Bicyclo[1.1.1]pentanes
(BCPs) have become established as attractive
bioisosteres forpara-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.