Hiroshi Shiragami

Synthesis of 9-(2-Hydroxyethoxymethyl)guanine (Acyclovir) from Guanosine

Abstract A convenient synthesis of 9-(2-hydroxyethoxymethyl)guanine (acyclovir) from guanosine by chemical transpurination was developed. The isomerization of the 7-isomer to the desired 9-isomer and the purification of the 9-isomer was achieved simply by concentration, heating and further crystallization.

Synthesis of 1-(2,3-Dideoxy-β-d-glycero-pent-2-enofuranosyl)thymine (d4T; Stavudine) from 5-Methyluridine †

Abstract A practical synthetic method of d4T (3) from 5-methyluridine (2a) was developed. The Marumoto-Mansuri method was modified using 2′,3′-O-methoxy-ethylidene-5-methyluridine (10) as an intermediate to afford 1-(3,5-di-O-acetyl-2-bromo-2-deoxy-β-D-ribofuranosyl)thymine (6a) in high yield with less formation of by-products. The reaction mechanism was also discussed. †Dedicated to Dr. Yoshihisa Mizuno on the occasion of his 75th birthday.

A novel method for the synthesis of ddA and F-ddA via regioselective 2'-O-deacetylation of 9-(2,5-DI-O-acetyl-3-bromo-3-deoxy-β-D-xylofuranosyl) adenine

Abstract Regioselective 2′-O-deacetylation of 9-(2,5-di-O-acetyl-3-bromo-3-deoxy-β-D-xylofuranosyl)adenine (1) is achieved by treatment of 1 with β-cyclodextrin (β-CyD) / aq. NaHCO3 or N2H4·H2O / EtOH. The 9-(5-O-Acetyl-3-bromo-3-deoxy-β-D-xylo-furanosyl)adenine (2) obtained is a common intermediate for the synthesis of 2′,3′-dideoxy-adenosine (ddA) (7) and 9-(2-fluoro-2,3-dideoxy-β-D-threo-pentofuranosyl)-adenine (F-ddA) (9).

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.

Synthesis of 2′,3′-Dideoxypurinenucleosides via the Palladium Catalyzed Reduction of 9-(2,5-Di-O-acetyl-3-bromo-3-deoxy-β-d-xylofuranosyl)purine Derivatives †

Abstract Practical method to produce 2′,3′-dideoxypurinenucleosides from 9-(2,5-di-O-acetyl-3-bromo-3-deoxy-β-D-xylofuranosyl)purines (1) was developed. High ratio of 2′,3′-dideoxynucleoside to 3′-deoxyribonucleoside was obtained by selecting the reaction conditions (solvent, pH and/or base), or changing 2′-acyloxy leaving group. The reaction mechanism was studied by deuteration experiments of 1a and 1-(3,5-di-O-acety1-2-bromo-2-deoxy-β-D-ribofuranosyl)thymine (12). †Dedicated to Dr. Yoshihisa Mizuno on the occasion of his 75th birthday.

AN ECONOMICAL SYNTHESIS OF FAMCICLOVIR

An economical synthesis of famciclovir from N-2-acetyl-7-benzylguanine by a novel regioselective alkylation with the diester cyclopropane compound was developed.