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Principal Investigator: Rudi Fasan
Organization: UNIVERSITY OF TEXAS DALLAS
Fiscal Year: 2024
Award: $389,367
Funding agency: National Institute of General Medical Sciences
Metalloprotein catalysts for asymmetric synthesis
Project Summary
The exquisite chemo-, regio-, and stereoselectivity of enzymes make them attractive tools for organic synthesis, in
particular for the generation of optically active synthons and intermediates for the synthesis of pharmaceuticals and other
biologically active molecules. Reflecting this notion, there have been growing interest and efforts within the
pharmaceutical industry toward developing efficient, selective, cost-effective, and sustainable enzyme-catalyzed
transformations for drug synthesis and manufacturing. Progress in this direction is critically hampered, however, by the
inherently limited range of chemical transformations catalyzed by natural enzymes as compared to those accessible
through chemical methods. During the previous grant period, we have demonstrated that myoglobin—a small, robust, and
structurally tunable heme-containing protein—, constitutes a highly promising, versatile, and robust scaffold for
developing efficient and stereoselective biocatalysts for abiological carbene transfer reactions. Building upon this
foundational work and other exciting preliminary results, the proposed research aims at investigating and extending the
scope of these hemoprotein catalysts to a range of new, asymmetric carbon-carbon and carbon-heteroatom bond forming
transformations useful for the synthesis of optically active building blocks and complex organic scaffolds of direct value
for medicinal chemistry and drug discovery. Synergizing with these efforts, complementary strategies based on rational
mechanism-guided design and combinatorial/high-throughput approaches will be implemented to expedite the discovery
and optimization of myoglobin-based carbene transferases with enhanced catalytic efficiency, expanded reactivity, and
fine-tuned stereoselectivity. The studies above will be complemented by detailed mechanistic studies on these reactions
and catalysts using a combination of experimental, spectroscopic, computational, and structural methods. These studies
will furnish key insights into the kinetic, structural, and electronic properties of reaction intermediates and they will shed
light into structural determinants underlying catalyst-controlled reactivity and stereoselectivity, enabling a deeper
understanding of these processes and informing further catalyst design. The synthetic value of these methodologies will be
further demonstrated through their application to the stereoselective synthesis of drug molecules and in support of focused
medicinal chemistry projects. Successful completion of this research is expected to make available new efficient,
selective, and sustainable biocatalytic strategies for promoting asymmetric carbene transfer reactions, which will create
new opportunities for the synthesis and discovery of biologically active molecules.
Terms: <Acceleration><Address><Alkenes><Amines><Carbon><Catalysis><Chemicals><Chemistry><Complex><Crystallographies><Crystallography><Development><Drug Compounding><Drug Industry><Drug Preparation><Drug Synthesis and Chemistry><Drugs><Electronics><Engineering><Enzyme Gene><Enzymes><Fe element><Ferroprotoporphyrin><Generations><Goals><Grant><H-bond><Heme><Heme Proteins><Hemeproteins><Hydrogen Bonding><In Situ><Iron><Kinetics><Lead><Libraries><Ligands><Light><Mediating><Medication><Medicinal Chemistry><Metalloproteins><Metals><Methodology><Methods><Modeling><Myoglobin><Natural Products><Olefins><Optics><Organic Chemistry><Organic Synthesis><Pb element><Pharmaceutic Chemistry><Pharmaceutic Industry><Pharmaceutical Agent><Pharmaceutical Chemistry><Pharmaceutical Industry><Pharmaceutical Preparations><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Photoradiation><Preparation><Process><Property><Proteins><Protoheme><Reaction><Reagent><Research><Structure><System><Therapeutic><Transferase><Transferase Gene><Variant><Variation><Work><amine><carbene><catalyst><combinatorial><cost effective><density><design><designing><developmental><drug discovery><drug synthesis><drug/agent><electronic><electronic device><ferroheme><heavy metal Pb><heavy metal lead><hemoprotein><human disease><insight><interest><manufacture><methylene><naturally occurring product><non-Native><nonnative><novel><optical><pharmaceutical><pharmacologic><preparations><rational design><scaffold><scaffolding><screening><screenings><structural determinants><structural factors><theories><tool><toxic metal>