Stereoselective Synthesis of Photoreactive Peptidomimetic ?-Secretase Inhibitors.

Division of Molecular Pharmacology & Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York, United States
The Journal of Organic Chemistry (Impact Factor: 4.64). 11/2004; 69(21):7344-7. DOI: 10.1021/jo0486948
Source: PubMed

ABSTRACT The first asymmetric synthesis of novel, potent photoreactive gamma-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 PtO(2)-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 gamma-secretase activity in the plasma membrane of intact cells.

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