Synthesis of 9-(2,3-Dideoxy-2-fluoro-β-d-threo-pentofuranosyl)adenine (FddA) via a Purine 3‘-Deoxynucleoside

Abstract

A synthesis of 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine (1, FddA) via a 6-chloro-9-(3-deoxy-beta-D-erythro-pentofuranosyl)-9H-purine (9), which was readily obtained from inosine (5), is described. Fluorination at the C2'-beta position of the purine 3'-deoxynucleoside with diethylaminosulfur trifluoride was improved by the introduction of a 6-chloro group and proceeded in moderate yield. Purine 3'-deoxynucleoside derivatives were also subjected to nucleophilic reactions with triethylamine trihydrofluoride and gave the desired fluorinated nucleoside in good yield. The safety and yield of the fluorination process were greatly improved by the use of triethylamine trihydrofluoride. The influence of the sugar ring conformation and 6-chloro group on the rate of the nucleophilic reaction against elimination are also discussed.

The Synthesis of an Antiviral Fluorinated Purine Nucleoside: 3'-α-Fluoro-2',3'-dideoxyguanosine

“…Previously, we succeeded in significantly improving the fluorination yield of 6-chloropurine-3'-deoxyriboside with DAST during the synthesis of FddA 1 (2b,19). We speculated that the introduction of a chlorine atom at the 6-position of the purine base might have a beneficial influence -even on the reactivity of the C3'-position of the riboside.…”

The Chemoenzymatic Synthesis of 2-Chloro- and 2-Fluorocordycepins

“…base of readily available natural ribonucleosides, 5a,b,7-9,12, [14][15][16][17] and (ii) the convergent synthesis of nucleosides by the condensation of heterocyclic base with suitably protected glycosylated reagent. 5c,6,10,11,13 Both approaches suffer from well-known shortcomings, which are inherent in the chemistry of nucleosides, such as a multistage character, the need for the introduction of the base and sugar protective groups followed by their removal after the glycoside bond formation, the absence of regioselectivity of the glycoside bond formation, and finally purification of the desired compounds by column chromatography resulting in the low yields of the desired end products.…”

“…nose donor in the synthesis of 2-halogenated derivatives 9 and 3 of cordycepin (Scheme 3). Inosine (4) was transformed into 2′,5′-di-O-acetyl-3′-deoxyinosine (7) essentially as described by Takamatsu et al (54% overall yield) 17 with some modifications. Treatment of inosine (4) with trimethyl orthoacetate in DMF in the presence of catalytic amounts of dichloroacetic acid gave the derivative 5, condensation of which with acetyl bromide afforded, after workup and silica gel column chromatography, the xylo-bromide 6 in 78% combined yield (cf.…”

“…4 A large number of publications devoted to the chemical synthesis of cordycepin and related 3′-deoxyribonucleosides have been reviewed; 5 reports relevant to this publication are also available. [6][7][8][9][10][11][12][13][14][15][16][17] In biological fluids, cordycepin undergoes deamination by ubiquitous adenosine deaminase (ADA) to give 3′-deoxyinosine (8), which is devoid of biological activity. 4 For this reason, the study of the biological activity of cordycepin is carried out with the simultaneous application of an ADA inhibitor 18 or using 2-fluoro(chloro) derivatives of cordycepin [3′d 2F(Cl) Ado], which are resistant to the action of a variety of adenosine deaminases from diverse sources.…”

Fluorinated Nucleosides as Antiviral and Antitumor Agents

“…The same group later provided another synthetic sequence starting from inosine 8 [10][11]. The 6-chloropurine 3′-deoxyriboside 10 was obtained in 5 steps via 2′,5′-diacetyl compound 9 in 50% overall yield.…”