ORGANIC
LETTERS
2004
Vol. 6, No. 9
1357-1360
Highly Stereoselective Intermolecular
Oxy-Michael Addition Reaction to
r,â-Unsaturated Malonate Esters
David J. Buchanan, Darren J. Dixon,* and Felix A. Hernandez-Juan
Department of Chemistry, UniVersity of Cambridge, Lensfield Road,
Cambridge CB2 1EW, U.K.
Received January 30, 2004
ABSTRACT
The highly diastereoselective oxy-Michael addition of the “naked” anion of (6S)-methyl δ lactol to alkylidiene-, arylidene-, and heteroarylidene-
malonate derivatives leading to the direct formation of THP*-protected â-hydroxy ester derivatives is described. Subsequent acid-mediated
deprotection affords the enantioenriched aldol products in quantitative yields.
The stereoselective addition of oxygen-centered nucleophiles
to Michael acceptors has received little attention over the
years despite the potential utility of the protected hydroxyl
products in synthesis.1 Our group2 and others3 have been
involved in the development of such chiral water equivalents
for addition to highly reactive nitro olefin acceptors4 and to
this end the highly diastereoselective oxy-Michael addition
of the “naked” anions of enantiopure δ lactols has been
described. Although useful for the asymmetric synthesis of
1,2-amino alcohols, we believed an extension of this
chemistry to incorporate other Michael acceptors, while
maintaining reaction efficiency and diastereoselectivity,
would expand significantly the utility and scope of the
reaction.
Herein, we wish to describe work leading to the first highly
diastereoselective oxy-Michael reaction of a chiral water
equivalent to alkylidene-, arylidene-, and hetereoarylidiene-
malonate Michael acceptors.5,6 Our initial studies focused
on the attempted addition of the “naked” alkoxide of
6-methyl δ lactol 1 to R,â-unsaturated esters and lactones.
However, all attempts to make an oxygen-carbon bond
failed, and either starting material was returned unreacted
or the alkoxide facilitated the dimerization of the Michael
acceptor.7
(1) Reviews: (a) Misra, M.; Luthra, R.; Singh, K. L.; Sushil, K. In
ComprehensiVe Natural Products Chemistry; Barton, D. H. R., Nakunisha,
K., Meth-Chon, O., Eds.; Pergamon: Oxford, UK, 1999; Vol. 4. p 25. (b)
Staunton, J.; Wilkinson, B. Top. Curr. Chem. 1998, 195, 49.
It was clear that further activation of the Michael acceptor
was required for successful oxygen-carbon bond formation.
(2) (a) Adderley, N. J.; Buchanan, D. J.; Dixon, D. J.; Laine´, D. I. Angew.
Chem., Int. Ed. 2003, 35, 4241-4244. (b) Buchanan, D. J.; Dixon, D. J.;
Scott, M. S.; Laine´, D. I. Tetrahedron: Asymmetry 2004, 15, 195-197.
(3) (a) Enders, D.; Haertwig, A.; Raabe, G.; Runsink, J. Angew. Chem.,
Int. Ed. 1996, 35, 2388-2390. (b) Enders, D.; Haertwig, A.; Raabe, G.;
Runsink, J. Eur. J. Org. Chem. 1998, 1771-1792. (c) Enders, D.; Haertwig,
A.; Runsink, J. Eur. J. Org. Chem. 1998, 1793-1801.
(4) For diastereoselective/nonenantioselective additions to nitro olefin
acceptors, see: (a) Dumez, E.; Faure, R.; Dulce`re, J.-P. Eur. J. Org. Chem.
2001, 2577-2588. (b) Yakura, T.; Tsuda, T.; Matsumura, Y.; Yamada, S.;
Ikeda, M. Synlett 1996, 985-986.
(5) For nonenantioselective additions of oxygen-centered nucleophiles
to benzylidene(or alkylidene)malonates and related Michael acceptors,
see: (a) Cavicchioli, M.; Marat, X.; Monteiro, N.; Hartmann, B.; Balme,
G. Tetrahedron Lett. 2002, 43, 2609-2611. (b) Marat, X.; Monteiro, N.;
Balme, G. Synlett 1997, 845-847. (c) Monteiro, N.; Balme, G. J. Org.
Chem. 2000, 65, 3223-3226.
(6) For asymmetric diastereoselective substrate-controlled additions of
achiral oxygen-centered nucleophiles, see, for example: Paquette, L. A.;
Tae, J.; Arrington, M. P.; Sadoun, A. H. J. Am. Chem. Soc. 2000, 122,
2742-2748.
10.1021/ol049820x CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/06/2004