[F32] Development of a Three-Component Iron-Catalyzed Difluoromethylation Reaction
Ente: National Institute of General Medical Sciences
Scadenza: 2029-05-31
Importo max: 75.880 EUR
Paese: US
Descrizione
Project Summary/Abstract
The incorporation of difluoromethyl (–CF2H) group has become a leading strategy in pharmaceutical
development to enhance drug performance due to –CF2H’s unique and profound bioisosteric activity for
hydroxyls, amines, and thiols as a result of its hydrogen bond ability. Presently, transition metal-mediated
approaches for the direct incorporation of the –CF2H group is an attractive methodology in the context of selective
late-stage functionalization of complex molecules. While there is an abundance of synthetic methods employing
this approach for the formation of the traditional carbon(sp2)-CF2H bonds, general protocols for the formation of
more challenging carbon(sp3)-CF2H bonds are still limited. Hence, there is an urgent and unmet need to develop
new, sustainable, and efficient synthesis methods to accelerate the synthesis and evaluation of bioactive
compounds containing C(sp3)-CF2H bonds.
The hallmark of this proposal is the development of three-component iron-catalyzed difluoromethylation
reactions mediated through iron metal for the formation of C(sp3)–CF2H bonds. To achieve this objective, I will
put forward two strategies. The strategies differ not in the specific C(sp3)–CF2H bond that is to be formed, but in
the distinct, yet complementary, mechanistic manifold of introducing the difluoromethyl group into the organic
substrate. The first approach employs HCF2–X electrophiles as •CF2H radical precursors which can, through
strategic manipulation of reaction conditions, engage with a “radical lynchpin” and subsequently C(sp3)–CF2H
bond formation with a well-defined iron-species (Aim 1). The second strategy will implement the use of
organozinc reagent, [(DMPU)2Zn(CF2H)2], as a nucleophilic source of –CF2H group to be transmetalated into the
iron catalytic cycle as a complementary route to synthesize the C(sp3)–CF2H bond (Aim 2). To bolster these
efforts, I plan to implement advanced spectroscopic techniques (Mössbauer spectroscopy and single-crystal X-
ray diffraction) as well as computational chemistry to accelerate the development of three-component iron-
catalyzed difluoromethylation reactions.
While both approaches target the development of iron-mediated synthetic methods that permit the direct
incorporation of the –CF2H group, the mode of introduction is different. In doing so, this research project will
foster the growth in knowledge in iron catalysis. The long-term goal of this proposal is to expand the fundamental
research of domestically manufactured metals in the U.S., such as earth-abundant iron, for the development of
synthetic methods that permit expedient access to high-value molecules in an economical, sustainable, and safe
manner all while fostering and refining our knowledge and understanding of it.
Istituzione: UNIVERSITY OF CALIFORNIA LOS ANGELES
PI: Lupita Sarahi Aguirre
Progetto: 1F32GM165088-01
Settori: National Institute of General Medical Sciences
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