Diversity‐Oriented Synthesis of Macrocycle Libraries for Drug Discovery and Chemical Biology

The identification of new bioactive small molecules is increasingly reliant upon the synthesis and screening of chemical libraries. The extent of structural diversity and the proportion of unique scaffolds in a library are commonly acknowledged to be the most important factors in determining its success in identifying new biologically relevant compounds. Particularly important in this respect are macrocycles, which display unique physicochemical attributes and are used in many clinical applications. Despite these advantages, macrocycles remain under-represented in many contemporary screening collections, predominantly due to their synthetic intractability. Diversity-oriented­ synthesis is a powerful method for the construction of deliberately diverse collections of small molecules, and many research groups are working to apply its principles to the synthesis of structurally and functionally diverse macrocyclic libraries. In this short review we introduce why macrocycles are promising chemotypes in screening libraries, especially for challenging biological targets such as protein–protein interactions, and we review a collection of strategies developed in our laboratory for the diversity-oriented synthesis of macrocycle libraries. We analyse a selection of the macrocycle collections generated using these approaches and conclude with our perspective on future directions of the field. 1 Introduction 1.1 Chemical Libraries in Drug Discovery and Chemical Biology 1.2 Macrocycles in Screening Collections 1.3 Diversity-Oriented Synthesis 2 Build/Couple/Pair 2.1 Strategy Overview 2.2 Typical B/C/P Strategies 2.3 Advanced B/C/P Strategies 2.4 Two-Directional Synthesis 3 Alternative Approaches to Macrocycle Library Synthesis 4 Discussion and Concluding Remarks