Enantioselective synthesis of cyclopropanes by aldehyde homologation

Article abstract of DOI:10.1002/anie.200461106

An efficient method for the enantioselective preparation of structurally diverse cyclopropanes has been developed. Sequential homoaldol coupling and activation steps result in a three-carbon homologation of an aldehyde to give a nonracemic, stereochemical

Full text of DOI:10.1002/anie.200461106

Angewandte
Chemie
Cyclopropanes
representative example. Aliphatic aldehydes, including steri-
cally hindered substrates, resulted in high yields of (Z)-
homoaldol adducts 3–5 with high anti selectivity as expected
(Table 1). In addition aromatic aldehydes, including benzal-
dehyde and tolualdehyde, performed well in the coupling
reaction to provide 6 and 7, respectively (Table 1). In each
Enantioselective Synthesis of Cyclopropanes by
Aldehyde Homologation**
Christina A. Risatti and Richard E. Taylor*
1
case, the diastereoselectivity was > 95:5 by crude H NMR
analysis.
The prevalence of cyclopropane-containing compounds with
biological activity, whether isolated from natural sources or
rationally designed pharmaceutical agents, has inspired
chemists to find novel and diverse approaches to their
synthesis.[1] We recently reported an efficient two-step
homoaldol/activation sequence that resulted in the isolation
of racemic 1,2-disubstituted cyclopropyl aldehydes.[2] Herein
we demonstrate the successful preparation of enantiomeri-
cally enriched and diastereomerically pure 1,2,3-trisubstituted
cyclopropyl aldehydes by asymmetric metalation chemistry.
In essence, this two-step procedure provides a three-carbon
homologation of an aldehyde to give a nonracemic, stereo-
chemically rich cyclopropyl aldehyde, [Eq. (1)].
Table 1: Trisubstituted cyclopropanes from O-enecarbamates.[a]
Homoaldol adduct
Yield [%]
Cyclopropane
Yield [%], e.r.
92
91, 93:7
85
84
87
89
82, 92:8
96, 93:7
92, 83:17
73, 90:10[b]
[a] Reaction conditions:Tf 2O, 2,6-lutidine, toluene, À788C to À508C.
[b] Two minor diastereomers were also observed in this case (5:1:1
ratio).
Hoppe et al. have elegantly demonstrated that homoaldol
adducts are readily available from (E)-butenyl N,N-diisopro-
pylcarbamates 1 through deprotonation with nBuLi/(À)-
sparteine complex and transmetalation with Ti(OiPr)4.[3]
Condensation with an aldehyde was shown to provide O-
enecarbamates 2 with high diastereoselectivity and good
enantioselectivity [Eq. (2)].
Exposure of homoaldol adducts 3–7 to triflic anhydride
and 2,6-lutidine provided good to excellent yields of 1,2,3-
trisubstituted cyclopropyl aldehydes 8a–12a (Table 1). In
contrast to our previous study[2] these cyclization substrates
were more sensitive to the reaction conditions. When our
standard activation conditions were employed, in CH2Cl2,
multiple products were observed. However, when the reac-
tion solvent was conducted in toluene, the inherent rate and
alternative reaction pathways could be reduced such that the
reaction was driven toward the formation of the desired
cyclopropyl aldehyde products 8a–12a. The enantiomeric
purity of the cyclopropane derivatives was determined by
reduction of the aldehyde with lithium aluminum hydride and
analysis of the Mosher esters.[4] The observed enantiomer
ratios corresponded well with expected enantioselectivity of
the starting homoaldol adducts,[3] suggesting the cyclization
step proceeds in a stereospecific manner.
The aliphatic systems provided high yields and diaster-
eoselectivity for the cyclopropyl aldehyde products 8a–10a.
In each case, the ring closure takes place with inversion of
configuration at the alcohol center.[5] In contrast, reduced
diastereoselectivity was observed upon activation of homo-
aldol adduct 7. The inductively donating methyl group
appears to promote equilibration of the oxonium ion
intermediate 13 through the homoallylic cation 14 [Eq. (3)].
Under these conditions no products resulting from elimina-
tion were observed.
Carbamate 1 is readily prepared through condensation of
N,N-diisopropyl carbamyl chloride with crotyl alcohol in
refluxing pyridine. A series of aldehydes were applied to the
described homoaldol conditions using the crotyl substrate as a
[*] C. A. Risatti, Prof. R. E. Taylor
Department of Chemistry and Biochemistry
University of Notre Dame
251 Nieuwland Science Hall, Notre Dame, IN 46556-5670 (USA)
Fax:( +1)574-631-6652
E-mail:taylor.61@nd.edu
[**] Support of this work by the National Science Foundation (CHE-02-
10918) is gratefully acknowledged. C.A.R. thanks Eli Lilly for support
through an ACS Division of Organic Chemistry Graduate Fellow-
ship.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 6671 –6672
DOI: 10.1002/anie.200461106
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6671

Communications
8b–12b in good to excellent yield. Again, the enantioselec-
tivity of the cyclopropane products corresponded well with
the expected enantiomer ratios from the homoaldol coupling,
suggesting the cyclization step proceeds with complete
stereospecificity.
In this system, cyclization of the aliphatic substrates 18–20
proceeded cleanly in CH2Cl2. However, care was taken with
the activated aryl systems, and toluene was used as the
reaction solvent. It is notable that, in contrast to O-
enecarbamate substrate 7, activation of N-enecarbamate 22
provided 12b as a single diastereomer. The iminium ion
intermediate, present in solution prior to quenching, is
apparently more stable than the corresponding oxonium ion
intermediate, and therefore, an equilibrium with its homo-
allylic cation is not relevant (Figure 1). Although the method
Ideally one would like access to both enantiomers of the
cyclopropyl aldehyde products. In fact, Beak et al. have
demonstrated that N-(tert-butoxycarbonyl)-N-(p-methoxy-
phenyl)cinnamyl amine 15 and N-(tert-butoxycarbonyl)-N-
(p-methoxyphenyl)-3-cyclohexylallylamine 16 undergo asym-
metric deprotonation by an nBuLi/(À)-sparteine complex
[Eq. (4)].[6] However, in this case, transmetalation with
Ti(OiPr)3Cl followed by quenching with an aldehyde fur-
nished the enantiomeric, complementary homoaldol adducts.
Figure 1.
has been applied to 1,2,3-trisubstituted cyclopropyl aldehydes
containing a methyl substituent, alternative allylamine deriv-
atives are expected to provide diversely substituted cyclo-
propanes and broaden the scope of this two-step three-carbon
homologation procedure.
In conclusion we have demonstrated the stereospecific
cyclization of enantiomerically enriched homoaldol adducts.
This chemistry is a remarkably efficient method for the
homologation of readily available aldehydes to give non-
racemic, stereochemically rich 1,2,3-trisubstituted cyclo-
propyl aldehydes.[7] Application of this method to the
preparation of biologically relevant cyclopropanes is cur-
rently underway in our laboratories and will be reported in
due course.
The aldehydes used previously to generate the O-enecar-
bamates were subjected to the Beak homoaldol protocol. To
complement the earlier work, the substrates were preformed
with crotylamine 17, and the yields and selectivities corre-
sponded nicely with those observed by Beak for the
cyclohexyl and cinnamyl systems. The (Z)-N-enecarbamates
18–22 were isolated with predominantly anti stereochemistry
and the diastereoselectivity was > 95:5 by crude H NMR
analysis (Table 2). Homoaldol adducts 18–22 were activated
with triflic anhydride and 2,6-lutidine to provide aldehydes
1
Table 2: Trisubstituted cyclopropanes from N-enecarbamates.[a]
Homoaldol adduct
Yield [%]
Cyclopropane
Yield [%], e.r.
Received: June 28, 2004
69
91, 90:10
Keywords: cations · cyclization · cyclopropanes · small ring
systems · synthetic methods
.
66
73
70, 94:6
86, 91:9
[1] H. Lebel, J.-F. Marcoux, C. Molinaro, A. B. Charette, Chem. Rev.
2003, 103, 977.
[2] R. E. Taylor, C. A. Risatti, F. C. Engelhardt, M. J. Schmitt, Org.
Lett. 2003, 5, 1377.
[3] For a lead reference, see: K. R. K. Prasad, D. Hoppe, Synlett 2000,
1067.
[4] J. S. Dale, H. S. Mosher, J. Am. Chem. Soc. 1973, 95, 512.
[5] R. E. Taylor, F. C. Engelhardt, M. J. Schmitt, H. Yuan, J. Am.
Chem. Soc. 2001, 123, 2964.
[6] a) M. C. Whisler, L. Vaillancourt, P. Beak, Org. Lett. 2000, 2, 2655;
b) M. C. Whisler, P. Beak, J. Org. Chem. 2003, 68, 1207.
67
68
96, 94:6
70, 92:8
[7] During review of this manuscript we learnt of
a similar
investigation. See the preceding Communication in this issue:
R. Kalkofen, S. Brandau, B. Wibbeling, D. Hoppe, Angew. Chem.
2004, 116, 6836; Angew. Chem. Int. Ed. 2004, 43, 6667.
[a] Reaction conditions:Tf 2O, 2,6-lutidine, toluene, À788C to À508C.
R1 =para-methoxyphenyl, R2 =tert-butoxycarbonyl.
6672
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Angew. Chem. Int. Ed. 2004, 43, 6671 –6672