The catalytic enantioselective addition of glyoxylate cyanohydrin to imines to afford -keto--amino acid equivalents is reported. Sterically tuned aminobenzothiadiazine catalysts provided high yields and stereoselectivities (up to 100% yield, 99% ee, >99:1 dr) for both aromatic and aliphatic imines and the stereodivergent synthesis of both diastereomers was achieved. The optimal catalytic system was scalable, even with a low catalyst loading. The resulting adducts were converted into various chiral building blocks, including -amino acid analogues, which are important motifs in medicinal chemistry, while maintaining a high enantiomeric excess.

β-Amino-α-ketoacids are important unnatural amino acids that exhibit unique bioactivity and reactivity derived from the highly electrophilic carbonyl group at the α-position. Despite the broad utility of the motif, reliable synthetic methods for β-amino-α-ketoacids have been limited to the oxidative homologation of α-amino acids based on a chiral-pool approach. In this article, we report an alternative practical method for the asymmetric synthesis of β-amino-α-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 α-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 β-amino-α-ketoacids that maintain their optical purity, and these can be used for the decarboxylative formation of amides without purification by column chromatography. Peptide-α-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-α-ketoamides with retention of the stereo-information was achieved by using the cyanohydrin motif at the highly reactive α-carbonyl group, and the synthesis of an α-ketoamide-containing medicine, Telaprevir, was accomplished without any epimerization.

Regio-and stereoselective decarboxylative aldol reactions of a 1,3-acetonedicarboxylic acid monoester were achieved using an aminobenzothiadiazine organocatalyst. The products were obtained with perfect regioselectivity and moderate to good enantioselectivity using various aromatic aldehydes. Subsequently, the thus obtained adducts were efficiently converted various chiral building blocks.Chiral β,δ-dihydroxycarboxylic acid moieties represent an important structural motif in various pharmaceuticals and bioactive natural products (Scheme 1a). [1][2][3][4] For example, atorvastatin, which inhibits