Cyclopropane structural units from homoaldol adducts

Article abstract of DOI:10.1021/ol034448r

(Matrix presented) An efficient two-step homologation of aldehydes to cyclopropylaldehydes has been developed. Activation of homoaldol adducts derived from O-enecarbamates and N-enecarbamates provided high yields of cyclopropylaldehydes with good to excel

Full text of DOI:10.1021/ol034448r

ORGANIC
LETTERS
2003
Vol. 5, No. 8
1377-1379
Cyclopropane Structural Units from
Homoaldol Adducts
Richard E. Taylor,* Christina A. Risatti, F. Conrad Engelhardt, and
Michael J. Schmitt
Department of Chemistry and Biochemistry, UniVersity of Notre Dame,
251 Nieuwland Science Hall, Notre Dame, Indiana 46556-5670
taylor.61@nd.edu
Received March 13, 2003
ABSTRACT
An efficient two-step homologation of aldehydes to cyclopropylaldehydes has been developed. Activation of homoaldol adducts derived from
O-enecarbamates and N-enecarbamates provided high yields of cyclopropylaldehydes with good to excellent levels of trans/cis selectivity.
Trapping of the intermediate oxonium ion and iminium ion intermediates has also been demonstrated, leading to direct isolation of cyclopropyl
carbinol and cyclopropylamine products.
Progress in the area of diastereo- and enantioselective
methods for cyclopropane construction1 has been largely
focused on the modification of allylic alcohols through
intramolecular rhodium carbenoid intermediates2 or inter-
molecular Simmons-Smith chemistry.3 In contrast, our most
recent report included a remarkably efficient route to
nonracemic, diastereomerically pure 1,2,3-trisubstituted cy-
clopropanes in just two simple steps from readily available
homoallylic alcohols, Scheme 1.4 The stereochemistry of the
cyclopropane product 3, both absolute and relative, is
controlled by the starting material 1 and the constraints
imparted by transition state A. For our first generation
approach we chose Y ) CH2SiR3 to exploit the stabilization
of the â-silicon effect. Herein we report an investigation of
substrates that contain a heteroatom-substituted olefin, (Y
) -OR, NR2). The presence of an electron-rich olefin in the
cyclization substrates should result in a faster ring closure
and directly provide a cyclopropylaldehyde upon workup.
More importantly, these substrates can be prepared in a single
step from homoaldol addition reactions. The overall process
represents an efficient two-step homologation of aldehydes
to cyclopropylaldehydes.
Yamamoto has previously demonstrated high γ-selectivity
of silyloxyallylbarium reagents with carbonyl compounds
such as aldehydes and ketones.5 A number of representative
homoaldol adducts 5a-e were prepared using a modified
Yamamoto protocol, Scheme 2. At this point we envisioned
that activation of the homoallylic alcohol would lead to
Scheme 1
(1) Donaldson, W. A. Tetrahedron 2001, 57, 8589.
(2) See: Doyle, M. P.; Austin, R. E.; Bailey, A. S.; Dwyer, M. P.;
Dyatkin, A. B.; Kalinin, A. V.; Kwan, M. M. Y.; Liras, S.; Oalmann, C. J.;
Pieters, R. J.; Protopopova, M. N.; Raab, C. E.; Roos, G. H. P.; Zhou,
Q-.L.; Martin, S. F. J. Am. Chem. Soc. 1995, 117, 5763 and references
therein.
(3) For a lead reference, see: Charette, A. B.; Lemay, J. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1090.
(4) Taylor, R. E.; Engelhardt, F. C.; Schmitt, M. J.; Yuan, H. J. Am.
Chem. Soc. 2001, 123, 2964.
10.1021/ol034448r CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/28/2003

Scheme 2
cyclopropylaldehyde formation through an oxygen-stabilized
cyclopropylcarbinyl cationic intermediate. Despite the elec-
tronic and steric differences between these substrates, high
yields of cyclopropylaldehydes were obtained in each case,
Table 1. Much to our surprise, however, the cyclopropane
Figure 1. Transition state leading to cyclopropanes.
propanes in the allyltrimethylsilane system (X ) CH2). This
suggests a significant energy difference (∆∆G) between B-1
and B-2 when X ) CH2.8 In contrast, the isolation of cis-
cyclopropyl aldehydes from the activation of homoallylic
alcohols 5 suggests that when X is an oxygen atom B-1 and
B-2 are significantly closer in energy. Although the steric
volume of a methylene is greater than that of an oxygen atom,
the trans/cis ratios in Table 1 are best explained by a
combination of steric and electronic factors. It is clear that
the increase in rate of cyclization has led to a decrease in
diastereoselectivity.
Table 1. Cyclopropanes from Yamamoto Homoaldol Adducts
We rationalized that the trans/cis selectivity could be
improved by attenuating the reactivity of the enol ether
functionality. We prepared O-enecarbamates using the
method of Hoppe,9 Scheme 3. Allyl carbamate 7 was lithiated
Scheme 3
products were obtained with varying trans/cis selectivity but
always favoring the trans-isomer. The sterically encumbered
cyclohexyl substrate 5c is indeed more selective than the
other aliphatic substrates 5a and 5b. The loss of selectivity
observed in the phenyl substrate 5d may be attributed to an
increased rate of cyclization due to conjugation.
Previous studies in this area have shown that homoallylic
participation proceeds with inversion of configuration.6 Two
transition states are possible: (1) B-1, which has a trans
relationship between the C1 and C3 substituents, and (2) B-2,
which has a cis relationship between C1 and C3 substituents,
Figure 1.7 It is important to note that we had not previously
observed the formation of cis-1,2-disubstituted vinylcyclo-
with n-BuLi in the presence of (-)-sparteine and, after
transmetalation with Ti(OiPr)4, quenched with aldehydes to
provide 8a and 8b in good yield. The O-enecarbamates 8
were subjected to triflic anhydride activating conditions,
which yielded cyclopropylaldehydes 6b and 6c in excellent
yield and high trans/cis selectivity. These results provide
additional support for the importance of electronic factors
for the control of trans/cis selectivity. Despite the use of
(-)-sparteine in the lithiation step, the homoaldol adduct and
thus the cyclopropylaldehyde was prepared without any
significant degree of enantioselectivity.10
(7) Suzuki was the first to present transition states related to those
depicted in Figure 1 (ref 6b).
(8) In systems more closely related to the allylsilane chemistry, White
and Suzuki also observed, independently, exclusive trans cyclopropane
formation. See: (a) White, J. D.; Jensen, M. S. J. Am. Chem. Soc. 1993,
115, 2970. (b) Nagasawa, T.; Handa, Y.; Onoguchi, Y.; Ohba, S.; Suzuki,
K. Synlett 1995, 739.
(5) Yanagisawa, A.; Yasue, K.; Yamamoto, H. Synlett 1993, 686.
(6) (a) White, J. D.; Jensen, M. S. J. Am. Chem. Soc. 1993, 115, 2970.
(b) Nagasawa, T.; Handa, Y.; Onoguchi, Y.; Ohba, S.; Suzuki, K. Synlett
1995, 739. (c) Krief, A.; Provins, L. Synlett 1997, 505. (d) Taylor, R. E.;
Ameriks, M. K.; LaMarche, M. J. Tetrahedron Lett. 1997, 38, 2057. (e)
Taylor, R. E.; Engelhardt, F. C.; Yuan, H. Org. Lett. 1999, 1, 1257. (f)
Taylor, R. E.; Schmitt, M. J.; Yuan, H. Org. Lett. 2000, 2, 601. (g) See ref
4 of this manuscript.
(9) For a lead reference, see: Prasad, K. R. K.; Hoppe, D. Synlett 2000,
1067.
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Org. Lett., Vol. 5, No. 8, 2003

We also explored the use of N-enecarbamates prepared
by a method developed by Beak.11 N-Boc-N-(p-methoxyphen-
yl)-allylamine was metalated with n-BuLi/(-)-sparteine and
then reacted directly with a variety of aldehydes to provide
homoaldol products 10a-e, Scheme 4. The enantioselectivity
A key aspect of the ring-closure reaction presented here
is the stabilization of the cyclopropylmethyl carbocation by
heteroatom substitution. We have found that it is possible
to trap the intermediate oxonium and acyliminium ions, with
weak nucleophiles, to directly provide cyclopropyl carbinols
and cyclopropylmethylamines, respectively. As shown in
Scheme 5, O-enecarbamate 8a underwent cyclization/
Scheme 4
Scheme 5
of the process was shown to be negligible, but inclusion of
(-)-sparteine, as above, was shown to increase the efficiency
of the deprotonation step. Each of these substrates was
activated under our previously optimized conditions to
provide cyclopropylaldydes 6a-e.
allylation by activation under standard conditions, but in the
presence allyltributylstannane. The allylated adduct 11 was
isolated in 92% yield after reductive removal of the car-
bamate. In addition, cyclopropylamine 12 could be prepared
efficiently from N-enecarbamate 10b by in situ reduction of
the intermediate acyliminium ion with triethylsilane. In each
case, the cyclopropane product was isolated in higher yield
and greater trans selectivity than when the reaction was
performed without the in situ trapping reagent.
Table 2. Cyclopropanes from Beak Homoaldol Adducts
In summary, we have developed a method to homologate
aldehydes to cyclopropylaldehydes in just two steps. The
cyclizations are efficient and in many cases provide a high
degree of trans/cis selectivity. The intermediate oxonium and
iminium ions can be trapped with nucleophiles to directly
provide cyclopropyl alcohols and amines. Hoppe6 and Beak7c
have already shown that γ-substituted allyl titanium and
aluminum species can provide 3-substituted homoaldol
adducts with high enantioselectivity. Activation of these
substrates would then provide access to enantiopure 1,2,3-
trisubstituted cyclopropanes. Efforts along these lines as well
as additional enantioselective approaches are currently being
explored in our laboratory and will be reported in due course.
Acknowledgment. Support was provided by the National
Science Foundation through CHE-0210918 and the Early
Career Award CHE-9733253. F.C.E. and M.J.S. thank the
University of Notre Dame for support through J. Peter
Fellowships. C.A.R. thanks the University of Notre Dame
for partial support through a Nieuwland Fellowship. R.E.T.
thanks Dow Agroscience for support of this work and Eli
Lilly for a Grantee Award.
As is clear from these substrates the increased steric bulk
and attenuated electronics associated with the cation-stabiliz-
ing carbamate leads to greater trans/cis selectivity in the ring-
closure step and a highly efficient method for the preparation
of cyclopropylaldehydes.
Supporting Information Available: Full experimental
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(10) The enantioselectivity of the ring closures were determined by
Mosher ester analysis of cyclopropylcarbinols obtained by NaBH4 reduc-
tion: Dale, J. S.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(11) Weisenburger, G. A.; Beak, P. J. Am. Chem. Soc. 1996, 118, 12218.
(b) Weisenburger, G. A.; Faibish, N. C.; Pippel, D. J.; Beak, P. J. Am.
Chem. Soc. 1999, 121, 9522. (c) Whisler, M. C.; Vaillancourt, L.; Beak, P.
Org. Lett. 2000, 2, 2655.
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