Nonnatural amino acids
Nonnatural amino acids are important building blocks as chiral intermediates in small-molecule drug synthesis, and they also play a crucial role in peptide synthesis. Researchers at Vanderbilt University's Vanderbilt Institute of Chemical Biology in Nashville, Tennessee recently reported on their work that addresses one of the limitations in peptide synthesis, the difficulty of incorporating nonnatural amino acids in peptides and controlling stereoselectivity. The team developed a novel way of making amide linkages (1).Amides typically are made by combining the acyl group from a carboxylic acid derivative with an amine with the elimination of water. Although dehydrative approaches generally are used in amide formation, oxidative and radical-based methods also can be used. In amide-bond formation, carbon and nitrogen bear electrophilic and nucleophilic character, respectively, during the carbon–nitrogen bond-forming step (2).
The researchers' different approach instead used a-halonitroalkanes as the acyl source. The amines and nitroalkanes were activated by an electrophilic iodine source that led directly to amide products. Preliminary observations supported a mechanism in which the polarities of the two reactants were reversed during carbon–nitrogen bond formation relative to traditional peptide synthesis. The nitroalkanes as acyl-anion equivalents provided a conceptually new route to amide and peptide synthesis and one that might allow for efficient peptide synthesis that relies on enantioselective methods (1, 2).
The researchers addressed this problem through the Strecker synthesis, but used an organocatalyst that avoids the problem of using a precious metal catalyst to control a key step in the synthesis. The Strecker synthesis, which involves the reaction of an imine or imine equivalent with hydrogen cyanide, followed by nitrile hydrolysis, is used for the synthesis of racemic a-amino acids. In an asymmetric Strecker synthesis, stoichiometric amounts of a chiral reagent can yield enantiomerically enriched a-amino acids on gram and kilogram scales. The researchers reported that Strecker syntheses using substoichiometric quantities of a chiral reagent could be an alternative, but catalytic methods in this approach have been limited to preparative scales because of the complexity of the catalysts and the need to use hazardous cyanide sources (3, 4).
Instead, the researchers used a relatively simple chiral amido-thiourea catalyst to control the key hydrocyanation step for the syntheses of highly enantiomerically enriched nonnatural amino acids. The catalyst is compatible with aqueous cyanide salts, which are safer and easier to handle than other cyanide sources, thereby potentially making the method adaptable to large-scale synthesis. The researchers used this method to obtain enantiopure amino acids that are not readily prepared by enzymatic methods or by chemical hydrogenation (3, 4).