Chemoenzymatic Path Yields Chiral Amides

By combining an enzymatic reaction step with follow-up chemical synthesis steps, a team led by Dick B. Janssen and Ben L. Feringa of the University of Groningen, in the Netherlands, has developed a simple and efficient method for transforming inexpensive racemic mixtures of chiral compounds into valuable enantiopure products (Angew. Chem. Int. Ed., DOI: 10.1002/anie.201105164). This enantioconvergent synthesis approach, so named because it converts a pair of enantiomers to the single-enantiomer product via different pathways, provides double the yield possible when compared with standard methods that only go after the molecule with the desired stereochemistry in a racemic mixture. The researchers chose to target amides substituted in the α-position by an N, O, or S substituent. α-Substituted amides are important chiral building blocks in medicinal chemistry for the synthesis of antibiotics and peptide-based enzyme inhibitors, among other compounds. The researchers first used a haloalkane dehalogenase enzyme to convert racemic brominated amides into a mixture of bromo- and hydroxyl-substituted amides. In subsequent chemical steps they added the desired N, O, or S nucleophile, such as benzylamine, phenol, or ethanethiol, to convert the intermediates into the enantiopure α-substituted amide.