Polysubstituted bicyclo-[2.1.1]-hexanes as benzene isosteres for medicinal chemistry

Abstract

Bicyclo[2.1.1]hexanes (BCHs), 2-oxabicyclo[2.1.1]hexanes (oxaBCHs), and 1- or 2-azabicyclo[2.1.1]hexanes (1- or 2-azaBCHs) are emerging as valuable bioisosteres of meta- and ortho-disubstituted benzenes in drug design. These sp³-rich scaffolds offer conformational rigidity and improved physicochemical properties compared to their flat aromatic counterparts. Historically, a lack of robust synthetic methods for these bicyclic hydrocarbons has limited their widespread application. However, over the past five years, significant advances have been made—primarily through [2π + 2π] cycloadditions of 1,5-dienes and [2π + 2σ] cycloadditions between bicyclo[1.1.0]butanes (BCBs) and π-systems. These approaches have enabled diverse bond disconnections and substitution patterns, allowing for the exploration of a range of exit vectors. This review aims to summarize the methodologies reported between 2020 and early 2025, providing readers with an overview of the synthetic strategies developed and a focus on the exit vectors achieved, ultimately serving as a guide to the currently accessible building blocks.