Project Summary/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.
