Conquering the Synthesis and Functionalization of Bicyclo[1.1.1]pentanes

[Image: see text] Bicyclo[1.1.1]pentanes (BCPs) have become established as attractive bioisosteres for para-substituted benzene rings in drug design. Conferring various beneficial properties compared with their aromatic “parents,” BCPs featuring a wide array of bridgehead substituents can now be accessed by an equivalent variety of methods. In this perspective, we discuss the evolution of this field and focus on the most enabling and general methods for BCPs synthesis, considering both scope and limitation. Recent breakthroughs on the synthesis of bridge-substituted BCPs are described, as well as methodologies for postsynthesis functionalization. We further explore new challenges and directions for the field, such as the emergence of other rigid small ring hydrocarbons and heterocycles possessing unique substituent exit vectors.