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- Title
A Multidimensional Diversity-Oriented Synthesis Strategy for Structurally Diverse and Complex Macrocycles.
- Authors
Nie, Feilin; Kunciw, Dominique L.; Wilcke, David; Stokes, Jamie E.; Galloway, Warren R. J. D.; Bartlett, Sean; Sore, Hannah F.; Spring, David R.
- 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.
- Subjects
MACROCYCLIC compound synthesis; HETEROCYCLIC compounds spectra; MACROCYCLIC compounds; MOLECULAR structure of macrocyclic compounds; DRUG development; MACROMOLECULAR synthesis
- Publication
Angewandte Chemie International Edition, 2016, Vol 55, Issue 37, p11139
- ISSN
1433-7851
- Publication type
Article
- DOI
10.1002/anie.201605460