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Fragment-based domain shuffling approach for the synthesis of pyran-based macrocycles.
|Publication Type||Journal Article|
|Authors||Comer, E., Liu H., Joliton A., Clabaut A., Johnson C., Akella LB, and Marcaurelle LA|
|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.|
|Year of Publication||2011|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Date Published (YYYY/MM/DD)||2011/04/26|