Synthesis of (2R, 3R, 4R, 5S)-5-tert-Butyloxycarbonylamino-3,4-Dihydroxy-2-1sopropyl-3,4-O,O-Isopropylidene-6-CyctohexyI-Hexanoic Acid

Abstract

The dipeptidic dihydroxyethylene isostere (27, 3R, 4R, 5S)-5-tert-butyloxy-carbonylamino-3,4-dihydroxy-2-isopropyl-3,4-O,O-isoprop-ylidene-6-cyclohexyl-hexanoic acid, 15, is a representative building block of an important class of unnatural dipeptide mimics. This pseudo-dipeptide of Cha-Val is considered to be a transition-state analog mimic that produces potent inhibitors of the enzyme renin when incorporated into angiotensinogen substrate peptide sequence (1). The same strategy has also been proven successful in the development of potent inhibitors of other aspartyl proteases, including HIV protease (2). This synthetic method has been proven successful in the preparation of 100-g-scale quantity of this important building block, which was used in the preparation of a potent HIV protease inhibitory peptidomimetic, PNU-75875, which was proven effective in the treatment of SIV-infected monkeys (3).