Rapid Access to 2-Substituted Bicyclo[1.1.1]pentanes

15 November 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


The replacement of aryl rings with C(sp3)-rich structures has garnered significant interest in drug discovery due to the potential for improved pharmacokinetic properties upon substitution. In particular, 1,3-difunctionalized bicyclo[1.1.1]pentanes (BCPs) have been widely adopted as bioisosteres for para-substituted arene rings, appearing in a number of lead pharmaceutical candidates. Due to their medicinal importance, multiple methods have been developed to efficiently synthesize these 1,3-difunctionalized BCPs. However, despite the pharmaceutical value of 2-substituted BCPs as replacements for ortho- or meta-substituted arene rings, general and rapid syntheses of these scaffolds remain elusive. Current approaches to 2-substituted BCPs rely on installation of the bridge substituent prior to BCP core construction, leading to lengthy step counts and often non-modular sequences. While challenging, direct functionalization of the strong bridge BCP C–H bonds would offer a more streamlined pathway to diverse 2-substituted BCPs. Here we report a generalizable synthetic linchpin strategy for bridge functionalization via radical C–H abstraction of the BCP core. Through mild generation of a strong hydrogen atom abstractor, we rapidly synthesize novel 2-substituted BCP synthetic linchpins in one pot. These synthetic linchpins then serve as common precursors to complex 2-substituted BCPs, allowing one step access to a number of previously inaccessible electrophile and nucleophile fragments at the 2-position via two new metallaphotoredox protocols. Altogether, this platform enables the expedient synthesis of four pharmaceutical analogs, all of which show similar or improved properties compared to their aryl-containing equivalents, demonstrating the potential of these 2-substituted BCPs in drug development.



Supplementary materials

Supplementary Information
Experimental details, property data and characterization data for isolated compounds


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