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.

Public Health Relevance

Chiral amines are essential structural components in numerous pharmaceutical agents and bioactive natural products. The proposed research will develop a biocatalytic platform for the asymmetric assembly of 1,2- aminoalcohols and 1,2-diamines using a nitrene transfer mechanism. Directed evolution of heme proteins will serve as the principal tool for the optimization of the proposed asymmetric amination processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32GM133126-01
Application #
9760580
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lees, Robert G
Project Start
2019-05-06
Project End
2022-05-05
Budget Start
2019-05-06
Budget End
2020-05-05
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
California Institute of Technology
Department
Engineering (All Types)
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125