Fragment-based domain shuffling approach for the synthesis of pyranbased macrocycles

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 17; p. 6751
• Main Authors: Comer, Eamon, Liu, Haibo, Joliton, Adrien, Clabaut, Alexandre, Johnson, Christopher, Akella, Lakshmi B, Marcaurelle, Lisa A
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 26-04-2011
• Subjects: Chemical reactions; Chemical synthesis; Correlation analysis; Solid solutions
• ISSN: 0027-8424; 1091-6490

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. [PUBLICATION ABSTRACT]