Identification of BACE-1 inhibitors through directed C(sp 3 )-H activation on 5-oxo-pyrrolidine-3-carboxylic acid derivatives.

Convenient synthesis of stereochemically dense 5-oxo-pyrrolidines was obtained from succinic anyhdride and imines 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. These fully substituted 5-oxopyrrolidines were found to be able to inhibit BACE-1 enzyme with sub-micromolar activity, thanks to the interaction of the key aryl appendage introduced by C(sp 3 )-H activation within BACE-1 S2' subsite.