Combinatorial Synthesis of Peptide Mimetics Containing Unnatural Amino Acid Utilizing Homogeneous Catalyzed Reactions

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The secondary structures (β-sheet, β-turn, α-helix) of protein play an important role in their interactions with receptors and enzymes to control a multitude of biological processes. Many researchers have been engaged in the development of mimics of these secondary structure motifs for drug discovery efforts and in particular the utilization of combinatorial libraries of these "templates" to probe biological structure-activity relationship. Much attention has been directed toward solid-phase methods development for the synthesis of libraries for use in biological discovery efforts.(i) Conformationally constrained 10-membered cyclic diamide was designed and synthesized. Sequential asymmetric hydrogenation of bis-cinnamic acid derivatives provided the core part of the HIV protease inhibitor in enantiomerically pure form.(ii) Palladium-catalyzed Mizoroki-Heck reaction of solid-supported dehydroalanine with various aryl iodides, followed by rhodium-catalyzed asymmetric hydrogenation afforded a library of peptides containing unnatural amino acids.(iii) Palladium-catalyzed carbonylation-cyclization of peptides including iodobenzyl amine derivatives furnished a library of cyclic peptides containing a benzene ring connecting at the ortho, metha, and para-positions.