A Review of Strategies for the Development of Alkyl Prolines in Drug Discovery

Among all natural α-amino acids, proline represents a singularity. Due to the presence of the pyrrolidine ring, proline includes a secondary amino group, that does not contain a hydrogen atom when involved in an amide bond. A variety of synthetic analogues have been developed in the last years, based on ring substitutions, incorporation of heteroatoms into the ring, expansion or contraction of the pyrrolidine ring. The present review focuses on chemical synthesis of mono substituted derivatives of proline containing leucine, isoleucine, valine side chains, and other alkyls, including the contribution of literature from 2004 to 2015 or earlier where necessary.