Synthesis 2016; 48(10): 1474-1482
DOI: 10.1055/s-0035-1560420
paper
© Georg Thieme Verlag Stuttgart · New York

Squaramide-Catalyzed Michael Addition as a Key Step for the Direct Synthesis of GABAergic Drugs

Eva Veverková
Comenius University in Bratislava, Faculty of Natural Sciences, Department of Organic Chemistry, Mlynska dolina, Ilkovičova 6, 84215, Bratislava, Slovakia   Email: radovan.sebesta@fns.uniba.sk
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Stanislav Bilka
Comenius University in Bratislava, Faculty of Natural Sciences, Department of Organic Chemistry, Mlynska dolina, Ilkovičova 6, 84215, Bratislava, Slovakia   Email: radovan.sebesta@fns.uniba.sk
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Rastislav Baran
Comenius University in Bratislava, Faculty of Natural Sciences, Department of Organic Chemistry, Mlynska dolina, Ilkovičova 6, 84215, Bratislava, Slovakia   Email: radovan.sebesta@fns.uniba.sk
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Radovan Šebesta*
Comenius University in Bratislava, Faculty of Natural Sciences, Department of Organic Chemistry, Mlynska dolina, Ilkovičova 6, 84215, Bratislava, Slovakia   Email: radovan.sebesta@fns.uniba.sk
› Author Affiliations
Further Information

Publication History

Received: 26 November 2015

Accepted after revision: 05 February 2016

Publication Date:
11 March 2016 (online)

Abstract

Enantioselective organocatalytic Michael additions serve as the key step in syntheses of chiral drugs based on γ-aminobutyric acid. The applicability of various squaramide catalysts for these Michael-type reactions has been assessed. Very good results in terms both activity and enantioselectivity were obtained in the Michael addition of dimethyl malonate to β-nitrostyrenes. On the other hand, a complementary approach, the addition of nitromethane to cinnamaldehydes, worked well with a squaramide catalyst possessing an adjacent pyrrolidine moiety. The corresponding Michael adducts obtained in the best conditions are suitable chiral intermediates for the synthesis of therapeutically useful GABA derivatives. Polymer-immobilized squaramides afforded the Michael adduct in high enantiomeric purity, but yield deterioration was observed between runs. Two different formal total syntheses of baclofen have also been accomplished.

Supporting Information

 
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