ORGANIC
LETTERS
2002
Vol. 4, No. 21
3611-3614
Diamine-Catalyzed Asymmetric Michael
Additions of Aldehydes and Ketones to
Nitrostyrene
Alexandre Alexakis* and Olivier Andrey
Chimie Organique, Sciences II, UniVersity of GeneVa, Quai Ernest Ansermet,
CH-1211, GeneVa, Switzerland
Received July 17, 2002
ABSTRACT
The direct Michael addition of aldehydes and ketones to nitrostyrene, catalyzed by N-i-Pr-2,2′-bipyrrolidine, is described. The desired 1,4-
adducts are obtained in excellent yield with enantioselectivities up to 85% ee and dr up to 95:5 of the syn product.
The Michael addition is one of the most important C-C
bond-forming reactions in organic chemistry.1 Except for the
reaction catalyzed by L-proline developed by Wiechert,
Hajos, and Parrish,2 the nonmetallic asymmetric catalysis was
only reported very recently. L-Proline3 is the most widely
used catalytic organic system in asymmetric Michael addi-
tion, aldolization, Mannich-type reaction, and R-amination
of ketones.
Other amines also seem to be potentially interesting
organic catalysts, but only a few examples using amines in
asymmetric catalysis have been reported.4 Barbas has shown
that reactions involving enamine intermediates can be
catalyzed by pyrrolidine-type amines.5 He has reported
asymmetric Michael addition of ketones to alkylidene
malonates6 and of aldehydes to nitrostyrene7 catalyzed by
diamines containing a pyrrolidine moiety.
Recently, we have reported a new, asymmetric synthesis
of 2,2′-bipyrrolidine8 1, which could be an interesting catalyst
for Michael reactions. Herein we report the addition of
aldehydes and ketones to nitrostyrene9 catalyzed by chiral
diamines. This reaction leads to interesting functionalized
compounds that could be converted into substituted pyrro-
lidines or γ-amino acids.
(1) Perlmutter, P. Conjugate Addition Reaction in Organic Synthesis;
Tetrahedron Organic Chemistry Series 9; Pergamon Press: Oxford, 1992.
(2) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl.
1971, 83, 492. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39,
1615.
(3) For recent examples of proline-catalyzed reactions, see: (a) List, B.;
Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423. (b) Enders, D.; Seki,
A. Synlett 2002, 26. (c) Kumaragurubaran, N.; Juhl, K.; Zhuang, W.;
Bogevig, A.; Jorgensen, K. A. J. Am. Chem. Soc. 2002, 124, 6254. (d)
Cordova, A.; Watanabe, S.-i.; Tanaka, F.; Notz, W.; Barbas, C. F., III. J.
Am. Chem. Soc. 2002, 124, 1866. (e) Cordova, A.; Notz, W.; Zhong, G.;
Betancort, J. M.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1842. (f)
Co´rdova, A.; Notz, W.; Barbas, C. F., III. J. Org. Chem. 2002, 67, 301. (g)
Thayumanavan, R.; Dhevalapally, B.; Sakthivel, K.; Tanaka, F.; Barbas,
C. F., III. Tetrahedron Lett. 2002, 43, 3817. (h) List, B.; Pojarliev, P.; Biller,
W. T.; Martin, H. J. J. Am. Chem. Soc 2002, 124, 827. (i) Sakthivel, K.;
Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc 2001, 123, 5260. (j)
Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975. (k) List, B. J. Am. Chem.
Soc 2000, 122, 9336. (l) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am.
Chem. Soc. 2000, 122, 2395. (m) List, B.; Lerner, R. A.; Barbas, C. F., III.
J. Am. Chem. Soc. 2000, 122, 2395. (n) List, B.; Lerner, R. A.; Barbas, C.
F., III. Org. Lett. 1999, 1, 59.
(4) (a) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett 2001, 1245. (b)
Zhang, F.-Y.; Corey, E. J. Org. Lett. 2000, 2, 1097.
(5) Bui, T.; Barbas, C. F., III. Tetrahedron Lett. 2000, 41, 6951. For our
part, we have confirmed the implication of enamine in the addition of 3,3-
dimethylbutyraldehyde catalyzed by pyrrolidine, which showed the presence
of the corresponding enamine by GC-MS.
(6) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas, C. F.,
III. Tetrahedron Lett. 2001, 42, 4441.
(7) Betancort, J. M.; Barbas, C. F., III. Org. Lett. 2001, 3, 3737.
(8) Alexakis, A.; Tomassini, A.; Chouillet, C.; Roland, S.; Mangeney,
P.; Bernardinelli, G. Angew. Chem., Int. Ed. 2000, 39, 4093.
10.1021/ol026543q CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/12/2002