A Brief Overview of Two Major Strategies in Diversity-Oriented Synthesis: Build/Couple/Pair and Ring-Distortion

Abstract

In the interdisciplinary research field of chemical biology and drug discovery, diversity-oriented synthesis (DOS) has become indispensable in the construction of novel small-molecule libraries rich in skeletal and stereochemical diversity. DOS aims to populate the unexplored chemical space with new potential bioactive molecules via forward synthetic analysis. Since the introduction of this concept by Schreiber, DOS has evolved along with many significant breakthroughs. It is therefore important to understand the key DOS strategies to build molecular diversity with maximized biological relevancy. Due to the length limitations of this mini review, we briefly discuss the recent DOS plans using build/couple/pair (B/C/P) and ring-distortion strategies for the synthesis of major biologically relevant target molecules like natural products and their related compounds, macrocycles, and privileged structures.

Keywords: build/couple/pair; diversity-oriented synthesis; macrocycle; natural product; privileged structure; ring-distortion.

Figure 1

(A) A schematic representation of the B/C/P strategy. (B) Outline of lycopodium alkaloids and their unnatural scaffolds with their respective pairing patterns. (C) Outline of the B/C/P strategy for the construction of libraries consisting of macrocycles and medium-sized rings. (D) A pDOS library established via the B/C/P strategy for the inhibition of protein–protein interactions.

Figure 2

(A) Schematic representation of the ring-distortion strategy. (B) The complexity-to-diversity (CtD) strategy for the construction of diverse and complex compounds starting from readily available natural products. (C) The ring-distortion strategy for the construction of macrocyclic lactone and lactam libraries. (D) The ring-distortion strategy for the construction of biologically relevant benzannulated small molecules.