Year: 2026
Type: article
Abstract: Bicyclo[1.1.1]pentane (BCP) has emerged over the past decade as a valuable three-dimensional bioisostere for benzene, attracting considerable interest in pharmaceutical research for its ability to improve drug-like properties. Although [1.1.1]propellane has traditionally served as the key precursor to mono- and 1,3- disubstituted BCPs, the growing demand for multisubstituted and bridge-functionalized BCP derivatives has spurred the development of alternative, propellane-free synthetic strategies. Recent advances toward these highly strained and sterically hindered ring systems can be broadly organized into three mechanistic categories: intramolecular diradical couplings, carbene-mediated ring expansions, and two-electron disconnections. This Perspective highlights these emerging methodologies, assesses their scope and limitations, and offers an outlook on remaining synthetic challenges and their implications for medicinal chemistry. Bicyclo[1.1.1]pentane (BCP) is a valuable three-dimensional bioisostere of benzene. This Perspective highlights emerging, propellane-free strategies to access multisubstituted and bridge-functionalized BCP derivatives, assesses their scope and limitations, and outlines remaining challenges.
Source: Nature Communications
Authors: Chang Liu, Wenyuan Li, Renzhe Li, Rohan R. Merchant, Yuzuru Kanda, Tian Qin
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $6,990
OpenAlex ID: W7122653700