ORGANIC
LETTERS
2011
Vol. 13, No. 3
374-377
Asymmetric Organocatalytic
Double-Conjugate Addition of
Malononitrile to Dienones: Efficient
Synthesis of Optically Active
Cyclohexanones
Xue-ming Li, Bo Wang, Jun-min Zhang, and Ming Yan*
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical
Sciences, Sun Yat-sen UniVersity, Guangzhou 510006, China
Received October 22, 2010
ABSTRACT
9-Amino-9-deoxyepiquinine efficiently catalyzed the double-conjugate addition of malononitrile to dienones. A number of 1,1,2,6-tetrasubstituted
cyclohexanones were prepared in good yields, diastereoselectivities, and excellent enantioselectivities.
In the past decade, asymmetric organocatalysis has been
developed to be a powerful tool for the synthesis of chiral
compounds.1 Organocatalytic conjugate addition of nucleo-
philic reagents to Michael acceptors is one of the most useful
strategies.2 A wide variety of nucleophilic reagents have been
used successfully. While those nucleophilic reagents with
potential Michael acceptors were adopted, cascade conjugate
additions occurred and provided chiral cyclic compounds
(Scheme 1, eq 1).3,4 However, to our knowledge, the
application of nucleophilic reagents with two active meth-
ylene protons in double asymmetric conjugate addition to
dienones has not been developed. Such a transformation is
valuable for the preparation of chiral hexanones (Scheme 1,
eq 2). In previous studies, intramolecular double-conjugate
additions were applied for the synthesis of polycyclic natural
products.5 Base-promoted double-conjugate additions of
malononitrile, malonates, and isocyanoacetates to dienones,6
divinyl esters,7 and divinyl sulfone8 were reported to give
cyclic products. However asymmetric versions of the trans-
(1) For selected reviews of the organocatalysis, see: (a) Bertelsen, S.;
Jørgensen, K. A. Chem. Soc. ReV. 2009, 36, 2178. (b) Dondoni, A.; Massi,
A. Angew. Chem., Int. Ed. 2008, 47, 4638. (c) Guillena, G.; Na´jera, C.;
Ramo´n, D. J. Tetrahedron: Asymmetry 2007, 18, 2249. (d) Dalko, P. I.
EnantioselectiVe Organocatalysis; Wiley-VCH: Weinheim, 2007. (e) Pel-
lissier, H. Tetrahedron 2007, 63, 9267. (f) Gaunt, M. J.; Johansson, C. C. C.;
McNally, A.; Vo, N. T. Drug DiscoV. Today 2007, 12, 8.
(4) (a) Ma, A. Q.; Ma, D. W. Org. Lett. 2010, 12, 3634. (b) Li, H.; Zu,
L. S.; Xie, H. X.; Wang, J.; Jiang, W.; Wang, W. Org. Lett. 2007, 9, 1833.
(5) Ihara, M.; Fukumoto, K. Angew. Chem., Int. Ed. 1993, 32, 1010.
(6) (a) Rowland, A. T.; Filla, S. A.; Coutlangus, M. L.; Winemiller,
M. D.; Chamberlin, M. J.; Czulada, G.; Johnson, S. D.; Sabat, M. J. Org.
Chem. 1998, 63, 4359. (b) Rowland, A. T.; Gill, B. C. J. Org. Chem. 1988,
53, 434. (c) Otto, H. H.; Triepel, J.; Schmelz, H.; Meyer-Schaar, J. Arch.
Pharm. 1976, 309, 786. (d) Tan, J.; Xu, X. X.; Zhang, L. J.; Li, Y. F.; Liu,
Q. Angew. Chem., Int. Ed. 2009, 48, 2868. (e) Padmavathi, V.; Reddy,
T. V.; Ramana, Reddy; K, V.; Reddy, K. A.; Reddy, D. B. Indian J. Chem.
B 2001, 40B, 667. (f) Reddy, D. B.; Padmavathi, V.; Reddy, M. M. Indian
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Andrews, B. I.; Kociok-Ko¨hn, G.; Carbery, D. R. J. Org. Chem. 2010, 75,
7491.
(2) For the reviews of organocatalytic asymmetric conjugate addition,
see: (a) Almasi, D.; Alonso, D. A.; Najera, C. Tetrahedron: Asymmetry
2007, 18, 299. (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 11, 1701.
(3) For the reviews of organocatalytic cascade reactions, see: (a) Grondal,
C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167. (b) Alba, A. N.;
Companyo, X.; Viciano, M.; Rios, R. Curr. Org. Chem. 2009, 13, 1432.
(c) Enders, D.; Grondal, C.; Huettl, M. R. M. Angew. Chem., Int. Ed. 2007,
46, 1570
.
10.1021/ol102570b 2011 American Chemical Society
Published on Web 12/28/2010