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.     

2'-chloro-2',3'-dideoxy-3'-fluoro-d-ribonucleosides: synthesis,stereospecificity, some chemical transformations,and conformational analysis

The synthesis of methyl 5-O-benzoyl-2-chloro-2,3-dideoxy-3-fluoro-beta-d-ribofuranoside (5) and its use as a glycosylating agent for persilylated thymine, N(6)-benzoyladenine, and N(4)-benzoylcytosine are described (Scheme 1). The 2'-chloro-2',3'-dideoxy-3'-fluoro-d-ribonucleosides 10-12 synthesized were transformed to 2',3'-dideoxy-3'-fluoro-alpha- and -beta-d-erythro-pentofuranoside nucleosides of thymine (13a,b), adenine (14a,b), and cytidine (15a,b) by treatment with tributyltin hydride in the presence of alpha,alpha'-azobisisobutyronitrile (Scheme 2). Treatment of 2'-chloro-2',3'-dideoxy-3'-fluoro-d-ribonucleosides with 1 M MeONa/MeOH under reflux for 1-5 h afforded 2',3'-didehydro-2',3'-dideoxy-2'-chloro-d-pentofuranosyl nucleosides as the principal products (47-81%) of the reaction, along with recovered starting nucleoside (11-33%) (Scheme 3). Easy HF elimination was also observed in the case of the 2'-azido-2',3'-dideoxy-3'-fluoro-beta-d-ribofuranosides of thymine (17) and adenine (20) (Scheme 3). The role of conformational peculiarities of 2'-chloro-2',3'-dideoxy-3'-fluoro-d-ribonucleosides as well as of 17 and 20 in the observed exclusive elimination of HF is discussed. The conformational analysis of a rather broad palette of 2,3-dideoxy-3-fluoro-2-(X-substituted)-d-ribofuranosides was performed with the aid of the PSEUROT (version 6.3) program, using (i) the recently reparametrized Karplus-type relation (Chattopadhyaya and co-workers. J. Org. Chem. 1998, 63, 4967) and (ii) empirical bond angle correction terms suggested by us. The predictive power of the Brunck and Weinhold model (J. Am. Chem. Soc. 1979, 101, 1700) of the gauche effect between atoms and groups as a conformational driving force acting upon the pentofuranose ring is explored. Their model invokes maximum antiperiplanar sigma <--> sigma stabilization when the donating bond is the least polar one and the acceptor orbital is at the most polarized bond and is found at least as satisfactory, and in various specific cases more so than, as rationalizations on the basis of the preference of the gauche vs the trans conformation of two vicinal electronegative substituents (Wolfe. Acc. Chem. Res. 1972, 5, 102).     

New synthesis of 2',3'-didehydro-2',3'-dideoxynucleosides.

The 3'-iodonucleoside 4 and the 3'-O-methylsulfonylthymidine 9 have been synthesized by condensation of silylated uracils 2 with methyl 5-O-tert-butyldiphensilyl-2,3-dideoxy-3-iodo-D-threo-pentofuran oside (3) and methyl 5-O-tert-butyldiphenylsilyl-2-deoxy-3-methylsulfonyl-D-erythro- pentofuranoside (8), respectively. The nucleoside 4 and 9 produced the corresponding 2',3'-didehydro-2',3'-dideoxynucleosides 5 in an elimination reaction on treatment with sodium methoxide. The compounds 5b showed no antiviral activity against HIV-1.     

De novo synthesis of 4'-ethoxy nucleoside analogues

Butenolides 5a and 13 were used as optically active templates in the de novo synthesis of 4'-disubstituted nucleoside analogues. The butenolides were reduced and acylated in situ to give acetates 10 and 14. Vorbrüggen coupling gave the protected nucleoside analogues 11 and 15. Reduction of 11 gave 4'-ethoxy-2',3'-dideoxythymidine (6) and deprotection of 15 gave 4'-ethoxy-2',3'-dideoxydidehydrothymidine (7). The cis-dihydroxylation of a variety of butenolides occurred with the major product formed from oxidation of the beta-face.     

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.     

Synthesis and conformational analysis of new cyclobutane-fused nucleosides

[structure: see text]. A stereselective synthesis of 3-oxabicyclo[3.2.0]heptane nucleoside analogues, which were designed as conformational mimics of the anti-HIV agents 2',3'-didehydro-2',3'-dideoxythimidine (stavudine, d4T) and 2',3'-didehydro-2',3'-dideoxyadenosine (d4A), is described. The target compounds were prepared by condensation of a common intermediate bicyclic acetate, derived from a homochiral 2(5H)-furanone, with pyrimidine and purine bases under modified Vorbrüggen conditions. The conformational behavior of the synthesized nucleoside analogues was studied by NMR spectroscopy and X-ray crystallography.     

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.     

Stereocontrolled syntheses of deoxyribonucleosides via photoinduced electron-transfer deoxygenation of benzoyl-protected ribo- and arabinonucleosides

The stereocontrolled, de novo syntheses of beta-2'-deoxy-, alpha-2'-deoxy-, beta-3'-deoxy-, and beta-2', 3'-dideoxyribonucleosides are described. Strategically protected ribose, arabinose, and xylose glycosylation precursors were synthesized bearing C2-esters capable of directing Vorbrüggen glycosylation. The key step is the regioselective deoxygenation of the desired hydroxyl group as either the benzoyl- or 3-(trifluoromethyl)benzoyl derivative. This deoxygenation is accomplished via a photoinduced electron-transfer (PET) mechanism using carbazole derivatives as the photosensitizer. The syntheses of the desired deoxynucleoside generally proceed in three steps from a common, readily available precursor.     

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 novel L-2',3'-dideoxy-2'-trifluoromethyl-4'- thiocytidines from alpha-trifluoromethyl-alpha,beta-unsaturated ester

A short and efficient synthesis of L-2',3'-dideoxy-2'-trifluoromethyl-4'-thiocytidines is described. (2R,4S/2S,4S)-5-(tert-Butyldimethylsiloxy)-2-trifluoromethylpentan-4-olide (3a and 3b) are prepared from alpha-trifluoromethyl-alpha,beta-unsaturated ester (1) in three steps and converted to compounds 6a and 6b. The corresponding 1-O-acetyl derivatives 8a and 8b were obtained via the usual Pummerer rearrangement from 6a and 6b in two steps, which were in turn used to synthesize L-4'-thiocytidines 10a and 10b.     

A simplified and efficient route to 2'-O, 4'-C-methylene-linked bicyclic ribonucleosides (locked nucleic acid).

A novel efficient method for the synthesis of locked nucleic acid (LNA) monomers is described. The LNA 5',3'-diols containing thymine, 4-N-acetyl- and 4-N-benzoylcytosine, 6-N-benzoyladenine, and 2-N-isobutyrylguanine as nucleobases were prepared via convergent syntheses. The method is based on the use of the common sugar intermediate 1,2-di-O-acetyl-3-O-benzyl-4-C-methanesulfonoxymethyl-5-O-methanesulfonyl-D-erythro-pentofuranose (8) that easily can be prepared from D-glucose in multigram scale. Four different nucleobases were stereoselectively coupled to 8 using a modified Vorbrüggen procedure to give the corresponding 4'-C-branched nucleoside derivatives. Subsequent ring closing furnished the protected LNA nucleosides. The 5'-O-mesyl groups were efficiently displaced by nucleophilic substitution using sodium benzoate. Saponification of the 5'-benzoates followed by catalytic removal of the 3'-O-benzyl groups afforded the free LNA diols. The exocyclic amino groups of adenosine and cytidine were selectively acylated to give 4-N-acetyl- or 4-N-benzoyl-LNA-C and 6-N-benzoyl-LNA-A. The isobutyryl group of guanine was retained during the preparation of 2-N-isobutyryl-LNA-G. The LNA-T diol and base-protected LNA diols can be directly converted into LNA-phosphoramidites for automated chemical synthesis of LNA containing oligonucleotides.     

Synthesis,photochemical synthesis and antitumor evaluation of novel derivatives of thieno[3',2':4,5]thieno[2,3-c]quinolones

The novel derivatives of thieno[3',2':4,5]thieno[2,3-c]quinolones 6a, 6b, 7, 10a and 10b were synthesized in multistep synthesis starting from thiophene-3-carboxaldehyde and malonic acid reacting in aldol condensation or from 3-bromothiophenes or methyl 4-bromothiophene-2-carboxylate reacting in Heck reaction. They resulted in corresponding substituted thienylacrylic acids 3a-c, which were cyclized into thieno[2,3-c]thiophene-2-carbonyl chlorides 4a-c and converted into thieno[2,3-c]thiophene-2-carboxamides 5a-d. Prepared carboxamides were photochemically dehydrohalogenated into corresponding substituted thieno[3',2':4,5]thieno[2,3-c]quinolones 6a-d. Compound 7 was prepared from 6d by alkylation with N-[3-(dimethylamino)propyl]chloride hydrochloride in the presence of NaH. Compounds 10a and 10b were prepared from 6c in the multistep synthesis over acid 8 and acid chloride 9. Compounds 6a, 6b, 7, 10a and 10b were found to exert cytostatic activities against malignant cell lines: pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal carcinoma (Hep2), colon carcinoma (CaCo-2), melanoma (HBL), and human fibroblast cell lines (WI-38). The compound 6b, which bears the 3-dimethylaminopropyl substituent on quinolone nitrogen and methoxycarbonyl substituent on position 9, exhibited marked antitumor activity. On the contrary, compound 7, which also bears the 3-dimethylaminopropyl substituent on the quinolone nitrogen but anilido substituent on position 9, exhibited less antitumor activity than the others.     

Total synthesis of (+)-blasticidin s

The first total synthesis of the peptidyl nucleoside antibiotic, blasticidin S (1), has been achieved by the coupling reaction of cytosinine (3) and blastidic acid (2). A key step in the synthesis of cytosinine (3) is the sigmatropic rearrangement of allyl cyanate 24; this reaction provided efficient and stereoselective access to 2,3-dideoxy-4-amino-D-hex-2-enopyranose (26 a). Further elaboration of 26 a gave methyl hex-2-enopyranouronate 29, and cytosine N-glycosylation of 31 using the Vorbrüggen conditions for the silyl Hilbert-Johnson reaction furnished the differentially protected cytosinine (32) in 11 steps from 2-acetoxy-D-glucal (14) (4.0 % overall yield). Synthesis of the Boc-protected blastidic acid 47 in nine steps starting from chiral carboxylic acid 35 (23 % overall yield) utilized Weinreb's protocol for the preparation of benzyl amide 38 and Fukuyama's protocol for the synthesis of the secondary amine 40. Assembly of the protected cytosinine (32) and blastidic acid (47) by the BOP method in the presence of HOBt, and finally elaboration to 1 by deprotection of the fully protected 54 established the total synthesis of blasticidin S (1).     

Synthesis of 5-Substituted-3-[(2’R,4’R)-4’-Hydroxy-2’-hydroxymethyltetrahydrofuran-4’-yl]-1,2,4-oxadiazoles and Their Epimers

The syntheses of 5-substituted-3-[( 2' R, 4' R)-4 ' -hydroxy-2 ' -hydroxymethyltetra-hydrofuran-4' -yl]D-1 ,2, 4-oxadiazoles and their epimers were accomplished with the aid of th construction of 1,2, 4-oxadiazoles by condensation of O-acylated cyanohydrins with hydroxylamine via intramolecular transacylation and subsequent cyclization.     

Diastereoselective synthesis of some carbocyclic 2′-oxa-3′-aza-nucleosides

Two strategies for the synthesis of isoxazolidinyl nucleosides as potential antiviral agents are reported: a one-step approach based on 1,3-dipolar cycloaddition of D-lyxosyl nitrone with N,N-dibenzyl-9-vinyl adenine, and a two-step methodology based on the Vorbrüggen nucleosidation of the 5-acetoxyisoxazolidine. The chiral D-lyxosyl nitrone undergoes regioselective 1,3-dipolar cycloadditions with N,N-dibenzyl-9-vinyl adenine and vinyl acetate giving 5-substituted isoxazolidines as a mixture of four diastereoisomers in good yields. The condensation of 5-acetoxyisoxazolidine with silylated uracil, thymine, and N-acetylcytosine proceeded with moderate to good stereoselectivity with the formation of the expected isoxazolidinyl β-and α-nucleosides. Dedicated to Prof. Dr. E. Lukevics on the occasion of his 70th birthday __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 01, pp. 14–21, Januvary, 2007.     

Facile preparation of the oxetane-nucleosides

Efficient and practical large scale synthesis of suitably protected 1',2'-oxetane locked purine and pyrimidine nucleosides for incorporation in oligo-DNA or -RNA by solid-phase synthesis is reported. A high regio and stereoselectivity with preferential formation of the beta-anomer in the glycosylation reaction, using the Vorbrüggen procedure, was achieved by a convergent synthetic procedure with orthogonal protection strategy using either 1,2-di-O-acetyl-3,4-O-isopropylidene-6-O-(4-toluoyl)-d-psicofuranose or 2-O-acetyl-6-O-benzyl-1,3,4-tri-O-(4-toluoyl)-d-psicofuranose as the glycosyl donor.     

Synthesis of thiopyrano[4″,3″:4′,5′]pyrido[3′,2′:4,5]furo[3,2-d]pyrimidines

<正>Reactions of the 6-hydroxy-thiopyrano[3,4-c]pyridine-5-carbonitrile derivative 1 withα-halo-carbonyl compounds gave the ortho-substituted intermediates 2a-c which were converted into furo[2,3-b]thiopyrano[4,3-d]pyridines 3a-c by fusion of a furan moiety under basic conditions.Further cyclization of 3a-c led to a fusion of a pyrimidine ring,yielding the tetracyclic products 6,7 and 8.In addition,condensation of 6 with various aromatic aldehydes afforded the corresponding imines 9a,b.Mannich reaction of 7 gave products 10a,b.     

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).     

Substituted 2-aminonicotinamides in the synthesis of pyrido[2,3-d]pyrimidin-4(1H)-ones, 2,3-dihydropyrido- [2,3-d]pyrimidin-4(1H)-ones, and 11b,12-dihydropyrido- [2',3':4,5]pyrimido[2,1-a]isoindole-5,7-diones

The reactions of 2-aminonicotinamides with triethyl orthoformate, carboxylic acids chlorides, aldehydes, and 2-formylbenzoic acid were studied. As a result pyrido[2,3-d]pyrimidin-4(1H)-ones, 2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-ones, and 5,7,11b,12-tetrahydropyrido[2',3':4,5]pyrimido- [2,1-a]isoindole-5,7-diones were obtained.