Department of Organic Chemistry, University of Geneva, Geneva, Switzerland.
Chem Asian J. 2020 May 15;15(10):1562-1566. doi: 10.1002/asia.202000309. Epub 2020 Apr 20.
We report design, synthesis and evaluation of a series of naphthalenediimides (NDIs) that are bridged with short peptides. Reminiscent of peptide stapling technologies, the macrocycles are conveniently accessible by a chromogenic nucleophilic aromatic substitution of two bromides in the NDI core with two thiols from cysteine sidechains. The dimension of core-bridged NDIs matches that of one turn of an α helix. NDI-stapled peptides exist as two, often separable atropisomers. Introduction of tertiary amine bases in amino-acid sidechains above the π-acidic NDI surface affords operational anion-π catalysts. According to an enolate chemistry benchmark reaction, anion-π catalysis next to peptides occurs with record chemoselectivity but weak enantioselectivity. Catalytic activity drops with increasing distance of the amine base to the NDI surface, looser homocysteine bridges, mismatched, shortened and elongated α-helix turns, and acyclic peptide controls. Elongation of isolated turns into short α helices significantly increases activity. This increase is consistent with remote control of anion-π catalysis from the α-helix macrodipole.
我们报告了一系列萘二酰亚胺（NDIs）的设计、合成和评价，这些 NDIs 是通过短肽桥接的。这些大环化合物类似于肽订书钉技术，可以通过 NDI 核心中的两个溴与半胱氨酸侧链上的两个巯基之间的显色亲核芳香取代反应方便地获得。核心桥接 NDIs 的尺寸与α螺旋的一转相匹配。NDI 键合的肽存在两种，通常可以分离为两种非对映异构体。在π酸性 NDI 表面上方的氨基酸侧链中引入叔胺碱可提供操作型的阴离子-π催化剂。根据烯醇化物化学基准反应，紧邻肽的阴离子-π催化具有创纪录的化学选择性，但对映选择性较弱。随着胺碱与 NDI 表面之间距离的增加、同型半胱氨酸桥接的松弛、不匹配、缩短和延长的α螺旋转弯以及无环肽对照，催化活性下降。将孤立的转弯拉长为短的α螺旋会显著增加活性。这种增加与从α螺旋宏观偶极子远程控制阴离子-π催化一致。
