期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 55, 期 37, 页码 11139-11143出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201605460
关键词
diversity-oriented synthesis; macrocycles; molecular diversity; synthesis design; synthetic methods
资金
- Biotechnology and Biological Sciences Research Council Funding Source: Medline
- Wellcome Trust Funding Source: Medline
- EPSRC [EP/K039520/1, EP/J016012/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/J016012/1, EP/K039520/1] Funding Source: researchfish
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.
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