Synthesis of phosphine containing amino acids: utilization of peptide synthesis in ligand design

Combinatorial chemistry has recently burst on the scene as a valuable tool for the discovery of new drug candidates. The ability to synthesize hundreds of compounds for screening is a useful complement to rational drug design. There are many similarities between the design of new therapeutic agents and the development of new asymmetric ligands, the most important of which is the limitation of a rational design strategy. For this reason a program was begun that would allow the use of combinatorial technology in the development of new ligands for transition metal catalyzed asymmetric reactions. Because of the large number of catalytic reactions they are involved in the system was based around phosphine ligands. This paper reports the synthesis of phosphine derivatives of alanine, proline, and the aromatic amino acids tyrosine and hydroxyphenylglycine. Examples of the use of these amino acids in the synthesis of peptides possessing helical and beta-turn secondary structures are presented. Metal complexes of these peptide-based ligands are used in hydrogenation and alkylation reactions.