title: Rules of Macrocycle Topology: A [13]-Macrodilactone Case Study.
abstract: Shape is an inherent trait of a molecule that dictates how it interacts with other molecules, either in binding events or intermolecular reactions. Large-ring macrocyclic compounds in particular leverage their shape when they are selectively bound by biomolecules and also when they exhibit macrocyclic diastereoselectivity. Nonetheless, rules that link structural parameters to the conformation of a macrocycle are still rudimentary. Here we use a structural investigation of a family of [13]-macrodilactones as a case study to develop rules that can be applied generally to macrocycles of different sizes and with a variety of functionality. A characteristic "ribbon" shape is adopted by the [13]-macrodilactones in the absence of stereogenic centres, which exhibits planar chirality. When one stereogenic centre at key positions on the backbone is incorporated into the structure, the planar chirality is dictated by the configuration of the centre. In cases where two stereogenic centres are present, their relationships can either reinforce the characteristic ribbon shape or induce alternative shapes to be adopted. The rules established in the case study are then applied to the analysis of a structure of the natural product migrastatin. They lay the groundwork for the development of models to understand macrocycle-biomolecule interactions and for the preparation of macrocycles with designed properties and activities.
authors.affiliation: Department of Chemistry, University of Connecticut, 55 N. Eagleville Road, U3060, Storrs, CT, 06269-3060, USA.
authors.forename: Anniefer N
authors.initials: AN
authors.lastname: Magpusao
authors.affiliation: Department of Chemistry, University of Connecticut, 55 N. Eagleville Road, U3060, Storrs, CT, 06269-3060, USA.
authors.forename: Kelli
authors.initials: K
authors.lastname: Rutledge
authors.affiliation: Department of Chemistry, University of Connecticut, 55 N. Eagleville Road, U3060, Storrs, CT, 06269-3060, USA.|Department of Theoretical Chemistry, VU University Amsterdam, De Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Trevor A
authors.identifier: http://orcid.org/0000-0002-5128-1004
authors.initials: TA
authors.lastname: Hamlin
authors.affiliation: Department of Chemistry, University of Connecticut, 55 N. Eagleville Road, U3060, Storrs, CT, 06269-3060, USA.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lawrence
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT, 06520, USA.
authors.forename: Brandon Q
authors.initials: BQ
authors.lastname: Mercado
authors.affiliation: Department of Chemistry, University of Connecticut, 55 N. Eagleville Road, U3060, Storrs, CT, 06269-3060, USA.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Leadbeater
authors.affiliation: Department of Chemistry, University of Connecticut, 55 N. Eagleville Road, U3060, Storrs, CT, 06269-3060, USA. mark.peczuh@uconn.edu.
authors.forename: Mark W
authors.identifier: http://orcid.org/0000-0002-3028-6551
authors.initials: MW
authors.lastname: Peczuh
keywords: macrocycles; planar chirality; stereochemistry; structure; synthesis