Conquering the Synthesis and Functionalization of Bicyclo[1.1.1]pentanes

Bicyclo[1.1.1]pentanes(BCPs) have become established as attractivebioisosteres for para-substituted benzene rings indrug design. Conferring various beneficial properties compared withtheir aromatic "parents," BCPs featuring a wide arrayof bridgehead substituents can now be accessed by an equivalent varietyof methods. In this perspective, we discuss the evolution of thisfield and focus on the most enabling and general methods for BCPssynthesis, considering both scope and limitation. Recent breakthroughson the synthesis of bridge-substituted BCPs are described, as wellas methodologies for postsynthesis functionalization. We further explorenew challenges and directions for the field, such as the emergenceof other rigid small ring hydrocarbons and heterocycles possessingunique substituent exit vectors.