Combining the Castagnoli-Cushman reaction and directed C(sp3)-H activation for the short synthesis of densely functionalized
2-pyrrolidones as BACE-1 inhibitors Andrea Trabocchi, Lorenzo Baldini, Elena Lenci Department of Chemistry “Ugo Schiff”, University of Florence, Italy
The possibility of obtaining C(sp 3 )-rich structures combined to the increase of the molecular complexity through their functionalization in few steps and convenient processes represents a significant goal for synthetic chemists. In this view, directed Pd-catalyzed C(sp 2 /sp 3 )-H activation reactions soon emerged as powerful tools for activating non-acidic C-H bonds as novel sites of functionalization in high stereoselectivity, otherwise unexploitable. 1 Accordingly, we focused our interest to the short synthesis of densely functionalized 2-pyrrolidones by combining the Castagnoli-Cushman reaction with directed Pd-catalyzed C(sp 3 )-H functionalization, taking advantage of the developing carboxylic group properly derivatized with 8-aminoquinoline as a directing group. The extent of stereoselectivity was found dependent on the electronic content of the aryl iodide employed in the C-H functionalization. Interestingly, such short synthesis enabled the identification of new chemical entities with sub- micromolar activity towards BACE-1 enzyme, takin advantage of the additional aryl group as a key appendage for improved biological activity.
References 1. J. He, M. Wasa, K.S.L. Chan, Q. Shao, J.Q. Yu, Chem. Rev. 2017 , 117, 8754−8786
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