Synthesis and crystal structure of 2′-deoxy-2′-fluoro-4′-thioribonucleosides: substrates for the synthesis of novel modified RNAs

We report herein the synthesis of appropriately protected 2′-deoxy-2′-fluoro-4′-thiouridine (5), -thiocytidine (7), and -thioadenosine (35) derivatives, substrates for the synthesis of novel modified RNAs. The synthesis of 5 and 7 was achieved via the reaction of 2,2′-O-anhydro-4′-thiouridine (3) with HF/pyridine in a manner similar to that of its 4′-O-congener whereas the synthesis of 35 from 4′-thioadenosine derivatives was unsuccessful. Accordingly, 35 was synthesized via the glycosylation of the fluorinated 4-thiosugar 25 with 6-chloropurine. The X-ray crystal structural analysis revealed that 2′-deoxy-2′-fluoro-4′-thiocytidine (8) adopted predominately the same C3′-endo conformation as 2′-deoxy-2′-fluorocytidine.     

Synthesis of novel 4′-C-methyl-1′,3′-dioxolane pyrimidine nucleosides and evaluation of its anti-HIV-1 activity

The key glycosyl donor for the target molecule 12 was prepared by two-step sequences; (1) acetalization of tert-butyldimethylsilyloxyacetaldehyde with 3-bromopropanediol, (2) DBN-initiated β-elimination of the resulting 2-(tert-butyldimethylsilyloxy)methyl-4-bromomethyl-1,3-dioxolane 11. Electrophilic glycosidation between 12 and silylated pyrimidine nucleobase proceeded efficiently to provide a mixture of β- and α-anomers of the respective glycosides 14 and 15. Tin radical-mediated reduction of the bromomethyl functional group of 14 and 15 gave protected 4′-C-methyl-dioxorane uracil- 16 and thymine nucleoside 17. The respective cytosine nucleoside 18 was synthesized from 16. De-silylation of 4′-methyl-1′,3′-dioxolane pyrimidine nucleosides 16–18 gave the target molecules. Evaluation of the anti-HIV-1 activity of the β- and α-anomers of the novel 4′-C-methyl-1′,3′-dioxolane nucleosides 22β,α–24β,α revealed that none of the nucleoside derivatives possess anti-viral activity against HIV-1 and show cytotoxicity against MT-4 cells at 100 μM.     

Nucleophilic substitution approach to 4′-substituted thymidines by employing 4′-benzenesulfonyl leaving group

Synthesis of 4′-substituted thymidines was investigated based on nucleophilic substitution using organosilicon and organoaluminum reagents. Two substrates having a benzenesulfonyl leaving group at the 4′-position were prepared for this purpose: 1-[4-benzenesulfonyl-3,5-bis-O-(tert-butyldimethylsilyl)-2-deoxy-α-l-threo-pentofuranosyl]thymine (8α) and the 4′-(benzenesulfonyl)thymidine derivative (8β). The reaction of 8α with organosilicon reagents (Me₃SiCH₂CHCH₂ and Me₃SiN₃) in combination with SnCl₄ gave preferentially the 4′-substituted β-d-isomer: the 4′-allyl (12β) and 4′-azido (15β) derivatives, respectively. The reaction of 8α with AlMe₃, however, gave the 4′-methyl-α-l-isomer (16α) as the major product, presumably through an ion pair mechanism. By employing the substrate 8β in this reaction, the 4′-methylthymidine derivative (16β) was obtained exclusively in high yield. The 4′-ethyl (20β) and 4′-cyano (24β) derivatives were also synthesized by reacting 8β with the respective organoaluminum reagent.     

3′-Selective modification of a 4′,5′-didehydro-5′-deoxy-2′,3′-epoxyuridine using nucleophiles

1-(2,3-Anhydro-5-deoxy-4,5-didehydro-α-l-erythro-pent-4-enofuranosyl)uracil 4 was obtained by the treatment of 5′-iodo-2′,3′-epoxyuridine 5 with LiHMDS in excellent yield. The pyrimidine nucleoside 4 possesses quite unique vinyl epoxide moiety within the molecules. The reactions of 4 with a variety of nucleophiles gave 3′-substituted pyrimidine nucleosides without the formation of the corresponding 2′-substituted isomers. In the case of NaN₃ or PhSH, the corresponding 5′-adduct was obtained as a minor product together with the expected 3′-adduct.     

Efficient synthesis of novel dipyridoimidazoles and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives

Novel dipyrido[1,2-a;3′,4′-d]imidazoles 7a-d, dipyrido[1,2-a;4′,3′-d]imidazoles 8a,c and pyrido[1′,2′;1,2]imidazo[4,5-d]pyridazine derivatives 9a-d were synthesized by two pathways: thermal electrocyclic reaction of 3-alkenylimidazopyridine-2-oximes 10 and direct condensation of ethyl glycinate (or hydrazine) with 2,3-dicarbonylimidazo[1,2-a]pyridines 11.     

5′-Noraristeromycin possessing a C-1′ cyclopentyl double bond: a new carbanucleoside structural prototype

Prior to this work only two examples of carbanucleosides possessing a C-1′/C-6′ double bond had been reported and they were minor derivatized side products arising during other targeted syntheses. To develop this structural feature into a new class of potential antiviral agents, the 5′-nor derivative of aristeromycin with such an olefinic structure (6) represents the first example. In this regard, treatment of (1′S,2′S,3′S,4′R,5′S)-6-chloro-9-(2′,3′-isopropylidenedioxy-6′-oxabicyclo[3.1.0]hex-4′-yl)purine (7) with sodium methoxide yielded 6 via an E′₂-like elimination pathway. A convenient way to the C-4′ epimer of 6 (that is, 17) also arose during these studies and is described. Antiviral analysis of 6 and 17 failed to produce any significant activity.     

Synthesis of 4′-benzoyloxycordycepin from adenosine

With an aim to synthesize 4′-substituted cordycepins, the 4′-benzoyloxy precursor (9) was prepared from adenosine through an electrophilic addition (iodo-benzoyloxylation) to the 4′,5′-unsaturated derivative (5) and subsequent radical-mediated removal of the 3′-iodine atom of the resulting adducts (6). Usefulness of 9 was briefly verified by synthesizing the 4′-allyl (12) and 4′-cyano (13) analogues of cordycepin.     

Synthesis of a series of novel 2′,3′-dideoxy-6′,6′-difluoro-3′-thionucleosides

A series of novel 2′,3′-dideoxy-6′,6′-difluoro-3′-thionucleosides 1a-d, analogues of 3TC that has high biological activities against HIV and HBV, have been synthesized from the gem-difluorohomoallyl amine 7 in a straightforward fashion. Our synthesis featured the construction of thiofuranose skeleton through ring closure of key intermediates and installation of pyrimidine ring with amino group in compounds 13a,b.     

Application and details of photoinduced oxidative cyclization of 5-(4′,9′-methanocycloundeca-2′,4′,6′,8′,10′-pentaenylidene)pyrimidine-2,4,6(1,3,5H)-triones and related compounds

As novel methodology for synthesizing the furan ring, a photoinduced oxidative cyclization of 5-(4′,9′-methanocycloundeca-2′,4′,6′,8′,10′-pentaenylidene)pyrimidine-2,4,6(1,3,5H)-triones (7a-c) and related compounds 9a-c was accomplished to give 5,10-methanocycloundeca[4,5]furo[2,3-d]pyrimidine-2,4(1,3H)-dionylium tetrafluoroborates (8a-c⁺·BF₄⁻) and related compounds 2a-c⁺·BF₄⁻, respectively. In the photoinduced oxidative cyclization, the molecular oxygen in air is used as oxidant and the reaction proceeds under mild conditions to give desired products without byproducts, and thus, it is interesting from the viewpoint of the green chemistry. On the reactions of the mono-substituted derivatives 7d,e and 9e,f, the selectivity of the photoinduced cyclizations were reversed as compared with those of the DDQ-promoted oxidative cyclizations. By the NMR monitoring of the reactions of 7a and deuterated compound 7a-D₂ under degassed conditions, the details of the reaction pathway were clarified and rationalized on the basis of the MO calculation by the 6-31G^∗ basis set of the MP2 levels as well.     

Synthesis of (3′R,5′S)-3′-hydroxycotinine using 1,3-dipolar cycloaddition of a nitrone

To synthesize (3′R,5′S)-3′-hydroxycotinine [(+)-1], the main metabolite of nicotine (2), cycloaddition of C-(3-pyridyl)nitrones 3a, 3c, and 15 with (2R)- and (2S)-N-(acryloyl)bornane-10,2-sultam [(2R)- and (2S)-8] was examined. Among them, l-gulose-derived nitrone 15 underwent stereoselective cycloaddition with (2S)-8 to afford cycloadduct 16, which was elaborated to (+)-1.     

A simple and stereodivergent strategy for the synthesis of 3′-C-branched 2′,3′-dideoxynucleosides exploiting (Z)-but-2-en-1,4-diol and (R)-2,3-cyclohexylideneglyceraldehyde

Barbier type additions of allylic bromide 4, derived from (Z)-but-2-en-1,4-diol 2 to (R)-2,3-cyclohexylideneglyceraldehyde 1 were performed through mediation with Zn employing Luche’s procedure and also with low valent Cu, Co, and Fe which were produced via bimetal redox strategy in THF to afford 5c,d as the major products. From these, 5a,b were prepared following an oxidation-reduction protocol. Compound 5c was exploited as a representative starting material to develop a simple and inexpensive strategy toward the synthesis of 3′-C-branched 2′,3′-dideoxynucleosides having stereodiversity at 3′- and 4′-positions.     

Studies on bis(1′-ortho-carboranyl)benzenes and bis(1′-ortho-carboranyl)biphenyls

Reactions between the C,C′-dicopper(I) derivative of ortho-carborane and ortho-, meta- and para-diiodobenzene are reported. The reaction with 1,2-C₆H₄I₂ unexpectedly afforded 2,2′-bis(1′-ortho-carboranyl)biphenyl, [HCB₁₀H₁₀CC₆H₄]₂2, whereas reactions with 1,3- or 1,4-C₆H₄I₂ provided alternative routes to 1,3-bis(1′-ortho-carboranyl)benzene 3 and 1,4-bis(1′-ortho-carboranyl)benzene 4, respectively. The crystal structure of the biphenyl derivative 2 revealed significant distortions in the biphenylene framework attributable to the proximity of the two bulky carborane cages. UV absorption spectra and electrochemical data on 2 and 3 showed little electronic communication between the two carborane cages in either, and negligible π-conjugation between the two ortho-phenylene rings in 2. However, substantial evidence was found of electronic communication between the carborane cages via the para-phenylene bridge in 4. B3LYP/6-31G^∗ computations have been carried out on compounds 2 and 4, on 4,4′-bis(ortho-carboranyl)biphenyl 6 and on 1,2-bis(1′-ortho-carboranyl)benzene 7. Those on 2, 4 and 6 show the computed geometries to be in very good agreement with the experimental geometries: those on 7 allowed the reported molecular geometry of this compound to be revised and revealed a long cage C–C bond of 1.725(3) Å.     

Diversity of coordination modes in the polymers based on 3,3′,4,4′-biphenylcarboxylate ligand

Four new compounds [Ni₂(4,4′-bpy)(3,4-bptc)(H₂O)₄]_n (1), [Ni(4,4′-bpy)(3,4-H₂bptc)(H₂O)₃]_n (2), [Mn₂(2,2′-bpy)₄(3,4-H₂bptc)₂] (3) and {[Mn(1,10-phen)₂(3,4-H₂bptc)]·4H₂O}_n (4) (3,4-H₄bptc=3,3′,4,4′-biphenyltetracarboxylic acid, 4,4′-bpy=4,4′-bipyridine, 2,2′-bpy=2,2′-bipyridine, 1, 10-phen=1, 10-phenanthroline), have been prepared and structurally characterized. In all compounds, the derivative ligands of 3,4-H₄bptc (3,4-bptc⁴⁻ and 3,4-H₂bptc²⁻) exhibit different coordination modes and lead to the formation of various architectures. Compounds 1 and 2 display the three-dimensional (3D) framework: 1 shows a 3,4-connected topological network with (8³)(8⁵·10) topology symbol based on the coordination bonds while in 2, the hydrogen-bonding interactions are observed to connect the 1D linear chain generating a final 3D framework. 3 exhibits the 2D layer constructed from the hydrogen-bonding interactions between the dinuclear manganese units. Complex 4 shows the double layers motif through connecting the 1D zigzag chains with hydrogen-bonded rings. The thermal stability of 1-4 and magnetic property of 1 were also reported.     

Synthesis of 1′-fluorouracil nucleosides as potential antimetabolites

The first synthesis of 1′-fluoronucleosides, which has long been synthetic targets as the potential antimetabolites, was achieved. Electrophilic fluorination of the 1′-position occurred to form an anomeric mixture of 1′-fluorouridine derivatives, when the lithium enolate, prepared from 3′,5′-O-tetraisopropyldisiloxane-1,3-diyl (TIPDS)-protected 2′-ketouridine (10) and LiHMDS, was treated with an electrophilic fluorinating agent such as NFSI (13). Subsequent reduction of the 2′-keto-moiety of the resulting β-nucleoside gave the protected 1′-fluorouridine 16 and its arabino-type congener 17. Alternatively, nucleophilic fluorination was also successful. Thus, treatment of 2′,3′,5′-tri-O-acetyl-1′-phenylselenouridine (20) with DAST/NBS produced the 1′-fluorouridine triacetate (21) and its α-anomer 22.     

A convenient synthesis of substituted 2,2′:6′,2″-terpyridines

The 2,2′:6′,2″-terpyridines 7a-c were prepared in good yield by reacting α-acetoxy-α-chloro-β-keto-esters 3a-c with bis-amidrazone 4 and 2,5-norbornadiene 6 in ethanol at reflux. Compounds 3a and 3b gave the 2,2′:6′,2″-terpyridines 9a and 9b, respectively, in moderate yield when treated with compound 4 and enamine 8.     

Synthesis of furan 4′-thio-C-nucleosides, their methylsulfonium and sulfoxide derivatives. Evaluation as glycosidase inhibitors

A series of furan C-nucleosides having a sulfur atom in the sugar ring were synthesised. The α and β anomers of 3-ethoxycarbonyl-2-methyl-5-(4′-thio-d-erythrofuranosyl)furans 10 and 11 were obtained by acid treatment of (4′-S-acetyl-4′-thio-d-arabino-tetritol-1-yl)furan 9. Oxidation of 10 with m-chloroperbenzoic acid gave sulfoxide 12 as one epimer at the sulfur atom whereas 11 was transformed into sulfoxide 13 as an epimeric mixture. S-Methylation of 10 and 11 with methyl triflate led to sulfonium salts 14 and 15. The prepared compounds were found to be moderate inhibitors of α-l-fucosidase.     

Synthesis, crystal and molecular structure of gold(I) thiophenolate with 4′-ferrocenyl[1,1′]biphenylisocyanides

The syntheses of ferrocenylbiphenylisocyanide gold(I) thiophenolato complexes are described. The preparative route starts from ferrocenylphenylbromide and proceeds in six steps to yield the desired gold(I) complexes, (thiophenolato)gold{(4′-ferrocenyl[1,1′]biphenyl-4-yl)isocyanide} (11) and (thiophenolato)gold{(4′-ferrocenyl-3,5-dimethyl[1,1′]biphenyl-4-yl)isocyanide} (12) in good yields. The synthetic pathways were developed as a first step toward realizing the goal of preparing metallomesogens based on ferrocenyl-polyphenylenes coordinated to gold(I) thiophenolates, in which long chain alkoxy groups are substituted para to sulfur on the phenyl ring. The crystal structures of (chloro)gold{(4^′-ferrocenyl[1,1′]biphenyl-4-yl)isocyanide} (9) and 12 are reported. Complex 9 crystallizes in the space group P2₁/c and 12 crystallizes in P2₁/n. Complexes 9 and 12 show short intermolecular Au-Au contacts of 3.3765(7) Å and 3.3334(3) Å, respectively.     

A new synthetic procedure to spiro[cyclohexane-1,3′-indoline]-2′,4-diones

A new synthetic pathway to spiro[cyclohexane-1,3′-indoline]-2′,4-diones was found starting from 3-chloromethylene-2-indolones 1 and Danishefsky's diene 2. Their synthesis consists of several steps involving the formation of the cycloadducts, the 6-chloro-4-trimethylsilyloxy-2-methoxyspiro[cyclohex-3-en-1,3′-indolin]-2′-one derivatives, transformed into spiro[cyclohexa-2,5-dien-1,3′-indoline]-2′,4-diones via 6-chloro-spiro[cyclohex-2-en-1,3′-indoline]-2′,4-dione intermediates. The reduction of spiro[cyclohexa-2,5-dien-1,3′-indoline]-2′,4-diones gave spiro[cyclohexane-1,3′-indoline]-2′,4-diones 7. Using a ‘one pot reaction’, starting from 1 and 2, compounds 7 were obtained in satisfactory overall yield.     

A convenient synthesis of 1′-H-spiro-(indoline-3,4′-piperidine) and its derivatives

A simple synthetic route has been developed to prepare 1′-H-spiro(indoline-3,4′-piperidine) (1d). Dialkylation of 2-fluorophenylacetonitrile with N-(tert-butyloxycarbonyl)-bis(2-chloroethyl)amine (5) gave 6. Deprotection of Boc followed by cyclization resulted 1d in 67% overall yield. Selective Boc or Cbz protection of 1′-N gave 1a or 1b with 90 and 85% yield, respectively. Thus, in a five-step procedure, 1a and 1b were synthesized from commercially available reagents in over 50% overall yield. All 3 compounds (1a, 1b and 1d) can be utilized as templates to synthesize compounds for GPCR targets.     

The novel transition metal free synthesis of 1,1′-biazulene

Reaction of 1-azulenyl methyl sulfoxide (1) under acidic conditions gave the 1,1′-biazulene derivative 3. Methylmercapt groups of 3 were readily converted to formyl groups by Vilsmeier reaction to afford 3,3′-diformyl-1,1′-biazulene (4), which reacted with pyrrole in the presence of acetic acid to give the parent 1,1′-biazulene (5). Reaction of 5 with pyridine in the presence of Tf₂O gave 3,3′-dihydropyridyl-1,1′-biazulene derivative 6. 3,3′-(4-Pyridyl)-1,1′-biazulene (7) was obtained by the reaction of 3 with KOH in EtOH at room temperature in good yield.