Enantioselective Syntheses of (-)-(R)-Rolipram, (-)-(R)-Baclofen and Other GABA Analogues via Rhodium-Catalyzed Conjugate Addition of Arylboronic Acids

Abstract

Highly enantioselective syntheses of two important gaminobutyric acid (GABA) analogues, the antispastic drug (-)-(R)-Baclofen and the antidepressant agent (-)-(R)-Rolipram, are reported. Key-steps in both syntheses are the Rh-catalyzed asymmetric 1,4-additions of arylboronic acids to 4-aminobut-2,3-enoic acid derivatives.Because of the crucial importance of g-aminobutyric acid (GABA) in various nervous system functions, GABA analogues are of great interest in medicinal chemistry. 1 For example, the strongly lipophilic b-substituted analogue 4-amino-3-(4-chlorophenyl)butyric acid (1, Baclofen) is until now the only available selective agonist of the GABA B receptor. 2 Of particular interest is the cyclic GABA analogue 4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-one (2, Rolipram), known for its potent inhibitor activity of the cardiac cyclic AMP phosphodiesterase, found in brain tissue. 3 It has been disclosed that for both compounds the (R)-enantiomers are responsible for the pharmacological activities. 2,3 Therefore, short and efficient syntheses of the enantiomerically pure GABA analogues (R)-Baclofen and (R)-Rolipram are of great interest.Several stereoselective syntheses of (R)-Baclofen 4 and (R)-Rolipram 3,5 have already been reported. Some of these syntheses require more than ten steps and proceed generally with a relatively low overall yield. In this paper, we describe shorter and more efficient syntheses of these compounds from a common precursor based on asymmetric catalysis (Scheme 1). 6 Key steps of our syntheses are Rh(I)-catalyzed asymmetric conjugate additions of arylboronic acids to the substrates 3a-c (Scheme 2). Scheme 1 Scheme 2 Downloaded by: York University libraries. Copyrighted material.