Combinatorial Method Delivers Selective Polyene Epoxidations

The terpenoid alcohol farnesol possesses three double bonds, each of which differs only slightly in its chemical environment. Phillip A. Lichtor and Scott J. Miller of Yale University report a method for selectively epoxidizing just one of those double bonds by using peptide-based catalysts (Nat. Chem., DOI: 10.1038/nchem.1469). The epoxidation strategy features small peptides that contain aspartic acid as the key catalytic component. During the catalytic cycle, aspartic acid’s carboxylic acid side chain is activated with a carbodiimide. This species generates a transient peracid when it reacts with hydrogen peroxide. The peracid, in turn, epoxidizes double bonds. Lichtor and Miller used a combinatorial synthesis approach to vary the amino acids around the critical aspartic acid residue. In doing so, they discovered catalysts that selectively epoxidize the double bond closest to farnesol’s alcohol functional group. The catalysts turned out to be enantioselective as well, producing just one epoxide isomer with greater than 80% enantiomeric excess. The Yale group was also able to use its combinatorial strategy to find a catalyst that selectively epoxidizes the double bond in the middle of farnesol, a reaction that hasn’t been reported until now.