Selective acetylation reactions of hyaluronic acid benzyl ester derivative

Abstract

The reaction of hyaluronic acid benzyl ester derivative ( 1) with trimethyl orthoacetate in the presence of an acid catalyst in N,N-dimethylformamide gave the expected 4,6-orthoester 2, along with its hydrolysed products the 6- O- ( 3) and the 4- O- ( 4) acetate hyaluronic acid benzyl esters as minor components. Acid hydrolysis of 2 followed by O-4→O-6 acetyl migration using t-butylamine afforded a mixture which contained the 6-acetate 3 as the major and the 4-acetate 4 as the minor compound. Synthesis of a mixture of 2′,3′,6- ( 6) and 2′,3′,4- ( 7) tri-acetates was achieved by peracetylation of 2 followed by treatment with aqueous acetic acid. Compound 1 on treatment with 2,2-dimethoxypropane in dimethyl sulfoxide in the presence of p-toluenesulfonic acid afforded the corresponding 4,6- O-isopropylidene derivative 8. The 2′,3′-di- O-acetate 10 was obtained from 8 by conventional acetylation followed by de-acetylation using trifluoroacetic acid. Acetylation of 1 with acetic anhydride in a mixture of N,N-dimethylformamide and pyridine gave the expected 2′,3′,4,6-tetraacetate derivative 11. In order to facilitate the NMR assignments of the acetate groups in 3– 11, the 2′,3′-diacetate-4,6-di(trideuterioacetate) 12 and the 2′,3′-di(trideuterioacetate)-4,6-diacetate 13 were prepared. The effect of substituents on conformational changes around the glycosidic linkages has been investigated.