Targeted Derivatization of Medicines via Novel C-H Functionalization
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Date
2015-12
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The Ohio State University
Abstract
The most ubiquitous bond in pharmaceuticals rests between carbon and hydrogen and until
recently, however, the C-H bond has been ignored as a target for synthetic manipulation because
of its inherently inert nature and the significant energetic barrier associated with bond breakage.
The utilization of C-H bonds as a means of activation for desired functional groups reduces multi-
step syntheses to a single reaction, which drastically diminishes classical labor- and resource-
intensive strategies for the production of complex molecules. Additionally, structural analogs of
multifaceted, biologically active molecules can easily be obtained without having to individually
construct each member of a library of substrates from scratch. This innovative process may be
applied to potential anti-cancer drug candidates to increase their potency, effectivity, and
bioactivity by targeted functionalization, which may allow for an accelerated opportunity to
discover enhanced medicines directly from abundant precursors. The initial hypothesis for this C–
H directed reaction was derived from the radical-based mechanism of the Hofmann-Löffler-
Freytag reaction. As a way of generalizing this protocol to medicines, it has been sought to exclude
the harsh halogenation typically required for the sequential 1,5-hydrogen shift and cyclization.
Thus far, a method has been devised to directly cyclize amines to create a five-membered
pyrrolidine ring from unbiased long-chain amine substrates through the generation of iodine in
situ via mild reagents. Our research is currently focused on optimization and generalization of
this method to explore a variety of substrates that offer medicinal relevance. This development of
direct C–H activation has numerous applications in the medicinal, chemical, and biological target
elucidation and offers a rewarding potential for increased efficacy in modern synthetic strategies.
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Keywords
C-H Functionalization, activation