Highly Stereoselective, Organocatalytic Mannich-type Addition of Glyoxylate Cyanohydrin: A Versatile Building Block for the Asymmetric Synthesis of β-Amino-α-ketoacids

beta-Amino-alpha-ketoacids are important unnatural amino acids that exhibit unique bioactivity and reactivity derived from the highly electrophilic carbonyl group at the alpha-position. Despite the broad utility of the motif, reliable synthetic methods for beta-amino-alpha-ketoacids have been limited to the oxidative homologation of alpha-amino acids based on a chiral-pool approach. In this article, we report an alternative practical method for the asymmetric synthesis of beta-amino-alpha-ketoacid equivalents based on a highly stereoselective organocatalyzed Mannich-type addition using glyoxylate cyanohydrin. The optimal aminothiourea catalyst provides a wide variety of adducts from N-Boc imines in excellent yield and stereoselectivity (up to 100% yield, 99% ee, 94:1 dr), and the reaction can be applied to the direct use of alpha-amido sulfones as imine precursors, which significantly expands the substrate scope. The experimental structure-activity relationships and computational studies indicated that steric repulsion with the substituent on the amine moiety and the attractive interaction with the bis(trifluoromethyl)phenyl group might contribute to the high diastereoselectivity and that the thiourea scaffold provides a narrower catalytic pocket compared to benzothiadiazine due to the difference in the length of the intramolecular hydrogen bonding, which results in excellent enantioselectivity. The asymmetric adducts can be readily converted into beta-amino-alpha-ketoacids that maintain their optical purity, and these can be used for the decarboxylative formation of amides without purification by column chromatography. Peptide-alpha-ketoacids were also prepared via intramolecular acyl migration as a key step and applied to decarboxylative peptide coupling with dipeptides that bear various unprotected functional groups and to [2 + 2 + 2] sequential peptide coupling. Furthermore, the efficient synthesis of peptide-alpha-ketoamides with retention of the stereo-information was achieved by using the cyanohydrin motif at the highly reactive alpha-carbonyl group, and the synthesis of an alpha-ketoamide-containing medicine, Telaprevir, was accomplished without any epimerization.

Automated summary

This article presents an alternative practical method for the asymmetric synthesis of beta-amino-alpha-ketoacid equivalents, utilizing a highly stereoselective organocatalyzed Mannich-type addition using glyoxylate cyanohydrin. The optimal aminothiourea catalyst provides a variety of adducts with excellent yield and stereoselectivity, and the reaction can be applied to a wider range of imine precursors. Experimental and computational studies reveal the factors contributing to the high diastereoselectivity and enantioselectivity of the reaction.