Nucleic acid related compounds. 53. Synthesis and biological evaluation of 2′-deoxy-β-threo-pentofuranosyl nucleosides. "Reversion to starting alcohol" in Barton-type reductions of thionocarbonates

Abstract

CLERCQ. Can. J. Chem. 66, 1258 (1 988). Treatment of selectively 3',5'-protected P -D -~y l~f~r a n~~y l nucleosides (4) with phenyl chlorothionocarbonate and DMAP followed by hydrogenolysis of the resulting (2'-0-phenoxythiocarbonyl) phenyl thionocarbonate esters (6) with tributylstannane/AIBN, and deprotection, gave 2'-deoxy-P-D-threo-pentofuranosyl nucleosides (7). Formation of a by-product bis(nuc1eosid-2'-y1)thionocarbonate dimer (8) was detected in the uracil nucleoside reaction sequence. Its subsequent reduction provides one explanation for "reversion to starting alcohol" in Barton-type deoxygenation reactions. Only the guanine 2'-deoxynucleoside analogue (76) Chem. 66, 1258Chem. 66, (1988.La rtaction des nucltosides de P-D-xylofurannosyle prottgts stlectivement en 3',5' (4) avec du chlorothionocarbonate de phCnyle et du DMAP, suivie d'une hydrogtnolyse des esters thionocarbonates de (0-phtnoxythiocarbonyl-2') de phtnyle (6) avec le tributylstannane/AIBN et d'une dtprotection, conduit aux nuclCosides du dtsoxy-2' P-D-thre'o-pentofurannosyle (7). Dans la suite de rtactions impliquant le nucltoside d'uracile, on a dttectt la formation du dimtre du thionocarbonate de bis-(nuclCosidy1-2') (8) comme sous-produit. Sa rtduction substquente permet d'expliquer la ccrtversion vers I'alcool de dtpart~ qui est observte dans des rtactions de dtsoxygtnation du type de Barton. L'analogue dCsoxy-2' nucltoside de la guanine (7b) est le seul i prtsenter une activitt antivirale (faible) (contre le virus herpts simplex de type 1).[Traduit par la revue]Methods for the synthesis of P-D-xylofuranosyl nucleosides via base-sugar coupling (ref. 1, and references therein) and for selective 2'-deoxygenation of nucleosides (2) have been developed by us previously. We now report combination of these approaches to give 2'-deoxy-P-D-threo-pentofuranosyl nucleosides (7) and their evaluation for antiviral activity in several cell systems.In the pioneering studies of the Cambridge group, Michelson and Todd (3) reported preparation of the 02,C3'-cyclonucleoside of thymidine and its hydrolysis to give 1-(2-deoxy-P-Dthreo-pentofuranosy1)thy mine (7e) in 1955. Fox and Miller (4) and Horwitz et al. (5) later described careful characterization of this product. An analogous procedure was employed (6) for the preparation of 1-(2-deoxy-P-D-threo-pentofuranosy1)uracil ( 7 4 .Goodman and co-workers (7) first prepared 9-(2-deoxy-P-Dthreo-pentofuranosy1)adenine (7a) (and its 3'-deoxy isomer) by nucleophilic ring opening (oxirane) of 9-(2,3-anhydro-P-D1yxofuranosyl)adenine with benzylthiolate followed by desulfurization. Analogous (acid-catalyzed) ring opening with bromide followed by hydrogenolysis with tributylstannane gave alternative access to the isomeric adenine 2'-(7a) and 3'-deoxythreo nucleoside products (8). Ikehara's 8-mercaptoadenineo or the previous paper in this series, see ref. 23.'~uthor to whom inquiries may be addressed at the Department of Chemistry, Brigham Young University, Provo, Utah 84602, U.S.A. S8,C2'-cyclonucleoside desul...

Xylose‐DNA Containing the Four Natural Bases

“…-Monomers. The synthesis of 2'-deoxy-P-~-xyloguanosine (1) was first described by Robins and coworkers [6]. It was performed by condensation of 1,2-di-0 -acetyl-3,5-di-O -benzoyl-P-D-xylofuranose with N,-acetylguanine followed by deacetylation and subsequent deoxygenation of the 2'-OH group.…”

“…Determination of the Michaelis-Menten constants according to [2]. [6]. Compound 5 (2.8 g, 10 mmol) and dihutyltin oxide (2.5 mmol, 10 mmol) were suspended in MeOH (250 ml) and refluxed for 3 h. After cooling to r.t. and addition of Et3N (2 1 ml),p-toluenesnlfonyl chloride was added, and stirring was continued for another 20 min.…”

“…9-(2'-Deoxy-~-~-threo-pentofuranosyl)guanine (1) [6]. Compound 2 (1.0 g, 3.6 mmol) was dissolved in H,O (200 ml) under warming, then cooled to 30°, and adenosine deaminase (EC 3.5.4.4, calf intestine mucosa; 50 pg) was added.…”

Synthesis of 2′-Deoxy-α-l-threofuranosyl Nucleoside Triphosphates

“…Using standard deoxygenation conditions with α,α′-azobisiso­butyronitrile (AIBN) as a radical initiator and the tributyl­stannane as the proton source and thione scavenger, we observed efficient conversion of 3a – d′ to 4a – d′ for each nucleoside, except protected TNA cytidine derivative 3b . ,, In this case, the reaction consistently produced a mixture of compounds that included 2b as a side product . In an effort to avoid this problem, we pursued milder reaction conditions that included the use of triethylborane and tris­(trimethylsilyl)­silane as alternative reagents for the homolytic deoxygenation of the 2′-hydroxyl group. , Dry oxygen was introduced into the reaction, which triggered a radical cascade and resulted in the clean synthesis of 4a – d′ within 30 min at room temperature.…”

3′-Substituted Thymine α-L-nucleoside Derivatives as Potential Antiviral Agents: Synthesis and Biological Evaluation

“…1b). As a pursuit of our ongoing work on sugar-modified nucleoside analogues (Gosselin et al, 1986(Gosselin et al, , 1987(Gosselin et al, , 1990Robins et al, 1988;Puech et al, 1989a,b;Genu-Dellac et et., 1991), the rationale for envisaging these molecules stems from an attempt to investigate the structure-activity relationship of nucleoside analogues in order to develop more effective antiviral agents.…”