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.

项目总结/摘要 酶能够催化化学反应，具有精确的位点和立体选择性， 环境友好的条件。因此，开发新的生物催化方法用于不对称 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治疗剂。该提案的重点是产生和 用氮烯立体选择性制备1，2-氨基醇和1，2-二胺的血红素蛋白 传递机制该提案的具体目标包括：1）一种新的生物催化氨羟化反应， 用于合成对映体富集的1，2-氨基醇的烯烃，和2）新的生物催化烯烃二胺化， 获得立体化学上明确定义的邻位二胺。一个结构多样的血红素蛋白的大型文库， 阿诺德实验室将评估这些血红素蛋白催化的不对称氮烯转移过程。的 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来优化。 饱和诱变和易错PCR技术。拟议的研究将提供新的途径， 生物重要手性胺的可持续和高对映选择性合成。进一步理解 对血红素蛋白质构效关系的研究将为开发其他血红素蛋白质的研究奠定基础。 对映选择性氮烯转移反应