Practical and enantioselective amino acid synthesis via novel catalytic ring opening processes

Abstract

A novel methodology for the kinetic resolution (KR) of tetrachloroisopropoxycarbonyl (TCIC) substituted oxazinones via alcoholysis to afford enantioenriched and orthogonally protected β-amino acids has been developed. Upon catalytic ring opening of the oxazinone, the TCIC-subunit can be converted to an N-phthalimido-protected amino acid ester in one pot, rendering the synthetically useful bis-protected amino acid products; all other available methodologies furnish the benzoyl amide product which lacks synthetic utility. The methodology uses a novel bifunctional cinchona alkaloid-based organocatalyst to promote the reaction with outstanding levels of enantiocontrol, obtaining S factors of up to 101 for the process. The first organocatalytic protocol for the dynamic kinetic resolution (DKR) of TCIC-substituted oxazinones has also been developed; enabling access to chiral, orthogonally protected β-amino acid with modest levels of enantiocontrol.

The first catalytic, enantioselective protocol for the cycloaddition between imines and enolisable anhydrides has been developed. By carefully tuning the electronics of the imine via the placement of electron withdrawing substituents on the nitrogen atom, we have been able to employ bifunctional cinchona alkaloid-based organocatalysts to promote the reaction and furnish chiral lactam products bearing two chiral stereocentres. The methodology furnishes diastereomeric mixtures of the trans and cis products in up to 80% and 79% ee respectively.

A novel methodology using fluoride ion as a chiral nucleophilic catalyst has been developed. The methodology uses quinine-derived quaternary ammonium bromides in conjunction with KF to generate a ‘chiral’ fluoride ion in situ to carry out the enantioselective desymmetrisation of meso-anhydrides via alcoholysis. The methodology afforded the corresponding hemiester products with reasonable levels of enantiocontrol.