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Synthesis of Biologically Active Molecular Scaffolds via Enzyme-Catalyzed Asymmetric Carbene Transfer

通过酶催化不对称卡宾转移合成生物活性分子支架

基本信息

批准号：
9258319
负责人：
David Kingsland Romney
金额：
$ 5.71万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2018-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Enzymes are powerful tools for synthetic chemistry not only because they can catalyze reactions with exceptional levels of reactivity, but also because they can be tuned using directed evolution to achieve high selectivity in situations that would be intractable for small-molecule catalysts. Enzyme engineering has also enabled the heme-dependent monooxygenase cytochrome P450BM3, to catalyze carbene transfer reactions between diazoesters and mild nucleophiles, a reaction type that is completely absent in nature. The focus of this proposal is to expand the synthetic utility of this methodology by using directed evolution of P450BM3 to develop carbene transfer catalysts that can synthesize biologically important molecular scaffolds that are difficult to access with existing methods. The specific aims are: (1) to evolve P450BM3 variants to synthesize enantioenriched di- and triarylmethanes via asymmetric carbene insertion into N-H and O-H bonds; and (2) to extend the substrate scope to include electron-rich arenes and apply this methodology to the asymmetric synthesis of 3,3-disubstituted indole and α,α-disubstituted glycine derivatives. The di- and triarylmethane motif is prevalent in numerous synthetic drug candidates, but is difficult t synthesize asymmetrically, partly because the area surrounding the chiral center has local symmetry that makes enantioselection difficult for small-molecule catalysts. The use of enzymes is advantageous, however, because an enzyme's active site creates a chiral environment that interacts with the entire structure of the substrate. In the second aim, the application of carbene transfer to electron-rich arenes constitutes a novel approach to enzyme-catalyzed C-C bond formation, which is usually accomplished with aldolases. The indole and glycine derivatives that we propose to make with this method are found in numerous bioactive natural and synthetic compounds, and thus there is continued demand for new methods to synthesize these structures asymmetrically. We will characterize the enzymes that result from this project with a variety of techniques, such as X-ray crystallography, in order to elucidate the mechanisms of selectivity and assist in the future development of enzyme catalysts for other reaction types.

描述(申请人提供)：酶是合成化学的强大工具，不仅是因为它们可以催化具有非凡反应水平的反应，还因为它们可以通过定向进化进行调整，以在小分子催化剂难以处理的情况下实现高选择性。酶工程还使依赖于血红素的单加氧酶细胞色素P450BM3能够催化重氮酸酯和温和的亲核试剂之间的卡宾转移反应，这是一种自然界中完全不存在的反应类型。本建议的重点是通过使用定向的方法来扩展该方法的综合效用 P450BM3的进展是为了开发卡宾转移催化剂，这种催化剂可以合成用现有方法难以获得的具有生物重要性的分子支架。具体目标是：(1)发展P450BM3变体，通过不对称卡宾插入N-H和O-H键来合成对映体丰富的二芳基和三芳基甲烷；(2)扩大底物范围，包括富电子芳烃，并将该方法应用于3，3-二取代吲哚和α，α-二取代甘氨酸衍生物的不对称合成。二芳基和三芳基甲烷基序广泛存在于许多合成候选药物中，但很难不对称地合成，部分原因是手性中心周围的区域具有局部对称性，这使得小分子催化剂的对映选择性变得困难。然而，酶的使用是有利的，因为酶的活性部位创造了一个与底物的整个结构相互作用的手性环境。第二个目的是卡宾的应用转移到富含电子的芳烃构成了一种新的酶催化的C-C键形成方法，这通常是通过醛缩酶来完成的。我们建议用这种方法合成的吲哚和甘氨酸衍生物存在于许多具有生物活性的天然和合成化合物中，因此对不对称合成这些结构的新方法的需求持续存在。我们将用X射线结晶学等多种技术对该项目产生的酶进行表征，以阐明选择性的机理，并为未来开发用于其他反应类型的酶催化剂提供帮助。