Sasaki Yoshikazu, Niida Ayumu, Tsuji Takashi, Shigenaga Akira, Fujii Nobutaka, Otaka Akira
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
J Org Chem. 2006 Jun 23;71(13):4969-79. doi: 10.1021/jo0606002.
In peptides and proteins, the peptide bond between an amino acid and proline exists as an equilibrium mixture of the cis-imide and trans-imide due to the low energy barrier in their interconversion. This feature greatly influences the structure and function of the proline-containing peptides and proteins. Therefore, restricting the amide bond with an (E)- or (Z)-alkene should provide a promising method for elucidating the structure-activity relationships of the peptide and the proteins. In this report, the regio- and stereoselective synthesis of cis-alanylproline (Ala-Pro) type (Z)-alkene dipeptide mimetic is described. The key steps of this synthesis are to introduce a C3 unit onto a gamma-phosphoryloxy-alpha,beta-unsaturated-delta-lactam with an organocopper-mediated anti-S(N)2' reaction and subsequently construct a five-membered proline-like cyclic structure with an intramolecular Suzuki coupling reaction. Hydrolysis of the amide bond in the resulting bicyclic lactam yields the desired cis-Ala-Pro type (Z)-alkene dipeptide isostere. The presented synthetic methodology should be applicable to the general syntheses of other cis-aminoacylproline type (Z)-alkene dipeptide mimetics.
在肽和蛋白质中，由于氨基酸与脯氨酸之间的肽键在顺式酰亚胺和反式酰亚胺之间相互转化的能量势垒较低，所以以顺式酰亚胺和反式酰亚胺的平衡混合物形式存在。这一特性极大地影响了含脯氨酸的肽和蛋白质的结构与功能。因此，用（E）-或（Z）-烯烃限制酰胺键应为阐明肽和蛋白质的构效关系提供一种有前景的方法。在本报告中，描述了顺式丙氨酰脯氨酸（Ala-Pro）型（Z）-烯烃二肽模拟物的区域和立体选择性合成。该合成的关键步骤是通过有机铜介导的反S(N)2'反应将一个C3单元引入到γ-磷酰氧基-α,β-不饱和-δ-内酰胺上，随后通过分子内铃木偶联反应构建一个五元脯氨酸样环状结构。所得双环内酰胺中酰胺键的水解产生所需的顺式-Ala-Pro型（Z）-烯烃二肽类似物。所提出的合成方法应适用于其他顺式氨酰基脯氨酸型（Z）-烯烃二肽模拟物的一般合成。
