Studies on the diastereoselective preparation of bis-cyclopropanes

Article abstract of DOI:10.1021/jo961235p

The identification of two natural products, FR-900848 and U-106305, has stimulated interest concerning the relationship between configurational isomerism, conformational isomerism, and biological activity of polycyclopropanes. Efforts to investigate the relationship between configurational and conformational isomerism through molecular modeling suggest that significantly different three-dimensional structures will result from unique primary structures. Any effort to address these issues demands that stereoselective methods for the preparation of polycyclopropanes be developed. We have investigated the application of zinc-carbenoid cyclopropanation in the presence of chiral dioxaboralanes to the preparation of eight stereochemically unique bicyclopropanes. The frans-vinylcyclopropane starting materials demonstrated very little substrate-induced stereoselectivity, while the cis-vinylcyclopropane demonstrates modest to excellent stereocontrol. A model for the substrate-based stereocontrol is proposed. We also used the spectroscopic data gathered in this investigation to probe the substrate-mediated stereocontrol in the rhodium(II)-catalyzed cyclopropanation of vinylcyclopropanes with ethyl diazoacetate.

Full text of DOI:10.1021/jo961235p

8792
J . Org. Chem. 1996, 61, 8792-8798
Stu d ies on th e Dia ster eoselective P r ep a r a tion of
Bis-cyclop r op a n es
Cory R. Theberge, Christopher A. Verbicky, and Charles K. Zercher*
Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824
Received J uly 1, 1996X
The identification of two natural products, FR-900848 and U-106305, has stimulated interest
concerning the relationship between configurational isomerism, conformational isomerism, and
biological activity of polycyclopropanes. Efforts to investigate the relationship between configu-
rational and conformational isomerism through molecular modeling suggest that significantly
different three-dimensional structures will result from unique primary structures. Any effort to
address these issues demands that stereoselective methods for the preparation of polycyclopropanes
be developed. We have investigated the application of zinc-carbenoid cyclopropanation in the
presence of chiral dioxaboralanes to the preparation of eight stereochemically unique bicyclopro-
panes. The trans-vinylcyclopropane starting materials demonstrated very little substrate-induced
stereoselectivity, while the cis-vinylcyclopropane demonstrates modest to excellent stereocontrol.
A model for the substrate-based stereocontrol is proposed. We also used the spectroscopic data
gathered in this investigation to probe the substrate-mediated stereocontrol in the rhodium(II)-
catalyzed cyclopropanation of vinylcyclopropanes with ethyl diazoacetate.
The recent identification of two novel polycyclopropan-
Even though the preparation of polycyclopropanes
(chains of cyclopropane rings connected by a single σ
bond) is not a recent phenomenon,6 many studies on the
asymmetric synthesis of polycyclopropanes have been
stimulated by the identification of these two natural
products.2,3,5,7 Unlike most of the early synthetic ap-
proaches to polycyclopropanes, efforts directed toward the
preparation of FR-900848 (1), U-106305 (2), or analogous
polycyclopropanes require that the multiple cis-trans- and
syn-anti-stereochemical relationships be controlled. It is
this mandate of stereocontrol that makes the preparation
of polycyclopropanes particularly challenging. We report
here the details of our investigation into the diastereo-
selective preparation of bis-cyclopropanes. We also uti-
lize the unique spectroscopic data of each individual bis-
cyclopropane to investigate the stereoselectivity of bis-
cyclopropane formation through the use of rhodium
carbenoids.
ated natural products, FR-900848 (1) and U-106305 (2),
has aroused our interest in developing strategies for the
stereoselective preparation of polycyclopropanated fatty
amides. Reported by the Fujisawa Company in 1990, FR-
900848 has attracted attention due to its combination of
unusual biological activity and unprecedented structure.1
FR-900848 (1) contains a 5,6-dihydrouridine moiety, a
5′-deoxy-5′-amino ribose, and a remarkable fatty amide
side chain possessing five cyclopropane units, four of
which are located consecutively. At the time of its
isolation, no stereochemical assignment had been made
for the multiple stereogenic centers on the fatty amide;
however, recent efforts by Falck and by Barrett have
demonstrated that the fatty amide chain possesses a
repeating trans-syn-trans-polycyclopropane network.2 This
information was utilized in two successful total syntheses
of FR-900848.3
The isolation of a second member of the polycyclopro-
panated fatty amide natural product family was reported
in 1995.4 This natural product, U-106305 (2), is an
inhibitor of cholesteryl ester transfer protein (CEPT), an
enzyme responsible for the redistribution of cholesteryl
esters. The structural analogy of U-106305 to FR-900848
suggested a similar trans-syn-stereochemistry. This
expectation was confirmed by a recent total synthesis.5
Resu lts a n d Discu ssion
Our interest in studying the relationships of polycy-
clopropane configuration and conformation to the chem-
istry and biochemistry of polycyclopropanated fatty acids
demanded access to all possible stereochemical relation-
(6) (a) Smith, L. I.; Rogier, E. R. J . Am. Chem. Soc. 1951, 73, 3840.
(b) Slabey, V. A. J . Am. Chem. Soc. 1952, 74, 4928. (c) Dehmlov, E. V.
Tetrahedron 1972, 28, 175. (d) Martelli, J .; Carrie, R. Tetrahedron
1978, 34, 1163. (e) Feldman, K. S.; Simpson, R. E. J . Am. Chem. Soc.
1989, 111, 4878. (f) Buchert, M.; Reibig, H.; Chem. Ber. 1992, 125,
2724. (g) Kleveland, K.; Skatteboel, L. Acta Chem. Scand., Ser. B 1975,
B29, 191. (h) Doering, W. von E.; Roth, W. R. Tetrahedron 1963, 19,
715. (i) Kazimirchik, I. V.; Lukin, K. A.; Bebikh, G. F.; Zefirov, N. S.;
Mehler, K. Zh. Org. Khim. 1983, 19, 2523. (j) Lehmkuhl, H.; Mehler,
K. Liebigs Ann. Chem. 1982, 2244. (k) Wiberg, K. B.; Bartley, W. J . J .
Am. Chem. Soc. 1960, 82, 6375.
(7) (a) Barrett, A. G. M.; Kasdorf, K.; Williams, D. J . J . Chem. Soc.,
Chem. Commun. 1994, 1781. (b) Barrett, A. G. M.; Doubleday, W. W.;
Tustin, G. J .; White, A. J . P.; Williams, D. J . J . Chem. Soc., Chem.
Commun. 1994, 1783. (c) Theberge, C. R.; Zercher, C. K. Tetrahedron
Lett. 1994, 35, 1981. (d) Armstrong, R. W.; Maurer, K. W. Tetrahedron
Lett. 1995, 36, 355. (e) Barrett, A. G. M.; Tustin, G. J . J . Chem. Soc.,
Chem. Commun. 1995, 355. (f) Barrett, A. G. M.; Doubleday, W. W.;
Kasdorf, K.; Tustin, G. J .; White, A. J . P.; Williams, D. J . J . Chem.
Soc., Chem. Commun. 1995, 407. (g) Theberge, C. R.; Zercher, C. K.
Tetrahedron Lett. 1995, 36, 5495.
X Abstract published in Advance ACS Abstracts, November 15, 1996.
(1) Yoshida, M.; Ezaki, M.; Hashimoto, M.; Yamashita, M.; Shige-
matsu, N.; Okuhara, M.; Kohsaka, M.; Horikoshi, K. J . Antibiot. 1990,
43, 748-754.
(2) (a) Falck, J . R.; Mekonnen, B.; Yu, J . Abstracts of Papers; 209th
National Meeting of the American Chemical Society, Anaheim, CA;
American Chemical Society: Washington, DC, 1995; ORGN 57. (b)
Barrett, A. G. M.; Kasdorf, K.; White, A. J . P.; Williams, D. J . J . Chem.
Soc., Chem. Commun. 1995, 649. (c) Barrett, A. G. M.; Kasdorf, K.;
Tustin, G. J .; Williams, D. J . J . Chem. Soc., Chem. Commun. 1995,
1143. (d) Barrett, A. G. M.; Doubleday, W. W.; Kasdorf, K.; Tustin, G.
J . J . Org. Chem. 1996, 61, 3280.
(3) (a) Barrett, A. G. M.; Kasdorf, K. J . Chem. Soc., Chem. Commun.
1996, 325. (b) Falck, J . R., Mekonnen, B.; Yu, J .; Lai, J .-Y. J Am. Chem.
Soc. 1996, 118, 6096.
(4) Kuo, M. S.; Zielinski, R. J .; Cialdella, J . I.; Marschke, C. K.;
Dupois, M. J .; Li, G. P.; Kloosterman, D. A.; Spilman, C. H.; Marshall,
V. P. J . Am. Chem. Soc. 1995, 117, 10629.
(5) Barrett, A. G. M.; Hamprecht, D.; White, A. J . P.; Williams, D.
J . J . Am. Chem. Soc. 1996, 118, 7863.
S0022-3263(96)01235-2 CCC: $12.00 © 1996 American Chemical Society

Diastereoselective Preparation of Bis-cyclopropanes
J . Org. Chem., Vol. 61, No. 25, 1996 8793
Sch em e 1
ships. We were interested in developing an iterative
strategy by which we could prepare any isomeric com-
bination of cyclopropanes while efficiently controlling
their diastereomeric relationship. We set as our goal the
preparation of the eight bis-cyclopropane stereoisomers
3-10 using a stereoselective, iterative process. The
successful preparation of these eight stereoisomers would
demonstrate the likely utility of this iterative approach
in the preparation of diverse stereoisomeric polycyclo-
propanes.
Scheme 1. Although we commenced our studies on the
cyclopropanation of racemic allylic alcohols by utilizing
the samarium-promoted methodology of Molander and
Haring,8 better yields of bis-cyclopropanes were obtained
with the Furukawa modification of the Simmons-Smith
reaction.9,10 In both cases, it was demonstrated that the
stereoselective incorporation of the second cyclopropane
ring while relying on the initial cyclopropane’s stereo-
centers was ineffective. Therefore, it was believed that
the stereoselective preparation of bis-cyclopropanes 3-10
could only be accomplished through the use of a reagent-
stereocontrolled process.
We began to explore cyclopropanation methods that
utilize stereocontrolling elements other than the preex-
isting cyclopropane stereocenters. The use of a reagent-
controlled process for bis-cyclopropane formation requires
that the absolute stereochemistry be controlled in the
first cyclopropanation event. Although many methods
exist for the asymmetric incorporation of individual
cyclopropanes,11 we eventually turned to the recently
reported methodology of Charette and co-workers in
which a chiral noncovalently bound dioxaboralane de-
rivative is utilized as a directing group in the Furukawa
cyclopropanation.12 Both high yields and high enantio-
meric excesses have been reported when using an L-
tartrate-derived dioxaboralane 11 as the chiral inducing
agent. Dioxaboralane 11 is formed from n-butylboronic
acid and (R,R)-(+)-N,N,N ′,N ′-tetramethyltartardiamide,
Retrosynthetic analysis of bis-cyclopropanes 3-10 sug-
gests that suitable precursors would be allylic alcohols
obtained by reduction of an ester. The generation of
diastereomerically enriched bis-cyclopropanes from these
allylic alcohols requires that a methylene unit be incor-
porated in a diastereofacially selective fashion with the
most likely source of the unsubstituted methylene unit
arising from a metallocarbenoid. The crucial selection
of either the cis- or trans-stereochemistry for the second
cyclopropane ring can be controlled through formation
of appropriate olefin stereochemistry utilizing Horner-
Emmons reaction variations. Although this E or Z
stereocontrol is not always trivial, once established, the
stereospecific zinc-carbenoid reaction will generate the
respective trans- or cis-cyclopropane. Therefore, the
greatest challenge of preparing diastereomerically en-
riched polycyclopropanes lies not in the control of cis- or
trans-stereochemistry, but in the efficient control of the
relative syn- or anti-stereochemistry.
(8) Molander, G. A.; Harring, L. S. J . Org. Chem. 1989, 54, 3525.
(9) (a) Simmons, H. E.; Smith, R. D. J . Am. Chem. Soc. 1958, 80,
5323. (b) Simmons, H. E.; Smith, R. D. J . Am. Chem. Soc. 1959, 81,
4256.
(10) (a) Furukawa, J .; Kawabata, N; Nishimusa, J . Tetrahedron Lett.
1966, 3353. (b) Furukawa, J .; Kawabata, N.; Nishimura, J . Tetrahedron
1968, 24, 53.
(11) Arai, I.; Mori, A.; Yamamoto, H. J . Am. Chem. Soc. 1985, 107,
8254.
(12) (a) Charette, A. B.; J uteau, H. J . Am. Chem. Soc. 1994, 116,
2651. (b) Charette, A. B.; Prescott, S.; Brochu, C. J . Org. Chem. 1995,
60, 1081.
Our initial investigations on the formation of bis-
cyclopropanes from allylic alcohols was performed on
racemic allylic alcohols generated in a fashion similar to

8794 J . Org. Chem., Vol. 61, No. 25, 1996
Theberge et al.
Sch em e 2
Sch em e 3
while the enantiomeric D-tartrate-derived dioxaboralane
12 is generated from the (S,S)-tartaramide. Cyclopro-
panation of cinnamyl alcohol via this strategy resulted
in the efficient, enantioselective (89% ee) preparation of
trans-2-phenylcyclopropylmethanol (13) (Scheme 1).
Chiral GC analysis of the trifluoroacetate derivative 14
using a trifluoroacetyl-derivatized γ-cyclodextrin column
was performed to determine the ratio of enantiomers. The
data received from the chiral chromatography proved to
be consistent with the enantiomeric excess estimated
using published optical rotation values.13
Oxidation of the enantiomerically enriched (hydroxy-
methyl)cyclopropane (13) to aldehyde 15 with catalytic
tetrapropylammonium perruthenate (TPAP) and N-
methylmorpholine N-oxide14 was followed by formation
of the R,â-unsaturated ethyl ester 16 using a classical
Horner-Emmons reaction. It was possible to separate
the minor cis-product from the desired trans-isomer by
careful chromatography on silica.15 Following the
DIBAL-H reduction of 16, the enantiomerically enriched
bis-cyclopropane precursor allylic alcohol 17 was in hand.
Application of Charette’s cyclopropanation protocol to
the allylic alcohol 17 made possible the preparation of
the trans-syn-trans-bis-cyclopropane 3 in 67% yield (ratio
3:4; 10:1) using the L-tartrate-derived dioxaboralane 11
and the trans-anti-trans-bis-cyclopropane 4 in 72% (ratio
3:4; 1:10) yield using the D-tartrate-derived dioxaboralane
12. A third cyclopropanation was conducted on chiral
17 in the absence of dioxaboralane. By comparison of
the 13C-NMR data generated from the reagent-controlled
processes, the anti diastereomer 4 was identified as the
major product (ratio 3:4; 1:1.3) in the substrate-stereo-
controlled cyclopropanation reaction.16
substrate-controlled cyclopropanation reactions on com-
pound 19. The syn-diastereomer 5 was produced utilizing
the D-tartrate-derived dioxaboralane 12 and the anti-
diastereomer 6 using the L-tartrate-derived dioxabo-
ralane 11. Each substrate-mediated reaction gave a
modest diastereomeric excess, while cyclopropanation in
the absence of chiral dioxaboralane provided once again
very little substrate-based stereocontrol.
In order to prepare the cis-cyclopropane precursors 25
and 27 for the four remaining bis-cyclopropanes 7-10,
(Z)-3-phenyl-2-propenol 20 was synthesized by the method
of Pelter.18 This allylic alcohol was subjected to cyclo-
propanation in the presence of L-dioxaboralane 11 to give
the (hydroxymethyl)cyclopropane (21) in 90% yield
(Scheme 3). The optical purity (83% ee) of the trifluoro-
acetyl derivative 22 was determined by chiral GC analy-
sis, since conflicting optical rotation values had been
reported in the literature.19,20 Oxidation of 21 with
TPAP/NMO gave the enantiomerically enriched aldehyde
23, which was subjected to E-selective Horner-Emmons
reaction conditions to yield the R,â-unsaturated ester 24.
Purification of 24 by chromatography and reduction with
DIBAL-H provided the allylic alcohol 25.
The diastereomerically enriched bis-cyclopropanes 7
and 8 were produced by directed cyclopropanations on
25 utilizing the L- and D-tartrate-derived dioxaboralanes
11 and 12, respectively. It was significant to note that
the cis-anti-trans-bis-cyclopropane 8 was formed quite
selectively (ratio of 7:8; 1:>10), while the preparation of
the cis-syn-trans-bis-cyclopropane 7 was poorly stereo-
selective (ratio of 7:8; 2.5:1). Cyclopropanation of the
allylic alcohol in the absence of dioxaboralane demon-
strated that the existing cyclopropane stereocenters exert
significant influence on the resulting stereochemistry
favoring the formation of the cis-anti-trans-bis-cyclopro-
pane 8 (ratio of 7:8; 1:9). Therefore, the use of D-tartrate-
derived dioxaboralane 12 in the cyclopropanation of 25
The formation of trans-cis-bis-cyclopropanes 5 and 6
required the incorporation of a Z-olefin into the allylic
alcohol 19 (Scheme 2). The Z-selective Horner-Emmons
reaction developed by Still and co-workers17 proceeded
with excellent selectivity to give optically active 18. The
E and Z isomers were separated, and a subsequent
DIBAL-H reduction gave the desired allylic alcohol 19.
We again performed the two reagent-controlled and one
(13) Yasui, S. C.; Keiderling, T. A. J . Am. Chem. Soc. 1987, 109,
2311.
(14) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(15) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(16) The ratio of isomers was determined by acquisition of a 13C-
NMR spectrum such that full relaxation of all carbons was assured
and integration of the corresponding 13C resonances between the two
diastereomers. When it was impossible to determine the corresponding
13C resonances between the two diastereomers, averages of multiple
resonances were compared.
(18) Pelter, A.; Ward, R. S.; Little, G. M. J . Chem. Soc., Perkin Trans.
1 1990, 2775.
(19) Scholl, B.; Hansen, H.-J . Helv. Chim. Acta 1986, 69, 1936.
(20) Aratani, T.; Nakanisi, Y.; Nozaki, H. Tetrahedron 1970, 26,
1675.
(17) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.

Diastereoselective Preparation of Bis-cyclopropanes
J . Org. Chem., Vol. 61, No. 25, 1996 8795
Ta ble 1. Yield s a n d Dia ster eoselectivities in th e
Sch em e 4
F or m a tion of Bis-cyclop r op a n es 3-10a
to form the cis-anti-trans-bis-cyclopropane 8 was es-
sentially unnecessary since it merely duplicated the
substrate-based selectivity. The application of the L-
tartrate-derived dioxaboralane 11 to the cyclopropanation
of 25 resulted in mismatched stereodirecting elements
that made the preparation of bis-cyclopropane 7 the least
selective in this series.21
The allylic alcohol 27, the precursor to the final two
bis-cyclopropanes 9 and 10, was prepared by application
of a Z-selective HWE reaction to aldehyde 23, followed
by reduction with DIBAL-H (Scheme 4). The syn- and
anti-bis-cyclopropanes 9 and 10 were obtained by ap-
plication of Charette’s cyclopropanation methodology
utilizing the dioxaboralanes 12 and 11, respectively.
Some substrate-based stereocontrol was observed in the
absence of dioxaboralane (ratio of 9:10; 1:2.8), although
it was less pronounced than in the formation of bis-
cyclopropanes from compound 25.
a
Reagents and conditions: (a) Et2Zn, CH2I2; (b) Et2Zn, CH2I2,
11; (c) Et2Zn, CH2I2, 12.
significantly reduced by the influence of the proximal
hydroxyl group.
The significant anti-selectivity observed in the cyclo-
propanation of 25 and 27 is likely due to steric interac-
tions between the zinc-alcohol complex and the pendent
phenyl ring. Rotation about the cyclopropyl-olefin bond
in order to alleviate this steric interaction results in
carbenoid addition providing the anti-isomers. The cis-
Z-isomer 27 experiences destabilizing sterics interactions
in both of its gauche conformers, which results in an
attenuation of this anti-selectivity.
Discu ssion
The stereoselectivity observed in bis-cyclopropane for-
mation is summarized in Table 1. While most of the bis-
cyclopropane isomers were formed in modest to good
diastereoselectivities through the application of a reagent-
controlled process, there are remarkable variations in the
product distributions in the substrate-controlled reac-
tions. An understanding of the stereoselectivity of the
substrate-directed reactions requires an appreciation of
the multiple conformers that exist in these vinyl cyclo-
propane systems.22 However, it would be naive to as-
sume that the selective formation of the anti-isomer in
all of the substrate-stereocontrolled reactions could be
explained by comparison of the low energy trans-
conformation alone. In fact, formation of the favored
anti-isomers appears to be at first analysis of the result
of attack on the most sterically hindered face of the olefin.
The anti-preferences observed in the substrate-stereo-
controlled reactions of the trans-cyclopropanes 17 and 19
were small, yet reproducible. A strong anti-preference
observed in analogous vinylcyclopropane systems by
Barrett was proposed to be the result of an interaction
between the electron-rich cyclopropane σ-bond and alkene
π-system.7e Similar analysis of compounds 17 and 19
predicts the observed anti-preference, although it is
Rh od iu m -Ca ta lyzed Ch em istr y
The bis-cyclopropane isomer prepared with the least
selectivity through the reagent-mediated stereocontrolled
process described above was the cis-syn-trans-isomer 7.
Although we have been able to attribute this difficulty
in forming the syn-isomer to the overwhelming substrate-
based anti-selective cyclopropanation reaction, we desired
to prepare bis-cyclopropane 7 in a more selective fashion.
Many synthetic methods exist which promote the forma-
tion of cyclopropanes from olefins. One potential syn-
thetic route to bis-cyclopropane formation would involve
transition metal-mediated addition of ethyl diazoacetate
(EDA) to an appropriate vinylcyclopropane. Since the cis-
cyclopropanes 25 and 27 showed a significant preference
for anti-addition and since trans-cyclopropane formation
is preferred in the rhodium-catalyzed reactions involving
diazo esters,23 we predicted that compound 7 might be
formed selectively through the rhodium(II) diacetate
mediated addition of ethyl diazoacetate to the cis-
vinylcyclopropane (29).
(21) We have recently reported a substrate-mediated sulfur-ylide
strategy in which enhanced stereoselectivity is observed in the
preparation of 7. Cebula, R. E. J .; Hanna, M. R.; Theberge, C. R.;
Verbicky, C. A.; Zercher, C. K. Tetrahedron Lett. Accepted for publica-
tion.
(22) Runge, W. In The Chemistry of the Cyclopropyl Group; J ohn
Wiley and Sons: New York, 1987; Part 1, p 66.
(23) (a) Doyle, M. P. Acc. Chem. Res. 1986, 19, 348. (b) Doyle, M.
P.; Dorow, R. L.; Buhro, W. E.; Griffin, J . H.; Tamblyn, W. H.; Trudell,
M. L. Organometallics 1984, 3, 44. (c) Doyle, M. P.; Griffin, J . H.;
Bagheri, V.; Dorow, R. L. Organometallics 1984, 3, 53.

8796 J . Org. Chem., Vol. 61, No. 25, 1996
Theberge et al.
Sch em e 5
of eight unique bis-cyclopropane isomers. The efficiency
of this reagent-controlled approach suggests that the
preparation of many polycyclopropane isomers should be
possible. We have been able to use these diastereomeri-
cally enriched bis-cyclopropanes to analyze the efficiency
of bis-cyclopropane formation through the rhodium-
catalyzed diazoester addition to olefins. The various
factors that control the diastereoselectivity of these
various processes are not entirely clear, but the confor-
mational preferences of the cis- and trans-vinylcyclopro-
panes have been proposed as important factors.
The racemic aldehydes 15 and 23 were converted to
vinylcyclopropanes (28) and (29), which were exposed to
ethyl diazoacetate (EDA) and rhodium(II) acetate to
provide a mixture of bis-cyclopropyl ethyl esters24,25
(Scheme 5). The reaction products were reduced with
DIBAL-H and purified by chromatography, and the 13C-
NMR spectrum of the rhodium-carbenoid derived bis-
cyclopropanes was compared to the spectra of compounds
3-10 in order that the approximate product ratios could
be elucidated (Scheme 5).
When the trans-vinylcyclopropane (28) was exposed to
ethyl diazoacetate in the presence of rhodium(II) acetate
and reduced, the trans-trans-bis-cyclopropanes 3 and 4
were formed as the major products (60%) in a 1:1.4 ratio.
The trans-cis-bis-cyclopropane isomers 5 and 6 made up
40% of the product mixture in a ratio of nearly 1:1. Doyle
has proposed that the preferred trans-selectivity in
rhodium(II) catalyzed cyclopropanations is the result of
electronic stabilization of the transition state, which leads
to the trans-cyclopropane products through the interac-
tion of the developing electrophilic carbon of the olefin
with the nucleophilic carbonyl oxygen. Our results not
only are in concert with Doyle’s model, but they also
reinforce our previous observation that little olefin facial
selectivity is observed with the trans-substituted vinyl-
cyclopropanes.
When the cis-vinylcyclopropane (29) was exposed to
these same rhodium(II)-mediated reaction conditions,
equal amounts of the cis-trans-bis-cyclopropanes 7 and
8 were observed. While it is true that increasing the
steric bulk of monosubstituted olefins has been shown
to lead to enhanced trans-selectivity,23 we were intrigued
that the newly formed cyclopropane rings in 7 and 8 were
exclusively trans. Although this result appears to stand
in contrast to the results of our study with the trans-
vinylcyclopropane 28, we feel the differences in product
selectivity can be accurately ascribed to the intrinsic
steric bulk differences of the trans- and cis-cyclopropane
substituents of 28 and 29. Nevertheless, we were
surprised that no facial (syn-anti) selectivity was ob-
served in the reaction of 29. The reason for no facial
selectivity is not perfectly clear; however, steric interac-
tion of the carbenoid’s carboxy ester functionality with
the pendent cyclopropane would be expected to destabi-
lize contribution of either gauche-conformer. The result-
ing trans-conformational preference would allow nearly
equal access to the two faces and result in equal amounts
of syn- and anti-isomers.
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. Unless otherwise
indicated, all reagents and solvents were commercially avail-
able and used without further purification. Tetrahydrofuran
(THF), diethyl ether, and dimethoxyethane (DME) were
distilled from sodium/benzophenone. Methylene chloride (CH2-
Cl2) was distilled from phosphorus pentaoxide, dimethylform-
amide (DMF) from calcium hydride, and dimethyl sulfoxide
(DMSO) from calcium hydride and stored over 4 Å sieves. All
reactions were performed under a nitrogen atmosphere using
magnetic stirrers unless indicated otherwise. Proton spectra
were obtained at 360 MHz, and 13C spectra were obtained at
90 MHz. TLC plates supplied by EM (Merck) of silica gel 60
F254 at 250 mm thickness were used and were visualized with
shortwave UV and anisaldehyde stain. Chromatography was
conducted according to the procedure of Still17 using Baker
40 mm silica gel. The term “concentrated under reduced
pressure” refers to the use of a rotary evaporator equipped
with a water aspirator. All optical rotations were conducted
with samples in chloroform solution (unless indicated other-
wise), and concentrations are given in g/mL. Mass spectral
analyses were carried out by chemical ionization using NH3
as the carrier gas. High-resolution mass spectrometry was
performed by the University of California at Riverside Mass
Spectrometry Facility.
Rep r esen ta tive P r oced u r e for E-Olefin P r ep a r a tion .
To a round-bottom flask was added 1.67 g (7.44 mmol) of
triethyl phosphonoacetate and 150 mL of THF. The solution
was stirred vigorously at 0 °C while 4.65 mL of a 1.6 M solution
of n-BuLi in hexanes (7.44 mmol) was added. The reaction
was stirred for 10 min before 0.903 g (6.20 mmol) of the
appropriate aldehyde (15 or 23) in 30 mL of THF was added
via cannula. The reaction was stirred at room temperature
for 2.5 h and the reaction mixture quenched with saturated
aqueous citric acid. The organic layer was removed, and the
aqueous portion was washed with diethyl ether. The combined
organic solutions were dried over anhydrous magnesium
sulfate, filtered through Celite, and concentrated under re-
duced pressure to give a viscous yellow oil. The crude oil was
taken up in diethyl ether, washed with water, dried with
MgSO4, filtered through Celite, and concentrated under re-
duced pressure to give a yellow oil.
Eth yl (E)-3-(tr a n s-(1R,2S)-2-P h en ylcyclop r op yl)p r op e-
n oa te (16). The crude oil was chromatographed on silica
(200:1 hexanes:EtOAc) to yield pure 16 (72%) as a colorless
oil (and a small portion of the slightly impure Z-isomer (3%)
as a yellow oil) (22:1 ratio): [R]D ) +142.1° (c 0.0071); 1H NMR
δ (CDCl3) 7.31-7.01 (m, 5H), 6.59 (dd, 1H, J ) 9.8, 15.4 Hz),
5.89 (d, 1H, J ) 15.4 Hz), 4.18 (q, 2H, J ) 7.1 Hz), 2.17 (ddd,
1H, J ) 4.1, 6.1, 9.0 Hz), 1.81 (dddd, 1H, J ) 4.1, 5.3, 8.4,
9.8), 1.43 (ddd, 1H, J ) 5.2, 6.1, 8.4 Hz), 1.29 (ddd, 1H, J )
5.2, 5.3, 9.0 Hz), 1.28 (t, 3H, J ) 7.1 Hz); 13C NMR δ (CDCl3)
166.6, 151.6, 140.7, 128.4, 126.1, 125.8, 118.8, 60.1, 26.8, 26.7,
17.7, 14.3; HRMS calcd for C14H20NO2 (M + NH4+) 234.1494,
found 234.1488.
E t h yl (E)-3-(cis-(1R,2R)-2-P h en ylcyclop r op yl)p r op e-
n oa te (24). The oil was subjected to flash chromatography
(100:1 hexanes:EtOAc) to yield 24 (56%) as a colorless oil (and
a small portion of the Z-isomer (9%) as an impure yellow oil)
(6:1 ratio): [R]D ) -29.2° (c 0.0093); 1H NMR δ (CDCl3) 7.32-
7.16 (m, 5H), 6.25 (dd, 1H, J ) 10.5, 15.4 Hz), 5.91 (d, 1H, J
Con clu sion s
We have demonstrated that the preparation of diverse
bis-cyclopropanes is possible through the application of
a reagent-controlled process by the successful preparation
(24) Fischetti, W.; Heck, R. J . Organomet. Chem. 1985, 391.
(25) Brown, K. C.; Kodacek, T. J . Am. Chem. Soc. 1992, 114, 8336.

Diastereoselective Preparation of Bis-cyclopropanes
J . Org. Chem., Vol. 61, No. 25, 1996 8797
) 15.4 Hz), 4.07 (q, 2H, J ) 7.2 Hz), 2.57 (ddd, 1H, J ) 6.8,
8.4, 8.5 Hz), 1.99 (dddd, 1H, J ) 5.3, 8.4, 8.5, 10.5 Hz), 1.45
(ddd, 1H, J ) 5.3, 8.4, 8.4 Hz), 1.27 (ddd, 1H, J ) 5.3, 5.3, 6.8
Hz), 1.19 (t, 3H, J ) 7.2 Hz); 13C NMR δ (CDCl3) 166.2, 149.9,
137.4, 129.0, 128.3, 126.6, 120.2, 59.9, 25.5, 22.4, 14.2, 13.6;
HRMS calcd for C14H20NO2 (M + NH4+) 234.1494, found
234.1490.
Rep r esen ta tive P r oced u r e for Z-Olefin P r ep a r a tion .
To a flask were added 5.76 g (21.8 mmol) of 18-crown-6 and
1.52 g (4.8 mmol) of bis(2,2,2-trifluoroethyl) [(methoxycarbo-
nyl)methyl]phosphonate. The flask was charged with 50 mL
of THF, cooled to -78 °C, and stirred vigorously while 9.6 mL
(4.8 mmol) of a 0.5 M solution of potassium bis(trimethylsilyl)-
amide in toluene was added. The reaction was allowed to stir
for 10 min before 638 mg (4.36 mmol) of the appropriate
aldehyde (15 or 23) in 20 mL of THF was added via cannula.
The reaction was allowed to stir at room temperature for 2 h
and quenched with saturated aqueous ammonium chloride.
The THF layer was removed and the aqueous portion extracted
with diethyl ether. The combined organics were dried over
MgSO4, filtered through Celite, and concentrated under re-
duced pressure to give a yellow oil.
5.3, 8.6); 13C NMR δ (CDCl3) 141.9, 135.4, 128.3, 127.3, 125.8,
125.7, 59.0, 25.3, 22.7, 17.3.
(E)-3-(cis-(1R,2R)-2-P h en ylcyclopr opyl)-2-pr open ol (25).
The crude oil was purified by flash chromatography (10:1
hexanes:EtOAc) to yield compound 25 (90%) as a colorless oil:
[R]D ) -37.9° (c 0.0079); 1H NMR δ (CDCl3) 7.29-7.13 (m, 5H),
5.72 (dt, 1H, J ) 6.1, 15.3 Hz), 4.98 (dd, 1H, J ) 9.3, 15.3 Hz),
3.88 (d, 2H, J ) 6.1 Hz), 2.34 (ddd, 1H, J ) 5.5, 8.6, 8.6 Hz),
1.84 (dddd, 1H, J ) 5.5, 8.6, 8.6, 9.3 Hz), 1.35 (s, 1H), 1.25
(ddd, 1H, J ) 5.5, 8.6, 8.6 Hz), 1.02 (ddd, 1H, J ) 5.5, 5.5, 5.5
Hz); 13C NMR δ (CDCl3) 141.9, 135.4, 128.4, 127.3, 125.7,
125.6, 63.4, 23.2, 21.6, 11.6.
(Z)-3-(cis-(1R,2R)-2-P h en ylcyclopr opyl)-2-pr open ol (27).
The crude oil was purified by chromatography (10:1 hexanes:
EtOAc) to yield alcohol 27 (90%) as a colorless oil: [R]D
)
-154.0° (c 0.0224 CCl4); 1H NMR δ (CDCl3) 7.30-7.15 (m, 5H),
5.50 (dt, 1H, J ) 6.8, 10.9 Hz), 4.83 (dd, 1H, J ) 9.8, 10.9 Hz),
4.28 (d, 2H, J ) 6.8 Hz), 2.39 (ddd, 1H, J ) 5.4, 8.4, 8.4 Hz),
2.01 (dddd, 1H, J ) 5.4, 8.4, 8.4, 9.8 Hz), 1.33 (ddd, 1H, J )
5.2, 8.4, 8.4 Hz), 1.28 (s, 1H), 1.02 (ddd, 1H, J ) 5.2, 5.4, 5.4
Hz); 13C NMR δ (CDCl3) 138.5, 132.4, 129.0, 128.9, 128.0,
125.9, 58.8, 23.4, 17.3, 12.5.
Meth yl (Z)-3-(tr a n s-(1R,2S)-2-P h en ylcyclop r op yl)p r o-
p en oa te (18). The crude oil was subjected to flash chroma-
tography (100:1 hexanes:EtOAc), which yielded ester 18 (71%)
as a yellow oil (and a small portion of the impure E-isomer
(7%)) (10:1 ratio): [R]D ) +16.8° (c 0.0071); 1H NMR δ (CDCl3)
7.3-7.1 (m, 5H), 5.75 (d, 1H, J ) 11.4 Hz), 5.64 (dd, 1H, J )
11.4, 11.4 Hz), 3.70 (s, 3H), 3.25 (dddd, 1H, J ) 4.2, 5.0, 11.0,
11.4 Hz), 2.10 (ddd, 1H, J ) 4.2, 6.1, 9.0 Hz), 1.44 (ddd, 1H, J
) 5.0, 6.1, 11.0 Hz), 1.20 (ddd, 1H, J ) 5.0, 5.1, 9.0 Hz); 13C
Rep r esen ta tive P r oced u r e for F u r u k a w a -Mod ified
Sim m on s-Sm ith Cyclop r op a n a tion Utilizin g a Ta r tr a te-
Der ived Dioxa bor a la n e. A round-bottom flask that con-
tained 25 mL of methylene chloride was cooled to 0 °C, and
1.1 mL (0.0011 mol) of a 1.0 M solution of diethyl zinc in
hexanes was added. This solution was treated with 0.182 mL
(0.0022 mol) of methylene iodide, and the reaction was stirred
for 5 min. To this solution was added 10 mL of a methylene
chloride solution that contained 0.088 g (0.0005 mol) of allylic
alcohol (17, 19, 25, or 27) and, if desired, 0.148 g (0.000 55
mol) of the appropriate chiral dioxaboralane 11 or 12. The
reaction mixture was allowed to stir for 2 h, the reaction was
quenched with 50 mL saturated NH4Cl solution, and the
aqueous portion was extracted with EtOAc. The combined
organic solutions were dried over MgSO4, filtered through
Celite, and concentrated to give a yellow oil. If a dioxaboralane
was used, the crude oil was dissolved in 10 mL of diethyl ether
and stirred vigorously overnight with 10 mL of 5 N KOH. The
ether layer was washed with 1 N HCl, 5% NaHCO3, water,
and brine. The organic portion was dried over magnesium
sulfate, filtered through Celite, and concentrated under re-
duced pressure. The crude concentrate was subjected to flash
chromatography (10:1 hexanes:EtOAc) to yield a colorless oil.
NMR δ (CDCl3) 167.3, 153.1, 140.8, 128.4, 126.1, 126.0, 117.1,
+
51.0, 27.2, 23.9, 18.6; HRMS calcd for C13H18NO2 (M + NH4
220.1338, found 220.1347.
)
Meth yl (Z)-3-(cis-(1R,2R)-2-P h en ylcyclop r op yl)p r op e-
n oa te (26). The crude oil was subjected to chromatography
(100:1 hexanes:EtOAc), which provided ester 26 (64%) as a
yellow oil (and a small portion of the E-isomer (4%) as an
impure oil) (15:1 ratio): [R]D ) -335.4° (c 0.0061); 1H NMR δ
(CDCl3) 7.32-7.17 (m, 5H), 5.63 (dd, 1H, J ) 0.6, 11.3 Hz),
5.38 (dd, 1H, J ) 11.3, 11.3 Hz), 3.72 (s, 3H), 3.29 (ddddd, 1H,
J ) 0.6, 5.3, 8.3, 8.3, 11.3 Hz), 2.65 (ddd, 1H, J ) 6.7, 8.3, 8.3
Hz), 1.51 (ddd, 1H, J ) 5.2, 8.3, 8.3 Hz), 1.22 (ddd, 1H, J )
5.2, 5.3, 6.7 Hz); 13C NMR δ (CDCl3) 167.5, 151.5, 137.8, 129.3,
128.3, 126.5, 117.9, 51.0, 25.8, 19.5, 14.2; HRMS calcd for
C13H15O (M + H+) 203.1072, found 203.1066.
Rep r esen ta tive P r oced u r e for DIBAL-H Red u ction s.
A flask that contained 406 mg (1.87 mmol) of the appropriate
ester (16, 18, 24, or 26) was charged with 25 mL of THF, cooled
to -78 °C, and stirred vigorously during slow addition of 2.61
mL (3.92 mmol) of a 1.5 M solution of DIBAL-H in toluene.
The reaction was allowed to warm to room temperature, cooled
in an ice-water bath, and quenched by the slow sequential
addition of 0.2 mL of H2O, 0.2 mL of 2 N NaOH, 0.2 mL of
H2O, and 0.2 mL of 2 N NaOH. The quenched reaction was
allowed to stir overnight, dried with MgSO4, filtered through
Celite, and concentrated under reduced pressure.
(E )-3-(t r a n s-(1R ,2S )-2-P h e n ylcyclop r op yl)-2-p r op e -
n ol (17). The crude oil was purified by chromatography (10:1
hexanes:EtOAc) to yield compound 17 (72%) as a colorless oil:
[R]D ) +224° (c 0.0086); 1H NMR δ (CDCl3) 7.23-6.96 (m, 5H),
5.67 (dt, 1H, J ) 6.1, 15.3 Hz), 5.33 (ddt, 1H, J ) 1.2, 8.6,
15.3 Hz), 4.03 (dd, 2H, J ) 1.2, 6.1 Hz), 1.85 (ddd, 1H, J ) 4.4,
5.5, 8.8 Hz), 1.62 (dddd, 1H, J ) 4.4, 5.5, 8.5, 8.6 Hz), 1.35 (s,
1H), 1.14 (ddd, 1H, J ) 5.1, 5.5, 8.5 Hz), 1.02 (ddd, 1H, J )
5.1, 5.5, 8.8 Hz); 13C NMR δ (CDCl3) 142.1, 135.2, 128.3, 127.3,
125.61, 125.59, 63.4, 26.1, 25.1, 16.7.
(Z)-3-(t r a n s-(1R ,2S )-2-P h e n ylcyclop r op yl)-2-p r op e -
n ol (19). The crude oil was purified by flash chromatography
(10:1 hexanes:EtOAc) to yield compound 19 (80%) as a colorless
oil: [R]D ) +115° (c 0.0196); 1H NMR δ (CDCl3) 7.30-7.04 (m,
5H), 5.59 (dt, 1H J ) 6.8, 10.8 Hz), 5.07 (dd, 1H, J ) 9.8, 10.8
Hz), 4.28 (d, 2H, J ) 6.8 Hz), 1.92 (ddd, 1H, J ) 4.3, 5.7, 8.6
Hz), 1.84 (dddd, 1H, J ) 4.3, 5.3, 8.5, 9.8 Hz), 1.39 (s, 1H),
1.27 (ddd, 1H, J ) 5.0, 5.7, 8.5 Hz), 1.05 (ddd, 1H, J ) 5.0,
2-((1R,2S)-2-P h en ylcyclop r op yl)-(1S,2R)-1-(h yd r oxy-
m eth yl)cyclop r op a n e (3). Application of dioxaboralane 11
to allylic alcohol 17 (3(syn):4(anti) 10:1) (67%): [R]D ) +140°
1
(c 0.0016); H NMR δ (CDCl3) 7.20-6.92 (m, 5H), 3.45-3.32
(m, 2H), 1.62-1.56 (m, 1H), 1.42 (s, 1H), 1.15-1.08 (m, 1H),
0.97-0.65 (m, 4H), 0.37-0.26 (m, 2H); 13C NMR δ (CDCl3)
143.2, 128.1, 125.5, 125.2, 66.5, 24.3, 22.1, 20.0, 18.5, 13.9, 7.9;
HRMS calcd for C13H20NO (M + NH4+) 206.1545, found
206.1548.
2-((1R,2S)-2-P h en ylcyclop r op yl)-(1R,2S)-1-(h yd r oxy-
m eth yl)cyclop r op a n e (4). Application of dioxaboralane 12
to allylic alcohol 17 (3(syn):4(anti) 1:10) (72%): [R]D ) +85° (c
0.0023); 1H NMR δ (CDCl3) 7.25-6.98 (m, 5H), 3.47-3.37 (m,
2H), 1.80 (s, 1H), 1.68-1.61 (m, 1H), 1.17-1.10 (m, 1H), 0.98-
0.73 (m, 4H), 0.47-0.36 (m, 2H); 13C NMR δ (CDCl3) 143.2,
128.1, 125.5, 125.2, 66.5, 24.4, 21.8, 19.3, 18.6, 14.4, 8.6.
2-((1R,2S)-2-P h en ylcyclop r op yl)-(1R,2R)-1-(h yd r oxy-
m eth yl)cyclop r op a n e (5). Application of dioxaboralane 12
to allylic alcohol 19 (5(syn):6(anti) 10:1) (81%): [R]D ) +116°
1
(c 0.0015); H NMR δ (CDCl3) 7.25-7.00 (m, 5H), 3.73-3.57
(m, 2H), 1.80-1.72 (m, 1H), 1.45 (s, 1H), 1.22-1.11 (m, 1H),
1.03-0.80 (m, 4H), 0.70-0.64 (m, 1H), 0.18-0.12 (m, 1H); 13
C
NMR δ (CDCl3) 143.0, 128.3, 125.5, 125.4, 63.7, 22.9, 21.8, 18.9,
+
18.6, 16.0, 8.3; HRMS calcd for C13H20NO (M + NH4
)
206.1545, found 206.1531.
2-((1R,2S)-2-P h en ylcyclop r op yl)-(1S,2S)-1-(h yd r oxy-
m eth yl)cyclop r op a n e (6). Application of dioxaboralane 11
to allylic alcohol 19 (5(syn):6(anti) 1:6) (78%): [R]D ) +25° (c
0.0016); 1H NMR δ (CDCl3) 7.25-7.00 (m, 5H), 3.76-3.53 (m,
2H), 1.80-1.72 (m, 1H), 1.42 (s, 1H), 1.22-1.11 (m, 1H), 1.03-

8798 J . Org. Chem., Vol. 61, No. 25, 1996
Theberge et al.
0.80 (m, 4H), 0.72-0.66 (m, 1H), 0.21-0.16 (m, 1H); 13C NMR
δ (CDCl3) 142.9, 128.3, 125.5, 125.4, 63.8, 23.3, 21.6, 18.9, 18.7,
15.8, 8.9.
Cyclop r op a n a t ion of 25 in t h e a b sen ce of ch ir a l
d ioxa bor a la n e: (7(syn):8(anti) 1:9) (82%).
Cyclop r op a n a t ion of 27 in t h e a b sen ce of ch ir a l
d ioxa bor a la n e: (9(syn):10(anti) 1:2.8) (85%).
2-((1R,2R)-2-P h en ylcyclop r op yl)-(1S,2R)-1-(h yd r oxy-
m eth yl)cyclop r op a n e (7). Application of dioxaboralane 11
to allylic alcohol 25 (7(syn):8(anti) 2.5:1) (81%): [R]D ) +6° (c
0.0096); 1H NMR δ (CDCl3) 7.34-7.16 (m, 5H), 3.39-3.30 (m,
1H), 2.81-2.74 (m, 1H), 2.17-2.10 (m, 1H), 1.25 (s, 1H), 1.07-
1.00 (m, 1H), 0.93-0.85 (m, 2H), 0.81-0.71 (m, 1H), 0.51-
0.45 (m, 1H), 0.36-0.27 (m, 2H); 13C NMR δ (CDCl3) 139.5,
128.8, 128.1, 125.9, 66.9, 21.7, 21.2, 21.1, 16.5, 10.2, 9.7; HRMS
calcd for C13H20NO (M + NH4+) 206.1545, found 206.1547.
2-((1R,2R)-2-P h en ylcyclop r op yl)-(1R,2S)-1-(h yd r oxy-
m eth yl)cyclop r op a n e (8). Application of dioxaboralane 12
to allylic alcohol 25 (7(syn):8(anti) 1:>10) (79%): [R]D ) +83°
Gen er a l P r oced u r e for th e Rh od iu m Ca r ben oid -Med i-
a ted Cyclop r op a n a tion a n d Su bsequ en t DIBAL-H Re-
d u ction of 28 a n d 29. Into a round-bottom flask was added
1.0 equiv of the vinylcyclopropane 28 or 29, benzene (0.1 M),26
and a catalytic amount of Rh2(OAc)4. The solution was stirred
while 1 equiv of ethyl diazoacetate dissolved in benzene (0.2
M) was added over a 8.5 h period. The reaction mixture was
filtered through Celite and concentrated under reduced pres-
sure. The crude product was chromatographed on silica (40:1
hexanes:EtOAc) to separate the mixture of bis-cyclopropyl
ethyl esters, starting material, and ethyl cycloheptatrienoate.
The bis-cyclopropyl esters were transferred into a round-
bottom flask, and 25 mL of THF was added. The flask was
cooled to -78 °C, excess DIBAL-H in toluene was added, and
the reaction mixture was allowed to warm to room tempera-
ture. The reaction mixture was cooled to 0 °C, quenched by
the sequential addition of 2 N NaOH and H2O, and stirred
overnight during which time a white granular precipitate
formed. The quenched reaction mixture was dried with
MgSO4, filtered through Celite, and concentrated under re-
duced pressure. The crude concentrate was chromatographed
on silica (10:1 hexanes:EtOAc) to yield a mixture of bis-
cyclopropanes 3-10 that were identified by 13C NMR.
Rea ction of 28. Yield of bis-cyclopropyl esters: 38%. Yield
of ethyl cycloheptatrienoate: 25%. Recovered starting mate-
rial 28: 10%. Yield of DIBAL-H reduction: 85%.
1
(c 0.0054); H NMR δ (CDCl3) 7.34-7.16 (m, 5H), 3.28-3.17
(m, 1H), 2.89-2.81 (m, 1H), 2.20-2.12 (m, 1H), 1.25 (s, 1H),
1.20-1.10 (m, 1H), 0.93-0.85 (m, 1H), 0.81-0.71 (m, 1H),
0.70-0.64 (m, 1H), 0.43-0.37 (m, 1H), 0.36-0.27 (m, 2H); 13
C
NMR δ (CDCl3) 139.5, 129.6, 128.0, 125.9, 66.7, 21.4, 20.0, 19.8,
15.9, 9.4, 8.3.
2-((1R,2R)-2-P h en ylcyclop r op yl)-(1R,2R)-1-(h yd r oxy-
m eth yl)cyclop r op a n e (9). Application of dioxaboralane 12
to allylic alcohol 27 (9(syn):10(anti) 5:1) (79%): [R]D ) +17°
1
(c 0.0066); H NMR δ (CDCl3) 7.32-7.15 (m, 5H), 3.74-3.67
(m, 1H), 3.60-3.53 (m, 1H), 2.18-2.10 (m, 1H), 1.30 (s, 1H),
1.11-0.79 (m, 4H), 0.65-0.48 (m, 2H), 0.17-0.10 (m, 1H); 13
C
NMR δ (CDCl3) 139.5, 128.4, 128.0, 125.7, 63.6, 21.5, 18.3, 18.1,
14.7, 11.1, 9.7.
2-((1R,2R)-2-P h en ylcyclop r op yl)-(1S,2S)-1-(h yd r oxy-
m eth yl)cyclop r op a n e (10). Application of dioxaboralane 11
to allylic alcohol 27 (9(syn):10(anti) 1:5) (80%): [R]D ) +8° (c
0.0052); 1H NMR δ (CDCl3) 7.32-7.15 (m, 5H), 3.88-3.79 (m,
1H), 3.66-3.58 (m, 1H), 2.27-2.19 (m, 1H), 1.45 (s, 1H), 1.11-
0.79 (m, 4H), 0.65-0.57 (m, 1H), 0.22-0.10 (m, 2H); 13C NMR
δ (CDCl3) 139.2, 129.3, 127.9, 125.8, 64.2, 21.4, 18.1, 17.4, 14.9,
Rea ction of 29. Yield of bis-cyclopropyl esters: 14%. Yield
of ethyl cycloheptatrienoate: 32%. Recovered starting mate-
rial 29: 25%. Yield of DIBAL-H reduction: 96%.
Ack n ow led gm en t. We would like to acknowledge
the support of the donors of the Petroleum Research
Fund, administered by the American Chemical Society
(25689-G1), and the National Institutes of Health (R15
GM51064).
10.4, 10.3; HRMS calcd for C13H20NO (M + NH4): 206.1545,
+
found 206.1555; HRMS calcd for C13H20NO (M + NH4
206.1545, found 206.1548.
)
Cyclop r op a n a t ion of 17 in t h e a b sen ce of ch ir a l
d ioxa bor a la n e: (3(syn):4(anti) 1:1.3) (78%).
Cyclop r op a n a t ion of 19 in t h e a b sen ce of ch ir a l
d ioxa bor a la n e: (5(syn):6(anti) 1:1.3) (79%).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation of 13-15, 21-23, 28, and 29 and
1H and 13C NMR spectra of 3-10, 13, 15-19, 21, and 23-27
(41 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
(26) Methylene chloride was also used as a solvent in this reaction
sequence. The yield of bis-cyclopropyl ester formation was slightly
higher since none of the competing cycloheptatrienoate was formed.
The stereoselectivity of the process was indistinguishable when moving
between methylene chloride and benzene.
J O961235P