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Synthesis and applications of highly functionalized 1-halo-3-substituted bicyclo[1.1.1]pentanes.

ABSTRACT: Bicyclo[1.1.1]pentanes (BCPs) are important bioisosteres of 1,4-disubstituted arenes, tert-butyl and acetylenic groups that can impart physicochemical benefits on drug candidates. Here we describe the synthesis of BCPs bearing carbon and halogen substituents under exceptionally mild reaction conditions, via triethylborane-initiated atom-transfer radical addition ring-opening of tricyclo[1.1.1.01,3]pentane (TCP) with alkyl halides. This chemistry displays broad substrate scope and functional group tolerance, enabling application to BCP analogues of biologically-relevant targets such as peptides, nucleosides, and pharmaceuticals. The BCP halide products can be converted to the parent phenyl/tert-butyl surrogates through triethylborane-promoted dehalogenation, or to other derivatives including carbonyls, alcohols, and heterocycles.

SUBMITTER: Caputo DFJ

PROVIDER: S-EPMC6001403 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Synthesis and applications of highly functionalized 1-halo-3-substituted bicyclo[1.1.1]pentanes.

Caputo Dimitri F J DFJ Arroniz Carlos C Dürr Alexander B AB Mousseau James J JJ Stepan Antonia F AF Mansfield Steven J SJ Anderson Edward A EA

Chemical science 20180521 23

Bicyclo[1.1.1]pentanes (BCPs) are important bioisosteres of 1,4-disubstituted arenes, tert-butyl and acetylenic groups that can impart physicochemical benefits on drug candidates. Here we describe the synthesis of BCPs bearing carbon and halogen substituents under exceptionally mild reaction conditions, via triethylborane-initiated atom-transfer radical addition ring-opening of tricyclo[1.1.1.01,3]pentane (TCP) with alkyl halides. This chemistry displays broad substrate ...[more]

PMID: 29997886

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