Rapid and efficient syntheses of tryptophans using a continuous-flow quaternization–substitution reaction of gramines with a chiral nucleophilic glycine equivalent

Abstract

A continuous-flow quaternization reaction of gramines with MeI (<1 min) followed by a substitution reaction with a chiral nucleophilic glycine-derived Ni-complex (S)-2 (<1 min) has successfully been developed to afford the corresponding alkylated Ni-complexes 3 in good yields with excellent diastereoselectivity, based on the results of a one-pot quaternization–substitution reaction of gramines with (S)-2 in a batch process. The continuous-flow process allowed the safe and efficient scale-up synthesis of 3j (84% yield, 99% de, 540 g h⁻¹) to give 7-azatryptophan derivative (S)-4j readily by an acid-catalyzed hydrolysis reaction followed by protection with an Fmoc group. The present method for the rapid and efficient syntheses of enantiopure unnatural tryptophan derivatives from various gramines and (S)-2 will be useful to further promote peptide and protein drug discovery and development research.