Synthesis of sulfur-containing chiral ligands for transition metal-catalyzed asymmetric nucleophilic addition to carbonyl compounds

Abstract

A series of thiolated β-amino-alcohols and thiophene-based β-amino-alcohols had been synthesized by condensation between an aldehyde containing sulfur atom and an appropriate chiral amino-alcohol followed by reduction with sodium borohydride. The reactions provided a series of chiral thiolated β-amino-alcohol ligands in 73-89% and chiral thiophene-based β-amino-alcohols in 49-95% yield. These synthesized compounds were evaluated as ligands for asymmetric addition of nitromethane to carbon atom of aldehydes (nitro-aldol or Henry reaction) in the presence of 13.5 mol% of Cu(II) acetate and 15 mol% of ligand to give the β-nitroalcohol product in moderate to excellent yields and in up to 88% ee when chiral thiophene-based β-amino-alcohol possessing phenyl substituent at the β position of amino-alcohol was used as a ligand. In addition, the catalyst loading was successfully reduced to 5 mol% while the enantioselective induction is still very effective. The absolute configuration of all products from the reactions where the (R)-ligand was employed, was confirmed to be S. A transition state model to explain the enantioselectivity of the reaction is proposed. Moreover, this group of chiral catalysts showed their catalytic ability not only in an asymmetric nitro-aldol reaction but also in an asymmetric borohydride reduction, asymmetric borane reduction, asymmetric benzoylation as well as asymmetric Michael addition of indole to benzylidene malonate.