Synthesis of ω-Oxo Amino Acids and trans-5-Substituted Proline Derivatives using Cross-methathesis of Unsaturated Amino Acids

A range of 7-oxo, 8-oxo and 9-oxo amino acids, analogues of 8-oxo-2-aminodecanoic acid, one of the key components of the cyclic tetrapeptide apicidin, has been prepared by a three-step process involving copper-catalysed allylation of serine-, aspartic acid- and glutamic acid-derived organozinc reagents, followed by cross-metathesis of the resulting terminal alkenes with unsaturated ketones, and hydrogenation. The intermediate 7-oxo-5- enones underwent a highly diastereoselective (dr ≥96:4) acid-catalyzed aza-Michael reaction to give trans-2,5-disubstituted pyrrolidines, 5-substituted proline derivatives. The azaMichael reaction was first observed when the starting enones were allowed to stand in solution in deuterochloroform, but can be efficiently promoted by catalytic amounts of dry HCl