ORGANIC LETTERS
Direct Asymmetric Organocatalytic Michael Reactions of r,r-Disubstituted Aldehydes with β-Nitrostyrenes for the Synthesis of Quaternary Carbon-Containing Products
2004 Vol. 6, No. 15 2527-2530
Nobuyuki Mase,† Rajeswari Thayumanavan, Fujie Tanaka,* and Carlos F. Barbas III* The Skaggs Institute for Chemical Biology and the Departments of Chemistry and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
[email protected];
[email protected] Received April 30, 2004
ABSTRACT
Direct asymmetric catalytic Michael reactions have been performed using chiral-amine/acid bifunctional catalysts. Performed with 0.3 equiv of (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine and 0.3 equiv of trifluoroacetic acid as the catalyst, the reaction of r,r-dialkylaldehydes with (E)β-nitrostyrene provided the r,r-dialkyl Michael products in up to 96% yield with up to 91% ee. With respect to enantioselectivity, L-proline was a poor catalyst of this class of Michael reactions.
The organocatalytic direct asymmetric Michael reaction is one of the most powerful and efficient methods for carboncarbon bond formation to provide enantiomerically enriched nitroalkanes.1,2 Use of R,R-disubstituted aldehydes should provide direct access to Michael products possessing an allcarbon quaternary stereocenter. Although reactions of unmodified R-monosubstituted aldehydes or ketones have been described,3 there are few reports of the use of R,Rdisubstituted aldehydes.3j,q,4,5 The synthesis of all-carbon
quaternary stereogenic centers is considered a challenging topic in asymmetric synthesis. As detailed in this communication, we investigated the direct Michael reaction of R,R-disubstituted aldehyde donors with (E)-β-nitrostyrenes acceptors to generate all-carbon quaternary stereogenic centers. We have recently described organocatalytic direct asymmetric aldol reactions using R,R-disubstituted aldehydes as aldol donors to synthesize β-hydroxyaldehydes with stereo-
† Present address: Department of Molecular Science, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Hamamatsu 432-8561, Japan. (1) Enamine-based organocatalytic Michael reactions: (a) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas, C. F., III. Tetrahedron Lett. 2001, 42, 4441-4444. (b) Betancort, J. M.; Barbas, C. F., III. Org. Lett. 2001, 3, 3737-3740. (c) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 36113614. (d) Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett. 2003, 5, 2559-2561. (e) Melchiorre, P.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 4151-4157. (f) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260. (g) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III. Synthesis 2004, 1509-1521.
(2) Iminium-based organocatalytic Michael reactions: (a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370-4371. (b) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172-1173. (c) Halland, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 83318338. (d) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 7894-7895. (e) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 1192-1194. (f) Halland, N.; Hansen, T.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 4955-4957. (g) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 661665. (h) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 1272-1277.
10.1021/ol049196o CCC: $27.50 Published on Web 06/22/2004
© 2004 American Chemical Society
Scheme 1.
Direct Cross-Aldol Reaction of R,R-Disubstituted Aldehyde
Table 1. Organocatalyzed Direct Michael Reactions for the Synthesis of Quaternary Carbon
entry
catalysta
additive (equiv)
time (h)
yield (%)
eeb (%)
1c 2 3 4 5 6 7 8 9 10
4 5 6 7 8 9 10 10 11 12
AcOH (1.5)
12 48 48 48 96 96 0.5 24 96 96
84 87 79 72
