Biocatalytic Methods for the Asymmetric Synthesis of Amines

胺不对称合成的生物催化方法

• 批准号: 9760580
• 负责人: Yang Yang
• 金额: $ 6.16万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-06 至 2022-05-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760580
• 关键词: Alkenes; Amination; Amines; Amino Alcohols; Anti-Bacterial Agents; Antineoplastic Agents; Antiviral Agents; Benign; Biological; Biology; Chemicals; Clinical; Cytochrome a; Development; Diamines; Directed Molecular Evolution; Engineering; Enzymes; Esters; Hemeproteins; Hydroxylamine; Libraries; Methods; Mutagenesis; Natural Products; Nature; Pharmacologic Substance; Preparation; Process; Protein Engineering; Reaction; Research; Site; Structural Biochemistry; Structure; Structure-Activity Relationship; Synthesis Chemistry; Techniques; Transition Elements; Variant; Work; anticancer activity; base; bioactive natural products; catalyst; chemical reaction; heme a; improved; metalloenzyme; mutant; nitrene; novel; screening; small molecule; small molecule therapeutics; structural biology; tool

Project Summary/Abstract Enzymes are capable of catalyzing chemical reactions with exquisite site and stereoselectivity under environmentally benign conditions. Thus, the development of new biocatalytic methods for the asymmetric synthesis of pharmaceutically important amines is highly desirable. Chiral aminoalcohols and diamines are ubiquitous structural motif in biologically active natural products and clinically important small molecule therapeutics with antibacterial, antiviral and anticancer activity. The focus of this proposal is to generate and evolve heme proteins for the stereoselective preparation of 1,2-aminoalcohols and 1,2-diamines using a nitrene transfer mechanism. The specific aims of this proposal include 1) a new biocatalytic aminohydroxylation of alkenes for the synthesis of enantioenriched 1,2-aminoalcohols, and 2) a new biocatalytic olefin diamination to access stereochemically well-defined vicinal diamines. A large library of structurally diverse heme proteins in the Arnold lab will be evaluated for these heme protein-catalyzed asymmetric nitrene transfer processes. The catalytic activity and stereoselectivity of heme proteins will be optimized via directed evolution using site saturated mutagenesis and error prone PCR techniques. The proposed research will afford new avenues for the sustainable and highly enantioselective synthesis of biologically important chiral amines. Further understanding of the structure-activity relationship of heme proteins will pave the way for the development of other enantioselective nitrene transfer reactions.

项目概要/摘要 酶能够在一定条件下催化具有精细位点和立体选择性的化学反应。 环境友好的条件。因此，开发新的不对称生物催化方法 非常需要合成药学上重要的胺。手性氨基醇和二胺是 生物活性天然产物和临床重要小分子中普遍存在的结构基序 具有抗菌、抗病毒和抗癌活性的疗法。该提案的重点是产生和 进化血红素蛋白，用于使用氮宾立体选择性制备 1,2-氨基醇和 1,2-二胺 转移机制。该提案的具体目标包括 1) 一种新的生物催化氨基羟基化 用于合成对映体富集的 1,2-氨基醇的烯烃，以及 2) 一种新的生物催化烯烃二胺化 获得立体化学明确的邻位二胺。结构多样的血红素蛋白的大型库 阿诺德实验室将对这些血红素蛋白催化的不对称氮烯转移过程进行评估。这 血红素蛋白的催化活性和立体选择性将通过使用位点的定向进化进行优化 饱和诱变和容易出错的 PCR 技术。拟议的研究将为 具有生物学意义的手性胺的可持续且高度对映选择性合成。进一步了解 血红素蛋白结构-活性关系的研究将为其他蛋白的开发铺平道路 对映选择性氮宾转移反应。