Stereoselective Synthesis of Photoreactive Peptidomimetic γ-Secretase Inhibitors

The first asymmetric synthesis of novel, potent photoreactive γ-secretase inhibitors 2 and 3 has been accomplished. Two stereoselective methods for the preparation of lactone 9 are described. Protected benzophenone intermediate 19 is prepared via an aldol-elimination reaction followed by a PtO₂-catalyzed asymmetric hydrogenation. Two routes leading from 19 to compounds 2 and 3 are evaluated. The application of 3 as an activity-based probe has been demonstrated by localizing γ-secretase activity in the plasma membrane of intact cells.