A Multidimensional Diversity-Oriented Synthesis Strategy for Structurally Diverse and Complex Macrocycles
Authors
Nie, Feilin
Kunciw, DL
Wilcke, D
Stokes, JE
Galloway, Warren
Publication Date
2016-09-05Journal Title
Angewandte Chemie International Edition
ISSN
1433-7851
Publisher
Wiley
Volume
55
Issue
37
Pages
11139-11143
Language
English
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Nie, F., Kunciw, D., Wilcke, D., Stokes, J., Galloway, W., Bartlett, S., Sore, H., & et al. (2016). A Multidimensional Diversity-Oriented Synthesis Strategy for Structurally Diverse and Complex Macrocycles. Angewandte Chemie International Edition, 55 (37), 11139-11143. https://doi.org/10.1002/anie.201605460
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.
Keywords
diversity-oriented synthesis, macrocycles, molecular diversity, synthesis design, synthetic methods
Sponsorship
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).
Funder references
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)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1002/anie.201605460
This record's URL: https://www.repository.cam.ac.uk/handle/1810/262549
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International
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