An Alternative Synthetic Route to (3 R,5 S,1′ S)-5-{1′-[(tert -Butyloxycarbonyl)amino]-3′-methylbutyl}-3-methyldihydrofuran-2(3 H)-one, a Precursor of a Leu-Ala Hydroxyethylene Isostere

An improved synthetic route to (3R,5S,1′S)-5-{1′-[(tert-butyloxycarbonyl)amino]-3′-methylbutyl}-3-methyldihydrofuran-2(3H)-one, a lactone precursor of the Leu-Ala (2R,4S,5S) hydroxyethylene isostere found in many peptidomimetic aspartyl protease inhibitors of Alzheimer's disease, is devised. Alkylation of N-Boc-leucinal with the lithium salt of benzyl propargyl ether instead of ethyl propiolate is the key toward a more reproducible and efficient route to obtain the title lactone from N-Boc-l-leucine in six steps, and an overall yield of 16%.