Synthesis of 2-phenyloxazole derivatives containing amino acids as insulinsensitivity enhancers for treatment of type II diabetes

The search for Insulin Sensitivity Enhancers (ISE) for use in the treatment of Non-insulin Dependent Diabetes Mellitus (NIDDM) has led to the preparat ion of N- [(phenylmethoxy)carbonyl] -O-[[4- [2-(2 -phenyl-4-oxazolyl)ethoxy lphenyl]methyl]-L-serine (1) and 7-[2-(2-phenyl-4-oxazolyl)ethoxyl]-L-1,2,3 ,4-tetrahydro-N-Cbz-isoquinoline-3-carboxylic acid (2), that contain a 2-ph enyloxazole moiety linked to an amino acid in place of the 2,4-thiazolidine dione pharmacophore. The 2-phenyloxazole was incorporated into 1 and 2 in h igh yield by alkylation of 4-hydroxybenzaldehyde or methyl 7-1,2,3,4tetrahy dro-N-benzyloxycarbonyl-fiydroxyi with 2-(2phenyl-4-oxazolyl)ethyl p-toluen esulfonate (16). Successful incorporation of serine into 1 required use of an N-trityl protecting group to minimize Pelimination and epimerization at the alpha -center.