SYNTHESIS OF METHYLENE-EXPANDED OXETANOCIN ISONUCLEOSIDES IN BOTH ENANTIOMERIC FORMS

We report a novel route to isonucleosides of the 'methylene-expanded' oxetanocin class, in both the D-and L-enantiomeric forms, e.g., compou nds L-(+)-2a, D-(-)-2a, and L-(-)-2b, beginning with the simple, known mono-p-bromobenzyl ether 3 of the very inexpensive 2-butene-1,4-diol. Sharpless asymmetric epoxidation of 3 gave either (-) or (+)-4 depend ing on the chirality of the tartrate used. The p-bromobenzyl ether was used since the epoxide product is crystalline and can be recrystalliz ed to high optical purity. Opening of the epoxide with vinylmagnesium bromide gave the 1,3-diol 5, the primary alcohol of which was protecte d as the silyl ether 6. Treatment of 6 with iodonium bis(sym-collidine ) perchlorate afforded the desired 5-(iodomethyl)tetrahydrofuran-3-ol 8 with loss of the bromobenzyl cation in the key step in the synthetic scheme. This iodide 8 was then converted into the bis(silyloxy)-prote cted alcohol 15 by acetylation to give the acetate 10, displacement of iodide with acetate, hydrolysis, and selective protection of the prim ary alcohols. The alcohol 6 could also be converted into 15 via initia l acetylation and then iodocyclization to give 10. The diol 5 could al so be converted into 15 by a similar route involving bis-acetylation a nd iodocyclization followed by functional group transformations. The t osylate of 15 was displaced with the anion of adenine or thymidine to give, alter final desilylation, the desired isonucleosides-the D-adeno sine analogue (-)-2a and the L-adenosine and thymidine analogues (+)-2 a and(-)-2b. All of the stereochemistry of the final products is deriv ed from the first step of the synthesis, namely, the Sharpless asymmet ric epoxidation of 3. The biological activity of the new compounds L-( +)-2a and L-(-)-2b against HIV was determined in the anti-HIV drug-tes ting system of the National Cancer Institute. The adenosine analogue L -(+)-2a was inactive in this screen, while the thymidine analogue L-(- )-2b showed moderate anti-HIV activity (IC50 > 2 x 10(-4) M, EC50 = 8 x 10(-7) M, TI50 > 250).