title: A Multidimensional Diversity-Oriented Synthesis Strategy for Structurally Diverse and Complex Macrocycles.
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.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: Feilin
authors.initials: F
authors.lastname: Nie
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: Dominique L
authors.initials: DL
authors.lastname: Kunciw
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: David
authors.initials: D
authors.lastname: Wilcke
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Stokes
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: Warren R J D
authors.initials: WR
authors.lastname: Galloway
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: Sean
authors.initials: S
authors.lastname: Bartlett
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: Hannah F
authors.initials: HF
authors.lastname: Sore
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK. spring@ch.cam.ac.uk.
authors.forename: David R
authors.initials: DR
authors.lastname: Spring
keywords: diversity-oriented synthesis; macrocycles; molecular diversity; synthesis design; synthetic methods