Highly enantioselective synthesis and potential biological activity of chiral novel nucleoside analogues containing adenine and naturally phenol derivatives

This paper described an efficient synthetic strategy for chiral acyclic nucleoside analogues containing both the phenoxy components of some bioactive natural compounds and a heterocyclic base. The phenoxy components with adenine moiety were incorporated into the chiral acyclic nucleoside analogues through two key synthetic tactics. Chiron 5-(R)-menthyloxy-2(5H)-furanone 5 was obtained in good yield from the cheap starting material furfural via a valuable synthetic route. The asymmetric Michael addition of 5 with adenine and the subsequent reduction reaction afforded the key chiral intermediate, 2-(R)-(9′-adeninyl)-1,4-butanediol 8. The absolute configuration of 8 was established by X-ray crystallography. The intermolecular dehydration reaction between 2-(9′-adeninyl)-1,4-butanediol 8 and phenoxy components 9 on treatment with diethyl azodicarboxylate and triphenylphosphine was carried out to give the chiral acyclic nucleoside analogues 1a-1e. The regioselectivity of the reaction was established by NMR methods, especially through ¹³C NMR shifts and NOE effect observed in the target molecule 1c, as well as by HMBC/HMQC experiments. The target compounds were tested for inhibition of cytopathogenicity against different cancer cells and exhibited potential anticancer activity.     

24,24-Dimethylvitamin D3-26,23-lactones and their 2α-functionalized analogues as highly potent VDR antagonists

Novel vitamin D receptor (VDR) antagonists, 24,24-dimethyl-1α-hydroxyvitamin D₃-26,23-lactones (8 and 9) and their C2α functionalized analogues (8a-c and 9a-c) were efficiently synthesized and their biological activities were evaluated. The construction of vitamin D₃ triene skeleton was achieved by palladium-catalyzed alkenylative cyclization of A-ring precursor enyne (22 and 22a-c) with CD-ring bromoolefin having a 24,24-dimethyl-α-methylene-γ-lactone unit on the side chain (13 and 14). The CD-ring precursors 13 and 14 were prepared by using chromium-mediated allylation of the aldehyde 10 derived from vitamin D₂. On the other hand, the A-ring enyne having 2α-(3-hydroxypropyl) group (22b) was newly synthesized from epoxide 15 using regio- and stereoselective alkylation methodology. The potency of the antagonistic activity of the newly designed analogues (8 and 9) increased up to 12 times that of TEI-9647 (2). Furthermore, introduction of the three motifs, that is, a methyl (8a and 9a), an ω-hydroxypropyl (8b and 9b) or an ω-hydroxypropoxyl group (8c and 9c) into the C2α position of 8 and 9, respectively, resulted in remarkable enhancement, up to 89 times, of the antagonistic activity on VDR.     

Synthesis and binding ability of bile acid-based receptors for recognition of flavin analogues

Novel cholaphanes 6a,b, based on lithocholic and deoxycholic acids, were synthesised through 3a,b by a sequence of reactions involving Cs-salt methodology of macrocyclisation. Cholaphanes 6a,b and acyclic steroidal receptors 3a,b bind flavin analogues via three hydrogen bonds in CHCl₃.     

Silylative N-hydroxyalkylation of amide compounds: application to the synthesis of acyclic alditol-based nucleoside analogues

A rare silylative hydroxyalkylation of amide compounds with chiral aldehydes has been developed utilizing a Lewis acid-Lewis base promoter system consisting of an equimolecular mixture of tert-butyldimethylsilyl trifluoromethanesulfonate and N-diisopropylethylamine. This approach culminated in the synthesis of several enantiopure acyclic nucleoside representatives comprising thymidine analogues 6, 7, 9, 10, 12 and 13, uridine analogues 15 and 16, and 6-chloropurine derivatives 18 and 19.     

Synthesis of (S,Z)-3-[(1H-indol-3-yl)methylidene]hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one: an alternative, enaminone based, route to unsaturated cyclodipeptides

A series of racemic and enantiopure (S,Z)-3-[(1H-indol-3-yl)methylidene]hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one (cyclic Pro-ΔTrp) dipeptide analogues were prepared. Racemic analogues 6a-c were prepared by direct coupling of racemic cyclodipeptide enaminone (R,S)-5 with various indole derivatives. On the other hand, enantiopure analogues were prepared through a copper(I) catalyzed vinyl amidation reaction in which acyclic (S)-Pro-ΔTrp dipeptide analogues 20 and 21 were formed. Acyclic dipeptides were cyclized to enantiopure (S)-Pro-ΔTrp dipeptide analogues 24 and 25. For coupling reactions, vinyl bromides were prepared in several steps. From ethyl acetate (7), enaminone 8 was prepared and coupled with 2-methylindole and 2-phenylindole to give 9 and 10. Direct bromination of 3-(indole-3-yl)propenoates 9 and 10 at position 2 results in vinyl bromides 11 and 12. The Boc protecting group on the indole nitrogen 1′ in vinyl bromides 11 and 12 was introduced, before the copper(I) catalyzed coupling with N-Boc prolinamide 18 was performed. Enantiomeric purity of chiral intermediates and final products was determined mostly by HPLC or ¹H NMR spectroscopy and X-ray diffraction.     

Efficient synthesis of cephalotaxine- and deoxyharringtonine analogues by a trimethylaluminium-mediated domino reaction

The synthesis of cephalotaxine- and cephalotaxine amide analogues 14a-c and 16a-c as well as of the deoxyharringtonine analogues 5a,b was performed employing a trimethylaluminium-mediated domino reaction of 9a-c and 8 to give the spirocyclic compounds 7a-c, which was followed by a palladium catalyzed α-arylation.     

N-Glycosylation of 2,3-dideoxyfuranose derivatives having a (diethoxyphosphorothioyl)difluoromethyl group at the 3α-position

Lewis acid-mediated N-glycosylation of 2,3-dideoxyribofunanosides having a (diethoxyphosphorothioyl)difluoromethyl group at the 3α-position with silylated nucleobases was examined. The phosphorothioyldifluoromethyl was found to be an effective functional group for the diastereoselective synthesis of β-N¹-pyrimidine-nucleotide analogues 26 and 28-30. However, the method was not useful for the diastereoselective synthesis of adenine nucleotide analogues. The nucleotide analogue 26 was transformed to the difluoromethylenephosphonate analogue 31 of thymidine-3′-phosphate by oxidation with m-CPBA, followed by aqueous work-up.     

Reaction of quinidine acetate, epiquinidine and its acetate in superacid: formation of gem-difluoro derivatives with or without rearrangement

In HF-SbF₅, quinidine 1a or its dihydrochloride cyclises previously obtained with usual acids. A similar reaction is observed in the presence of CCl₄. Under similar conditions quinidine acetate 1b and epiquinidine acetate 2b dihydrochlorides both yield 10,10-difluoro derivatives epimeric at C-3, 6 and 7, and 9c and 10b, and a rearranged difluoro derivative 8b and 11b, respectively. Epiquinidine 2a leads to the expected analogues 10a and 11a and to a ketone 9a. Formation of gem-difluoro compounds implies chloro intermediates at C-10, precursors of α-chlorocarbenium ions, which are trapped by a fluoride ion and which lead by halogen exchange to the products.     

Novel dinuclear iron(0) complexes from α,β-unsaturated ketones β-positioned with sulfide and sulfoxide groups

The reaction of Fe₂(CO)₉ with α,β-unsaturated ketones analogues containing β-positioned sulfoxide group 2a-2d afforded dinuclear Fe(0) complexes 3a-3d and 5 which were characterized by IR, mass spectrometry, ¹H and ¹³C NMR spectroscopy, the structures of 3a, 3c and 5 were established by X-ray diffraction analysis.     

TTF and TCNQ analogues derived from a new benzo-fused thiopyranyl building block

TTF-type and TCNQ-type analogues (9-12) have been prepared from a new benzo-fused thiopyranyl precursor 8. The synthetic conditions of 8 were optimized. An anomaly was observed in the ¹H NMR spectrum of 9. The crystal structures of 9 and 10 show distorted conformations and ordered packing geometries connected by short contacts. Electronic and redox properties of 9-12 were investigated by UV-vis spectroscopy and cyclic voltammetry. Both 9 and 10 exhibited p-type OFET performances.     

Guignardins A–F,spirodioxynaphthalenes from the endophytic fungus Guignardia sp. KcF8 as a new class of PTP1B and SIRT1 inhibitors

Six new guignardins A–F (1–6) were isolated from the cultures of endophytic fungus Guignardia sp. KcF8 derived of a mangrove plant Kandelia candel, along with three known analogues, palmarumycins C₁ (7), BG1 (8), and JC1 (9). Compounds 2, 3, 7, and 8 showed antimicrobial activities. Compounds 5–7 exhibited significant cytotoxicities against 10 human tumor cell lines. Compound 3 also displayed significant inhibitory activity against human protein tyrosine phosphatase 1B and histone deacetylase silent information regulator T1enzymes, two key targets for the treatment of diabetes. This is the first report on the anti-PTP1B and anti-SIRT1 activities of spirodioxynaphthalenes.     

Addition of 2-tert-butyldimethylsilyloxythiophene to activated quinones: an approach to thia analogues of kalafungin

The uncatalyzed reaction of 2-tert-butyldimethylsilyloxythiophene 2 with 1,4-quinones bearing either an electron withdrawing acetyl or a carbomethoxy group at C-2, was investigated. No reaction was observed using 1,4-quinones 8 and 9 bearing an ester group at C-2 whereas use of 1,4-quinones 10 and 11 bearing an acetyl group at C-2 only provided low yields of the silyloxythiophenes 15 and 16 resulting from electrophilic substitution of the silyloxythiophene by the 1,4-quinone. Use of the Lewis acids InCl₃, Cu(OTf)₂ and BF₃·Et₂O were investigated in an effort to improve the yield of the desired annulation reaction. BF₃·Et₂O proved to be the optimum catalyst for the synthesis of thiolactone naphthofuran adducts 14 and 18 from 1,4-naphthoquinones 9 and 11, respectively. Reaction of 2-tert-butyldimethylsilyloxythiophene 2 with 1,4-benzoquinones 8 and 10 bearing a carbomethoxy or an acetyl group at C-2, respectively, afforded thiolactone benzofuran adducts 13 and 17, respectively, catalyzed by either InCl₃ or Cu(OTf)₂. Addition of 2-tert-butyldimethylsilyloxythiophene 2 to 3-acetyl-5-methoxy-1,4-naphthoquinone 12 afforded adduct 19 that underwent oxidative rearrangement to thiolactone pyranonaphthoquinone 20 using ceric ammonium nitrate in acetonitrile, thus providing a novel approach for the synthesis of a thia analogue of the pyranonaphthoquinone antibiotic kalafungin.     

Ferrocene-indole hybrids for cancer and malaria therapy

We report the synthesis, characterization, and cytotoxic and antimalarial activity of ferrocene-indole hybrids 8-14. The 2-phenylindole scaffold was chosen because of its potent antimitotic activity and ferrocene was chosen following the development of ferrocifens, ferrocene derivatives of tamoxifen, which are prototypes of a new family of organometallic anti-estrogens. Ferrocene-indole hybrids 8-14 and their corresponding organic analogues 1-7 showed only moderate antimalarial activities, while ferrocene-indole hybrids 11 and 12 showed excellent in vitro activities against the A549 human carcinoma cell line, with IC₅₀ values of 5 and 7 μM respectively. These ferrocene-indole hybrids were up to 25-fold more potent as cytotoxic agents than their purely organic analogues.     

Diels-Alder reactions of acyclic α-cyano α,β-alkenones: a new approach to highly substituted cyclohexene system

The Diels-Alder reactions of a variety of acyclic α-cyano α,β-unsaturated ketones 8 have been investigated. With the assistance of boron trichloride, these compounds were found to undergo the cycloaddition readily with dienes to give the corresponding adducts 9 in good to high yields. In addition, some of 9 could be further subjected to the reductive alkylation reactions using lithium naphthalenide (LN) and an appropriate alkylating agent, thus allowing for the generation of highly substituted cyclohexenes 10 with the replacement of the cyano group with an alkyl substituent.     

The chemistry of zerumbone. Part 5: Structural transformation of the dimethylamine derivatives

Zerumbone (1) and its 6,7-epoxide (2) react with ammonia and dimethylamine regio- and stereospecifically, affording monoamines 3, 4, 7 and 8. All adducts have the same relative configuration at C2 and C3. The conjugate amination is thermodynamically controlled to arrive at a single diastereomer. At 15°C 7 reacts with cyanide to give aminonitrile 10 as the single product, while at 30°C, acyclic aminonitrile 11 is also formed. The reaction with 8 affords at 0°C bicyclic aminonitrile 12 of the asteriscane skeleton, while at 30°C or higher temperature, mixtures of 12 and tricyclic nitriles 13 and 13′ are obtained. Refluxing of 7, 8 and 10 in aqueous acetonitrile promotes scission of the zerumbone ring by retro-Mannich reaction to provide acyclic aldehydes 16-18, respectively. The dimethylamino group of 7, 8 and 10 is eliminated stereospecifically by Cope- and base-catalyzed eliminations to regenerate the zerumbone skeleton in the products 1, 2 and 21. Cope elimination of 12 results in a mixture of 13 and 13′ by deaminative transannular etherification.     

Synthesis of acyclic nucleoside analogues based on 1,2,4-triazolo[1,5-a]pyrimidin-7-ones by one-step Vorbrüggen glycosylation

New acyclovir analogues were obtained by reaction of 1,2,4-triazolo[1,5-a]pyrimidin-7-ones 4a–i with (2-acetoxyethoxy)methyl acetate 5 in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) as catalyst (Vorbrüggen procedure). Coupling between compounds 4a–f and 5 led to a mixture of N3- and N4-isomers 6 and 7, respectively. On the contrary, the reaction of compounds 4g–i with 5 proceeded selectively with formation of N3-isomers only. It was found that the ratio of 6a–f and 7a–f depends on the presence or the absence of N,O-bis(trimethylsilyl)acetamide (BSA). Glycosylated products 6a–f and 7a–f underwent reversible isomerization under TMSOTf treatment. The ratio of glycosylated products of the coupling reaction between 4 and 5 was thermodynamically controlled. A similar reaction occurred if ZnCl₂ was chosen as a catalyst, although lower yields of the acyclic analogues of nucleosides were observed. The glycosylation of other purines (adenine and guanine) can be achieved via the non-BSA modification of the Vorbrüggen procedure.     

Chemical characterisation of oxidative degradation products of Δ-THC

The chemical analysis of a sample of Δ⁹-THC, which had been stored in an ethanol/propylene glycol solution for 5 years, resulted in the isolation of several hydroxylated Δ⁹-THC derivatives, the main of which were trans-cannabitriol monoethyl ether (4) and trans-propanediol ethers 7 and 8. cis-Cannabitriol monoethyl ether (5) and the oxidised derivatives 3 and 6 were detected in lesser amounts. The structure elucidation of the unprecedented cannabinoids 3, 5, 7 and 8 was achieved mainly by NMR techniques. Full NMR assignment of compounds 4 and 6 were also made. The detection of cannabitriol (6) and the corresponding solvent-adduct analogues (compounds 4-8) was in agreement with the decomposition mechanisms previously proposed for Δ⁹-THC. The isolation of the endoperoxide 3 represents indirect evidence of the existence of unstable precursors that were suspected to be intermediates in the non-enzymatic oxidation pathway of Δ⁹-THC. Both isomers of cannabitriol monoethyl ether exhibited weak affinity at either CB₁ (K_i=2.25, 6.30 μM) or CB₂ cannabinoid receptors (K_i=1.97, 3.13 μM), the trans isomer always being more potent than the cis isomer.     

Synthesis of 1,4-disilacyclohexa-2,5-dienes

Title compounds of the type 2,3,5,6-tetraphenyl-1,4-di-X-1,4-di-Y-1,4-disilacyclohexa-2,5-diene wherein X=Y=NMe₂ (4); X=NMe₂, Y=Cl (cis, trans-5); X=NMe₂, Y=Me [(trans)-6] and X=t-Bu, Y=Cl (trans-8) were synthesized from Si₂(NMe₂)₅Cl, sym-Si₂(NMe₂)₄Cl₂, sym-Si₂(NMe₂)₄Me₂, and sym-Si₂Cl₄(t-Bu)₂, respectively, in the presence of diphenylacetylene at 200 °C. Similarly the analogous title compound from the combination of 1-phenyl-1-propyne and Si₂(NMe₂)₅Cl [X=Y=NMe₂ (cis and trans-7) was synthesized. In all cases where cis/trans diastereomers could arise from two different silicon substituents (5, 6, 8) the trans isomer was the sole or dominant product. Evidence for the intermediacy of the silylene Si(NMe₂)₂ in these reactions was gained from a trapping experiment. Compound 4 upon treatment with SiCl₄, SiBr₄ or PI₃ provided the corresponding 1,1,4,4-tetrahalo derivatives 9a-c, respectively. Treatment of 4 with MeOH or PhOH gave the 1,1,4,4-tetramethoxy and tetraphenoxy analogues 9d and 9e, respectively. The tetrachloro derivative 9a upon LAH reduction led to the corresponding tetrahydro compound 10, while the reaction of 9a with H₂O gave the tetrahydroxy derivative 11. Allowing (trans)-6 to react with SiCl₄ provided a ca. 1:1 cis/trans ratio of the derivative 12 in which X=Cl, Y=Me, and possible pathways that rationalize this loss of stereochemistry are proposed. Synthesis of trans-13 in which X=t-Bu, Y=H was achieved by LAH reduction of 8. All of the title compounds except 8 experience free phenyl rotation at room temperature. At −30 °C this rotation in 8 is essentially halted. The molecular structures of 4, 8, 9c, 9e, 10 and 13 were determined by X-ray crystallography.     

Synthesis and properties of bis(heteroazulen-3-yl)methyl cations and bis(heteroazulen-3-yl)ketones

The synthesis and properties of a novel type of bis(heteroazulen-3-yl)methyl cations, bis(2-oxo-2H-cyclohepta[b]furan-3-yl)methyl cation salt and nitrogen analogues, (9a-c·PF₆⁻) and (9a-c·BF₄⁻), as well as bis(heteroazulen-3-yl)ketones (12a-d) are studied. The synthetic method was based on a TFA-catalyzed electrophilic aromatic substitution on the heteroazulenes (6a-d) with paraformaldehyde to afford the corresponding disubstituted methane derivatives 7a-d, followed by oxidative hydrogen abstraction with DDQ, and subsequent exchange of the counter-anion by using aq. HPF₆ or aq. HBF₄. In addition, the reaction of 7a-d with 2.2 equiv. amounts of DDQ afforded carbonyl compounds 12a-d. The delocalization of the positive charge of 9a-c was evaluated by the ¹H and ¹³C NMR spectral data. The thermodynamic stability of cations 9a-c was evaluated to be in the order 9a<9b<9c on the basis of their reduction potentials measured by cyclic voltammetry (CV) and pK_R+ values (2.6-10.3) obtained spectrophotometrically. The reduction waves of cations 9a-c were irreversible, suggesting the dimerization of the radical species generated by one-electron reduction. This was demonstrated by the reduction of 9a·BF₄⁻ with Zn powder to give dimerized product 14a. In addition, the quenching of 9a·BF₄⁻ with MeOH/NaHCO₃ gives ether derivative 15a, which is proposed for the precursor for synthesizing tris(heteroazulene)-substituted methyl cations bearing two different heteroazulene-units.     

Synthesis of sulfur containing analogues of the soluble guanylate cyclase inhibitor 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazin-1-one NS2028

Sulfur analogues of the soluble guanylate cyclase (sGC) inhibitor NS2028 1a are synthesized. Treating 8-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one oxime (6) with 1,1′-thiocarbonyldiimidazole (1.1 equiv) gave the carbamothioate 8-bromo-4H-[1,2,4]oxadiazolo[3,4-c][1,4]benzoxazine-1-thione (3a) in 83% yield. Alternatively reacting NS2028 1a with P₂S₅ (0.5 equiv) affords the carbamothioate 3a in 80% yield. Similar treatment of 8-aryl substituted NS2028 analogues 1b-d with P₂S₅ gave the carbamothioates 3b-d in 64-91% yields. Although quite stable, the carbamothioates 3a-d could be thermally isomerized in the presence of Cu (10 mol %) to afford the thiocarbamates 4a-d in high yields. Interestingly, in the case of carbamothioate 3a Pd and In metals also facilitated the isomerization. Furthermore, treatment of the thiocarbamates 4a-d with P₂S₅ (0.5 equiv) affords the carbamodithioates 5a-d in 72-89% yields. All new compounds are fully characterized including single crystal X-ray data for carbamothioate 3a and thiocarbamate 4a. Finally, a mechanism is proposed for the carbamothioate to thiocarbamate isomerization.