Practical syntheses of antiviral nucleosides

Guanosine produced by fermentation is one of the nucleosides most readily available on an industrial scale. We have recently developed several processes leading to known antiviral agents starting with guanosine. The processes involve enzymatic transglycosylation for stavudine (d4T), chemical transpurination for acyclovir and ganciclovir, and novel alkylauon for penciclovir and famciclovir. Introduction 5'-Guanylic acid (Guanosine 5'-monophosphate, 5'-GMP) is one of the nucleotides widely distributed in nature and has been isolated from hydrolyzates of yeast RNA in 191 1 (ref. 1). Since the disodium salt of 5'-GMP was recognized as a good flavor enhancer (ref. 2) and later found to be a major flavor component of shiitake mushroom (lentinus edodes sing.), much attention has been paid to the industrial process for 5'-GMP. Combining a biological process for the production of guanosine 1 and a direct phosphorylation process of the unprotected nucleoside, an industrial process for 5'-GMP was commercialized in Japan. Having 1 available in quantity at a reasonable cost, we envisioned establishing a practical process for manufacturing the major known antiviral nucleosides such as stavudine 2, acyclovir 3, ganciclovir 4, penciclovir 5 and famciclovir 6. In order to realize this, we carried out extensive studies on enzymatic transglycosylation, chemical transpurination and novel N9-selective alkylation of guanine derivatives. Here we wish to report the practical syntheses of antiviral nucleosides starting with 1.