Synthesis Of Isoxazoline Substituent Hydroxyproline With Hydantoin By Liquid Phase Synthesis On PEG4000

Recently, the techniques of soluble polymer support to synthesize small molecule libraries were applied successfully to combinatorial chemistry and parallel synthesis. Synthetic approaches that utilise soluble polymers termed liquid-phase chemistry, couple the advantages of homogeneous solution chemistry ( high reactivity, lack of diffusion phenomena and ease of analysis ) with those of solid phase methods ( use of excess reagents and easy isolation and purification of products ).The hydroxyproline motif is found in many compounds with biological activity. For example, they have been shown to act as protease inhibitors and receptor antagonists. Also, both hydantoin and isoxazoline heterocycles are structural elements which frequently impart biological activity. Indeed, a large number of hydantoins have been prepared for various biological applications, both medicinal and agro-chemical.At chapter 1, the development of liquid-phase chemistry, especially the reagents and reactions loaded on PEG, was reviewed.At chapter 2, we reviewed the development of hydroxyproline, hydantoin and isoxazoline in solution-phase and liquid-phase first. We loaded alkyne substituent hydroxyproline on PEG followed with reaction with in situ generated nitrile oxides through 1,3-dipolar cycloaddition. At last we cleavaged the small molecule from PEG with triethylamine and isocyanate or isothiocyanate to give isoxazoline substituent hydroxyproline with hydantoin in 90% yields and 85~98% purity.