Kinetic resolution of alcohols catalyzed by tripeptides containing the N-alkylimidazole substructure
Kinetic resolution of alcohols catalyzed by tripeptides containing the N-alkylimidazole substructure
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DOI：
10.1021/ja973892k
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发表时间：
1998-02-25
影响因子：
15
通讯作者：
Ruel, EM
中科院分区：
文献类型：
--
作者：
Miller, SJ;Copeland, GT;Ruel, EM
肽-底物相互作用经常解释酶的特异性。分子间氢键、疏水效应、静电和溶剂重组的综合作用是导致选择性的精确酶-底物结合的核心。将这些概念应用于小分子催化剂的设计有望使低分子量类酶系统的发展成为可能。在这种情况下，我们正在研究含有非蛋白质原性氨基酸的合成肽，这些氨基酸具有催化活性，最终目标是开发用于不对称合成的选择性肽基催化剂。在这里，我们报告了设计和合成新的功能肽，催化某些仲醇的动力学分解。3,4我们最初的设计重点是肽1（方案1），它含有3-（1-咪唑基）-(S)-丙氨酸（IA）作为n端氨基酸。在IA内是n -甲基咪唑（NMI）亚结构，它能够通过亲核机制催化乙酸酐对仲醇的酰化。我们认为，将IA整合到短的折叠肽中，可以在肽主链产生的手性环境附近形成酰基咪唑中间体（例如，1-Ac） 8。特别地，我们将IA引入到由脯氨酸- r -氨基异丁酸框架定义的易倾转结构中。c端(R)-R-甲基苄酰胺的掺入是为了使带电的酰基咪唑离子与催化剂（1-Ac）的苯基形成π堆积。4 e, 10
Peptide-substrate interactions frequently account for the specificity of enzymes. The combined effect of intermolecular hydrogen bonding, hydrophobic effects, electrostatics, and solvent reorganization is at the heart of the precise enzyme-substrate associations which lead to selectivity. 1 The application of these concepts to the design of small molecule catalysts promises to make the development of low-molecular-weight enzyme-like systems possible. 2 In this context, we are investigating synthetic peptides containing nonproteinogenic amino acids that impart catalytic activity with the ultimate goal of developing selective peptide-based catalysts for asymmetric synthesis. Herein we report the design and synthesis of new, functional peptides that catalyze the kinetic resolution of certain secondary alcohols. 3, 4 Our initial design focused on peptide 1 (Scheme 1), which contains 3-(1-imidazolyl)-(S)-alanine (IA) as the N-terminal amino acid. 5, 6 Within IA is the N-methylimidazole (NMI) substructure, which is capable of catalyzing the acylation of secondary alcohols by acetic anhydride through a nucleophilic mechanism. 7 We felt that incorporation of IA into short, folded peptides would allow for the formation of an acyl imidazolium intermediate (eg, 1-Ac) 8 in proximity to the chiral environment created by the peptide backbone. In particular, we introduced IA into a predisposed-turn structure defined by the proline-R-aminoisobutyric acid framework. 9 Incorporation of the C-terminal (R)-R-methylbenzylamide was intended to create the possibility for π-stacking of the charged acylimidazolium ion with the phenyl group of the catalyst (1-Ac). 4e, 10