Journal
CHEMICAL SCIENCE
Volume 9, Issue 23, Pages 5295-5300Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c8sc01355a
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Funding
- EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine [EP/L015838/1]
- AstraZeneca
- Diamond Light Source
- Defence Science and Technology Laboratory
- Evotec
- GlaxoSmithKline
- Janssen
- Novartis
- Pfizer
- Syngenta
- Takeda
- UCB
- Vertex
- EPSRC [EP/M019195/1]
- Heinrich Hertz Foundation
- EPSRC [EP/M019195/1] Funding Source: UKRI
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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.
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