A Multidimensional Diversity-Oriented Synthesis Strategy for Structurally Diverse and Complex Macrocycles
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- 作者：Feilin Nie ; Dominique L. Kunciw ; Dr. David Wilcke ; Dr. Jamie E. Stokes ; Dr. Warren R. J. D. Galloway ; Sean Bartlett ; Dr. Hannah F. Sore and Prof. David R. Spring
- 刊名：Angewandte Chemie
- 出版年：2016
- 出版时间：September 5, 2016
- 年：2016
- 卷：128
- 期：37
- 页码：11305-11309
- 全文大小：4463K
- ISSN：1521-3757
文摘
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.