Diversity-Oriented Synthesis of Macrocyclic Scaffolds Utilizing Organo- and Metal Catalysis
Final Report Abstract
Small molecule modulators of biological targets play a crucial role in biology and medicine. In this context, diversity-oriented synthesis (DOS) provides strategies towards generating small molecules with a broad range of unique scaffolds, and hence 3-dimensionality, to target a broad area of biological space. In the presented study, an organocatalysis-derived DOS library of macrocycles was synthesized exploiting the pluripotency of aldehydes in a built/(couple)n/pair algorithm. The orthogonal combination of multiple diversity-generating organocatalytic steps with alkene metathesis enabled the synthesis of 51 distinct macrocyclic structures bearing 48 unique scaffolds in only 2-4 steps without the need for protecting groups. Furthermore, merging organocatalysis and alkene metathesis in a one-pot protocol facilitated the synthesis of drug-like macrocycles with natural product-like levels of shape diversity in a single step.
Publications
- Angew. Chem. 2014, 126, 13309; Angew. Chem. Int. Ed. 2014, 53, 13093
A. Grossmann, S. Bartlett, M. Janecek, J. T. Hodgkinson, D. R. Spring
(See online at https://doi.org/10.1002/anie.201406865)
