Biocatalytic Methods for the Asymmetric Synthesis of Amines

项目摘要/摘要 酶能够催化化学反应，具有精细的位置和立体选择性。 环境友好的条件。因此，开发新的不对称生物催化方法 合成具有重要药用价值的胺是非常可取的。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药物。这项提议的重点是产生和 进化血红素蛋白用于1，2-氨基醇和1，2-二胺的立体选择性合成 转移机制。这项建议的具体目标包括1)一种新的生物催化氨羟化反应 用于合成对映体富集型1，2-氨基醇的烯烃，以及2)一种新的生物催化烯烃缩合反应，以 获得立体化学定义良好的邻二胺。一个结构不同的血红素蛋白的大型文库 阿诺德实验室将对这些由血红素蛋白催化的不对称氮转移过程进行评估。这个 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 饱和突变和容易出错的聚合酶链式反应技术。拟议的研究将为 生物重要手性胺的可持续和高对映选择性合成。进一步了解 血红素蛋白构效关系的研究将为开发其他 对映体选择性的硝基转移反应。

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.