Biocatalytic Methods for the Asymmetric Synthesis of Amines

胺不对称合成的生物催化方法

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要酶能够用精致的位点和立体选择性催化化学反应环境良性条件。因此，开发不对称的新生物催化方法高度可取的是药物上重要的胺的合成。手性氨基醇和二聚体是生物活性天然产物和临床重要的小分子中无处不在的结构基序具有抗菌，抗病毒和抗癌活性的治疗剂。该建议的重点是生成和使用硝酸盐的1,2-氨基醇和1,2-二胺的立体选择制备进化血红素蛋白转移机制。该提案的具体目的包括1）一种新的生物催化氨基羟基化烯烃合成1,2-氨基醇的烯烃，以及2）一种新的生物催化烯烃胰岛素至访问立体化学上定义明确的导膜直径。一个大型的结构多样性血红素蛋白的文库这些血红素蛋白催化的不对称硝基转移过程将评估Arnold Lab。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来优化饱和诱变和误差易PCR技术。拟议的研究将为生物学上重要的手性胺的可持续和高度对映选择性合成。进一步的理解血红素蛋白质的结构活性关系将为其他人的发展铺平道路对映选择性硝基转移反应。