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

蛋白质的二级结构（β-sheet, β-turn, α-helix）在与受体和酶的相互作用中起着重要的作用，控制着许多生物过程。许多研究人员一直致力于开发这些二级结构基序的模拟物，以用于药物发现工作，特别是利用这些“模板”的组合文库来探索生物结构-活性关系。许多注意力都集中在固体相方法的发展，以合成文库，用于生物发现的努力。(1)设计合成了构象约束的十元环二胺。双肉桂酸衍生物的顺序不对称氢化反应提供了对映体纯形式的HIV蛋白酶抑制剂的核心部分。（ii）钯催化的固体负载脱氢丙氨酸与各种芳基碘化物的Mizoroki-Heck反应，随后铑催化的不对称氢化产生了含有非天然氨基酸的肽库。（iii）钯催化的含碘苯胺衍生物的多肽羰基环化，提供了一个含有苯环连接邻位、甲基和对位的环状肽库。

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.