Beckmann, Henning S G4; Nie, Feilin4; Hagerman, Caroline E4; Johansson, Karl Henrik5; Tan, Yaw Sing4; Wilcke, David4; Spring, David R4
1 Medicinal Chemistry Research, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet2 University of Cambridge3 Drug Research Academy M, Drug Research Academy, Faculty of Pharmaceutical Sciences, Københavns Universitet4 University of Cambridge5 Drug Research Academy M, Drug Research Academy, Faculty of Pharmaceutical Sciences, Københavns Universitet
A prerequisite for successful screening campaigns in drug discovery or chemical genetics is the availability of structurally and thus functionally diverse compound libraries. Diversity-oriented synthesis (DOS) provides strategies for the generation of such libraries, of which the build/couple/pair (B/C/P) algorithm is the most frequently used. We have developed an advanced B/C/P strategy that incorporates multidimensional coupling. In this approach, structural diversity is not only defined by the nature of the building blocks employed, but also by the linking motif installed during the coupling reaction. We applied this step-efficient approach in a DOS of a library that consisted of 73 macrocyclic compounds based around 59 discrete scaffolds. The macrocycles prepared cover a broad range of different molecular shapes, as illustrated by principal moment-of-inertia analysis. This demonstrates the capability of the advanced B/C/P strategy using multidimensional coupling for the preparation of structurally diverse compound collections.