Enantioenriched nitrogen-containing small molecules via stereoselective carbon-carbon bond construction

The University of North Carolina at Wilmington received a $369,199 Project Grant award from the National Institute of General Medical Sciences (NIGMS) Biomedical Research and Research Training Program (CFDA 93.859) to develop new stereoselective methods for the synthesis of nitrogen-containing small molecules with potential pharmaceutical applications. The key objectives are to 1) produce single enantiomer amine derivatives by enantioselective aziridine opening with enolate equivalents, and 2) develop catalytic, enantioselective epoxide openings for the synthesis of chiral nitrogen synthons. The expected outcomes include the synthesis of enantioenriched α-amino carbonyls and indoline derivatives for biological testing, provision of advanced research opportunities for undergraduate students, and the development of new catalytic, enantioselective reactions utilizing strained heterocycles. This award will enable the advancement of novel synthetic methods to generate valuable single enantiomer small molecules for potential use in pharmaceutical development and the enhancement of human health.

Abstract

New pharmaceuticals that contain chirality are typically marketed as single enantiomers. Limitations in enantioselective methods for the synthesis of organic, nitrogen-containing small molecules can hinder drug development. Ring opening of aziridines and epoxides by nucleophiles are efficient processes for producing chiral, nitrogen-containing small molecules. Chiral lewis acid catalysis has continued to advance for carbon-carbon bond forming reactions. What is not known are stereoselective methods for aziridine desymmetrization with ester enolate equivalents and enantioselective, palladium- catalyzed epoxide opening with indoles. The long-term goal is to discover novel stereoselective methods for biologically-active small molecule synthesis. The overall objective of the proposed research, which is the next step toward attainment of the long-term goal, is to develop enantioselective alkylation and arylation reactions by ring opening of strained heterocycles with carbon-carbon bond formation. This is driven by a central hypothesis that electron-rich carbon nucleophiles possess sufficient reactivity to produce diverse nitrogen-containing small molecules by stereoselective functionalization of strained heterocycles. The rationale that underlies the proposed research is that completion of this project will advance new aziridine and epoxide methods for enantioselective small molecule synthesis. Directed by strong preliminary data, the research plan includes objectively testing the central hypothesis and, thereby, attaining the objective of this application by pursuing the following two specific aims: 1) produce single enantiomer amine derivatives by aziridine opening with enolate equivalents, and 2) develop catalytic, enantioselective epoxide openings for the synthesis of chiral nitrogen synthons. The aims will operate with the working hypotheses that 1) enantioselective and diastereoselective aziridine opening with enolate equivalents will generate single enantiomer nitrogen-containing small molecules and 2) diphosphine-palladium (II) complexes possess novel reactivity for enantioselective carbon-carbon bond formation through epoxide ring opening with nitrogen heterocycles to enable a stereospecific oxidative 1,2-alkyl shift, making this approach innovative. The expected outcomes of our specific aims are as follows: first, synthesis of enantioenriched -amino carbonyls and indoline derivatives for testing by the nimh psychoactive drug screening program; second, provide advanced, individual research opportunities for undergraduate students with applications in the biomedical field; third, developing new catalytic, enantioselective reactions utilizing strained heterocycles. These outcomes will have a significant positive impact as unique single enantiomer small molecules will become available for pharmaceutical synthesis. Original chemical processes will be developed to generate valuable new disease treatments to enhance human health.