You are here

Proceedings of the National Academy of Sciences of the United States of America DOI:10.1073/pnas.1015255108

Fragment-based domain shuffling approach for the synthesis of pyran-based macrocycles.

Publication TypeJournal Article
Year of Publication2011
AuthorsComer, E, Liu, H, Joliton, A, Clabaut, A, Johnson, C, Akella, LB, Marcaurelle, LA
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue17
Pages6751-6
Date Published2011/04/26
ISSN0027-8424
Abstract

Complexity and the presence of stereogenic centers have been correlated with success as compounds transition from discovery through the clinic. Here we describe the synthesis of a library of pyran-containing macrocycles with a high degree of structural complexity and up to five stereogenic centers. A key feature of the design strategy was to use a modular synthetic route with three fragments that can be readily interchanged or "shuffled" to produce subtly different variants with distinct molecular shapes. A total of 352 macrocycles were synthesized ranging in size from 14- to 16-membered rings. In order to facilitate the generation of stereostructure-activity relationships, the complete matrix of stereoisomers was prepared for each macrocycle. Solid-phase assisted parallel solution-phase techniques were employed to allow for rapid analogue generation. An intramolecular nitrile-activated nucleophilic aromatic substitution reaction was used for the key macrocyclization step.

URLhttp://www.pnas.org/cgi/pmidlookup?view=long&pmid=21383141
DOI10.1073/pnas.1015255108
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/21383141?dopt=Abstract