Synthesis of 3'-fluoro-2',3'-dideoxy-2',3'-didehydro-4'-ethynyl-D- and -L-furanosyl nucleosides

An efficient procedure has been developed for the synthesis of 3'-fluoro-2',3'-dideoxy-2',3'-didehydro-4'-ethynyl D- and L-furanosyl nucleosides (1 and 2) starting from 2,3-O-isopropylidene-d-glyceraldehyde. The key intermediate 1-O-benzoyl-3E-fluoro-3,4-unsaturated-5,6-di(tert-butyldimethylsilyloxy)-2-hexanone 8 was obtained in nine steps with the overall yield of 22%. The alpha,beta-unsaturated ketone 8 was then treated with ethynylmagnesium bromide in a typical Grignard reaction procedure to afford the two intermediates 9 and 10, which after deprotection, oxidation, and acetylation gave the corresponding 4-ethynyl-substituted D- and L-sugar moieties 15 and 16, respectively. A series of D- and L-pyrimidine and purine nucleosides were prepared by the coupling of the sugar moieties with various silylprotected bases. The anomeric mixtures were obtained after condensation. After separation, the beta-isomers were further deprotected to yield the target nucleosides. All the newly synthesized 4'-substituted nucleosides were tested for their activities against HIV, among which the D-adenine derivative showed moderate anti-HIV activity (EC(50) = 25.1 microM) without significant cytotoxicity.     

Synthesis of some 3',5'-dideoxy-5'-C-phosphonomethyl nucleosides.

Ammonium [1-(3',5',6'-trideoxy-beta-D-erythro-hexofuranosyl)thymine]-6'- phosphonate (1), ammonium 3',5'-dideoxycytidine-5'-C-methylphosphonate (2) and 3',5'-dideoxyadenosine-5'-C-methyl phosphonic acid (3) have been synthesized and tested for anti-HIV activity. The key steps involved an Arbuzov reaction between triethyl phosphite and 3,5,6-trideoxy-6-iodo-1,2-O-isopropylidene-alpha-D-erythro- hexofuranose (7), followed by condensation with the appropriate nucleoside bases. The substances 1, 2 and 3 have been tested in vitro against HIV.     

Efficient synthesis of 2',3'-dideoxy-2'-amino-3'-thiouridine

[reaction: see text] Metal ion rescue experiments provide a powerful approach to establish the presence and role of divalent metal ions in the biological function of RNA. The utility of this approach depends on the availability of suitable nucleoside analogues. To expand the range of this experimental strategy, we describe the first synthesis of 2',3'-dideoxy-2'-amino-3'-thiouridine (12) in 19.5% overall yield starting from 2,2'-anhydrouridine (1).     

Synthesis of 2',3'-dideoxy-6',6'-difluorocarbocyclic nucleosides

2',3'-Dideoxy-6',6'-difluorouracils, a novel series of gem-difluoromethylenated carbocyclic nucleosides, were synthesized from (Z)-but-2-ene-1,4-diol in 14 steps. A notable step was the construction of the carbocyclic ring via ring-closing metathesis and the incorporation of gem-difluoromethylene group by way of silicon-induced Reformatskii-Claisen reaction of chlorodifluoroacetic ester 3.     

Stereoselective synthesis and conformational study of novel 2',3'-Didehydro-2',3'-dideoxy-4'-selenonucleosides

Stereoselective synthesis of novel 2',3'-didehydro-2',3'-dideoxy-4'-selenonucleosides (4'-seleno-d4Ns) 4a- c was accomplished via 4'-selenoribofuranosyl pyrimidines 11a- c, as key intermediates. 4'-Selenoribofuranosyl pyrimidines 11a- c were efficiently synthesized from d-ribose or d-gulonic gamma-lactone using a Pummerer-type condensation as a key step. Introduction of 2',3'-double bond was achieved by treating cyclic 2',3'-thiocarbonate with 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine.     

Synthesis of 2',3'-dideoxy-2'-trifluoromethylnucleosides from alpha-trifluoromethyl-alpha,beta-unsaturated ester

The treatment of alpha-bromo-alpha,beta-unsaturated esters 2 with FSO(2)CF(2)CO(2)Me and CuI in DMF/HMPA constitutes a new synthetic scheme for the preparation of alpha-trifluoromethyl-alpha, beta-unsaturated esters 3. The trifluoromethylation of (Z)/(E)-ethyl 3-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-bromo-2-propenoate (2e), which is derived from 1-(R)-glyceraldehyde acetonide, yields the key intermediate alpha-trifluoromethyl-alpha,beta-unsaturated esters 3e. This is transformed into anomeric acetates 8a and 8b and is used for the synthesis of a number of 2', 3'-dideoxy-2'-trifluoromethylnucleosides.     

Synthesis of new 2',3'-dideoxy-6',6'-difluoro-3'-thionucleoside from gem-difluorohomoallyl alcohol

[reaction: see text] 2',3'-Dideoxy-6',6'-difluoro-3'-thionucleoside 1b, an analogue of 3Tc that has high biological activities against HIV and HBV, has been synthesized from gem-difluorohomoallyl alcohol 3 in an efficient way. The key intermediate 4-amino-3,3-difluorotetrahydrothiophen-2-ylmethyl benzoate 15 was prepared from 2,2-difluoro-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]but-3-en-1-ol 3 in 11 steps. The construction of pyrimidine ring with the amino group of compound 15 gave the target compound 1.     

Stereoselective synthesis of carbocyclic L-4'-fluoro-2',3'-dideoxyadenosine

[formula: see text] L-(1'S,3'S)-9-[3-Fluoro-3-(hydroxymethyl)cyclopentan-1-yl]adenine 15 has been synthesized from ester 2, which can be conveniently prepared from 2,3-isopropylidene-D-glyceraldehyde 1 in six steps. The key ring closure has been accomplished through an intramolecular nucleophilic substitution reaction.     

Enzymatic and chemical stability of 2',3'-dideoxy-2',3'-didehydropyrimidine nucleosides: potential anti-acquired immunodeficiency syndrome agents

The enzymatic and chemical stability of three 2',3'-dideoxy-2',3'-didehydropyrimidine nucleosides has been studied. Chemical degradtion of the analogues was measured in the pH range of 1.0-9.0. 2',3'-Dideoxy-2',3'-didehydrocytidine (DDCN) degraded rapidly under acidic conditions, but the chemical stability was greater under basic conditions. The chemical degradation of 2',3'-dideoxy-2',3'-didehydrouridine (DDUN) and 2',3'-dideoxy-2',3'-didehydrothymidine (DDTN) was not pH dependent and was faster than that of cytarabine. Enzymatic degradation of DDCN, DDUN and DDTN was not observed in human plasma, though cytarabine was degraded enzymatically under the same conditions. DDCN was also not degraded in the presence of mouse kidney cytidine deaminase.