Asymmetric synthesis of warfarin derivates via homogenous and heterogenous iminium catalyisis

Abstract

This work is dedicated to the synthesis of warfarin and its analogues via acid-assisted asymmetric iminium catalysis, as well as the immobilisation of the catalyst and set-up of the reactions in continuous mode. This novel approach involves an amino acid-derived diamine catalyst, which comprises aprimary and tertiary amine moiety in combination with different atropisomeric flexible phosphoricacids or TFA. After proving the concept of diamine-catalysis, several parameters including the solvent,catalyst components and reaction conditions were screened to identify optimum conditions. Once the ideal diamine and acidic part, as well as the ideal conditions for iminium catalysis of warfarin derivates,were figured out, the pool of starting materials was widened to include various substrates rather than4-hydroxycoumarin. High yields and enantioselectivities could be achieved with various substrates,thereby proving the versatility of the newly developed concept of the iminium catalyst. To extend theversatility of the amino-acid derived catalyst, the scope was widened to the immobilisation of the catalyst via chemisorption and/or physisorption on a silica- or polyoxotungstate-support.