Highly enantio- and diastereoselective tandem generation of cyclopropyl alcohols with up to four contiguous stereocenters

Article abstract of DOI:10.1021/ja0539239

Three highly enantio- and diastereoselective one-pot procedures for the synthesis of cyclopropyl and iodocyclopropyl alcohols with up to four contiguous stereocenters are reported. Route 1 involves asymmetric addition of an alkylzinc reagent to an enal fo

Full text of DOI:10.1021/ja0539239

Published on Web 09/02/2005
Highly Enantio- and Diastereoselective Tandem Generation of Cyclopropyl
Alcohols with up to Four Contiguous Stereocenters
Hun Young Kim, Alice E. Lurain, Patricia Garc´ıa-Garc´ıa, Patrick J. Carroll, and Patrick J. Walsh*
Department of Chemistry, P. Roy and Diana T. Vagelos Laboratories, UniVersity of PennsylVania,
231 South 34th Street, Philadelphia, PennsylVania 19104-6323
Received June 14, 2005; E-mail: pwalsh@sas.upenn.edu
Scheme 1. Two Tandem Asymmetric Addition/Diastereoselective
Cyclopropanation Reactions
Numerous natural and unnatural products containing cyclopropyl
groups exhibit important biological activity.1-3 As a result, sub-
stantial effort has been devoted to the asymmetric synthesis of these
strained subunits.4,5 While asymmetric cyclopropanation of olefins
employing transition metal catalyzed decomposition of diazo com-
pounds can provide cyclopropanes with high selectivity,6 it has
proven to be very difficult to control enantioselectivity in Sim-
mons-Smith7-type cyclopropanations of olefins8,9 and allylic
alcohols.4,10-12
Given these limitations, we considered alternative strategies for
the stereoselective synthesis of cyclopropanes from achiral reagents.
We envisioned an enantioselective generation of an allylic zinc
alkoxide intermediate followed by a diastereoselective cyclopro-
panation. Preforming these reactions in tandem enables formation
of three C-C bonds and up to four stereocenters in a one-pot pro-
cedure with excellent stereoselectivity.
Table 1. Tandem Asymmetric Addition/Diastereoselective
Cyclopropanation of Enals (Scheme 1A)
Scheme 1, pathway A, shows our first method wherein the key
allylic zinc alkoxide intermediate is generated by asymmetric alkyl
addition to R,â-unsaturated aldehydes in the presence of 4 mol %
of Nugent’s (-)-MIB (1).13 Quenching this intermediate allows
determination of the enantioselectivity in the first C-C bond-
forming step (Table 1). In the one-pot addition/cyclopropanation
procedure, the allylic alkoxide intermediate is treated with either
EtZnCH2I or the more reactive CF3CH2OZnCH2I14 to furnish the
cyclopropyl alcohols in 64-91% yield. The enantioselectivities in
the addition of dimethylzinc, diethylzinc, and functionalized orga-
nozinc reagents were g89% with a range of enals. Furthermore,
1
only a single diastereomer was detected in the crude H NMR
spectra in each case.
We next explored the addition of vinyl groups to saturated
aldehydes in route to cyclopropyl alcohols (Scheme 1B). On the
basis of Oppolzer’s hydroboration/transmetalation15 method, we
generated vinylzinc reagents. In the presence of (-)-MIB, clean
vinylation of the aldehyde proceeds to furnish the allylic alkoxide
intermediates.
a Determined by crude 1H NMR analysis. b Stereochemistry assigned by X-ray
analysis. See the Supporting Information. c With 5 equiv of ZnEt2, 5 equiv of
CF3CH2OH, and 5 equiv of CH2I2.
Unfortunately, directed cyclopropanation of this intermediate was
complicated by low yields and diastereomeric ratios. We hypoth-
esized that the triethylborane byproduct formed in the transmeta-
lation step was reacting with the cyclopropanating reagent. To cir-
cumvent this problem, upon completion of the asymmetric addition,
the volatile materials, including the excess triethylborane, were
removed under reduced pressure. Diethylzinc and CH2I2 (5 equiv
each) were added at 0 °C. After 24 h, the reactions were worked
up to provide the cyclopropyl alcohols with 71-84% yield and
enantiomeric excesses g93% (Table 2). Cyclopropanations of allylic
alkoxides derived from vinyl additions to other aldehydes resulted
in lower conversions and require further optimization.
The results in Tables 1 and 2 indicate that our tandem addition/
cyclopropanation sequence gives similar diastereoselectivities to
the cyclopropanation of isolated chiral allylic alcohols.16,17 The
tandem reaction is, however, more efficient.
Wipf and co-workers reported a vinyl addition/cyclopropanation
sequence with imines to afford racemic cyclopropylamines. Analo-
gous reactions with aldehydes, however, were reported to be
unsuccessful.18
Biologically active 1,2,3-substituted cyclopropanes are also found
widely in natural products.1,2 A modular approach to these chiral
building blocks that allows flexibility for further elaboration of the
cyclopropane ring is desirable. With this in mind, we targeted the
stereoselective synthesis of iodocyclopropyl alcohols (eq 1). Despite
their utility in cross-coupling19 and metalation reactions,20,21 few
highly enantio- and diastereoselective syntheses of these valuable
intermediates have been reported.20
We explored the use of
iodoform in place of diiodomethane in the cyclopropanation step
of our tandem addition/cyclopropanation chemistry. This reagent
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10.1021/ja0539239 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Tandem Asymmetric Vinylation of Aldehydes:
Diastereoselective Cyclopropanation (Scheme 1B)
genic centers have been presented. Beginning with achiral starting
materials, initial enantioselective C-C bond formation is followed
by diastereoselective cyclopropanation. The advantages of these
methods are that (1) they circumvent the need to prepare and isolate
either racemic or enantioenriched allylic alcohols, (2) the initial
asymmetric C-C bond-forming step can be optimized by judicious
choice of catalyst,27 and (3) the enantio- and diastereoselectivities
are very high for almost all substrate classes. Using our one-pot
method, highly functionalized cyclopropanes are now easily ac-
cessible. We anticipate that the cyclopropyl alcohols outlined here
will find widespread utility in enantioselective synthesis.28
a Determined by crude 1H NMR analysis b Stereochemistry assigned by X-ray
analysis. See the Supporting Information.
Acknowledgment. This work was supported by the NIH
(GM58101) and the NSF (CHE-0315913). We are grateful to Prof.
Andre´ B. Charette for disclosure of results prior to publication (see
accompanying paper).
Table 3. Tandem Asymmetric Addition/Iodocyclopropanation
Supporting Information Available: Procedures and full charac-
terization, stereochemical assignments, and X-ray determinations of new
compounds (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
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1
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has been used in the synthesis of iodo-substituted cyclopropanes22
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alcohols were isolated in 56-80% yields with enantiomeric excesses
g89%. The high diastereomeric ratio observed in the generation
of the final three stereocenters attests to the ability of zinc to control
stereoselectivity in this reaction. We anticipate that the iodides can
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In summary, three expedient methods for the synthesis of
cyclopropyl and iodocyclopropyl alcohols with up to four stereo-
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