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J Am Chem Soc. 2020 Jan 7. doi: 10.1021/jacs.9b10646. [Epub ahead of print]

An Alkyne Linchpin Strategy for Drug:Pharmacophore Conjugation: Experimental and Computational Realization of a meta-selective Inverse Sonogashira Coupling.

Abstract

The late-stage functionalization (LSF) of pharmaceutical and agrochemical compounds by the site-selective activation of C-H bonds offers immediate access to diverse structural analogs and expands the accessible chemical space. We report a C-H functionalization LSF strategy that hinges on the use of an alkyne linchpin to assemble conjugates of sp2-rich marketed pharmaceuticals and agrochemicals with sp3-rich 3D-fragments and natural products. This is accomplished through a template-assisted inverse Sonogashira reaction that displays high levels of selectivity for the meta-position. This protocol is also amenable to distal structural modifications of α-amino acids. The transformation of alkyne functionality to other functional groups further highlights the applicative potential. Computational and experimental mechanistic studies shed light on the detailed mechanism. Turnover-limiting 1,2-migratory insertion of the bromoalkyne coupling partner occurs after relatively fast C-H activation. While this insertion occurs unselectively, regioconvergence results from one of the adducts undergoing a 1,2-trialkylsilyl migration to form the alkynylated product. A heterobimetallic Pd-Ag TS, which is essential for product formation, is explicitly implicated in the β-bromide elimination step.

PMID:
31910623
DOI:
10.1021/jacs.9b10646

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