Jiaxi Xu

Synthesis of N6-alkyl(aryl)-2-alkyl(aryl)thioadenosines as antiplatelet agents

A series of novel N(6)-alkyl(aryl)-2-alkyl(aryl)thioadenosines were synthesized, and their human antiplatelet aggregation activities were evaluated by the stimulation of adenosine 5-diphosphate (ADP). Some of these compounds showed strong activity, among which compound 5b(11) displayed the highest activity with an IC(50) value of 29 ± 3 μM. Furthermore, five compounds were tested against arachidonic acid (AA)-induced human platelet aggregation. The results showed that compound 5b(10) exhibited the highest activity with an IC(50) value of 3 ± 2 μM. The adenosine derivatives substituted with a phenethyl group at the N(6) position and a methylthio or ethylthio group at the C-2 position displayed high antiplatelet aggregation activity.

Stereochemistry and Mechanistic Insight in the [2k+2i+2i] Annulations of Ketenes and Imines

The stereochemistry and mechanistic insight in the annulations of one ketene molecule with two imine molecules ([2(k)+2(i)+2(i)] annulation) are studied by using six-membered 3,4-dihydroisoquinoline as an imine probe. A concerted hetero-Diels-Alder cycloaddition mechanism is proposed to explain the stereochemical outcomes. In most cases, the zwitterionic 2-aza-1,3-butadiene-type intermediates, generated from ketenes and imines, undergo endo hetero-Diels-Alder cycloaddition with the second imine molecule. For ketenes with electron-donating substituents, (2,4)-cis-(4,5)-cis-[2(k)+2(i)+2(i)] annuladducts formed stereospecifically, while, for ketenes with electron-accepting substituents, (2,4)-cis-(4,5)-trans-[2(k)+2(i)+2(i)] annuladducts are generated stereospecifically. The [2(k)+2(i)+2(i)] annulations of aryloxyketenes and 3,4-dihydroisoquinoline give stereodivergent products due to the occurrence of the stepwise nucleophilic annulation. However, in the [2(k)+2(i)+2(i)] annulations of seven-membered cyclic imine dibenzo[b,f][1,4]oxazepine, the zwitterionic aza-butadiene-type intermediates exclusively undergo exo hetero-Diels-Alder cycloadditions with another molecule of imine to yield (2,4)-trans-(4,5)-trans-[2(k)+2(i)+2(i)] annuladducts stereospecifically, regardless of the ketene substituents. The mechanistic model not only discloses the nature of the [2(k)+2(i)+2(i)] annulations, but also can be used to explain and predict the stereochemistry of the [2(k)+2(i)+2(i)] annuladducts from different ketenes and imines.

Ortho-Nitro Effect on the Diastereoselective Control in Sulfa-Staudinger and Staudinger Cycloadditions

The ortho-nitro effect was discovered in sulfa-Staudinger cycloadditions of ethoxycarbonylsulfene with linear imines. When an ortho-nitro group is present at the C-aryl substituents of linear imines, the sulfa-Staudinger cycloadditions deliver cis-β-sultams in considerable amounts, together with the predominant trans-β-sultams. In other cases, the above sulfa-Staudinger cycloadditions give rise to trans-β-sultams exclusively. Further mechanistic rationalization discloses that the ortho-nitro effect is attributed to its strong electron-withdrawing inductive effect. Similarly, the ortho-nitro effect also exists in Staudinger cycloadditions of ethoxycarbonyl ketene with the imines. The current research provides further insights into the diastereoselective control in sulfa-Staudinger and Staudinger cycloadditions.

Synthesis and Fungicidal Activity of Simple Structural 1,3-Thiazolidine-2-Thione Derivatives

GRAPHICAL ABSTRACT Abstract A series of simple structural 1,3-thiazolidine-2-thione derivatives with various substituents on the S-, N-, 4-, and 5-positions was synthesized with high yields from various vicinal amino alcohols via two steps and screened for their antifungal activity. Bioassay results reveal that some thiazolidine-2-thione derivatives show strong antifungal activities against P. capsici, G. zeae, S. sclerotiorum, A. alternata, B. cinerea, or R. solani. The SAR analysis indicates that N-acyl substituted and 4-alkyl substituents can enhance the antifungal activity. Notably, 4-isopropyl-N-propionylthiazoldine-2-thione shows excellent activity against B. cinerea and G. zeae with IC50 values at 3.7 μg/mL and 6.5 μg/mL, respectively, and 4-isobutyl-N-propionylthiazoldine-2-thione shows remarkable fungicidal activity against R. solani, S. sclerotiorum, and G. zeae with IC50 values at 1.0 μg/mL, 12.1 μg/mL, and 11.0 μg/mL, respectively.

Proton NMR investigations on 6‐alkylamino‐2‐alkylthioadenosine derivatives

Purine nucleosides have taken up an important role in living systems. Not only are purines the basic subunits of the nucleic acids, but they also interact with enzymes and other proteins as components of cofactors and signal molecules. Their modified nucleosides and nucleotides are very important classes of compounds used in the therapy of a wide variety of diseases, because they can act as antiviral, antitumor and antimicrobial agents. Purine nucleosides in which the alkylthio group at C-2 position and the alkylamine substituent at C-6 position typically excel in antiplatelet activities (Fig. 1). So the synthesis and characterization of the modified purine nucleosides have attracted the attention of our and other many scientific teams. The distribution of electrons around the purine skeleton affects not only its chemical properties and reactivity but also the nuclear magnetic resonance (NMR) parameters. The nature of the substituent is reflected in the NMR chemical shifts and nuclear spin–spin coupling constants, which makes NMR spectroscopy an excellent tool for investigating and interpreting the structure, reactivity and intermolecular interactions in terms of the electron distribution. The use of proton NMR spectroscopy could be a helpful tool to achieve it. Recently, we have published a complete analysis of proton NMR data for 6-alkylamino-2-alkylthioadenosine derivatives, andwe observed that two protons of SCH2 at C-2 of purine skeleton are split into one/two ‘dt’ or ‘dq’ coupling peaks, rather than canonical ‘t’ or ‘q’ peaks, but the reason is not clear. To reveal the general behaviors of the chemical shifts signals of SCH2 group depending on the configuration for SCH2-containing adenosine derivatives, two series of 6-alkyl(aryl)amino-2-alkyl(aryl) thioadenosines and 6-alkyl(aryl)amino-2-alkylthiopurines were synthesized, and their proton NMR spectroscopic properties were described.

Sulfur mediated propargylic C–H alkylation of alkynes

A transition-metal-free, sulfur mediated propargylic C–H alkylation reaction was realized through a one-pot procedure. The reaction design involves an initial addition between alkynes and triflic anhydride activated sulfoxides, and a subsequent [2,3]-sigmatropic rearrangement of the allenyl sulfur ylides generated under basic conditions to give propargylic C–H alkylation products.

Negative Ion Mass Spectral Fragmentation of N-Alkoxycarbonyl-1-Aminoarylmethyl Phosphonic Monoesters under Electrospray Ionization Conditions

Abstract The negative ion mass spectrometry of N-benzyloxycarbonyl and N-ethoxycarbonyl 1-aminoarylmethylphosphonic methyl, ethyl, and phenyl monoesters was investigated under electrospray ionization conditions. Their fragmentation pathways are proposed and supported by collisional activated dissociation product-ion spectrometry. All of the deprotonated molecules preferentially eliminate a molecule of benzyl alcohol or ethanol first to yield isocyanato-alkylphosphonate anions, which further generate phosphonate ions by the loss of carbon monoxide, phenol or alcohol, carbon monoxide plus arenes. The isocyanato-sulfonate anions can further cyclize to generate 3-aryl-2-phenoxy-1,2,4-oxaphosphazolidine-2,5-dione amide anions, which can undergo rearrangements by the loss of carbon dioxide, metaphosphorous acid phenyl ester, or carbon dioxide plus metaphosphorous acid phenyl ester, respectively, to give rise to nitrogen-containing anions. The title compounds show an obviously different fragmentation in the negative ion mode from that in the positive ion mode under the electrospray ionization conditions. GRAPHICAL ABSTRACT

Synthesis of 4-trifluoromethyl-β-sultams via sulfa-Staudinger cycloadditions

ABSTRACT A series of structurally diverse 4-trifluoromethyl β-sultams was conveniently synthesized via the sulfa-Staudinger cycloadditions of 2,2,2-trifluoroethanesulfonyl chloride with different imines under very mild conditions. The products were obtained in yields up to 75%, and in cis/trans ratios ranging from 59:41 to 12:78. GRAPHICAL ABSTRACT

A concise synthesis of cyclobrassinin and its analogues via a thiyl radical aromatic substitution

A simple and concise approach for the synthesis of cyclobrassinin has been developed through a thiyl radical-mediated intramolecular aromatic substitution, with benzoyl peroxide as an efficient initiator and oxidant. The current method can also be utilized in the synthesis of 6 and 7-membered ring cyclobrassinin analogues in moderate to good yields. The transformation involves a formal radical 6 and 7-endo-trig cyclization of the corresponding dithiocarbamate derivatives, which were generated from indole-3-methanamines and tryptophan.

Na2S2O8-mediated efficient synthesis of isothiocyanates from primary amines in water

We have developed two green, practical, and efficient procedures, including a one-pot one, to synthesize isothiocyanates from amines and carbon disulfide via desulfurization with sodium persulfate. Water is used as the solvent. Basic conditions are necessary for good chemoselectivity for isothiocyanates. Structurally diverse linear and branched alkyl amines and aryl amines are readily converted to isothiocyanates by the two procedures in satisfactory yields. Halogens, benzylic C–H bonds, methylthio, nitro, ester, alkenyl, electron-rich or -deficient (hetero)aryls, acetylenyl, and even phenolic and alcoholic hydroxyls are well tolerated. The one-pot procedure in water can also be used to realize the preparation of chiral isothiocyanates from chiral amines, and the modification of bioactive structures with free amino groups. In large-scale preparation, simple and practical purification procedures independent of column chromatography are developed.