Toward On-Demand Peptide Synthesis: Development and Application of Enantioselective Syntheses of Unnatural α-Amino Amides

Abstract

Unnatural amino acid derived fragments are present in a multitude of pharmaceuticals and biologically relevant molecules including complex peptides. Current preparative methods focus almost entirely on the enantioselective synthesis of the α-amino acid and rely on traditional condensative amide bond formation for peptide synthesis. Herein we report the development and application of a two-step protocol for the synthesis of unnatural α-alkyl α-amino amides, featuring enantioselective aza-Henry additions that feed directly into Umpolung Amide Synthesis (UmAS). The first and second enantioselective additions of bromonitromethane to N-Boc alkyl imines are reported. In the first, a known cinchona alkaloid-derived phase-transfer catalyst was leveraged to provide β-amino-α-bromonitroalkanes in high enantiopurity. The second method employs a bifunctional bis(amidine) catalyst to obtain the same β-amino-α-bromonitroalkanes with increased scope (access to both enantiomers) and in improved yield. In a separate study, mechanistic insight led to the development of UmAS utilizing N-iodosuccinimide (NIS) as a substoichiometric promoter, providing access to α-amino amides as a single diastereomer using fully enantioselective and catalytic methods. This two-step peptide synthesis protocol was applied to the synthesis of a fluorinated analogue of the natural product feglymycin, a tridecapeptide featuring nine arylglycine residues. Additionally, a protocol for the one-pot oxidative amidation of primary nitroalkanes was developed.