Taylor M. Sodano

Couple-close as a synthetic paradigm has the potential to change the way that synthetic organic chemists approach cyclic scaffold construction. One class of cyclic molecules that has been increasingly sought after is semisaturated cyclic scaffolds, whose specific blend of Csp ² - and Csp ³ -hybridized components confers distinct properties to these species. However, existing methods to construct these scaffolds are limited, often relying on arene saturation or annulations that require lengthy de novo syntheses. Herein, we describe a unified and highly modular couple-close strategy for the synthesis of semisaturated scaffolds. This approach installs bifunctional linkers onto aromatic rings through a range of bond-forming reactions, and subsequent cyclization furnishes semisaturated bicyclic adducts. Key to this approach is a mechanistically distinct cobalt-catalyzed dehydrogenative radical cyclization that proceeds efficiently even on electronically unbiased arenes, enabling a broad substrate scope under mild reaction conditions.

The unique chemistry of small, strained carbocyclic systems has long captivated organic chemists from a theoretical and fundamental standpoint. A resurgence of interest in strained carbocyclic species has been prompted by their potential as bioisosteres, high fraction of sp³ carbons, and limited appearance in the patent literature. Among strained ring systems, bicyclo[1.1.0]butane (BCB) stands apart as the smallest bicyclic carbocycle and is amongst the most strained carbocycles known. Despite the fact that BCBs have been synthesized and studied for well over 50 years, they have long been regarded as laboratory curiosities. However, new approaches for preparing, functionalizing, and using BCBs in “strain-release” transformations have positioned BCBs to be powerful synthetic workhorses. Further, the olefinic character of the bridgehead bond enables BCBs to be elaborated into various other ring systems and function as covalent warheads for bioconjugation. This review will discuss the recent developments in the synthesis and functionalization of BCBs as well as the applications of these strained rings in synthesis and drug discovery. An overview of the properties and the historical context of this interesting structure will be provided.