Synthesis of fluspidine via asymmetric NaBH4 reduction of silicon enolates of β-keto esters

Asymmetric NaBH4 reduction catalyzed by the Co(II) complex of a chiral diamidine-type sp(2)N ligand, Naph-diPIM-dioxo-iPr, was successfully applied to 3-silyloxycinnamate substrates without over-reduction, giving quantitatively 3-silyloxy-3-arylpropionates with an enantiomer ratio of up to 99:1. The high utility was confirmed on a 30-g scale using 0.1 mol% catalyst. Both Z and E substrates could be converted to a single enantiomeric product by changing the ligand chirality. The relationship between the ZIE stereochemistry and the absolute configuration of the 1,4-reduction product provided important information about the mechanism underlying enantioface selection. Combination of the asymmetric catalysis with two other key steps, Suzuki coupling with an N-protected tetrahydropyridine boronic acid derivative and intramolecular bromo etherification, realized an efficient synthetic route to both enan-tiomers of fluspidine. The new strategy permits the introduction of substituents on the two aryl groups and piperidine ring, allowing for structural variations toward the development of higher performance sigma 1 receptor antagonists. (C) 2018 The Authors. Published by Elsevier Ltd.