Synthesis of 2′‐Azido‐2′,3′‐didehydro‐2′,3′‐dideoxythymidine

Abstract

Compound 15 – the 2′‐azido analog of the anti‐HIV compound 2′,3′‐didehydro‐2′,3′‐dideoxythymidine – was synthesized. Treatment of 5′‐O‐trityl‐β‐D‐ribofuranosylthymine (1) with DAST or MSTF gave the 2,2′‐anhydro derivative 2. The latter and its 3′‐O‐benzoate 3 were used for the synthesis of the 2′‐azido‐2′‐deoxy derivatives 4 and 5. Two routes to the synthesis of 15 from 5 were investigated. (i) Treatment of 5 with DAST gave a mixture of the 5′‐O‐trityl derivatives 12 and 13 as well as 1‐(2‐azido‐2,3‐dideoxy‐3‐fluoro‐β‐D‐xylofuranosyl)thymine (16) along with 2,3′‐anhydro derivative 14 (2%). Detritylation of the mixture yielded 15 (39%) and 16 (12%). (ii) Mesylation of 5 gave 17 which yielded 15 upon saponification and detritylation. Compound 15 showed moderate inhibitory activity against HIV‐1 and HIV‐2 in MT‐4 cells.

2‘-Chloro-2‘,3‘-dideoxy-3‘-fluoro-d-ribonucleosides: Synthesis, Stereospecificity, Some Chemical Transformations, and Conformational Analysis

“…The preferred elimination of HF instead of HCl is unexpected on the basis of the greater strength of the C−F bond (105.5 kcal/mol) compared to that of the C−Cl bond (78.5 kcal/mol). A similar trend is displayed by 1-(2-azido-2,3-dideoxy-3-fluoro-β- d -ribofuranosyl)thymine ( 17 ): 35 treatment of 17 with 1 M MeONa/MeOH under reflux for 5 h furnished, after standard workup and subsequent chromatography, the vinyl azide 18 as the main product, along with the unconsumed starting compound 17 in 47% and 33% isolated yield, respectively.

3

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“…Found: C, 45.61; H, 3.96. The 1 H and 13 C NMR spectra are in accord with those measured for the same compound previously synthesized by an alternative procedure 40 and obtained as an amorphous powder.…”

“…39 The preferred elimination of HF instead of HCl is unexpected on the basis of the greater strength of the C-F bond (105.5 kcal/mol) compared to (2) 5/N 6Bz -adenine/SnCl4, 1.0:2.0:5.0, mol; CH3CN/1,2-dichloroethane (2:1, vol), reflux, 5 h (5 + 6, 7.5%; 8a, 9%, 8b, 66%); (3) 5/N 4Bz -cytosine/SnCl4, 1.0:2.0:3.0, mol; CH3CN, reflux, 5 h (5 + 6, 18%; 9a, 8%; 9b, 56%); (e) NH3/MeOH, rt, 24 h (10a, 28%; 10b, 55%; 11a, 78%; 11b, 83%; 12a, 80%; 12b, 78%). MeONa/MeOH under reflux for 5 h furnished, after standard workup and subsequent chromatography, the vinyl azide 18 40 as the main product, along with the unconsumed starting compound 17 in 47% and 33% isolated yield, respectively. Adenine nucleosides 8a,b, 11b, and 20 35 displayed a similar course of HF elimination on treatment with 1 M MeONa/MeOH under reflux, affording the corresponding vinyl chlorides 19 and 22 and the vinyl azide 21 (Scheme 3).…”

“…12,18,24 The structures of the olefins 16, 18, 19, 21, and 22 were confirmed by 1 H and 13 C NMR spectroscopy and are in agreement with the reported data for closely related compounds. 39,40,45 A qualitative inspection of the absolute values of 3 J FC1′ and 3 J FC5′ (Table S4) of the nucleosides 10a,b, 11a,b, 12b, 17, and 20 point clearly to a high preference for the S-type pentofuranose ring conformation. In this conformation, the F-C3′-C4′-C5′ and F-C3′-C2′-C1′ fragments are in antiperiplanar (ca.…”

2‘-Amino-2‘-deoxyuridine via an Intramolecular Cyclization of a Trichloroacetimidate

“…The opening of a 2,2‘- O -anhydro nucleoside by a 3‘- O -benzoate has been described whereby 3‘,5‘-di- O -benzoyl-2,2‘- O -anhydro- l -uridine upon treatment with boron trifluoride etherate afforded a mixture of 3‘,5‘- and 2‘,5‘-dibenzoates of l -uridine in 80% yield and a 3‘- N -phenylcarbamate have opened the 2,2‘-anhydrouridine linkage. The use of trichloroacetonitrile for this purpose is not readily evident from the chemical literature.…”