![Bicyclo[1.1.1]pentane is a rigid aliphatic hydrocarbon with a three-dimensional (3D), propeller-like shape and a molecular size which makes it a targeted bioisosteric replacement for phenylene and acetylene groups in medicinal chemistry. For the pharmaceutical application of BCP, simple, efficient, and cost-effective synthetic tools are required to enable the exploration of BCP’s potential as a bioisostere across a broad chemical space. The synthesis of BCP mono- and diketones remains a challenging task, limited by both substrate scope and expensive photocatalysts. Here we present a protocol for Friedel-Crafts acylation of (hetero)aromatic hydrocarbons with BCP acyl chlorides; in particular, the first method to access diaromatic BCP 1,3-diketones. Reaction optimization, substrate scope, and reactivity of the products are discussed. 35 mono- and diketones are reported accompanied by 7 examples of post-synthetic modifications. The synthesis of a BCP analogue of fenofibrate is reported.](https://cdn.bsky.app/img/feed_thumbnail/plain/did:plc:ls54voiihm3bxde2dkgrxbm3/bafkreigzyfnz4ckoa7ifg3rjuuzk7tt3vdih5xlizy6ledhqn5ua3urgie)
Bicyclo[1.1.1]pentane is a rigid aliphatic hydrocarbon with a three-dimensional (3D), propeller-like shape and a molecular size which makes it a targeted bioisosteric replacement for phenylene and acetylene groups in medicinal chemistry. For the pharmaceutical application of BCP, simple, efficient, and cost-effective synthetic tools are required to enable the exploration of BCP’s potential as a bioisostere across a broad chemical space. The synthesis of BCP mono- and diketones remains a challenging task, limited by both substrate scope and expensive photocatalysts. Here we present a protocol for Friedel-Crafts acylation of (hetero)aromatic hydrocarbons with BCP acyl chlorides; in particular, the first method to access diaromatic BCP 1,3-diketones. Reaction optimization, substrate scope, and reactivity of the products are discussed. 35 mono- and diketones are reported accompanied by 7 examples of post-synthetic modifications. The synthesis of a BCP analogue of fenofibrate is reported.
Check out our new #preprint 📢😀"Bicyclo[1.1.1]pentane Ketones via Friedel-Crafts Acylation" #BCP #isostere @chemrxiv.bsky.social
chemrxiv.org/engage/chemr... great work by Freya and Karolina and coop with #PavelMykhailiuk #EnamineLtd
🇺🇦 supported by @researchireland.ie @ias-tum.bsky.social