Ugi multicomponent reactions of optically active aldehydes and chiral aminoindanols: diastereoselective synthesis of bisamides relevant to SARS-CoV-2 Mpro inhibitors

Abstract

We have investigated diastereoselective Ugi-multicomponent reactions (Ugi-MCR) relevant to bis-amide scaffolds related to SARS-CoV-2 main protease (Mpro) inhibitors. The studies were mainly focussed on development of diastereoselective tools for generation of Ugi products. Ugi reactions using either chiral aldehyde or chiral amine provided bis-amide derivatives with marginal diastereoselectivity. However, the reaction with a matched combination of (R)-isopropylidene glyceraldehyde and (1S,2R)-aminoindanol derivatives provided good diastereoselectivity, up to a dr of 91 : 9. The stereochemistry of 1,2-aminoindanol plays an important role in diastereoselectivity. The stereochemical outcome of the MCR reaction was rationalized using Felkin transition state models. The Ugi-MCR products generated from these studies did not show any appreciable SARS-CoV-2 Mpro inhibitory activity.