Approaches to the synthesis of 2′-thio analogues of pyrimidine ribosides

Abstract

2'-Deoxy-2'-mercaptouridine (1 ) was obtained in 75% isolated yield by heating 2'-deoxy-2'-(4methoxybenzylthio) uridine (4a) with phenol in trifluoroacetic acid solution. When triphenylmethanol or 9-phenylxanthen-9-01 (5) was added to the products before work-up, compound (4c) or (4d) was obtained. Compound (4) was also obtained in satisfactory overall yield from crude (I), prepared in two steps from 2'-deoxy-2'-(t-buty1thio)uridine (4b). Treatment of compound (4d) first with acetic anhydride in pyridine and then with phosphoryl trichloride, triethylamine, and 1,2,4triazole in acetonitrile gave the triazolo compound (10) in 73% overall yield. Reaction between compound (1 0) and ammonia in dichloromethane [or dimethylamine in dioxane] followed by methanolic ammonia gave the cytidine derivative ( l l a ) [or ( l l b ) ] in good yield. When compounds (?la) and (11 b) were allowed to react with hydrochloric acid in 2-mercaptoethanol solution at room temperature, the hydrochloride salts of 2'-deoxy-2'-mercaptocytidine (2a) and its 4,4-di-N-methyl derivative (2b) were obtained in high isolated yields. The latter compounds readily underwent aerial oxidation in the presence of triethylamine in methanol solution to give the corresponding dimeric disulphides (12a) and (12b). The NMR spectra of the synthetic products are discussed.

Sugar-Modified Nucleosides in Past 10 Years, A Review

“…Treatment of 9-(β-D-arabinofuranosyl)adenine 366 with Ph 3 P and DEAD in 1,4-dioxane/DMF at 70 ˚C followed by treatment of anhydro [133] dO [134] dX [143] dQ [136] dR [137] dS [138] dP [135] dT [139] dU [140] dV [141] dW [142] X = H, OH oxygen is replaced by nitrogen, was synthesized by a route based on stereospecific formation of the azasugar substrates and their subsequent coupling with a suitable nucleic base. Thus, reaction of 2,3-O-isopropylidene-D-glyceraldehyde with pyrrole derivative 372 in the presence of BF 3 ·OEt 2 gave 373, which was converted to 375 by four steps.…”

Efficient Solid Phase Synthesis of Cleavable Oligodeoxynucleotides Based on a Novel Strategy for the Synthesis of 5′‐S‐(4,4′‐Dimethoxytrityl)‐2′‐deoxy‐5′‐thionucleoside Phosphoramidites

“…So we needed the 5'-S-[(MeO) 2 Tr]-protected amidites for an automated synthesis. We converted the 5'-S-[9(4'-methoxyphenyl)-9H-xanthen-9-yl]-5-thiothymidine (7) into the 5'-S-(4,4'-dimethoxytrityl)-5'-thiothymidine (4) [11] by treatment with AgNO 3 in MeOH and pyridine, trituration of the obtained Ag salt with MeOH/AcOH prior to H 2 S bubbling ( 3 8; yield 68% after workup), and treatment of the intermediate thiol 8 with (MeO) 2 TrCl in pyridine. The final phosphitylation of compound 4 with 2-cyanoethyl diisopropylphosphoramidochloridite in the presence of i Pr 2 NEt at 48 gave the corresponding modified phosphoramidite 5 in 73% yield [1b].…”

Carboxymethylsulfonylated Ribopyrimidines: Rational Design of Ribonuclease A Inhibitors Employing Chemical Logic

“…TLC was performed on precoated plates (Merck silica gel 60, F 254 ), and the spots were visualized with UV light or by charring the plates dipped in 5% H 2 SO 4 in MeOH and 5% vanillin in MeOH solutions. www.chemmedchem.org 3'-Deoxy-3'-(ethoxycarbonylmethylthio)uridine (8):C ompound 7 (0.30 g, 0.41 mmol) was converted into the corresponding deprotected thionucleoside following al iterature procedure, [34] and then, Et 3 N( 0.06 mL, 0.46 mmol) was added to as olution of the crude product (0.10 g, 0.38 mmol) in dry CH 2 Cl 2 (5 mL) at 0 8C. All 1 HNMR and 13 CNMR spectra were recorded in CDCl 3 ,[ D 6 ]DMSO, or D 2 O( by using HPLC-grade acetonitrile as in-ternal standard).…”

“…Although formation of the CÀSb ond from the a side of the furanose ring was easily achievedb yo pening uridine lyxoepoxide 3,t he introductiono ft he 2'-OH group from the a side required generation of the 2,2'-O-anhydro ring knownt oa ct as a" leaving group" under nucleophilic conditions. The free thiol group of 7 was exposed by using trifluoroacetic acid (TFA), [34] which also removed the protecting groups from the 2' and 5' sites. [33] Given that 2,2'-O-anhydrouridine is more stable than the 2,3'-isomer,i ntermediate 5 was easily attacked by the O2 atom of the uracil moiety to form 2,2'-O-anhydro compound 6.T he anhydro ring of 6 was protonated by using benzoica cid, and sodium benzoate attacked the 2'-position from the a side of the furanoser ing to produce fully protectedr ibonucleoside 7.…”