Efficient synthesis and reaction pathway studies of novel fused morpholine oxadiazolines for use as gamma secretase modulators

An efficient synthesis of fused morpholine oxadiazoline core structures was accomplished in an effort to identify optimum gamma secretase modulator leads in the treatment of Alzheimer’s disease. Reaction pathways were proposed for the key intramolecular cyclization reaction, and chemistry was designed to probe these hypotheses. A highly diastereoselective synthesis of potent GSM 27 was achieved. To further improve the synthesis, a second route was developed which successfully addressed the formation of a fused seven-member ring by-product, and provided opportunities to accelerate future SAR studies.