to give 42.3 g of dark brown liquid. Chromatography (elution with 20% ether/petroleum ether) on silica gel provided 20.5 g (54% over two steps) of 22 as a pale yellow liquid; IR (neat, cm"1) 3320, 2960, 2870, 1665, 1478, 1468, 1445, 1396, 1369, 1246, 1232, 1190, 1072, 1030, 986; XH NMR (300 MHz, CDC13) 5 4.25 (dd, J x=19.7 Hz, J 2 =12.2 Hz, 2H) , 2.51-2.33 (series of m, 3H) , 2.07-1.91 (m, 1H), 1.90-1.71 (m, 2H) , 1.43-1.20 (m, 2H), 0.89 (s, 9H) ; 13C NMR (75 MHZ, CDCl3) ppm 132.40, 128.88, 63.45, 43.61, 34.96, 32.13, 29.82, 27.20, 25.10; MS a/z (M+) calcd 202.1124, obsd 2 0 2 .1 1 2 1 . 5-tert-Butyl-l-cyclohexene-l-ethanol (23). OH (CH3)3C To a mechanically stirred mixture of tetrahydrofuran (200 ml) and tert-butyl alcohol (10.0 g, 135 mmol) under argon was added small chunks of sodium (17.7 g, 0.770 mol). The mixture was brought to a gentle reflux before a solution of 22 in tetrahydrofuran (50 ml) was introduced dropwise over 1 h. The mixture was refluxed for 15 h and cooled to 165 room temperature. The solution was decanted away from the excess sodium, quenched with methanol, diluted with ether ( 2 0 0 ml) , washed with brine ( 1 0 0 ml x 2 ) , dried over magnesium sulfate, filtered, and evaporated to provide 2 0 . 2 g of yellow liquid. Distillation at 85-87 °C/1.2 Torr gave 14.60 g (90%) of colorless liquid; IR (neat, c m -1) 3320, 2960, 2910, 2870, 2840, 1465, 1365, 1230, 1147, 1018, 920; XH NMR (300 MHz, CDC13) 6 5.66-5.63 (m, 1H) , 4.02-3.91 (m, 2H), 2.21-1.62 (series of m, 6 H), 1.37-1.20 (m, 1H), 1.18-1.02 (m, 1H), 0.86 (s, 9H); 13C NMR (75 MHz, CDC13) ppm 137.88, 122.72, 67.58, 44.21, 32.24, 27.29, 27.18, 26.30, 23.83; MS m/z (M+) calcd 168.1514, obsd 168.1518. Anal. Calcd for C n H 2 oO: C, 78.51; H, 11.98. Found: C, 78.43; H, 11.96. (5-tert-Butyl-l-cyclohexen-l-yl)methyl Phenyl Sulfide (24). SPh (CH3)3C To a magnetically stirred solution of tri-n-butylphosphine (17.11 g, 84.55 mmol) in benzene (200 ml) under argon was added N-(phenylthio)succinimide (17.52 g, 84.55 mmol) in one portion. The resulting dark solution was stirred at ambient temperature for 1 0 minutes before the addition of 23 (13.55 g, 80.52 mmol) as a solution in 166 benzene (30 ml) in one portion (slightly exothermic). The dark solution was stirred at room temperature for 3 h before rotary evaporation of benzene and chromatography (silica gel, elution with petroleum ether) to give 19.60 g (93%) of colorless liquid; IR (neat, cm -1) 3075, 3050, 2960, 2910, 2870, 2835, 1580, 1478, 1437, 1365, 1230, 1089, 1025, 740, 693; XH NMR (300 MHz, CDC13) 6 7.48-7.11 (m, 5H), 5.08-5.98 (m, 1H), 3.48 (s, 2H), 2.25-1.67 (series of m, 4H) , 1.38-1.17 (m, 1H), 1.17-0.84 (m, 2H), 0.87 (s, 9H); 13C NMR (75 MHz, CDCl3) ppm 136.84, 133.27, 130.12, 128.55, 126.00, 125.32, 44.29, 42.26, 32.23, 29.01, 27.19, 26.58, 23.52; MS m/z (M+) calcd 260.1599, obsd 260.1594. Anal. Calcd for C 1 7 H 2 4 S: C, 78.40; H, 9.29. Found: C, 78.42; H, 9.27. (5-1 ert-Butyl-1—cyclohexen-l-yl)methyl Bromide (25a). (CH3)3C A solution of triphenylphosphine (37.5 g, 143 mmol) in dichloromethane (375 ml) at 0 °C was treated dropwise with bromine (27.8 g, 143 mmol) over 1 h. The resulting mixture was stirred at 0 °C for 20 minutes after addition was complete. A solution of 23 (10.0 g, 59.4 mmol) in dichloromethane ( 1 0 0 ml) was added rapidly dropwise. 167 Starting material was consumed within 5 min. The mixture was washed with water ( 1 0 0 ml x 2 ) and brine ( 1 0 0 ml), dried over sodium sulfate, filtered, and evaporated to give a white oily solid. This solid was triturated with pentane (500 ml in portions of 100 ml with efficient crushing of solid) and the combined pentane extracts were evaporated to give 14.96 g of colorless liquid whose distillation at 0.3 Torr and 67-70 °C provided 11.6 g (84%) of colorless liquid; IR (neat, cm".1) 3040, 2960, 2870, 2835, 1475, 1465, 1432, 1393, 1365, 1208; *H NMR (300 MHz, CDC13) 6 5.89-5.81 (m. 1H) , 3.94 (s, 2H) , 2.24-1.70 (series of m, 5H) , 1.38-1.24 (m, 1H) , 1.15-0.98 (m, 1H), 0.88 (s, 9H) ,* 13C NMR (75 MHz, CDCl 3 ) ppm 134.92, 127.81, 44.08, 39.66, 32.25, 28.10, 27.19, 26.75, 23.28; MS m/z (M+) calcd 230.0670, obsd 230.0664. (5-tert-Butyl-l-cyclohexen-l-yl)methyl Chloride (25b). (CH3)3c A mixture of 5-tert-butyl-l-(hydroxymethyl)-1- cyclohexene (11.0 g, 65.4 mmol), carbon tetrachloride (60 ml), and triphenylphosphine (22.30 g, 85.0 mmol) was stirred at reflux for 3 h. The resulting mixture was filtered and cautiously concentrated at reduced pressure to provide a 168 colorless semi-solid. The semi-solid was washed with pentane (500 ml divided into 100 ml portions), and the pentane was evaporated carefully without heat to give 18.21 g of pale-yellow colored liquid which was distilled at 65-67 and 0.07 Torr °C to provided 11.1 g (91%) of 25b as a colorless liquid; IR (neat, cm-1) 3040, 2960, 2870, 2840, 1682, 1667, 1478, 1437, 1393, 1367, 1211, 6 8 8 ? 1H NMR (300 MHz, CDCl3) 6 5.83-5.74 (m, 1H) , 4.01 (s, 2H) , 2.25-1.70 (series of m, 5H), 1.40-1.21 (m, 1H), 1.20-1.00 (m, 1H), 0.90 (S, 9H) ; 13C NMR (75 MHz, CDC13) ppm 134.67, 127.19, 50.57, 44.08, 32.24, 27.65, 27.18, 26.54, 23.37; MS m/z (M+) calcd 186.1175, obsd 186.1190. 5-tert-Butyl-a-vinyl-l-cyclohexene-l-ettaanol (26). (CH3)3c Magnesium (325 mesh, 841 mg, 34.6 mmol) in each of two flasks was flame-dried under argon, cooled to ambient temperature, and suspended in tetrahydrofuran (25 ml). Anthracene (123 mg, 0.692 mmol) was added to the mixture followed by iodomethane (3 drops). The mixture was subjected to ultrasound for 16 h at room temperature. The magnetically stirred green-yellow suspension was cooled to -65 °C and chloride 25b was added in one portion. The 169 mixture was removed from cooling and immediately placed in the ultrasound bath at ambient temperature. Grignard reaction was immediately initiated. After 30 min, the supernatant was transferred via cannula to a pre-stirred ( 2 h) suspension of anhydrous cerium (III) chloride (6.45 g of heptahydrate which was dried at 140 °C/0.05 Torr for 4 h, 34.6 mmol) at -78 °C under argon in tetrahydrofuran (50 ml). The mixture was stirred vigorously for 30 minutes before freshly dried/distilled acrolein (1.45 g, 26.0 mmol) was added rapidly dropwise. The solution became colorless. The cooling bath was removed and the solution allowed to warm to 0 °C before addition of 1 N HC1 (75 ml) . After dilution with ether ( 1 0 0 ml), the organic part was separated, washed with water (50 ml x 2), brine (50 ml), dried over magnesium sulfate, filtered, and evaporated under reduced pressure to provide 1.47 g of colorless oil. Purification by MPLC (silica gel, elution with 1 0 % ethyl acetate/petroleum ether) yielded 690 mg (38%) of colorless oil consisting of a 1 : 1 mixture of racemic diastereomers, which solidified on standing, mp 44-46 °C; IR (neat, cm"1) 3380, 3080, 2965, 2920, 2880, 2840, 1640, 1478, 1458, 1437, 1395, 1367, 1120, 1028, 993, 923; XH NMR (300 MHz, CDCl3) 6 5.95-5.82 (m, 1H), 5.55 (s, 1H) , 5.26 (dt, Ji=17.2 Hz, J 2 =1.5 Hz, 1H) , 5.10 (dt, Ji=10.41 Hz, J 2 = 1 •5 Hz, 1H), 4.26-4.14 (m, 1H), 2.30-1.65 (series of m, 8 H) , 1.34-1.20 (m, 1H) , 1.16-0.98 (m, 1H) , 0 . 8 8 (s, 9H) ; 13C NMR (75 MHz, CDC13) ppm 140.77, 170 140.67, 134.34, 134.23, 125.20, 124.97, 114.25, 70.14, 69.81, 46.66, 45.93, 44.52, 44.39, 32.23, 32.20, 30.18, 30.10, 27.33, 27.19, 26.72, 26.60, 23.71; MS m/z (M+) calcd 208.1827, Obsd 208.1875. Anal. Calcd for C 1 4 H 2 4 O: C, 80.71; H, 11.61. Found; C, 80.54; H, 11.54. Bromoetherification of 5-tert-Butyl-a-vinyl-l-cyclohexene-l- ethanol (26). To a magnetically stirred solution of 26 (3.20 g, 15.4 mmol) in dichloromethane (100 ml) at 0 °C under argon and shielded from light was added recrystallized N-bromosuccinimide (2.88 g, 16.2 mmol). The solution was allowed to slowly reach room temperature over 7 h and stirred at room temperature for 9 h. Evaporation of solvent followed by purification by MPLC (silica gel, elution with 1 % ethyl acetate/petroleum ether) gave 1.80 g of yellow oil containing 28 and 29, 488 mg of colorless oily 31, and 411 mg of 30. The combined yield was 2.70 g (61%). Additionally, 550 mg of yellow oil was recovered by flushing the column with a more polar solvent mixture (2 0 % ethyl acetate/petroleum ether). This material, which appeared to be a complex mixture of bromoepoxides derived from 26, was reduced with sodium metal in ether to recover 26. 171 Spectral data for (2R*/3aK*,5R*,7a5*)-3a-Bromo-5-tert-butyl- octahydro- 2 -vinylbenzofuran (28). H (CH3)3C Br Obtained as a colorless liquid contaminated with a small amount of 29; IR (neat, cm"1) 2920, 2880, 1640, 1469, 1459, 1452, 1432, 1368, 1280, 1175, 1112, 1062, 1029, 986, 945, 928, 861, 770; XH NMR (300 MHz, CDC13) 8 5.97-5.82 (m, 1H), 5.31-5.07 (series of m, 2H), 4.53-4.38 (m, 1H), 4.09-4.04 (m, 1H) , 2.61-2.50 (m, 1H) , 2.40-2.32 (m, 1H) , 2.08-1.83 (series of m, 3H), 1.60-1.16 (series of m, 4H), 0.87 (s, 9H) ; 13C NMR (75 MHz, CDC13) ppm 138.81, 115.41, 80.76, 76.58, 64.21, 50.18, 43.28, 38.06, 31.97, 27.43, 25.03, 20.51; MS m/z (M+) calcd 286.0932, obsd 286.0941. Spectral data for (2fi*,3a5*,5S*/7afi*)-3a-Bromo-5-tert-butyl- octahydro-2-vinylbenzofuran (30). H (CH3)3C H Obtained as a colorless liquid; IR (neat, cm-1) 2960, 2870, 1635, 1450, 1430, 1367, 1294, 1190, 945, 735; XH NMR (300 MHz, CDCl 3 ) 8 6.12-5.97 (m, 1H) , 5.38-5.10 (series of 172 m, 2H), 4.97-4.83 (m, 1H), 4.61-4.54 (m, 1H), 2.82-2.71 (m, 1H) , 2.21-1.73 (series of m, 4H) , 1.65-1.08 (series of in, 4H) , 0.88 (s, 9H) ; 13C NMR (75 MHz, CDC13) ppm 139.83, 115.68, 83.29, 74.62, 58.35, 41.52, 39.23, 34.63, 31.99 29.69, 27.26, 20.21; MS m/z (M+-[C 4 H 9]) calcd 229.0228, obsd 229.0290. Spectral data for (2K*,3as*,5fi*,7afi*)-3a-Bromo-5-tert-butyl- octahydro-2-vinylbenzofuran (31). H (CH3)3c H Obtained as a colorless liquid; IR (neat, cm-1) 2960, 2870, 1635, 1470, 1450, 1430, 1367, 1292, 1240, 1195, 1100, 988, 940, 810, 735; XH NMR (300 MHz, CDC13) 8 6.10-5.95 (m, 1H) , 5.34-5.13 (m, 2H) , 4.90-4.80 (m, 1H) , 4.43-4.37 (m, 1H) , 2.53-2.25 (series of m, 2H), 2.20-1.75 (series of m, 3H), 1.60-1.36 (series of m, 4H), 0.87 (s, 9H); 13C NMR (75 MHz, CDC13) ppm 139.87, 115.67, 82.89, 74.03, 59.46, 41.94, 39.23, 32.86, 32.11, 29.27, 27.34, 20.21; MS m/z (M+-[C 4 H 9]) calcd 229.0228, Obsd 229.0252. 173 Reduction of the Mixture of (2£*,3afi*/5K*,7a^*)-3a~Bromo-5- tert-butyloctahydro- 2 -vinylbenzofuran (28) and (2K*,3a£*,5S*,7as*)-3a-Brono-5-tert-butyl-octahydro-2- vinylbenzofuran (29). To a magnetically stirred solution of 28 and 29 (1.80 g, 6.27 mmol) in dry ether (30 ml) under argon was added freshly cut and crushed sodium (433 mg, 18.8 mmol). The mixture was heated at reflux for 6 h. After complete consumption of starting material, the mixture was cooled to 0 °C and methanol was added dropwise to consume excess sodium. The resulting solution was washed with saturated ammonium chloride solution ( 1 0 ml), water ( 1 0 ml), and brine ( 1 0 ml) , dried over magnesium sulfate, filtered, and evaporated to give 1.26 g of yellow oil which solidified on standing. Purification by MPLC (silica gel, elution with 10 % ethyl acetate/petroleum ether) gave 1.11 g (85%) of white solid, mp 47-48.5 °C. The product was determined to contain 13 plus a small amount of 12 by 13C NMR analysis. Reduction of (2Je*,3a5*,55*/7afi*)-3a-Bromo-5-tert-butyl- octahydro-2-vinylbenzofuran (30) (13). To a magnetically stirred solution of 30 (411 mg, 1.43 mmol) in dry ether ( 1 0 ml) under argon was added freshly cut and crushed sodium (99 mg, 4.3 mmol). The mixture was heated at reflux for 3 h. After complete consumption of starting material, the mixture was cooled to 0 °C and 174 methanol was added dropwise to consume excess sodium. The solution was diluted with ether ( 1 0 ml), washed with saturated ammonium chloride solution (5 ml), water (5 ml) , and brine (5 ml) , dried over magnesium sulfate, filtered, and evaporated to give 370 mg of yellow oil. Purification of this material by MPLC (silica gel, elution with 10 % ethyl acetate/petroleum ether) gave 286 mg (96%) of white solid, mp 48-49 °C. The product was determined to be pure 13 by 13C NMR analysis. Reduction of (2JR*/3a5*,5fi*/7afi*)-3a-Bromo-5-tert-butyl- octahydro-2-vinylbenzofuran (31) (12). To a magnetically stirred solution of 31 (488 mg, 1.70 mmol) in dry ether ( 1 0 ml) under argon was added freshly cut and crushed sodium (117 mg, 5.1 mmol). The mixture was heated at reflux for 3 h. After complete consumption of starting material, the mixture was cooled to 0 °C and methanol was added dropwise to consume excess sodium. The solution was diluted with ether ( 1 0 ml), washed with saturated ammonium chloride solution (5 ml) , water (5 ml) , and brine (5 ml) , dried over magnesium sulfate, filtered, and evaporated to give 352 mg of yellow oil. Purification this material by MPLC (silica gel, elution with 10 % ethyl acetate/petroleum ether) gave 319 mg (90%) of 12 as a colorless liquid. The product was determined to be pure 36 by 13C NMR analysis. 175 Spectral data for (aS*,5S)-5-tert-Butyl-a-vinyl-l- cyclohexene-l-ethanol (13). H (CH3)3C Obtained as a colorlesssolid; IR (neat, cm-1) 3380, 3080, 2970, 2840, 1642, 1480, 1470, 1370, 1120, 992, 922; XH NMR (300 MHz, CDC13) 8 5.95-5.82 (m, 1H), 5.55 (s, 1H), 5.26 (dt, Ji=17.2 Hz, J 2 = 1 • 5 Hz, 1H) , 5.10 (dt, Ji=10.41 Hz, J 2 = 1 •5 Hz, 1H) , 4.26-4.14 (m, 1H) , 2.30-1.65 (series of m, 8 H), 1.34-1.20 (m, 1H) , 1.16-0.98 (m, 1H), 0.88(s, 9H); 1 3 C NMR (75 MHz, CDC13) ppm 140.78, 134.21, 125.15, 114.22, 69.81, 46.64, 44.37, 32.19, 30.18, 27.19, 26.71, 23.70. Spectral data for (aR*#5S*)-5-tert-Butyl-a-vinyl-l- cyclohexene-l-ethanol (1 2 ). H (CH3)3C Obtained as a colorless oil; IR (neat, cm"1) 3380, 3080, 2970, 2840, 1640, 1480, 1470, 1368, 1118, 993, 922; XH NMR (300 MHZ, CDC13) 8 5.95-5.82 (m, 1H), 5.55 (s, 1H), 5.26 (dt, Ji=17.2 Hz, J 2 = 1 • 5 Hz, 1H) , 5.10 (dt, J^ I O . 4 1 Hz, 176 J 2 = 1 •5 Hz, 1H) , 4.26-4.14 (m, 1H) , 2.30-1.65 (series of m, 8 H) , 1.34-1.20 (m, 1H) , 1.16-0.98 (m, 1H) , 0.88(s, 9H) ; 13C NMR (75 MHZ, CDC13) ppm 140.61, 134.30, 124.98, 114.28, 70.07, 45.89, 44.46, 32.22, 30.02, 27.16, 26.57, 23.67 (aS*,5 S*)-5-t er t-Butyl-a-vinyl-l-cyclohexene-l-ettaanol p-Ni trobenzoate (32). H (CH3)3C H OPNB A mixture of 13 (35.0 mg, 0.168 mmol), p-nitrobenzoyl chloride (62.4 mg, 0.336 mmol), pyridine (5 drops), and dichloromethane ( 1 ml) was stirred at room temperature for 2 h. The yellow colored solution was diluted with ether (10 ml), washed with saturated sodium bicarbonate solution (5 ml), water (5 ml) and brine (5 ml), dried over magnesium sulfate, filtered, and evaporated to provide 72.2 mg of white solid. MPLC (silica gel, elution with 2% ethyl acetate/petroleum ether) gave 52.5 mg (8 8 %) of 32 as a white solid, mp 83.5-85 °C; IR (KBr, cm-1) 3100, 2965, 2935, 2860, 2825, 1708, 1600, 1515, 1345, 1292, 1278, 1112, 1097, 942, 933, 864, 832, 711; *H NMR (300 MHz, CDCl 3 ) 6 8.26-8.11 (m, 4H) , 5.97-5.84 (m, 1H) , 5.72-5.60 (m, 1H) , 5.49 (s, 1H) , 5.40-5.14 (m, 2H) , 2.55-2.31 (m, 2H) , 2.04-1.82 (m, 3H) , 1.78-1.66 (m, 1H) , 1.31-1.15 (m, 1H) , 1.06-0.75 (m, 2H) , 177 0.85 (S, 9H) ; 13C NMR (75 MHz, CDC13) ppm 163.84, 150.52, 136.07, 136.01, 133.09, 130.62, 125.12, 123.49, 117.02, 74.84, 44.46, 43.28, 32.20, 30.51, 27.17, 26.68, 23.55. Spectral data for trans-4-tert-Butyl-2-methylenecydohexane- propanol (44). H (CH3)3C c h 2 Obtained as a colorless oil; IR (neat, cm-1) 3350, 3080, 1642, 1467, 1441, 1367, 1132, 1059, 960, 890; XH NMR (300 MHz, CDCl3) 6 4.71-4.67 (m, 1H) , 4.57-4.53 (m, 1H) , 3.67 (t, J=6.4 Hz, 2H), 2.00-1.90 (m, 1H) , 1.86-1.03 (series of m, 10H) , 1.00-0.83 (m, 2H) , 0.87 (s, 9H) ; 13C NMR (75 MHz, CDCl3) ppm 153.59, 104.26, 63.43, 50.72, 42.57, 38.46, 34.41, 32.47, 30.57, 28.31, 27.49, 18.04; MS m/z (M+) calcd 210.1984, obsd 210.1993. Anal. Calcd for C 14H 2 60: C, 79.94; H, 12.46. Found: C, 79.75; H, 12.39. 178 Spectral data for cis-4-tert-Butyl-2-methylenecyclohexane- propanol (43). (CH3)3C c h 2 Obtained as a colorless oil; IR (neat, cm-1) 3340, 3085, 2970, 2870, 1640, 1475, 1445, 1395, 1365, 1240, 1070, 890; XH NMR (300 MHz, CDC13) 8 4.66-4.59 (m, 2H) , 3.66 (t, J=6.4 Hz, 2H), 2.29-2.10 (series of m, 2H), 1.90-1.65 (series of m, 2H) , 1.60-1.03 (series of m, 9H) , 0.82 (s, 9H) ; 13C NMR (75 MHz, CDC13) ppm 152.36, 107.88, 63.06, 50.18, 42.63, 32.56, 32.41, 32.16, 31.07, 27.77, 27.38, 21.56; MS m/z (M+) calcd 210.1984, obsd 210.1990. Anal. Calcd for C 1 4 H 2 6 O: C, 79.94; H, 12.46. Found: C, 79.97; H, 12.45. endo,exo-2,3-Dibromonorbornane (33)22b. Br A mixture of norbornylene (29.2 g, 0.310 mol), 1,2-dibromotetrachloroethane (51.0 g, 0.160 mmol), and carbon tetrachloride (120 ml) was mechanically stirred in a one liter flask under argon while being irradiated with a GE 179 275 W sunlamp for 6 h. Evaporation at 20 Torr followed by column chromatography (CC14 eluent) on silica gel (5 cm x 18 cm) gave 43.9 g of impure 33 as a colorless liquid which was carried on without further purification. A small portion of the crude product was further purified by MPLC (silica gel, elution with petroleum ether) to obtain a pure sample for spectral characterization; IR (neat, cm-1) 2970, 2875, 1452, 1307, 1233. 1172, 950, 802, 760, 749; XH NMR (300 MHz, CDCl3) 6 4.48-4.45 (m, 1H), 3.89 (t, J=2.9 Hz, 1H), 2.52-2.47 (m, 2H), 2.05-1.86 (series of m, 2H) , 1.79-1.65 (m, 1H) , 1.57-1.49 (m, 2H) , 1.40-1.27 (m, 1H) ; 13C NMR (75 MHz, CDCl 3 ) ppm 61.95, 60.38, 47.28, 45.06, 35.29, 27.83, 23.31. 2-Bromo-2-norbornene (34)22b. To a magnetically stirred solution of freshly prepared potassium tert-butoxide (0.18 mol) in dry tert-butyl alcohol (150 ml) under argon with was added 33 (43.9 g of partially purified material, 0.16 mol). A white precipitate was immediately formed. The mixture was heated at reflux for 1 h to complete the reaction. After cooling to ambient temperature, the mixture was poured into 1:1 ice/water (500 180 ml) and extracted with petroleum ether (300 ml, 100 ml). The combined organic layers were washed with water (200 ml x 2 ) and brine ( 1 0 0 ml), dried over sodium sulfate, and concentrated at reduced pressure to provide 32.5 g of yellow liquid. Simple distillation of this liquid using an oil bath temperature of 80-110 °C yielded 23.1 g (83%) of 34 as a colorless liquid, bp 75-80 °C/20 Torr? IR (neat, cm"1) 2970, 2920, 2875, 1578, 1447, 1208, 1272, 1160, 1122, 1040, 955, 912, 865, 811, 684; XH NMR (300 MHz, CDC13) 5 6.01 (d, J=3.1 Hz, 1H), 2.90-2.84 (m, 2H), 1.75-1.57 (m, 3H), 1.24-1.10 (m, 3H) ; 13C NMR (75 MHz, CDC13) ppm 134.75, 125.51, 50.49, 48.06, 43.89, 25.89, 24.36. a-vinyl-2-bornene-2-ethanol (35). A magnetically stirred solution of 34 (7.00 g, 40.4 mmol) in dry tetrahydrofuran (125 ml) at -78 °C under argon was treated dropwise over 2 0 minutes with tert-butyllithium (52.3 ml of 1.7 M in pentane, 89.0 mmol). The resulting yellow solution was stirred at -78 °C for 30 minutes before the cooling bath was removed and the internal temperature allowed to reach 0 °C. After the internal temperature had reached 0 °C, butadiene monoxide (2.12 g, 30.3 mmol) was 181 added in rapid dropwise fashion to the solution. The yellow reaction mixture was allowed to warm to ambient temperature, stirred for 6 h, poured into a separatory funnel containing ice/water (100 ml), and extracted with petroleum ether (150 ml) . The organic phase was washed with water (100 ml x2) and brine ( 1 0 0 ml) prior to drying over sodium sulfate and concentration under reduced pressure to provide 5.28 g of pale yellow liquid. MPLC (silica gel, elution with 12% ethyl acetate/petroleum ether) of the yellow liquid gave 1.23 g (25%) of 35 as a colorless liquid which was susceptible to polymerization; IR (neat, cm-1) 3400, 3080, 3055, 2960, 2877, 1640, 1618, 1448, 1421, 1279, 1122, 995, 925, 878, 805, 780; *H NMR of the diastereomeric mixture (300 MHz, CDCl3) 6 5.97-5.80 (m, 1H); 5.72 (s, 1H), 5.32-5.18 (m, 1H) , 5.12-5.02 (m, 1H) , 4.29-4.14 (m, 1H) , 2.82-2.65 (m, 2H) , 2.40-2.16 (series of m, 2H) , 1.84 (s, 1H) , 1.70-1.51 (m, 2H) , 1.39-1.30 (m, 1H) , 1.14-0.91 (m, 3H) ; 13C NMR (75 MHz, CDC13) ppm 145.61, 145.48, 140.65, 140.45, 131.88, 131.28, 114.58, 114.34, 70.63, 70.46, 48.53, 45.58, 44.70, 42.37, 42.32, 38.20, 38.15, 26.26, 26.16, 24.48, 24.24. The racemic diastereomers were separated by repeated MPLC using a column packed with 10% silver nitrate on silica gel (elution with 2 0 % ethyl acetate/petroleum ether). 182 Spectral data for (aR*,lR*,4S*)-a-vinyl-2-norbornene-2- ethanol (14). Obtained as a colorless liquid; IR (neat, c m -1) 3380, 3080, 3056, 2970, 2875, 1640, 1618, 1450, 1425, 1332, 1280, 1121, 1000, 925, 880, 805, 781; XH NMR (300 MHz, CDC13) 8 5.97-5.80 (m, 1H); 5.72 (s, 1H),5.32-5.18 (m, 1H), 5.12-5.02 (m, 1H), 4.29-4.14 (m, 1H), 2.81 (d, J=1.4 Hz, 1H), 2.71 (s, 1H) , 2.41-2.25 (m, 2H) , 1.86 (s, 1H) , 1.70-1.51 (m, 2H) , 1.39-1.30 (m, 1H), 1.14-0.91 (m, 3H) ; 13C NMR (75 MHz, CDCl 3 ) ppm 145.52, 140.70, 131.26, 114.32, 70.66, 48.54, 45.61, 42.34, 38.18, 26.27, 24.49; MS m/z (M+) calcd 164.1201, obsd 164.1197. Anal. Calcd for C 1 1 H 1 6 O: C, 80.44; H, 9.82. Found; C, 80.29; H, 9.82. 183 Spectral data for (aS*,1R*,4S*)-a-Vinyl-2-norbornene-2- ethanol (15). Obtained as a colorless liquid; IR (neat, cm-1) 3385, 3075, 3042, 2960, 2870, 1638, 1612, 1445, 1420, 1275, 1120, 1021, 995, 925, 875, 803, 779; XH NMR (300 MHZ, CDC13) 8 5.97-5.80 (m, 1H) ; 5.72 (s, 1H) , 5.32-5.18 (m, 1H) , 5.12-5.02 (m, 1H), 4.29-4.14 (m, 1H), 2.82 (s, 1H), 2.76 (s, 1H) , 2.40-2.16 (series of m, 2H), 1.85 (s, 1H) , 1.70-1.51 (m, 2H), 1.39-1.30 (m, 1H), 1.14-0.91 (m, 3H); 13C NMR (75 MHz, CDCl 3 ) ppm 145.52, 140.64, 131.40, 114.41, 70.62, 48.59, 45.63, 42.36, 38.20, 26.29, 24.54; MS m/z (M+) calcd 164.1201, obsd 164.1172. Anal. Calcd for CnHuO: C, 80.44; H, 9.82. Found: C, 80.18; H, 9.91. 184 (aR*,1R*,4S*)-a-Vinyl-2-norbornene-2-ethanol 1-Naphthalenecarbamate (36). HN To a solution of 14 (40.1 mg, 0.244 mmol) in dichloromethane (2 ml) at 0 °C was added pyridine (1 drop) followed by 1-naphthylisocyanate (45.4 mg, 0.268 mmol). The solution was allowed to warm to room temperature and stirred for 1 h. The resulting colorless solution containing a small amount of white precipitate was diluted with ether ( 1 0 ml), washed with saturated ammonium chloride solution (5 ml x 2), water (5 ml), saturated sodium bicarbonate solution (5 ml), and brine (5 ml). The mixture was dried over magnesium sulfate, filtered, and concentrated to provide 8 6 . 1 mg of yellow oil. MPLC (silica gel, elution with 5% ethyl acetate/petroleum ether) gave 78.0 mg of 36 as a colorless oil which crystallized on standing, mp 79-80 °C (96%); IR (melt, cm-1) 3290, 3055, 2960, 2870, 1700, 1540, 1502, 1440, 1422, 1349, 1260, 1232, 1108, 1078, 1011, 985, 794; XH NMR (300 MHZ, CDCl3) 6 7.95-7.82 (m, 3H) , 7.67 (d, J=8.2 Hz, 1H) , 7.57-7.43 (m, 3H) , 6.98 (s, 1H) , 5.97-5.82 (m, 1H) , 5.70 (s, 1H) , 5.52-5.43 (m, 1H) , 5.34 (d, J=17.2 Hz, 1H) , 5.22 (d, J=10.5 Hz, 1H), 2.84-2.72 (m, 2H), 2.64-2.40 (series of m, 2H) , 1.70-1.56 (m, 2H) , 1.43-1.35 (m, 1H) , 185 1.13-0.96 (series of m, 3H) ; 13C NMR (75 MHz, CDC13) (two carbons were not differentiated) ppm 153.73, 144.43, 136.58, 134.04, 132.48, 130.96, 128.70, 126.15, 125.92, 125.77, 124.95, 120.42, 116.69, 74.56, 48.46, 45.17, 42.33 35.15, 26.29, 24.38? MS m/z (M+) calcd 333.1728, obsd 333.1770. Spectral data for (l£*,2s*,4£*)-3-Methylene-2-norbornane- propionaldehyde (45). CHO CH Obtained as a colorless liquid; IR (neat, c m -1) 3065, 2960, 2870, 2815, 2715, 1721, 1650, 1450, 1410, 1388, 871; XH NMR (300 MHz, CDC13) 6 9.79 (t, J=1.8 Hz, 1H), 4.87 (d, J=1.2 Hz, 1H), 4.63(s, 1H), 2.68 (s, 1H), 2.50 (td, Ji = 8 Hz, J 2 = 1 . 8 Hz, 2H) , 2.12 (s, 1H) , 1.95-1.82 (m, 1H) , 1.60-1.12 (series of m, 8 H) ; 13C NMR (75 MHz, CDC13) ppm 202.56, 159.83, 102.26, 47.87, 45.77, 42.85, 40.36, 35.76, 29.52, 28.69, 26.87; MS m/z (M+) calcd 164.1201, obsd 164.1237. Anal. Calcd for CnHi 6 0; C, 80.44; H, 9.82. Found: C, 80.22; H, 9.80. 186 2,4, 6 -Triisopropylbenzenesulfonic acid,[(1R)- 2 -bornylidene]- hydrazide (37) 2 4 a. CH(CH3)2 V'1 '3 NNHS02- 4 ~ V c H(CH3)2 CH(CH3)2 In a 500 ml round bottomed flask was placed 2,4,6-triisopropylbenzenesulfonylhydrazide (20.85 g, 69.86 mmol), (1R)-(+)-camphor (9.67 g, 63.51 mmol), acetonitrile (freshly distilled from calcium hydride) (32 ml), and concentrated hydrochloric acid (6.36 ml, 76.3 mmol). The white solids dissolved upon addition of the HC1 and the resulting colorless solution was magnetically stirred for 24 h. During this time a white precipitate was formed. After cooling to -10 °c for 4 h, the precipitate was removed by filtration and dissolved in dichloromethane (70 ml) , filtered, dried over sodium sulfate and concentrated to provide 22.78 g of 37 as a white solid, mp 196-199 °C (dec) (83%); IR (KBr, cm-1) 3430, 3240, 3045, 2960, 2930, 2870, 1662, 1600, 1560, 1460, 1428, 1391, 1370, 1338, 1323, 1170, 1035, 1010, 910, 885, 731, 675, 658; XH NMR (300 MHz, CDC13) 6 7.15 (s, 2H) , 7.10 (s, 1H) , 4.30-4.14 (m, 2H) , 2.97-2.81 (m, 1H), 2.30-2.19 (m, 1H), 1.94 (t, J=4.4 Hz, 1H); 1.88-1.70 (m, 2H) , 1.67-1.55 (m, 1H) , 1.36-1.04 (m, 2H) , 1.26 (d, J= 6 . 8 Hz, 12H) , 1.25 (d, J=6.9 Hz, 6 H) , 0.86 (s, 6 H) , 0.61 (S, 3H). 187 (aR*,iR,4 5)-a-vinyl-2-bornene-2-ethanol (38). CH. CH. CH. A magnetically stirred solution of 37 (20.6 g, 47.6 mmol) and N,N,N,N-tetramethyethylene diamine (100 ml) in hexane (100 ml) at -55 °C under argon was treated dropwise over 20 minutes with sec-butyllithium (100 ml of 1.30 M, 130 mmol). The resulting yellow solution was stirred at -55 °C for 2 h and allowed to warm to 0 °C as nitrogen was evolved. Butadiene monoxide (9.11g, 130 mmol) was added rapidly dropwise and the reaction mixture was allowed to warm to room temperature over 1.5 h and stirred overnight. The resulting pale yellow solution was cooled to 0 °C and quenched by the addition of ice. After dilution with ether (100 ml), the solution was washed with water (100 ml x 3), saturated ammonium chloride solution ( 1 0 0 ml), and brine (100 ml). The organic phase was dried over magnesium sulfate and concentrated to provide 1 2 . 2 g of green colored liquid. Column chromatography (silica gel, elution with 12% ethyl acetate/petroleum ether) on silica gel gave 4.24 g (43%) of 38 as a colorless liquid, 1.45 g (15%) of 39 as a colorless liquid susceptible to polymerization, and 4.20 g of unidentified polar material. Spectral data for 38 (A mixture of (aR*,1R*,4S*) and (aS*,1R*,45*) diastereomers) ; 188 IR (neat, cm"1) 3370, 2975, 2945, 2865, 1468, 1450, 1382, 1360, 1101, 990, 821, 732? XH NMR (300 MHz, CDCl 3 ) 6 5.96-5.80 (m, 1H), 5.80-5.66 (series of m, 1H) , 5.31-5.20 (m, 1H), 5.14-5.04 (m, 1H), 4.30-4.19 (m, 1H), 2.32-2.10 (m, 3H) , 1.96-1.72 (m, 2H) , 1.59-1.1.16 (series of m, 2H) , 0.98-0.96 (m, 1H) , 0.98 (s, 3H from one diastereomer), 0.97 (s, 3H from one diastereomer), 0.79 (s, 3H) , 0.77 (s, 3H) ; 13C NMR (75 MHz, CDCl 3 ) ppm 145.44, 145.36, 140.66, 130.33, 129.63, 114.54, 70.22, 56.65, 56.16, 54.52, 54.22, 51.45, 51.40, 36.49, 36.21, 31.45, 31.26, 25.78, 25.66, 19.71, 19.63, 11.47? MS m/z (M+) calcd 206.1671, obsd 206.1686. Spectral data for (E)- and (Z)-4-[(1R)-2-Bornen-2-yl] -2-buten-l-ol (39). ,CH CH. CH. OH Obtained as a mixture of E/z isomers; IR (neat, c m -1) 3330, 3040, 2980, 2945, 2863, 1610, 1450, 1382, 1370, 1360, 1090, 1005, 972, 800? XH NMR (300 MHz, CDCl3) 6 5.78-5.56 (m, 2H), 5.54-5.51 (m, 1H), 4.22-4.11 (m, 2H), 2.84-2.60 (m, 2H) , 2.25-2.17 (m, 1H) , 1.86-1.73 (m, 1H) , 1.53-1.39 (m, 1H) , 1.35-1.18 (m, 1H) , 1.00-0.83 (m, 2H) , 0.96 (s, 3H from one isomer), 0.95 (s, 3H from one isomer), 0.77 (s, 3H) , 0.75 (s, 3H) ; 13C NMR (75 MHz, CDCl3 ) ppm 147.65, 130.51, 130.16, 129.81, 129.34, 127.58, 63.72, 58.56, 56.33, 54.24, 189 51.36, 51.32, 31.45, 31.41, 30.94, 26.03, 25.95, 25.90, 19.70, 19.62, 11.41, 11.36; MS m/z (M+) calcd 206.1671, obsd 206.1623. Anal. Calcd for C 1 4 H 2 2 O: C, 81.50; H, 10.75. Found; C, 81.02; H, 10.69. Sharpless Kinetic Resolution to Obtain (a£,l£,4S)-a-Vinyl- 2 -bornene- 2 -ethanol (16). CH, ,CH, HO CH. Diastereomers 16 and 17 were partially separated by MPLC (elution with 12% ethyl acetate/petroleum ether) using a silica gel column impregnated with 1 0 % silver nitrate. Crushed, activated 3 A molecular sieves (100 mg) were placed in a 10 mlround bottomed flask under argon and the apparatus was flame dried for 20 minutes. After the flask had cooled, a 6:1 mixture of 16/17 was added (206.3 mg, 1.00 mmol) followed by dichlorome thane (3 ml) and L-(+)-diisopropyl tartrate (14.1 mg, 0.060 mmol). The mixture was cooled to - 8 °C and titanium tetraisopropoxide (14.2 mg, 0.050 mmol) was added with magnetic stirring. After 30 minutes, pre-dried cumene hydroperoxide (105.2 mg of 80%, 0.55 mmol) was added dropwise. The mixture was stirred at - 8 °C for 12 h and quenched with 5 ml of a 190 solution made from citric acid (22 g) and ferrous sulfate ( 6 6 g) in 200 ml of water. The mixture was stirred at 0 °C for 1 h and extracted with dichloromethane (25 ml) . The organic layer was stirred with 30% sodium hydroxide in brine (5 ml) for 1 h at 0 °C before it was separated, dried over sodium sulfate, and concentrated to provide 320.4 mg of yellow oil. MPLC (elution with 8 % ethyl acetate/petroleum ether) on silica gel gave 142.3 mg of 16 as a colorless liquid; [a]25D +4.3° (c 1.53, CHC13); IR (neat, cm-1) 3370, 2980, 2950, 2865, 1470, 1450, 1382, 1360, 1100, 990, 820, 732; XH NMR (300 MHz, CDC13) 6 5.96-5.80 (m, 1H) , 5.80-5.76 (m, 1H), 5.31-5.20 (m, 1H), 5.14-5.04 (m, 1H), 4.30-4.19 (m, 1H), 2.32-2.10 (m, 3H), 1.96-1.72 (m, 2H), 1.59-1.16 (series of m, 2H) , 0.98-0.96 (m, 1H) , 0.98 (s, 3H) , 0.79 (s, 3H) , 0.77 (s, 3H) ; 13C NMR (75 MHz, CDC13) ppm 145.40, 140.65, 130.42, 114.59, 70.22, 56.70, 54.26, 51.43, 36.54, 31.49, 25.81, 19.74, 19.66, 11.48; MS m/z (M+) calcd 206.1671, obsd 206.1623 Anal. Calcd for C 1 4 H 22O: C, 81.50; H, 10.75. Found: C, 81.80; H, 10.85. 191 Sharpless Kinetic Resolution to Obtain (aS,lR,4S)-a-Vinyl- 2-bornene-2-ethanol (17). CH. CH. CH. Diastereomers 16 and 17 were partially separated by MPLC (silica gel, elution with 12% ethyl acetate/petroleum ether) using a silica gel column impregnated with 10% silver nitrate. Crushed, activated 3 A molecular sieves (160 mg) were placed in a 10 ml round bottomed flask under argon and the apparatus was flame dried for 20 minutes under argon flow. After the flask had cooled, a 1:2 mixture of 16/17 was added (231.1 mg, 1.12 mmol) followed by dichloromethane (8 ml) and L-(+)-diisopropyl tartrate (15.8 mg, 0.067 mmol). The mixture was cooled to -8 °C and titanium tetraisopropoxide (15.9 mg, 0.056 mmol) was added with magnetic stirring. After 30 minutes, pre-dried cumene hydroperoxide (213 mg of 80%, 1.12 mmol) was added dropwise. The mixture was stirred at -8 °C for 15 h and quenched with 5 ml of a solution made from citric acid (22 g) and ferrous sulfate (66 g) in 200 ml of water. The mixture was stirred at 0 °C for 1 h and extracted with dichloromethane (25 ml). The organic phase was stirred with 30% sodium hydroxide in brine (5 ml) for 1 h at 0 °C before it was separated, dried over sodium sulfate, and concentrated to provide 522.7 mg of 192 yellow oil. . MPLC (silica gel, elution with 8% ethyl acetate/petroleum ether) gave 92.6 mg of 17 as a colorless liquid; [a)25D -27.6° (c 0.50, CHC13); IR (neat, cm-1) 3365, 2950, 2860, 1465, 1445, 1380, 1361, 1101, 991, 820, 732; XH NMR (300 MHZ, CDCl 3 ) 6 5.96-5.80 (m, 1H) , 5.5.74-5.66 (m, 1H) , 5.31-5.20 (m, 1H) , 5.14-5.04 (m, 1H) , 4.30-4.19 (m, 1H), 2.32-2.10 (m, 3H) , 1.96-1.72 (m, 2H) , 1.59-1.1.16 (series of m, 2H) , 0.98-0.96 (m, 1H), 0.97 (s, 3H) , 0.79 (s, 3H) , 0.77 (s, 3H) ; 13C NMR (75 MHz, CDCl 3 ) ppm 145.36, 140.65, 129.70, 114.60, 70.26, 56.18, 54.57, 51.49, 36.26, 31.29, 25.69, 19.73, 19.68, 11.50; MS m/z (M+) calcd 206.1671, obsd 206.1667. Anal. Calcd for C 1 4 H 2 2 O: C, 81.50; H, 10.75. Found: C, 81.62; H, 10.78. Spectral data for (l£,3S,4£)-2-Methylene-3-bornane- propionaldehyde (47). CH. CH. CHO CH. CH Obtained as a colorless liquid; IR (neat, cm-1) 3060, 2960, 2870, 2710, 1725, 1650, 1445, 1387, 1125, 1018, 780; XH NMR (300 MHz, CDCl 3 ) 6 9.80 (t, J=1.9 Hz, 1H), 4.76-4.62 (m, 2H), 2.58-2.45 (m, 1H), 2.45-2.36 (m, 2H), 2.12-1.97 (m, 1H) , 1.70-1.49 (m, 4H) , 1.45-1.08 (series of m, 2H) , 0.93 193 (s, 3H), 0.89 (s, 3H), 0.79 (s, 3H); 13C NMR (75 MHz, CDC13) ppm 202.36, 163.22, 100.56, 52.25, 47.05, 46.84, 42.55, 42.33, 35.24, 23.40, 19.89, 19.13, 19.02, 12.71? MS m/z (M+) calcd 206.1671, obsd 206.1707. Anal. Calcd for C 1 4 H 2 2 O: C, 81.50; H, 10.75. Found: C, 81.71; H, 10.88. Spectral data for (lfi,3£,4£)-2-Methylene-3-bornane- propionaldehyde (48). CH. CH. CHO CH. Spectral data for 48 was deduced from an inseparable mixture of 47 and 48? XH NMR (300 MHz, CDCl3) 6 9.80 (t, J=1.9 Hz, 1H), 4.76-4.65 (m, 2H), 2.58-2.45 (m, 2H), 2.00-1.70 (m, 2H), 1.70-1.49 (m, 4H) , 1.45-1.08 (series of m, 2H) , 0.92 (s, 3H) , 0.87 (s, 3H) , 0.82 (s, 3H) ? 13C NMR (75 MHz, CDC13) ppm 202.65, 164.36, 100.42, 52.32, 49.00, 48.27, 45.93, 44.08, 34.00, 23.93, 21.37, 20.29, 19.25, 12.50. 194 REFERENCES 1. For reviews see: (a) Desimoni, G.; Tacconi, G.; Barco, A.; Pollini, G. P. Natural Product Synthesis Through Pericyclic Reactions, ACS Monograph 180, American Chemical Society: Washington, D.C., 1983; pp. 267-338. (b) Hill, R. K. in Asymmetric Synthes is, Vol. 3, Morrison, J.D. Ed. ; Academic Press: New York, 1984; pp. 502-572. For further interesting examples see: (c) Paquette, L.A.; DeRussy, D.T.; Cottrell, C.E. J. Am. Chem. Soc. 1988, 110, 890. (d) Paquette, L.A.; Telaha, C.A.; Taylor, R.T.; Maynard, G.D.; Rogers, R.D.; Gallucci, J.C.; Springer, J.P. J. Am. Chem. Soc. 1990, 112, 265. 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Soc. 1989, 111, 4525. (c) Nugent, W. A.? Rajan Babu, T. V. J. Am. Chem. Soc. 1988, 110, 8561. (d) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1974, 95, 6136. 26. (a) Soderquist, J. A.; Rivera, I. Tetrahedron Lett. 1988, 29, 3195. (b) Hubbard, J. L. Tetrahedron Lett. 1988, 29, 3197. 27. Macdonald, T. L . ; Natalie, K. J., Jr.; Prasad, G . ; Sawyer, J. S. J. Or#. Chem. 1986, 52, 1124. 28. Ireland, R. E.; Thaisrivongs, S.; Dussault, P. H. J. Am. Chem. Soc. 1988, 110, 5768. b. (spectral data) Ireland, R. E.; Anderson, R. C. ; Badoud, R.; Fitzsimmons, B. J.; McGarvey, G. J.; Thaisrivongs, S.; WilCOX, C. S. J. Am. Chem. Soc. 1983, 105, 1988. 29. Mori, K . ; Masuda, S.; Suguro, T. Tetrahedron, 1981, 37, 1329. 30. Mori, K.; Kuwahara S.? Levinson, H. Z.? Levinson, A. R. Tetrahedron 1982, 38, 2291. 31. (a) A1 linger, N. A. J. Am. Chem. Soc. 1977, 99, 8127. (b) Burkert, U. and Allinger, N. A. Molecular Mechanics, American Chemical Society, Washington, D.C. (1982) . 32. Gajewski, J. J. ; Conrad, N. D. J. Am. Chem. Soc. 1979, 101, 2727 and references cited therein. 33. Fukui, K. Theory of Orientation and Stereoselect ion, Springer-verlag: Berlin, 1975; pp. 62-63. 34. Binkley, J. S.; Pople, J. A.; Hehre, W. J. J. Am. Chem. Soc. 1980, 102, 939. 198 35. Ireland, R. E. ; Varney, M. D. J. Org. Chem. 1983, 48, 1829. 36. The situation becomes less clear with cyclohexylidenes having an exocyclic methylene: Denmark, S. E.; Harmata, M. A.; White, K. S. J. Am. Chem. Soc. 1989, 111, 8878. 37. Brown, H. C,; Kawakami, J. H.; Liu, K.-T. J. Am. Chem. Soc. 1970, 92, 5536 and references cited therein. 38. Brown, H. C,; Kawakami, J. H.;Liu, K.-T. J. Am. Chem. Soc( 1973, 95, 2209 and references cited therein. APPENDIX A XH NMR SPECTRA FOR THE HALLER-BAUER METHODOLOGY STUDY 199 CH, f-BuQOCw (CH3)3Si 200 CH. y d " 6.SI fi.ai s.s i s.II S.SI S.II 2.SI 2.11 .51 201 c h 3 f-B u O O C ^ > (CH3)3Si T t 202 : i 'i i i | m i • j 111111111 j 11 TT 0. fit I.SI 1.11 s.m «.si M l rrij HOCH (CH3)3Si 204 ? c h 3 (CHgJgSiH-usi V- U. .11 i ea 1 33 ?’C3 : it 2.3 205 206 jj ; 2 :.y i.v? i.jj *.*i vu *.s» 207 to Q- 208 6.5 209 J n O.X I ■ X OT oX .51 .51 7.11 e.Sfl 6.11 S.SI S.II «.5I «.ll S.SI s.at 2.SI 210 1 17 * I' I* 1 • IS*& S M 15 • II*: I5't I* V 157 117 to c h 2o h (0 H 3 ) 3 0 ^ 7 k si(CH])3 f T ' I »■»"*' I »,♦'**■ I ' ' 1 i 1 * ’ 1 * ' 1 I" I 2.5 2.1 1.5 !. I .5 3.1 212 213 pn* 214 .S0 .S0 t.ei 7.50 7.II S.50 6*1 51 S. S.00 «.*• 1.01 S.S0 5.00 2.SI 2.00 1.50 1.00 .SI Si(CH3)3 o X ”o X O 7.St 7.ft 6.St 6.if S.Sf S.ff •r*«* f.Sf f.tf S. St 3.(1 2.51 2.tt 1 .1.51 I.If 215 216 o Q- CO 217 CL .00 .00 G.S0 6.00 S.SO S.10 I.Si 1.00 5.SB 3.00 2.50 2.00 1.50 218 to x . PH PH Si(CH3)3 O CO o m 219 220 f s.i APPENDIX B 1H NMR SPECTRA FOR THE MECHINISTIC INVESTIGATION OF THE HALLER-BAUER AND CRAM CLEAVAGE 222 223 CL 224 x 225 O 6.0 1 s.1 .B .I .1 S L B .SB IB L St I 2.11 2.SI s.MB .51 s .11 HOO Q. O 227 O .51 .51 Mil 51 6. 6.11 5.51 S.IS 1.53' I.II 3.51 3.11 2.51 2.11 228 Q. •s I 229 a a .si 1 . 1 .* .* 1 a a 1 . 2 a a 5 . 2 a a 0 . 3 O CL fi.ns O CL 231 — 4 CL CL X o Cl o OH CH, 232 233 I.II SI ) 5.88 •.'it SI SI ’.*8 *j8 6. 6.88 S.S* 5.88 f. 234 J >4. 'rOnK:L!j L_ 235 236 237 CL 238 CSI CM .SI .SI HI* ’ 6.M G.H 5.SI S.II *.SI «.II J.SI i.H 2.SI 2.11 3.1 . «.S «.• J.5 J.l 2.5 240 CL 241 O a. S.f S.f S.S 5.1 t.s t.l J5 J.l 7.5 242 O CL 243 O o CL 244 r»*n r»*n • Q_ fib* fib* 6.11 S.51 S.II I.SI ■ I.II S.SI S.II 2.SI 2.11 1.51 1.11 245 O Q. .51 .51 M I PM G.IIS 5.51 S.Cl 1.51 4.11 S.51 S.II 2.51 2.11 1.51 ' I.II 246 Q. O CL s. a s. 247 Q. 248 O M M 0.50 C na 5.58 5.01 I.VI I.II 3.51 *1 3 2.51 2.11 249 250 .si roo f.w ’,o ’,o z.ta /. .00 6.si nno s.m u.do i.'«* <.n j.si t .*» 253 rrn O x O O O 254 IK,; CP Cf» I I CD'Z C VI 2 tt **•'» tit I12 Q. Or, 9 CC'-i IVS M'9 M'9 IVS If. *9 tV 255 Q_ .56 .56 ’.«« 6.56 6.61 5.56 S.16 <.i! ‘.II 56 S. 5.66 2.56 2.66 256 ffl 257 TV -C Q. -C L k O O ' ™ ' s.si s.si ts.ai 4.;i a.ti 3.01 D ™ . 258 a ./: v.. CL CL CL HO 259 O ffn ffn ; CL II.II II.II 9.11 8.11 7.11 1.1| 5.11 i.ll 3.11 2.11 CH. fi.ll 4.M J-OI 2. II 260 261 OJ Pf« M l 51 G. (.11 S.SI 5.11 1.51 M l 3 51 HI 3. 2.51 2.11 , 51 J I.II .51 ?.st O.fe O.fe 262 ice: Q_ APPENDIX C *H NMR SPECTRA FOR THE STEREOCHEMICAL INVESTIGATION OF THE ANIONIC OXY-COPE REACTION 263 264 5 5 51 3.M 2.51 2.91 53 !. II II «.5l I.IS M I 5.51 5. E- SI SI E- M M . . 266 CSB 7.SO 7.SO 7.00 6.SO 6.00 9.50 9.00 4.90 4.00 3.90 3.00 2.90 2.00 1.90 1.00 .90 0.0 CHf H 267 268 LL 269 Q. O OCH, 0*TE 13-1 -91 SF 300 .133 ST 210.0 01 5000 .000 S! 32766 TO 16364 SM 4000 .000 H2/PT .244 PH 3 .5 RO 0 .0 AO 2 .048 R6 16 NS 24 TE 303 Fw 5000 02 50000..000 OP 7L PO LB .200 OB ■ 400 CX 40..00 CT 0..0 FI 9. 501P F2 . 499P MZ/CM 75..031 PPM/CM 250 SR 3366. 01 JwiL 70 27 271 O 6.00 6.00 S.SO S.00 4.50 4.00 272 LL a. 7.50 7.00 6.50 6.00 5.50 9.00 4.90 4.00 3.90 3.00 2.90 2.00 1.90 1.00 .90 0.0 ZLZ 274 275 rrn 276 rrn sr 300.133 (CH3)3C ST 210.0 01 4660.701 SI 32766 TO 32766 S* 3906.260 HZ/PT .236 pw 4.6 PO 0.0 40 4.194 Fm 4900 0? 60000.000 OP 10L PO 16 .200 06 0.0 CX 4C.OO CT 0.0 F 1 9.500P n -.497P «Z/C« 75.012 F>f>m/Cn .250 SP 3373.56 2 7 7 2 278 7.50 7.50 7.00 6.90 6.00 5.90 S.00 4.50 4.00 9.50 9.00 2.90 2.00 1.90 1.00 279 x 6.SC 6.SC S.00 7.SO 7.00 6.SO 6.00 S.SO 00 S. 4.50 4.00 3.SO 3.00 3.SO 3.00 I.SO 1.00 .SO (CH3)3c 280 H (CH3)3C h ' x o p n b sc«o ■r • 4. SO to co cot. 004 DATE 17-4-■90 SF 250..133 sr B3.0 01 4032..597 SI 3276S to 32760 SN 4237. 299 HZ/PT .259 PW S..0 RO 0..0 AO 3..067 86 20 NS IS TE 303 FW 5300 02 SOOOO. 000 OP 30L PO LB I..500 SB 0..0 CX 34..00 CT 0..0 FI 9.soiP F2 , 499P HZ/CM 73..563 PPH/C* .294 SA 2054..14 I 1 1.50 I 282 H Br (CH3)3C H 283 H (CH3)3c I*" VU32.001 OATE 17-4-90 250.193 63.0 4032.597 32766 n 32766 4237.216 HZ/PT .259 5.0 RO 0.0 AO 3.867 RO 20 NS 8 TE 303 FN02 50000.000 5300 OP 301 PO 18 .200 66 0.0 CX 34.00 CT 0.0 FI 9.500P F2 -.499P HZ/CM 73.563 PPN/CM .294 SR 2854.31 JUX- 1 I ■ 1 ■ 11 1 ■ ■ ■ I ■ 1 1 1 I *" 1 ■ I ' 1 1 ■ I 1 1 * ''1 1 ' . , . . . . j“i ~» ■ - , ■ . ■ . , . i i t , , . , - . r . , . 7.0 6.5 6.0 5.5 5.0 4.5 4.0 9.5 3.0 2.5 2.0 1.5 1.0 .5 0.0 PPM 284 285 CM m OD 8.90 8.90 8.00 7.90 7.00 6.50 6.00 S.SO 9.00 4.90 4.00 3.90 3.00 2.90 2.00 1.90 1.00 .90 0.0 H ,0H (CH3)3C DF0I6ALM.O02 DATE 14-4-90 CH, SF 300.133 ST 210.0 01 4666.70! SI 32788 TO 32766 S« 3906.250 HZ/PT .236 PM 4.5 AO 0.0 AO 4.194 A6 10 NS 10 TE 303 Fw 4900 02 50000.000 OP 101 PO .200 0.0 40.00 0.0 9.500P F2 -.SOOP KZ/CN 75.030 PPM/CM ___.250 SR 3366.19 JL 1- — I- - 1 1 ' " I.. , »T ’'■ T ’"i» — 9.00 6.50 6.00 7.50 7.00 6.50 6.00 S.SO 5.00 4.50 4.00 3.50 PPM 286 Of*. 004 0*TE 27-9-■90 tlH£ 10: H t SF 300. 133 SP02 300.130 ST 210.0 01 4860. 701 SI 22766 TO 32766 S« 3906. 250 H2/PT 236 P m 4.5 RO 0.0 *0 4 . 194 RC 10 MS 16 TE 303 OE 162. 5 OR 12 O m 126 Pm 4900 02 50000. 000 OP 101 PO Lfi 200 CB 0. 0 HC 0 OC 1.000 HZ/C* 75.030 PPm /C" 250 IS 4 SR 3367. 56 287 288 co 6.9 6.9 6.0 9.9 9.0 4.9 4.0 9.9 . 9.0 2.9 . 2.0 OKOEPt.002 CUt£ 13-9-90 Sf 300.133 SF02 300.130 ST 210.0 01 4666.701 SI 32769 TO 32766 H2/PT PC 303 OP 162.5 h Z/C« 75.024 7.50 7.00 1.00 5.00 4.00 3.50 3.00 2 .0 0 ! .50 .50t.oo 290 291 ffn 1.00 1.00 0.50 0.00 7.90 7.00 6.SO 6.00 5.50 5.00 4.90 4.00 3.50 3.00 2.90 t.00 1.90 1.00 ' .50 0.0 HN ,00 .00 .50 .00 9.00 6.60 6.00 7.50 7.00 6 .0 0 292 OENCOIO OiTE 22-9-90 TIk E 11:57 SF 300.133 SFQ2 300.130 Sr 210.0 01 <666.701 SI 32766 TO 32766 S" 3906.250 h Z/PT .236 P» no o.o *0 4.194 MSPS 116 10 TE 302 DE 162.1 OP 12 0* 126 Fm 4900 02 50000.000 OP 10L PO 16 .200 ce o.o ftC 3 OC 1.000 •m Z/Ck 76.779 .262 IS > ISP 3366 66 293 CH, ,CH, C * U 23-10*90 CH. U* E 10; 07 sr 300.133 SF02 300.130 Sf 210.0 01 *860.701 SI 32768 TO 32768 S« 3906.250 h Z/PT .238 303 162.5 On 128 *900 02 50000.000 OP 10L PO .200 OC 1.000 HZ/CN 75.02* PPM/CK .250 . 0.07.00 6.00 5.507.50 5.00 4.00 3.50 3.00 2 .0 0 1.00 294 CH, CH (1:1 mixture of epimers) HO CH, Sf 300.133 Sf02 300.130 ST 210.0 0! 5000.000 SI 32766 TO 32766 S* 4000.000 HZ/PT .244 PC 4.006 n S 303 50000.000 .2 0 0 OC 1.000 m Z/Cn 75.031 PPh /Ch .250 3368.16 7.50 7.00 6.SO 8.00 9.SO 9.00 4.00 3.90 2 .0 0 S.00 .50 295 POPO .005 0*TC 21-11 -90 U"E 21: 3« OH Sf 300. 133 sroz 300.130 sr 210.0 01 5000. 000 si 32766 ro 32766 s* 4000. 000 H2/PT 244 Pa 4,5 « D 0.0 AO 4.096 PC 20 n S 6 TE 303 DC 156. 6 OP 12 0« 125 Fa 5000 02 50000. 000 OP 7L PO 16 200 Gfi 0.0 NC 0 oc 1.000 HZ/CM 75. 031 PPM/CM 250 IS 5 SP 3366. 16 JL r—...... t. t...... 9.00 e.sc e.oo 7.so 7.00 6.so 2 .0 0 1.90 1.00 .50 296 297 O 0.50 0.50 6.00 7.50 7.00 6.50 6.00 9.50 5.00 4.50 4.00 3.90 3.00 3.50 3.00 i.SO, 1.00 .50 CH •CH, DATE 16-1-91 TIHE 0: 54 CH SI 32768 TO 16364 HZ/PT 3.5 L6 200 .50 7.50 7.00 6.00 5.50 S.00 4.00 3.00 2.00 1.50- 1.00 .50 298 299 — Hi O e HO. eH0 C'O 20iS OCt'OOC 2*9W3/ZM MO/Hdd 929*29 SZ2* COG dS CCfOOG »S 000*000* 960'F 9*t 99 002’ OOF* 000* I 0*05 to 000*0005 »’ ld/2H ►»2’ 0*00 20 000*00005 t* 9 bS 9t * C 90 0S-2I-F 31*0 sc 0*0 30 9*951 Od tF :jt 3-Ii SI S 21 s 92 IS 99Z2C 01 9912C *9 a toe 2 -0 621 ooos 0*012iS OCC'J3B 1 L dO ■d oa o» oa SN as 3N 30 3i * j (1:1 mixture of epimers) CHO CH, CH >0.00 0.50 e.oo 7.50 7.00 6.50 6.00 5.50 S.00 4.50 4.00t.00 .50 0.0 PPH 300 APPENDIX D 19F NMR RESONANCES FOR MOSHER ESTERS USED IN THE ANIONIC OXY-COPE STUDY 301 302 19F Resonances (PPM) (R)-alcohol (S)-alcohol OCH, -72.754 -72.749 .OCH, -72.650 -72.582 II Ph A £*och3 -72.708 -72.626 APPENDIX E X-RAY CRYSTAL STRUCTURES FROM THE ANIONIC OXY-COPE STUDY 303 304 (aR*,5R*)-5-ter t-Butyl-a—vinyl—l-cyclohexene—1-ethanol (32) H ( C H a f e C - ' U --- \ h OPNB xxxxxxxxxxxxxxxxxxxxxxxxxxx nnnnnnnnnnnnnnnnnnnnnzoooo UMHUMHUINHWHHNHWHHtOHMHHHHHHH MMHHHHPHHHHHID0)>ISU1AWNH u> m ►- o HO(005^a\01il»UMHO-'«'- — — — 3 i—^onnooonnononnnonooooonoonoo r—* r-^ r—i r-^ r“^ r—s r—» r—1 r—4 r"i r**> »“n r—i r**^ r““i r1^ ^"4 5‘ WWWWWMHHMHHHHHHHHHHHHVflOffyylWfO Final Fractional Coordinates for for Coordinates 04 N H27 C21LAP84 Fractional Final 1 1 1 t 1 1 1 I I I I I I I I I I I I I I I I I I I o o o © o o o o o o O o O o o o O o o o o o o o o o o OOOOOOOOOOOOOOOOOOOOOOOOOO 4 , 1 4 «••••••«•••••••• • •••••• rf* CJ h* to O o N> ro o H* O h- o NJ h-* to o X Wt-'H'MOOOMH'OOWWf-'H-f-'l-'Mt-'MH'l-'l-'H'P-'I'J X Ni 03 CO CJ © o CJ CJ CO VO 03 CJ ro 0> h-* to NJ CV vO H CJ 03 H H 03 © \ vO (Jl vO 4* VO *0 *vj 03 1—' O CJ Ov 03 fO to CJ «o N> o oo n o ro cn m cj 6) WU1s]i^i^Uli^>lU)(n03ai^lON)CDO\U1tfiOHHHHil>l-> OJp»»U)U)fON>#»UlCJUI(Orf»<»U>UlN)Mrs)MNJN)fvjrvJNjrOM I I I I I I I I I I I I I I I II II ...... I I I I I I I I I I I I I I I I I I I OOOOOOOOOOOOOOOOOOOOOOOOOO ooooooooooooooooooooooooooo • ••••••••••••••«••••••■••• UIiM j OA^UIUMMUU^O^^UIIONMHNIHHOOO UAUUUU^^WWNMNHOOOOOOOHOHHH *< vOUJC\'Jrf»UirO-(*VD03l->-«JU)ff\rO<»if»>f»OJU)OBI-,VDI-,U>'JH> lfii^WCDH>IWHUIOi&OOIflOvJMUUPvlMvlU'JW \ \ ANW (JIM i^il»UIOUINia(DIOUICDvlOsl<>H(JlCDvl^H ui^UIO'JlfiMOlCOH^MOsJMUi^OOOlUlUIOW'JO CP cr W OOlOOln^UIOI > 10 10 1 H uoooovohuoj <—'-VOOO l'J'IOO'J'JOI'-'OXBCDOSOl'JOlvl'l'JUIpftOlOl ooooooooooooooooooooooooooo OOOOOOOOOOOOOOOOOOOOOOOOOO ~jc\Ci^iooQ3Cooo-'Ja\uic'iinoui*»>(*u)>f»a\-*jinini*»inwN} N 'ja>CDvlU17IU1Uli^U1«aiU1U1Uli^O<‘UM U M I > A M H N 9\'JUim9'MMOJOcOO)lfl*HUU10lOrl>fflWOlfiUlff>HO OOPUIOUI'IOO\HO\UliniOHMlfl*>^NlMUIO(Jl03sl 'jNOJOuiyi030foaiO'f‘fflit»HNjai'jvfluiMuuMu<>'J oumu>u)U)aa)iBooo^a9CouiHviuu)A03sji»u;u ^ ^ A ^ ^ ^ ^ *—> A A A (Sj nmnnnnnnmionunnnnmmmionhnioio UIO\Ai^UIUi^AUINU'JilkUUUIONIOUM»£>U>IU1 a • ••••••••••••••••••••■a*** 03»vlit>MUU)<>IIOU)aiO\SllOHOO)ClUMUM«UMM ft) t->030)ui'0C3i->03i^i0'>JOvau)>^cj00OLn>p>Lnvr)^JLnv0Ln X3 < u o cn 306 Atoms Distance Atoms Distance o< 1 ) -- N 1.19(2) 0(2) N 1.22(2) 0(3) -- C ( 7 ) 1.32(2) 0(3) -- C (8 ) 1.47(2) 0(4) -- C ( 7 ) 1.18(2) N -- C(l) 1.47(2) C(l) -- C( 2) 1.39(2) C( 1 ) -- C( 6) 1.34(2) C (2) -- C (3 ) 1.40(2) C( 3) -- C (4 ) 1.38(2) C (4) -- C(5) 1.38(2) C (4 ) -- C (7 ) 1.52(2) C(5) -- C(6) 1.40(2) C(8) — C(9) 1.53(3) C(8) — C (ll) 1.52(2) C(9) — C(10) 1.30(3) C (ll) — C (12) 1.50(2) C( 12) -- C (13) 1.31(2) C( 12) -- C( 17) 1.45(2) C( 13) — C (14) 1.52(2) C( 14) -- C(15) 1.48(3) C(15) -- C(16) 1.49(2) C( 16) — C( 17) 1.54(2) C(16) — C(18) 1.51(2) C(18) -- C(19) 1.54(3) C( 18) — C( 20) 1.54(3) C (18) — C( 21) 1.52(2) Atoms Angle Atoms Angle C( 7) — 0(3) — C(8) 113(1) 0(1) — N — 0(2) 121(2) 0(1) — N — C(l) 121(2) 0(2) — N — C(l) 118(2) N — C(l) — C( 2 ) 118(2) N — C(l) — C(6) 120(2) C( 2) — C( 1) — C(6) 122(2) C(l) — C( 2) — C(3) 118(2) C( 2) — C (3) -- C (4 ) 120(2) C( 3) — C (4) — C(5) 121(2) C( 3) — C (4) — C( 7) 120(1) C(5) -- C (4) — C(7) 118(2) C(4) — C(5) — C(6) 118(2) C(l) -- C(6) -- C(5) 121(2) 0(3) -- C (7) -- 0(4) 129(2) 0(3) -- C( 7) -- C (4) 111(2) 0(4) -- C (7) -- C (4 ) 120(2) 0(3) -- C(8) -- C(9) 108(1) 0(3) -- C (8) -- C (ll) 105(1) C(9) -- C (8 ) -- C(ll) 110(2) C (8) -- C (9) -- C( 10) 116(2) C (8 ) -- C( 11) -- C (12 ) 114(1) C(ll) -- C (12 ) -- C (13 ) 120(2) C < 11) -- C (12 ) -- C( 17 ) 117(2) C( 13) -- C (12 ) -- C( 17) 123(2) C( 12) -- C( 13) -- C ( 14 ) 124(2) C ( 13 ) -- C (14 ) -- C( 15) 110(2) C (14 ) -- C (15) -- C (16) 113(2) C (15 ) -- C( 16) -- C( 17 ) 109(1) C (15) -- C( 16) -- C (18) 116(1) C (17 ) -- C( 16) -- C( 18) 113(1) C (12 ) -- C( 17 ) -- C( 16) 113(1) C( 16) -- C( 18) -- C< 19) 111(1) C( 16) -- C( 18 ) -- C ( 20 ) 112(2) C( 19) -- C( 18 ) -- C( 20) 104(2) C( 16) -- C( 18) -- C( 21) 114(2) C (19 ) C( 18) -- C( 21) 108(2) C ( 20 > -- C( 18) -- C( 21) 107(2) 307 (a R*,1R*,4 S*)-a-Vinyl-2-norbornene-2-ethanol 1-Naphthalenecarbamate (36) 308 Final Fractional Coordinates for C22 H23 N 02 Atom x/a y/b z/c B(eqv) 0(1) 0.1012(5) 0.8036(6) 0.0279(8) 4.12 0(2) 0.0173(4) 0.7791(6) 0.2010(9) 4.12 N -0.0320(5) 0.7409(7) -0.027(1) 3.33 C (l) 0.0267(8) 0.7742(9) 0.078(2) 3.43 C ( 2) -0.1198(7) 0.713(1) -0.004(1) 3.16 C( 3) -0.1556(8) 0.621(1) -0.067(1) 3.19 C (4 ) -0.1053(8) 0.551(1) -0.136(1) 3.67 C( 5) -0.144(1) 0.464(1) -0.193(1) 5.20 C (6 ) -0.232(1) 0.442(1) -0.181(2) 6.67 C(7) -0.281(1) 0.508(1) -0.117(2) 6.07 C (8 ) -0.2460(8) 0.598(1) -0 .054(1) 3.48 C (9 ) -0.2945(8) 0.666(1) 0.019(2) 5.39 C(10) -0.2564(8) 0.751(1) 0.079(1) 5.85 C (ll) -0.1691(7) 0.7770(9) 0.067(1) 4.16 C(12) 0.1704(7) 0.848(1) 0.125(1) 3.88 C(13) 0.150(1) 0.955(2) 0.14.9(2) 7.24 C( 14) 0.126(2) 1.009(2) 0.222(3) 13.06 C(15) 0.2533(7) 0.831(1) 0.057(1) 5.65 C(16) 0.334(1) 0.868(2) 0.139(2) 6.25 C (17) 0.394(1) 0.935(2) 0.097(2) 10.61 C(18) 0.467(2) 0.943(2) 0.201(3) 9.34 C(19) 0.513(1) 0.841(2) 0.187(2) 12.04 C(20) 0.452(1) 0.766(2) 0.227(2) 10.32 C(21) 0.373(1) 0.833(1) 0.268(2) 7.79 C(22) 0.433(1) 0.912(1) 0.332(2) 7.77 a B(eqv) - 4/3[a 2p, l+b2p22+<^P33+at>(cos7)Pi2+ac(oosP)P13+bc(cosa)p23] b Isotropic refinement. Atom x/a y /b z/c H( 1) C (4 ) ] -0.044 0.565 -0.135 H( 1) C(5) ] -0.111 0.420 -0.245 H( 1) C(6) ] -0.257 0.379 -0.219 H( 1) C (7) ] -0.341 0.492 -0.113 H( 1) C(9) ] -0.354 0.652 0.028 H(l) C (10)] -0.290 0.796 0.129 H( 1) C (ll) ] -0.143 0.838 0.108 H( 1) C(12) ] 0.180 0.820 0.216 H( 1) C( 13) ] 0.145 0.994 0.065 H( 1) C(14) ] 0.118 0.970 0.304 H( 2 ) C (14) ] 0.160 1.063 0.263 H (1) C(15) ] 0.258 0.760 0.034 H( 2) C(15) ] 0.247 0.871 -0.026 H (1) C( 17) ] 0.385 0.975 0.015 H (1) C (18) ] 0.502 1.002 0.208 H (1) C(19) ] 0.570 0.836 0.236 H( 2) C(19) ] 0.516 0.835 0.090 H (1) C(20) ] 0.430 0.722 0.152 H( 2) C(20) ] 0.481 0.725 0.300 H (1) C(21) ] 0.333 0.805 0.325 H ( 1) C(22) ] 0.477 0.889 0.404 H(2) C(22) 1 0.401 0.968 0.365 nonnnnn nooonnnnnzooo M H» M I HHHHWfflW^Ai^N)H W H H oonoooononozoo 03 vO VO 1 *0 tncnos IO W W W W W W W W W W W ^rOHHMHHOOUl ^ ^ ^ ^ ^ ^ ^ ^ ^W ^W ^fO H oa3^oc7scorowwwww w w I I Distance 1111 Atoms Distance Atoms I I I I I 1 I I I I I i i i i i i i ononft n o o nnnnnnnnno i i t i i f i i i i < i ^ ^ ^ *■“% * ~ S *•**+ rotO M M M M HH^OODO tntO WNHHH noooonnonooooo ' O 00 00 OS ON f^t-iwwwwwwwwww fOMHMHHHCJOSCDHfOMH MfO03«O*»U>©'~*ww|-»www ( f i l l ! r r ! J I J I i r nnnnn n nn onoooQOzon ^ ^ ^ ^ <•■»■* ^ ro ro ro H» M M M VO 03 OV 00 A H* W H m roVO I it* US © o w w w w w m ^ ro >-i|_#)-iMMMMMMMMMM)-' cooDrocsoscncnovo^os^tocn vO o vo o ro tororotororotororot-*> cn «P> it* ** © OOM HO WHOWCD 3 tofONJiorofoiororoHHHHM lO HfONfOrONNWHHHHfOHHHHHHH n o o n noooo o o n n n nnzon ro m M M vo *0 u> cn u> roCO MM O OS 03 ON cn nnnnoonnonnnzo I I I I I I I I fOHHHHHHCDffl* WW M I 1 I I I II I I I M VO 03 OS US fO O ■w w w -w w w O O o n o oo nnnn O O n o o n z <**s *•»» I t I I 1 I I I I I I I ro roM H» M M M M 03 00 os1^ CO ro I I I I I I I I I I I I I I -J ONcn ro ro ’ VO 03 nonnonnnnnnnnn 1 I t I I I fO WHNHHH vO nIUI* WH H I I I i I I t r lOOVflHONCnH^^'^^'-'^w nnnnnon n o o nn n o z o > *— •» ro ro ro roM tO ' M VO -0 - J cn 03 u i ro to o o ro00 M OS M w ^OOOHNHHOMtOHMHHfOH'HtO > «tfc^cncj*»cn’C»>*oju*fc^LJ£fc rofo*t*cn©03cncnc3tou)-oMvo-JM03©M 3 OAO\flOfOOO^OHPO<»Ul ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ uQ MfOrOfOfOrOHHHHfOHfOHHHHHH' (OfOIOfOfOHHMfOMHHHH U o VO APPENDIX F SAMPLE CALCULATION OF AMOUNTS OF AXIAL AND EQUATORIAL OXYANION FROM ROTATIONS 310 311 Reference Compounds: c h o [a]2 5 d +14.4° H 'CH3 (c 3.60, CHCl3) c h 2o h [a]2 5 D +8.62° H 'CH3 (C 3.65, CHCl3) Example: Observed [a]25D +3.7 (c 3.91, CHC13) for the aldehyde product 40. -14.4(1-x) + 14.4(x) = +3.7 -1 + 2X = 3.7/14.4 X = 0.63 Thus, the reaction proceeds to give 63% (S)-40. This corresponds to 63% equatorial oxyanion orientation during rearrangement. APPENDIX G MOLECULAR MECHANICS CALCULATIONS FOR THE OXY-COPE STUDY 312 313 Equatorial Bonding with Axial Oxyanion, (aR*,SS*) MM E = 40.44 kcal/mol a t o m i c eoa;DtmTCG .'Nr ■ec-ic.gv -f^ Efs - A T C W X Y T Y P E BOUND TO ATOMS C ( 1). 6 . 9 7 5 6 0 4 . 6 1 4 9 9 1 . 2 9 6 6 0 ( 1) 2. 6. IS. 16. C ( 2) 6 . 8 9 9 B 2 5 . 7 8 3 9 8 0 . 3 0 5 1 2 ( 1) 1. 3. 7. 17, E C - -3) - ' 13 ■ O 13 7 S 5 . 5 9 6 3 6 — 0 . 7 4 2 0 4 v ( - 1 7 ~ 2 . - - - 4. ' 18,-— 19,- C ( 4) 9 . 3 5 6 1 4 5 . 1 2 7 2 B - 0 . 1 7 5 0 1 ( 2) 3 y____ 5.___ 8, ______T7T- -37" ■7 . T t > j C W •t. / OU^.7 — rrTTunr — t 2 7 JTi 2(77 A “ / 7| *C*i i Ai C ( 8) 1 0 . 5 3 5 2 9 5 . 1 6 7 2 5 • 1 . 1 0 1 6 2 ( 1) 4 . 1 2, 2 3 , 2 4 , C < 9) 5 . 5 4 7 C 8 7 . 0 8 3 6 5 - 1 . 4 2 8 8 7 ( 1) 7 . 2 S i 2 6 . 2 7 , c< 10 4 . 5 2 8 2 6 6 . 5 3 4 9 7 0 . 7 8 1 2 2 ( 1) 7 . 2 S » 2 9 . 3 0 , £ } J - ^adssfi zasSxmonSSfcrsss;33x3r; H ( 16) 6 . 8 3 7 8 4 3 . 6 5 1 8 2 0 . 7 4 0 4 9 H i 1 7) 7 . 1 5 6 7 9 6 . 7 1 1 9 4 O . B 7 B S 9 H ( 18) 7 . 7 1 0 1 3 4 . 0 3 9 5 2 1 . 4 9 8 9 3 t e : e rf-* 39725! IK ' 2 3 ) 11. «J99iAi 1 2 7 1 -Ci. 96 9 7 4 4 . 5 2 9 4 9 7 . 3 6 3 0 3 - 1 . 7 8 9 6 3 h i 2 6 ) 6 . 0 3 - 1 . 0 7 8 5 3 H ( -.28) 3 . 5 2 2 7 8 ■J H ( 6 29 ) 9 - 36 2 1 0 ■iffV. 3 0 ) 4 . 9 1 7 8 7 ■•irrr H i 3 2 ) ....-■-,’8 3 4. 7 si 8 8 I . 6 6 0 5 9 IK 3 3 ) 4 . 6 8 ' 3 7 3 . 9 7 7 3 5 - O - 0 9 2 3 2 H i 3 4 ) .,47 6 . 2 1 6 4 7 -1 . 1 3 6 6 4 1 . 1 2 6 2 0 H < 3 6 ) 1 2 . 4 6 9 3 2 5.88660-9' H i 3 7 ) 9 . 5 3 5 9 9 6 . 9 6 0 7 4 H i 3 8 ) 1 0 . 5 3 6 2 3 6 . 3 6 7 4 2 INTlTPWAi. COUR'Dl! : -r-14CL. Kl&TAIiOE -4-4- rn4G- iC lH S T •S.OCOr: GENEKPKI ZED FORCE FTEL.0 PFAAi 1ETERS IN USE 314 Axial Bonding with Equatorial Oxyanion, (aR*,5 S*). MM E = 39.11 kcal/mol FINAL ATOMIC GGCaDIMATCG ■ PHEt-JOHDCD- ATOt“E> AATOM T O M X V Z7 TYPE EOUND 70 ATOMS C< 1) 4.6=207 —10.027S3 -5-4=037 < 1) 6 , 1 6 1 17, C< 2) 4.38803 -8.79749 -6.33629 ( 15 3 , 7 , 1 ci -e<-- 3 * ------5 t - 4 3 9 6 4 ------9 r 7 8 t 5 2 ~ - -7~46494- ( }> 4,— 19. 20, C( 4) 6.85309 -9.03440 -6.99345 ( 2) 5 , 8 . ______i . t ijt / . »v i 6t 21 * : V:v'. ■? * lO. i ; i 7 . 9 7 4 2 4 - 8 . 7 1 4 0 7 - 7 . 9 6 5 0 3 12. 24, 25, 2 . 7 7 4 8 9 - 7 . 3 0 2 0 8 - 7 . 3 3 7 4 2 26. 27, 28. C ( l O ) 1 . 9 8 0 7 3 - 8 . 3 3 9 6 9 - 5 . 6 3 7 6 0 29. 30, 31, H < 16) 3 . 8 9 5 8 2 - 1 0 . 1 2 2 8 2 - 4 . 6 3 7 5 3 ( 5 ) H < 17) 4 . 3 7 8 1 6 - 1 0 . 9 5 6 2 3 - 6 . 0 6 3 1 4 H C 18 ) 4 . 5 9 1 7 9 - 7 . 9 0 0 6 5 - 5 . 7 0 4 8 1 ( 5 ) *0520 ;Q.t-2 4 3 9 6 - 8 . 7 9 9 9 1 - 8 . 2 1 4 3 6 - 7 . 4 0 3 1 3 7 . 6 3 7 6 2 - S . 0 0 0 5 1 - 8 . 7 5 3 9 1 1 . 7 0 9 0 2 - 7 . 3 1 2 4 3 - a . 0 9 9 e a 3 .. 1 S 6 1 Soj6~ TE £^£a*i&9876‘ p;93123 ^^-5^9.7469 lO.'t 86866 5 ; 1 0 0 0 6 H ( 3 2 ) 1 . 3 6 3 9 7 - 9 . 8 1 6 6 7 — 7 • ( 5 ) 11 , H ( 3 3 ) 3 . 0 3 6 6 1 - 1 0 . 2 5 4 7 3 ” o .3 6 3 7 o ( 5 / 11, H C 3 4 ) 2 . 3 5 8 5 3 - 1 0 . 8 1 0 1 4 - 6 . 7 9 - ; 7 3 V vJ i 11 . ■ ,M;H(l36)¥V: .\?.'69523-V :V— 11^07759 : . - 6 . 9 6 5 0 3 ( 5 ? 13. ■ -A';,.;,'- •T.H(;;-37) • 6 . = 9 2 e O , r :r 11 ^ 4 1 8 2 3 - 7 . 0 4 7 4 2 < 5 ) 14. • ■ ’'’ H( ' 3G ) r ' 7 . 8 1 2 2 9 ^ .’•-12.03652 - 5 . 7 4 6 8 3 ( 5 ) 14, INTEPW iY- COORDINATE CQM3TRAINTS «EIX COMMAND) 1 E-IXen DISTANCE -(- 14---- S)— ■ 2.-OQ-RHG (CONST — GENERALIZED FORCE FIELD PARAMETERS IN USE 315 Axial Bonding with Axial Oxyanion, ( MM E = 39.96 kcal/mol 3.06 A ---- FIK m L- A T O M I C -GtjSAgl-NATeS- A N D DCi '■*’ »• , a .v .'v - — - '•• fekalluy s... 9 3 7 8 6 - B . 7 1 5 7 9 —7.9B263 ( 1) 7 3 0 5 7 - 7 . 4 9 6 8 3 -7.81677 < 1) 9 6 2 6 7 - 8 . 3 0 3 7 8 5.59629 ( 1) 37E1-3 S 55 .•■Sfcs-v,: 4 9 2 7 9 B 9 7 4 3 1 0 . 0 4 4 0 7 — 4 . 5 7 7 1 7 6 3 7 2 1 0 . 9 1 0 0 9 - 5 . 9 9 2 9 1 5FS3 7 3 7 5 — 79.--537 . B 4 7 C 8 — 5□^.iil4,60 . 7 0 4 2 3 J20);^i,Vv**5. 054'18js*S 27690 - < 0C\ . 0 1 5 6 1 - Q . 1 7 9 4 2 - 7 . 4 2 8 7 3 8 . 0 2 1 3 1 - B . 7 9 3 6 5 - 7 . 3=95£ 1 8 2 4 - 8 . 0 7 3 3 2 H ( 2 8 ) 2 4 2 9 2 -7.72252)% 9 l O W -0.14838}'v ~ H \ j O) 9 3 1 7 4 -9.1>15S13V - V- ■ 3 7 0 5 9 r6ST59 -<-55--- - 1 6 H < 3 6 ) o S J C o 1 1 . 0 8 5 5 9 - 6 .‘9 2 3 4 2 f-.?S<;.5) > 6 9 0 7 i l . 3 7 9 7 6 -6.93475:--^VS) 7 9 0 1 1 . 9 9 S 1 1 ' 6 9 3 6 2 :• < 5 ) i n t e r n a l c o u n d t.\v«rc cnwsuv.iMrc; (fix c g t i m a m o i : ■ f I *i CO—l:1 ICjt-A i iOC- - 8 . O S ). GENCRM. 17 «2C* FORCE FIELD F-’fiFiM-IETERS IN USE 316 Equatorial Bonding with Equatorial Oxyanion, (aR*,SR*). MM E = 39.52 kcal/mol — ptNf^-ATBwr-c- G o o n p r w fc o ■AND -OONPaO- - A 9 B H S ------ATOM X Y ZTYPE BOUND TOATOMS C < 1) 6 .9 8 5 6 2 4.68369 1.32569 ( 1> 2 a 6 . 1 5 . 16. C( 2 ) 6 .9 2 0 0 6 5.84685 0.32082 . . . . < 1 > ■ 1. 3.. 7 .. 17. c< •3) - ' ' • 8.04176 5.63997 - -0.71724- -<-11 — 2 » “*.-4. -18 s ■—T9r C ( 4) 9 .3 5 2 6 6 5.15720 -0.14106 < 2 ) 3,' 5 , 8 . I . i *7 . * + ' 7 0 J 0 ■ t . / o ~ + c j / i . i X I 2 / *+» o. C( B> 10.551 B9 5.18138 -1.06930 < 1) 4, 12. 23. 24, C( 9> 5.5S49S 7.14442 -1.42671 ( 1) 7 , 25. 26. 27. C< 10) 4.54330 6.64331 0.77379 ( 1) 7 . 23. 29. 30, 3 . 7 1 4 7 1 6 . 7 7 4 4 5 4 . 8 8 6 2 4 2 .“i jajs - r ay -0.91395 ( 5) -1.80010 ( 5) -1.07162 < 5) t r r \ 1 f’J I ti R i -t I t. i Jt'i.'i ‘ • J i-i I *r"I/ > * i—C* t«rJ ?nl- 1'i— I-i ■ ■ L»« ■ — -- r-v rtinTj ■ ‘1 "LifvC^)1 GENSRPi.izeo rorvcE f i e l d i n u s e 317 Exo Bonding with Axial Oxyanion, (aS+,iR*,4s*). MM E = 57.95 kcal/mol 4.02A 3.73 A FINAL ATOMIC COORDINATES AND BONDED ATOMS ATOM Y TYPE BOUND TO ATOMS CC 1) 0 . 5 7 2 3 4 - 0 . 3 3 3 9 6 - 0 . 6 4 0 9 1 - 2, Di 12. 1 3 , C < 2) 0 . 0 2 6 0 2 - 1 . 0 3 4 7 4 0 . 6 2 3 8 9 1. 3. 14 , 15. CC 3) 0 . 9 4 4 6 7 - 0 . 3 1 7 0 2 1 . 7 4 3 2 6 JL. « 4, 7. 1 6 . C< 4) 1.1I2e7 0 . 9 3 9 4 9 1 . 2 6 6 3 2 3 . 3, 17 . 1 8 . C< 5) 1 . 7 3 3 7 4 0 . 3 1 3 0 0 - O . O e 2 8 7 1, 4. - - 6, 1 9 C < 6) 2 . 8 0 0 1 7 — 0 . 4 3 1 4 4 0 . 3 4 8 2 1 3 , 7. 20 , CC 7) 2 . 3 1 0 0 6 - 1 . 0 9 4 2 2 1 . 4 4 2 9 7 3( 6. 8. CC 6) 2 . 9 3 9 1 8 - 2 . 2 2 4 1 8 2 . 1 8 9 9 7 C 1 ) 7 . 9. 2 1 . 22, C( 9) 4 . 2 7 8 0 3 - 1 . 7 1 6 9 7 2 . 8 1 3 0 6 C i ) 8 , IO, 2 3 . 24,. C( 105 4.91981 -0.83333 1 . 7 2 6 1 6 . c 2 ) 9 . 11 , 2 5 , C ( 11) 4 . 4 4 0 6 7 0 . 3 2 2 4 1 1 . 3 5 8 6 7 c 2 ) IO, 2 6 . 2 7 . H C 12) 0 . 9 2 2 0 5 - 1 . 0 5 3 7 6 - 1 . 4 2 3 2 3 c 5 ) 1, HC 13) -0.20802 0 . 3 1 7 9 3 - 1 . 0 9 4 1 7 < 5 ) 1. HC 14) 0.07728 —2-16633 0 . 3 4 6 0 1 c 5 ) 2 , HC 13) -1.03463 - 0 . 7 6 7 0 2 0 . 8 1 8 9 1 ■ c . 3 5 i L , HC 16) 0 . 5 3 7 7 6 - 0 . 6 3 9 9 3 2 . 7 9 4 3 9 ' c 5 ) 3 . HC 17) 1 . 7 7 5 9 1 1 . 5 5 1 7 7 1 . 9 1 7 7 9 • c 5 ) 4. n ( 13) 0 - 1 4 7 9 6 1 . 4 9 0 4 S 1 . 1 6 0 2 3 c 5 ) 4. ri ( 19) 2 . 0 9 8 6 6 1 . 3 3 0 6 9 — O. 7 2 6 3 1 c 3 ) S , H ( 2 0 ) 3 . 6 4 3 4 0 - C L 76 5 9 5 - 0 . 3 0 6 4 7 c 5 ) 6 , HC 2 1 ) 2 . 2 6 3 3 S - 2 . 6 7 0 9 2 2 . 9 3 9 3 4 c 5 ) 8 . H C 2 2 ) 3 . 1 7 9 4 9 - 3 . 0 2 3 2 2 1 . 4 4 2 6 6 c 5 ) 8 . HC 2 3 ) 4 . 9 3 3 5 3 - 2 . 5 3 4 5 0 3 . 0 6 3 0 3 c 5 ) 9 . O-C 2 4 ) 4 . 0 9 6 1 4 - 0 . 9 7 5 5 2 4 . 0 3 1 5 6 c:2 5 ) 9 , H C 2 3 ) 3 - 7 5 6 9 6 - 1 . 3 3 1 7 7 1 . 1 6 1 2 5 c 5 ) IO. H C 2 6 ) 3 . 6 8 3 0 9 0 . 8 6 5 1 6 1 . 9 5 1 4 8 c 5 ) 11 . HC 2 7 ) 4 . 9 1 6 6 5 O . 8 3 3 0 4 0 . 5 3 4 3 6 c 5 ) 1 1 . INTERNAL COORDINATE CONSTRAINTS (FIX CGMNANO) : FIXED DISTANCE ( II - 6) = 2.00 ANG (CONST = 3.00 5 GENERALIZED FORCE FIELD PARAMETERS IN USE 318 Endo Bonding with Equatorial Oxyanion, (aS*,1R*,4S*). MM E = 58.64 kcal/mol . A T O M I C COORDINATES A M O B O N D E D A T O M S ^ ■ , .* ■ ATOM f. Y *. TYPE BOUND TO ATOMS CC 1) 2 . 9 7 S 7 4 3 . 1 5 4 5 0 0.02233 < 1) 2 . 5, 12. 13. CC 2) 2 . 6 0 6 5 7 2 . 7 9 4 0 4 • 1 . 4 8 1 9 6 C l) 1 . 3, 14 . 15 , CC 3) 3 . 4 9 8 5 9 3 . 7 3 7 0 3 2 . 3 1 3 3 6 C 1 > 2 . 4,- - - 7 . - 1 6 , CC 4) 3 . 5 2 9 2 7 4 . 9 8 2 2 5 1.39482 C 1) 3 . 5, 17 . 18. C C 5) 4 . 1 0 7 9 7 4 . 1 9 1 8 9 O . 1 9 4 8 7 ( 1 > 1.» 4. 6 . 19, CC 6) 5 . 3 3 0 0 3 3 . 6 0 7 0 6 0 . 8 9 1 4 8 C 2 ) 5 v 7, 2 0 , CC 7) 4 . 9 5 4 6 9 3 . 3 5 4 0 4 2.16131 C 2) 3 . 6...... 8 . .. CC 8) 5.82787 2 . 8 3 4 8 2 3.27206 C 1) 7 . 9. 2 1 . 2 2 , CC V) 6.31951 1.41993 2 . 9 0 0 0 8 C 1) 8 . IO. 2 3 , 2 4 , CC IO) 6 . 7 3 7 2 6 1 . 5 3 7 4 0 1 . 4 5 3 4 2 ' < 2 ) 9 . 11 . 2 5 . i C C 11) 5 . 7 9 8 2 4 1 . 6 0 9 9 4 0 . 4 8 9 8 6 ( 2 ) , io.~- 2 6 . - 2 7 . HC 12 ) 3 . 2 7 6 0 7 2 . 2 8 1 9 4 - 0 . 6 0 2 6 7 < 5 ) 1. HC 13) 2 . 1 1 1 1 4 3 . 6 3 0 8 5 -0.49407 C 5) 1, H t 14) 2 . 7 8 8 6 1 1 . 7 2 4 9 3 I . 7 4 0 0 6 C 5 ) 2 , H{ 15) 1.52941 3.01150 1 . 6 7 7 0 6 C 5 ) 2. n ( 16) 3 . 1 6 8 3 7 3 . 9 4 2 6 2 3.35888 C 5) 3 , H ( 17) 4 . 2 0 7 4 3 5 . 7 9 0 5 7 1 . 7 6 3 1 7 C 5 ) 4 . H ( IS) 2 . 5 2 1 2 0 5 . 4 2 2 6 2 1.20484 C 5) 4 . H C IV) 4 . 3 3 7 6 3 4 . 8 1 6 3 7 — O . 7 0 0 9 6 ( 5 ) 5 * H< 2 0 ) 6 . 3 4 1 2 2 3 . 6 6 3 6 8 0 . 4 4 1 4 5 C 5 ) 6 . H C 2 1 ) 6 . 6 7 9 1 3 3 . 5 4 9 3 2 3.37696 < 5) , a - HC 22) 5 . 2 6 7 1 7 2 . 8 3 3 1 5 4.23657 C 5) B, H C 2 3 ) 5 . 4 5 8 4 9 0 . 7 1 3 7 3 2.97228 C 5) 9 , O - C 2 4 ) 7 . 3 6 0 3 7 0 . 9 2 1 2 3 3.75466 C 25) 9, H C 2 5 ) 7 . 8 0 4 1 7 1 - 6 5 3 2 3 1 . 1 9 1 2 2 C 5 ) IO. H i 2 6 ) 4 . 7 4 5 3 5 1 - 33 3 1 9 0.71971 C 5) 11 , K { 2 7 ) 6 - >.)733J 1 ! 7 2 1 12 - 0 . 5 7 7 2 5 C 55 11 . INTERNAL COORDINATE CONSTRAINTS CFIX CGIMAND) : FIXED DISTANCE C b - 11) - 2. «>:• ANG (CONST = 5. CO) GENERALISED FORCE FIELD RARAMSIER3 IN USE 319 Endo Bonding with Axial Oxyanion, («R*,i r *,4s*) MM E = 59.53 kcal/mol -r- 'J— . ^^iatsfpSro - AToTrs&J&7' u • C( 4) 4.44075 6 . 3 5 4 6 4 9 . 7 7 2 6 8 ( i) c < 5) 5 . 6 5 0 1 9 6.08454 8.85306 < i) 4. 6. 12, 18, c< 6) 5.S432S 7.12671 7 . 7 6 4 5 1 ( 2) 1, 5. 19 , ------&<—-4i)-- -- 1 .- 6 3 1 0 3 — ---- 7 .- 6 6 6 9 8 -- --- 7-,6-1943 — - (—Jri- - a.-- 9,- 1FH- 2 E W - c< 8) 1 . 9 1 8 3 7 S.91052 8,99788 (1) 3, 9. 11, 2 1 , c< 9) 0 . 9 7 0 2 7 7.13106 3.91408 < 1) 7. 8. 22. C ( IO ) 1 . 3 8 0 4 8 6.45300 6.70050 ( 1> 7, 11. 24, C ( 11 ) 1 . 6 4 1 1 0 S. 2 4 3 6 3 / . 6j46o \ 1) S , 1 0 . 26 , □ - ( 12) 3 . 6 9 1 6 3 4.74794 8.32453 (23) 5, Hi to/ O . 7vJl >*. % r H( 16) 4.64626 7.25436 1 0 . 4 0 0 1 3 H ( 17 ) 5 . 5 1 6 9 1 1 0 . 4 8 2 4 1 H i 18) 6 . 5 9 7 3 ) 6 . 2 2 3 8 5 9 . 4 2 4 9 9 w m m ■ ' 7:726231 ,.-•09/90198 fAv85492?9 '<‘-'8.“7 . 9 4 4 4 H i 2 4 ) & . 4 5 7 8 0 6 . 3 5 8 3 8 H ( 2 5 ) ^•00/14 6 . 4 6 2 7 . *7 ,'981 7 . 7 ‘X ' 3 . I H ( 2 6 ) 0 . 7 3 4 6 6 • 1 .90372 5 9 7 8 0 ? f> i- . ■ ■■ INTERNPl- COORDINATE -.CONSTRAINTS • ■'(FIX^CWMAND):. FIXED DISTANCE < 1 - 2) - 2.00 ANG (CONST = ‘7. ■ GENERALIZED FORCE FIELD FFTiAMETEKS IN USE 320 Exo Bonding with Equatorial Oxyanion, (a«*,lR*,4S*). MM E = 57.14 kcal/mol . A T O M I C COORDINATES AND BONDED ATOMS ATOMX Y Z TYFE BOUND TO ATOMS C C 1) 0 . 5 8 1 3 1 - 0 . 2 9 6 9 4 - 0 . 6 0 7 4 8 C 1 ) 2. 5. 12, 13, CC 2) 0 . 0 4 7 3 0 - 1 . 0 4 5 4 9 0 . 6 4 3 4 7 C 1; 1, 3. 14, 15. CC 3) 0 . 9 7 8 4 1 -0.53885 1.76906 C 1/ 2 » 4. 7 , 1 6 . C C 4) 1 . 1 4 3 8 0 0 . 9 2 9 9 1 1 . 3 2 7 7 9 C 1 > 3, 5. 17, .18. C C 5) 1 . 7 5 0 9 3 0.54140 -0.03895 C 1) I. 4. 6 , 19, C < 6) 2.81904 -0.46584 0 . 3 5 5 5 1 C 2> 5 * 7. 2 0 , C C 7) 2 . 3 4 0 2 4 - -1.10095 1.43762 C 2) 3 , 6. 8 , C C e) 2 . 9 9 8 2 9 - 2 . 2 5 5 9 4 2 . 1 5 2 7 4 C 1) 7, 9. 2 1 , 2 2 . CC 9) 4.29743 -1.71622 2.79073 C 1) 8 . IO. 2 3 , 2 4 . CCIO) 4 . 9 4 6 8 5 -0.90136 1.69520 C 2) 9 , 1 1 . 2 5 , CC II) 4 . 4 6 3 6 3 0.31622 1.37311 C 2) IO, 2 6 . 2 7 , HC 12) 0.92269 -0.99107 -1.41178 C 3) 1. HC 13) -0.20307 0 . 3 7 2 0 8 - 1 . 0 3 3 3 0 C 5) 1. HC 14) 0 . 0 9 6 2 4 -2.13316 0.53553 C 5) 2, H C 15) - 1 . 0 1 0 8 2 -0.76181 0.85726 C 5 ) 2 , H C 16) 0 . 6 3 2 2 3 — 0 . 6 8 8 7 3 2 . 8 1 8 7 8 C 5 ) 3 , H C 17) 1 . 8 1 6 1 1 1.52328 1.98722 C 5) 4. HC 18) O . 1 7 8 7 4 1 . 4 8 4 9 8 1 . 2 4 7 3 9 C 5) 4, HC 19) - 2.10779 1 . 3 9 3 7 8 -0.66416 C 5) 5 , HC 20) 3.66072 - 0 . 7 3 2 0 3 - 0 . 3 1 5 0 4 C 5 ) 6 . HC 2 1 ) 2 . 3 0 6 0 1 — 2 . 6 8 7 0 2 2 . 9 1 4 0 7 C 5) O * HC 2 2 ) 3 . 2 0 9 1 0 - 3 . 0 4 7 0 6 1 . 3 9 3 8 7 C 5) a . o - c 2 3 ) 5 . 1 5 3 2 6 - 2 . 7 4 2 0 2 3.31876 C25; 9 * H C 2 4 ) 4 . 0 2 5 5 9 -1.03755 3.63380 C 5 ) 9 , HC 2 5 ) 5 . 7 5 8 5 6 -1.34355 1.08903 C 5) IO. H C 2 6 ) 3 . 7 3 4 4 5 0.832B4 2.01492 C 5> 11 . H C 2 7 ) 4 . 9 1 3 9 9 0 . 9 0 7 3 7 0 . 5 5 1 0 7 C 5; 11 , COORDINATECONSTRAINTS '.FIX COMMAND): DIG I A N C E C 11 - 6) = 2. OO AMS CCGN3T = 5 CO! ZED FORCE FI ELD PARAMETER'S IN USE 321 Exo Bonding with Axial Oxyanion, (aS,lR,4S) MM E = 71.20 kcal/mol FINAL ATOMIC COORDINATES AND EONDED AUDI'S ATOM X Y 2 TYPE SOUND TO ATOrS C< 1) 0.66881 - -0.43641 ----- 0 . 7 4 8 8 2 - - -<--l)- *2"» “ "5t* . 1 6 r 17* C( 2) 0.14531 - -1.24911 _____ 0.46656 <11 1* 3* IB* 19* uv J>; i.ccOou v 1/ •*»* /* l^i* .iiLL-E NHB kH H i 1 * 4. O * 2 0 . ■ 2 . 7 9 1 6 8 — O . 4 2 9 Z 3 0 . 2 9 0 5 6 5 . 7. 2 1 . 2 . 3 5 2 0 9 - 1 . 0 8 9 7 7 1 . 3 8 0 5 0 3 . 6. 8 . 3 . 0 6 2 9 7 - 2 . 2 3 6 0 0 2 . 0 4 7 4 5 7 . 9, 2 2 , 2 3 , 3532 i t Oia B a 4 v ; C C T 3) • 72330 r: C < 1 4) - 0 . 4 0 1 4 3 1 .5 7 4 3 5 1 . 0 7 2 2 6 O - C 15) 4 . 4 2 7 3 5 1 . 0 4 8 0 0 3 . 7 7 1 2 6 ( 2 3 ) H ( 16) 1 . 1 5 4 7 3 1 . 0 8 5 7 2 1 . 5 1 6 0 3 6 4 8 2 8 S 6 J47 . 9415 5 9 4 5 3 -0 : -6g ftS3 2 . 4 5 9 B 1 - 2 . 6 8 3 2 6 2 . 8 7 0 5 5 - 3 . 0 3 4 4 5 1 . 2 7 3 3 6 5 .0 9 2 2 8 - 2 . 6 8 3 8 7 2 . 7 2 3 7 2 .j. r I 1-.-4 6 5 4 2 p,.;7.63~> H ( 2 6 ) 3 . 9 3 9 0 6 H T 27 ) 5 . 0 4 6 6 2 uO;; 79893 H ( 2 8 ) 0 . 9 7 6 B 7 - 0 . 5 6 6 1 2 Mt " 2 10 1 H ( 3 0 ) 0 . 2 3 4 7 - 2 . 0 6 0 9 3 3 . 1 7 3 4 6 2 . 2 6 8 8 7 . 3 6 1 3 5 L . 7 7 0 5 6 1 . 0417 3 9 9ill 3 1 0 1 7 3 . 0 2 1 9 1 H ( 3 4 ) - 0 . 2 3 9 2 0 - 2 . ' 6 0 3 3 7^ s ^^o.‘&78i2iS'r(.:5> : H < 3 5 ) - 1 . I 1 4 1 4 1 . 0 8 6 8 1. , • O.'37376(..3) .14v.yi':<.-s•>*< H ( 3 6 * - 0 . 9 5 3 3 3 1 . 6 6 1 8 4I - 2.03530^ I ( 5) !«• INTERNAL COORD IN AT E LQMjTRAI MTS (FIX CCSHIAND): -F t *EO -OrSTA NetE- -H- -6n- w -n H j ititiNST- O F / J l~ GENERALIZED f o r c e F I e l d PARAMETERS IN USE 322 Endo Bonding with Equatorial Oxyanion, (aS,lR,4S) MM E = 65.71 kcal/mol m m t■"rlNi m J'-< A ' j J k •A.-SiMi-A.i' ATOM Y 7YFE BOUND TO ATOMS 4.54713 6-99060 6.71799 < 2) 6'. 16* 17. 3.04230 7-64069 8.01706 ( 2) 3. . 7, 18. .jam ft \ rr'TgcTp "v.. ( >Sr.**i'v M rc<™ry>a Hi m C( 6) 1-87581 5.86430 B.95427 < 1) 3. 9. n i 15, C( 9) 0-93201 7.10230 8.87084 ( 1) 7 . 8, 13. 14. C< IO) 1.387IB 6.36553 6.62712 < 1) 7,‘ 11. 24, 25, rcrrT H< 16) 3.96624 6.06335 6.60361 H( 17) 4.43029 7.76706 5.93671 H( 18)59 A3.66858 8.53974 7.B5143 .... i .j) „7 ; — ---- H i S 3 ) ‘I t I - 9 7 2 5 " — : «3T5i3I3Ct3 i7rr^ — ..16083' H ( 2 4 ) 0 . 3 4 6 4 9 6 . 3 4 8 8 8 6 . 2 2 7 9 7 ( 5 ) 1 0 . H i 2 5 ) 2 . 0 4 0 4 4 6 . 3 7 9 3 3 5 . 7 2 5 7 9 i 5 ) 10 . H i 2 6 ) 0 . 7 7 4 5 7 4 . 4 8 8 8 3 7 . 6 1 4 7 8 < 5 ) 1 1, . 1 U,< -i~ it, s «. < » •*- • ij— Uwli .'9 ■ _ ' H i >2 8 ) ? + 0 i974C>6-i # # S C i 4 3 ^ Hi.-29) v-‘v 1,55-^87.91^7^aSfe W5302^^ptp);^.^ 3& H ( . 3 0 ) - . ■■ - 1 . - 1 4 1 3 9 -- d ; ■ 7 - 6 9 7 9 2 5^8<%7A77<3^aS5 )&a&5a$iX H < 3 1 ) 0 - uJtj'.O . -. 0^.7 / i'.l . 7 / 7M J V U J I4t H i 3 2 ) 0 . 5 1 7 3 1 9 . 0 4 3 9 8 9 . 8 0 1 5 9 { 5 ) 14. H i 3 3 ) 2 . 1 3 0 6 0 3 . 4 3 2 7 4 1 0 . 2 4 2 7 1 i 5 ) 14 , H i 3 4 ) 0 . 6 3 5 IS 4 . 5 4 3 8 9 I O . 1 7 8 4 0 i 5 ) 1 5 . u . '1 JU i_J", H i 3 6 ) 2 . 3 6 6 3 2 4 . 0 3 4 4 3 ; ‘ ■ l p ; 1 2 2 0 0 r ‘ ■ f '• S***' * : • ?$■'"- -rrtTgFNAl. COORBlMAT-e CO.'13 Tf i n H ,‘TC' (FIX COMItAfii 7+-:------FIXED DISTANCE ( 1 - 2) == 2. CO AfJZ-i iCCNGT = s. co) GENERAL I ZED FORCE FIFED i ■■{T-.fi IF I ERS IN USE 323 Endo Bonding with Axial Oxyanion, (aR,lR,4S). MM E = 66.56 kcal/mol 3.87 A 3.35 A' FINAL ATOMIC COORDINATES A N D EONDED ATOMS ATOM X V Z TYPE BOUND TO ATOMS CC 1) 4.5S433 7.02541 6.-76464 --- (-2)- -6. Hr. -- 17,-- CC 2) 3.06065 7.67500 0.05067 . < 2) 3,-• .7, IB. Lv j/ 3.^2-**/' o.o'tio, ■ 6. \ ..j -,» o * MEwBIipSM IsS T1 4 » .... 6. 12. 21. 5.55366 .11295 7.69679 < 2> 1. . 5, 22. 1. 62004 62253 .57793 C 1) 2, 9, IO. 23. 1.90006 5.89559 8.97980 c 1) 3. 9, 11. 15. Sffi© t^bcTQ*T~ i ™.ia aerfinsB ’ D r * &rrGg07B 1287“ ~29. 30. CC 14) S .14605 06033 ( 1) 31, 32, 3 j . CC 15) 1.69536 4.97899 18207 ( 1) 34. 35. 36. HC 16) 3.98474 6.11025 65402 ( 5) - — H,c;iil ? ) , ,rB.»-j7y2*2aa ssssksss^sss^sxsss^ns^r: H jC:41 8 ) ■ ^% #3.^9441-/ HC,;;1 9 ) ' ^V-ftC4164760. • ■-.••.v’& 7 A g & 7 Q 9 ^ p B <4 -■• ■ H C 2 0 ) : 4 . 3 0 7 7 5 .'.74-5.‘327J62'f.'^S jK sH to w h ,. a-’' :• ta a CJZL 1 > C* m w m m ( wJ f hi 1 HC 2 2 ) lj . .L 2L‘I vI-‘ i 7 . 9 9 0 5 9 7 . 7 1 4 0 9 C 5 ) 6 T HC 23) 1 . 2 2 4 9 8 8 . 3 9 2 1 3 7 . 1 9 5 7 3 ( S / 7 » tr /_ HC 2 4 ) O . 37-* 6. 3 -7 7 4 8 Or . ,LJ1 o o C 5 ) IO. —1 “i i v ■' ls!Gr------2.07028 t lint1 r^L ^xly.1,1." ■t ^C .:52- - IO-, ...... ------:------1.52366 1.59051 6.47794 6. o :-y INTER .Vi- CCCRDIN.YIS ! ONO i i 4 .i U i :. •:■ rf«-i.-vw«:o; 1- 17El? -8284-0:4.0 - 1--- 81— -- 4 7 ii4.j 4 .-Cj. 1 '.j » ■ - q . 0 0 it~ GENEKALI ZED FORCE FIEUJ PfttAinnERS IN USE > ■ Exo Bonding with Equatorial Oxyanion, (aR,lR,4S) MM E = 70.33 kcal/mol FINAL ATOMIC COORDINATES AND BONDED ATOMS ATOM X V Z TYPE BOUND TO ATOMS C< 1) 0.67881 -0.39100 -0.-6B701.' <-l> 2 1 • * 5? * 16* 17* C< 2) 0.13967 -1.18700 0.53222 ( 1) 1* 3.18. 19. ------CT -- 3)------O. ------“ U . U S 4 0 3 ------l':~ Z 5 4 4 ---- f l T * *+» / * 2.80339 -0.42596 0.33014 ( 2) - 1 . 0 6 8 2 8 1.44382 < 2) - 2 . 2 0 7 7 7 2.14003 < 1) 2 3 , 78733 - 0 . 3 3 9 9 5 1 . 6 3 3 1 1 1 . 1 2 9 7 5 5 . 2 4 5 6 2 - 2 . 7 1 2 3 4 3 . 2 1 3 6 0 16) 1 . 1 4 8 9 1 - 1 . 0 3 3 7 5 - 1 . 4 3 2 6 1 z / 2 ' § 4 5 iS*2V04519:59ss.:' 3.60)00 ;o: 70935'= K< 22) 2 . 4 2 3 0 3 - 2 . 6 0 8 3 6 2.97410 < 5) hi( 2 3 ) 3 . 1 7 7 1 4 - 3 . 0 2 8 4 2 1.39442 < 5) H ( 2 4 ) 4 . 2 0 8 3 9 - 0 . 9 4 2 4 3 3.47431 < 5) li( 2 5 ) 1 . 5 lo S l a 0 . 0 5 1 4 9 . ' H<- 26)' 3 . 9 8 8 3 4 , 0 . 8 8 2 9 0 8 H < 2 7 ) 5 . 0 7 2 8 3 6 0 . 0 . 7 5 HC.2S) 0 . 9 8 3 2 9 ••.-0.513'; _ H < 2 9 ) ■O: 6.'j3'4." 0.42583- K< 3 0 ) 0 . 2 0 5 1 6 - 1 . 9 8 9 4 7 3 . 2 3 9 2 7 < 5 ) K« 3 1 ) 2 . 5 4 0 1 8 2 . 5 3 3 1 0 1•83651 ( 5) ■+f\—53)H< 3 2 ) i . 1 14741 i.1674p^-;i 3 6 1 3 3 . 0 9 2 0 1 ( 5 ) H < 3 4 ) —0*. 1 5 2 5 8 2 . 6 7 7 2 0 5 ^ .7,70.73344 H ( j S) - 1 . 0 6 4 4 0 i . iaio6§k ; -‘0.-43465 H ( 3 6 ) - 0 . 8 8 9 3 8 l . 75651&:. •6.2. 09271 INTERNAL CGORDINATE CONSTRAINTS (FTX C O M M A N D ) :