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Principal Investigator: AARON APONICK
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2024
Award: $292,089
Funding agency: National Institute of General Medical Sciences
Project Summary/Abstract
This objective of this proposal is to develop new synthetic methods for the enantioselective synthesis of bioactive
molecules. Studies are centered on utilizing a new class of atropisomeric chiral biaryl ligand being developed in
our laboratory. Preliminary work has found that imidazole-based biaryl P,N-ligands excel at promoting
enantioselective copper catalyzed carbon-carbon bond-forming reactions. Our goal is to capitalize on the
differences in behavior between these ligands and existing biaryl ligands to enable new reaction technology for
applications in discovery chemistry. The research in this application is focused on gaining a mechanistic
understanding of the structural underpinnings responsible for new and unique reactivity imparted by this new
ligand scaffold. Our first aim outlines plans to develop new dearomatization reactions of nitrogen heterocycles.
In this aim we describe chemistry that will push the field past chiral carbocycles and single-heteroatom
heterocycles to heterocycles with >1 heteroatom. Through preliminary results we demonstrate addition to
pyridine, but more importantly pyrazine, pyridazine, and pyrimidine. These latter examples are unprecedented
in the literature and the success of these catalytic enantioselective dearomatization reactions is developed here
to provide rapid access to complex natural products like svetamycin B, saxitoxin, and batzellidine B as well as
additional chiral nitrogen-containing building blocks. The second aim is focused on catalytic enantioselective
addition reactions to C=N Bonds independent of nitrogen substitution. In catalytic enantioselective processes,
it is common for iminium ions to require 2 identical N-substituents to avoid the E/Z issue. We have found that
catalytic enantioselective alkynylation using StackPhos lifts this requirement and the use of two different N-
substituents is possible. This breakthrough allows the move from bis-protected amines (e.g. N,N-dibenzyl) to the
incorporation of groups needed for the synthesis. Here we capitalize on this for an expedient synthesis of
kopsanone and other chiral heterocycles such as morpholines. In addition, through preliminary results, we also
demonstrate that addition to imines and nitrones in high ee is possible, despite the E/Z-isomer issue. Extensive
preliminary results support these aims and we predict that the chemistry developed here will be of broad impact
to practitioners in academia and industrial settings, particularly the pharmaceutical and biotech sectors.
Terms: <3-D><3-Dimensional><3D><Academia><Acceleration><Aldehydes><Alkynes><Amines><Area><Behavior><Biology><Biotech><Biotechnology><Carbon><Catalysis><Characteristics><Chemicals><Chemistry><Clinical><Collection><Complex><Copper><Coupling><Cu element><Development><Elements><Goals><Gonyaulax Toxin><Health><Human><Imidazole><Imines><Industrialization><Ions><Isomerism><Laboratories><Lifting><Ligands><Literature><Methods><Mitilotoxin><Modern Man><Natural Products><Nitrogen><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phase><Piperazines><Position><Positioning Attribute><Preparation><Process><Pseudo-natural product><Pyrazines><Pyridazines><Pyrimidine><Reaction><Research><Route><Sampling><Saxitonin><Saxitoxin><Science><Structure><Synthesis Chemistry><Synthetic Chemistry><Technology><Transmission><Work><amine><catalyst><chiral molecule><design><designing><developmental><enantiomer><improved><isomer><morpholine><natural product inspired><natural product-like><naturally occurring product><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><nitrone><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><pharmaceutical><pre-clinical><preclinical><preparations><pyridine><quinoline><scaffold><scaffolding><screening><screenings><small molecule therapeutics><success><three dimensional><transmission process>