Copper-mediated synthesis of drug-like bicyclopentanes.

Abstract:

:Multicomponent reactions are relied on in both academic and industrial synthetic organic chemistry owing to their step- and atom-economy advantages over traditional synthetic sequences1. Recently, bicyclo[1.1.1]pentane (BCP) motifs have become valuable as pharmaceutical bioisosteres of benzene rings, and in particular 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as para-phenyl ring replacements2. These structures are often generated from [1.1.1]propellane via opening of the internal C-C bond through the addition of either radicals or metal-based nucleophiles3-13. The resulting propellane-addition adducts are then transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. Although this approach has been effective so far, a multicomponent reaction that enables single-step access to complex and diverse polysubstituted drug-like BCP products would be more time efficient compared to current stepwise approaches. Here we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicyclopentanes using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. This copper-mediated reaction operates on short timescales (five minutes to one hour) across multiple (more than ten) nucleophile classes and can accommodate a diverse array of radical precursors, including those that generate alkyl, α-acyl, trifluoromethyl and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which is substantially more metabolically stable than its commercial progenitor.

journal_name

Nature

journal_title

Nature

authors

Zhang X,Smith RT,Le C,McCarver SJ,Shireman BT,Carruthers NI,MacMillan DWC

doi

10.1038/s41586-020-2060-z

subject

Has Abstract

pub_date

2020-04-01 00:00:00

pages

220-226

issue

7802

eissn

0028-0836

issn

1476-4687

pii

10.1038/s41586-020-2060-z

journal_volume

580

pub_type

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