A multidimensional diversity-oriented synthesis strategy for structurally diverse and complex macrocycles

Journal article

Synthetic macrocycles are an attractive area in drug discovery. However, their use has been hindered by a lack of versatile platforms for the generation of structurally (and thus shape) diverse macrocycle libraries. Herein, we describe a new concept in library synthesis, termed multidimensional diversity-oriented synthesis, and its application towards macrocycles. This enabled the step-efficient generation of a library of 45 novel, structurally diverse, and highly-functionalized macrocycles based around a broad range of scaffolds and incorporating a wide variety of biologically relevant structural motifs. The synthesis strategy exploited the diverse reactivity of aza-ylides and imines, and featured eight different macrocyclization methods, two of which were novel. Computational analyses reveal a broad coverage of molecular shape space by the library and provides insight into how the various diversity-generating steps of the synthesis strategy impact on molecular shape.

Authors: Nie, F; Kunciw, DL; Wilcke, D; Stokes, JE; Galloway, WRJD

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: Angewandte Chemie International Edition
• Volume: 55
• Issue: 37
• Pages: 11139-11143
• Publication date: 2016-08-03
• DOI: 10.1002/anie.201605460
• EISSN: 1521-3773
• ISSN: 1433-7851
• Pmid: 27484830
• Language: English
• Keywords: macrocycles; diversity-oriented synthesis; synthetic methods; molecular diversity; synthesis design