Journal
NATURE CHEMISTRY
Volume 14, Issue 9, Pages 1068-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41557-022-00979-0
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Funding
- NIGMS [R35 GM 131680]
- AbbVie
- NSF Major Research Instrumentation Program [NSF CHE-1827457]
- NIH [3R01GM118510-03S1, 3R01GM087605-06S1]
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This study reports a single-step transition-metal-free multi-component approach for synthesizing versatile BCP boronates. Various alkyl-, aryl-, and alkenyl-functionalized BCP boronates were easily prepared by reacting commonly available carboxylic acids and organohalides.
Strained bicyclic substructures are increasingly relevant in medicinal chemistry discovery research because of their role as bioisosteres. Over the last decade, the successful use of bicyclo[1.1.1]pentane (BCP) as a para-disubstituted benzene replacement has made it a highly valuable pharmacophore. However, various challenges, including limited and lengthy access to useful BCP building blocks, are hampering early discovery research. Here we report a single-step transition-metal-free multi-component approach to synthetically versatile BCP boronates. Radicals derived from commonly available carboxylic acids and organohalides perform additions onto [1.1.1]propellane to afford BCP radicals, which then engage in polarity-matched borylation. A wide array of alkyl-, aryl- and alkenyl-functionalized BCP boronates were easily prepared. Late-stage functionalization performed on natural products and approved drugs proceeded with good efficiency to generate the corresponding BCP conjugates. Various photoredox transformations forging C-C and C-N bonds were demonstrated by taking advantage of BCP trifluoroborate salts derived from the BCP boronates.
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