title: Diversity-oriented synthesis of drug-like macrocyclic scaffolds using an orthogonal organo- and metal catalysis strategy.
abstract: Small-molecule modulators of biological targets play a crucial role in biology and medicine. In this context, diversity-oriented synthesis (DOS) provides strategies toward generating small molecules with a broad range of unique scaffolds, and hence three-dimensionality, to target a broad area of biological space. In this study, an organocatalysis-derived DOS library of macrocycles was synthesized by exploiting the pluripotency of aldehydes. 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 two to four 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.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW (UK) http://www-spring.ch.cam.ac.uk/
authors.forename: André
authors.initials: A
authors.lastname: Grossmann
authors.forename: Sean
authors.initials: S
authors.lastname: Bartlett
authors.forename: Matej
authors.initials: M
authors.lastname: Janecek
authors.forename: James T
authors.initials: JT
authors.lastname: Hodgkinson
authors.forename: David R
authors.initials: DR
authors.lastname: Spring
mesh_terms: D002384:Catalysis; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure
chemical_list: D047028:Macrocyclic Compounds
keywords: carbenes; macrocycles; metathesis; organocatalysis; synthetic methods