1318256-98-2Relevant academic research and scientific papers
Fragment-based domain shuffling approach for the synthesis of pyran-based macrocycles
Comer, Eamon,Liu, Haibo,Joliton, Adrien,Clabaut, Alexandre,Johnson, Christopher,Akella, Lakshmi B.,Marcaurelle, Lisa A.
scheme or table, p. 6751 - 6756 (2012/03/26)
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.
