Strategies for the Diversity-Oriented Synthesis of Macrocycles.

Abstract

Macrocycles have long been recognized as useful chemical entities for medicine, with naturally occurring and synthetic macrocycles clinically approved for use as prescription drugs. Despite this promise, the synthesis of collections of macrocycles has been historically challenging due to difficulties in the formation of large rings. Diversity-Oriented Synthesis (DOS) emerged in the early 2000s as a powerful strategic solution to the construction of diverse molecular libraries. This review details the various strategies developed within the field of DOS for the synthesis of macrocycle libraries, utilizing modern synthetic methodology to deliver structurally diverse collections of macrocyclic molecules, and the exploration of their therapeutic potential. Section 1 of this work details the use of algorithmic strategies and is divided into Build/Couple/Pair, Advanced Build/Couple/Pair, Initiate/Propagate/Terminate, Fragment-Based Domain Shuffling, Two-Directional Synthesis, and Successive Ring Expansion. Section 2 covers strategies based on ring distortion reactions, including Sequential Cycloaddition/Fragmentation, Ring Expansions, and Miscellaneous