Synthetic Routes to Approved Drugs Containing a Spirocycle

Abstract

The use of spirocycles in drug discovery and medicinal chemistry has been booming in the last two decades. This has clearly translated into the landscape of approved drugs. Among two dozen clinically used medicines containing a spirocycle, 50% have been approved in the 21st century. The present review focuses on the notable synthetic routes to such drugs invented in industry and academia, and is intended to serve as a useful reference source of synthetic as well as general drug information for researchers engaging in the design of new spirocyclic scaffolds for medicinal use or embarking upon analog syntheses inspired by the existing approved drugs.

Reduction of Triple Bond in [B12H11NCR]− Anions by Lithium Aluminum Hydride: A Novel Approach to the Synthesis of N-Monoalkylammonio-Substituted closo-Dodecaborates

“…Lithium aluminum hydride (LAH) is widely used for the reduction of various functional groups, including carbonyl groups [62,63], nitriles [64][65][66][67], and others [68,69]. Nitriles containing the -CN functional group can be reduced by LAH to primary amines [70].…”

Strain-enabled radical spirocyclization cascades: rapid access to spirocyclobutyl lactones and – lactams

“…Spirocyclic compounds are among the most important structural components of small-molecule drug candidates. 1 Due to their rigid conformation, substituents on spirocyclic scaffolds are well-defined in their spatial arrangement and, thus, allow for the orientation of various functional groups along the designated vectors. As a result, interactions of a ligand with a three-dimensional (3D) binding site can be attained more effectively with a spirocyclic motif than with flat aromatic compounds.…”

Entry to new spiroheterocycles via tandem Rh(II)-catalyzed O–H insertion/base-promoted cyclization involving diazoarylidene succinimides

“…Spirocyclic motifs have emerged as auspicious frameworks for modern drug design [ 1 – 2 ]. They are known to promote higher success rates, when targeting three-dimensional protein molecules [ 3 – 4 ].…”