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A Multidimensional Diversity-Oriented Synthesis Strategy for Structurally Diverse and Complex Macrocycles

Published version
Peer-reviewed

Change log

Authors

Nie, F 
Kunciw, DL 
Wilcke, D 
Stokes, JE 
Galloway, WRJD 

Abstract

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.

Description

Keywords

diversity-oriented synthesis, macrocycles, molecular diversity, synthesis design, synthetic methods

Journal Title

Angewandte Chemie International Edition

Conference Name

Journal ISSN

1433-7851
1521-3773

Volume Title

55

Publisher

Wiley
Sponsorship
Engineering and Physical Sciences Research Council (EP/J016012/1)
Royal Society (WM150022)
European Research Council (279337)
Engineering and Physical Sciences Research Council (EP/K039520/1)
The research leading to these results has received funding from the European Research Council under the European UnionÏs Seventh Framework Programme (FP7/2007–2013)/ ERC grant agreement no. [279337/DOS]. The authors also thank AstraZeneca, the EPSRC, the BBSRC, the MRC and the Wellcome Trust for funding. F.N. and D.L.K. thank the Gates Cambridge. F.N. also thanks Trinity College for a Krishnan-Ang Studentship. D.W. thanks the DFG for a postdoctoral fellowship (WI 4198/1-1). S.B. thanks the Herchel Smith Fund. The authors thank Dr John Davies for X-ray crystallography and Dr Andrew Bond for refinement (both from the University of Cambridge).