An alkyne linchpin strategy for drug:pharmacophore conjugation: Experimental and computational realization of a meta-selective inverse sonogashira coupling
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...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Chemical Society
2020
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| _version_ | 1797052509019176960 |
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| author | Porey, S Zhang, X Bhowmick, S Kumar Singh, V Guin, S Paton, R Maiti, D |
| author_facet | Porey, S Zhang, X Bhowmick, S Kumar Singh, V Guin, S Paton, R Maiti, D |
| author_sort | Porey, S |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T18:32:34Z |
| format | Journal article |
| id | oxford-uuid:0a2988fa-fc84-4766-a4f3-39ad79da391b |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:32:34Z |
| publishDate | 2020 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:0a2988fa-fc84-4766-a4f3-39ad79da391b2022-03-26T09:22:20ZAn alkyne linchpin strategy for drug:pharmacophore conjugation: Experimental and computational realization of a meta-selective inverse sonogashira couplingJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0a2988fa-fc84-4766-a4f3-39ad79da391bEnglishSymplectic Elements at OxfordAmerican Chemical Society2020Porey, SZhang, XBhowmick, SKumar Singh, VGuin, SPaton, RMaiti, DThe 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. |
| spellingShingle | Porey, S Zhang, X Bhowmick, S Kumar Singh, V Guin, S Paton, R Maiti, D An alkyne linchpin strategy for drug:pharmacophore conjugation: Experimental and computational realization of a meta-selective inverse sonogashira coupling |
| title | An alkyne linchpin strategy for drug:pharmacophore conjugation: Experimental and computational realization of a meta-selective inverse sonogashira coupling |
| title_full | An alkyne linchpin strategy for drug:pharmacophore conjugation: Experimental and computational realization of a meta-selective inverse sonogashira coupling |
| title_fullStr | An alkyne linchpin strategy for drug:pharmacophore conjugation: Experimental and computational realization of a meta-selective inverse sonogashira coupling |
| title_full_unstemmed | An alkyne linchpin strategy for drug:pharmacophore conjugation: Experimental and computational realization of a meta-selective inverse sonogashira coupling |
| title_short | An alkyne linchpin strategy for drug:pharmacophore conjugation: Experimental and computational realization of a meta-selective inverse sonogashira coupling |
| title_sort | alkyne linchpin strategy for drug pharmacophore conjugation experimental and computational realization of a meta selective inverse sonogashira coupling |
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