蛋白酶体抑制剂TMC-95A的大环肽类似物的合成。

Synthesis of macrocyclic peptide analogues of proteasome inhibitor TMC-95A.

作者信息

Berthelot Alexandra, Piguel Sandrine, Le Dour Gwennaël, Vidal Joëlle

机构信息

Institut de chimie de Rennes, Synthèse et électrosynthèse organiques, UMR 6510, Université de Rennes I, Campus de Beaulieu, F 35042 Rennes Cedex, France

出版信息

J Org Chem. 2003 Dec 12;68(25):9835-8. doi: 10.1021/jo035256c.

DOI:10.1021/jo035256c

PMID:14656119

Abstract

The synthesis of three constrained macrocyclic peptide analogues 1 of TMC-95A as potential proteasome inhibitors is described. The key step involves a Ni(0)-mediated macrocyclization of tripeptides 2 bearing halogenated aromatic side chains for the formation of the biaryl junction. In addition, an enantioselective preparation of l-7-bromotryptophan methyl ester 3 using a Corey-O'Donnell alkylation of the glycine benzophenone imine was achieved in good overall yield with very high ee (>85%) on a multigram scale.

摘要

描述了三种作为潜在蛋白酶体抑制剂的TMC - 95A的受限大环肽类似物1的合成。关键步骤涉及带有卤代芳族侧链的三肽2的Ni(0)介导的大环化反应，以形成联芳基连接。此外，通过甘氨酸二苯甲酮亚胺的Corey - O'Donnell烷基化反应，以高收率和非常高的对映体过量（> 85%）在多克规模上实现了l - 7 - 溴色氨酸甲酯3的对映选择性制备。