Application of the Lewis acid-Lewis base bifunctional asymmetric catalysts to pharmaceutical syntheses: stereoselective chiral building block syntheses of human immunodeficiency virus (HIV) protease inhibitor and beta3-adenergic receptor agonist.
Chiral building block syntheses of promising drugs were achieved using two types of catalytic stereoselective cyanosilylations of aldehydes promoted by Lewis acid-Lewis base bifunctional catalysts 1 and 2 as the key steps (diastereoselective cyanosilylation of amino aldehyde and enantioselective cyanosilylation). In the first part of this article, syntheses of chiral building blocks (6) of Atazanavir (3: human immunodeficiency virus (HIV) protease inhibitor) using the bifunctional catalyst 2 are discussed. The reaction of Boc-protected phenylalaninal 21 in the presence of 1 mol% catalyst 2 selectively afforded the anti isomer 22 as the major product (diastereomeric ratio=97 : 3), which was successively converted to the corresponding epoxide 6 in six steps. In the second part, we describe a chiral building block synthesis of beta(3)-adrenergic receptor agonists. The enantioselective cyanosilylation of 3-chlorobenzaldehyde (38) with 9 mol% catalyst 1 gave the chiral cyanohydrin 39, which was converted to beta-hydroxyethylamine 40 by reduction. Moreover, the chiral ligand of catalyst 1 could be recovered without column chromatography and reused without decreasing its activity.
Nogami
Hiroyuki
H
Chemicals Development Laboratories, Mitsubishi Rayon Co., Ltd., Konagawa, Japan. nogami_hi@mrc.co.jp
Kanai
Motomu
M
Shibasaki
Masakatsu
M
D000322:Adrenergic Agonists / Q000138:chemical synthesis* / Q000737:chemistry; D058667:Adrenergic beta-3 Receptor Agonists; D002384:Catalysis; D015195:Drug Design; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008024:Ligands; D015394:Molecular Structure; D013237:Stereoisomerism
D000322:Adrenergic Agonists; D058667:Adrenergic beta-3 Receptor Agonists; D017320:HIV Protease Inhibitors; D008024:Ligands