Mild and General Protocol for Selective Deacetylation of Acetyl/Benzoyl-Protected Carbohydrates.

Herein, we report a mild and general protocol for chemoselective deacetylation of mixed acetyl- and benzoyl-protected carbohydrates under mild acidic conditions. The protocol allows quick access to partially protected carbohydrates, which serve as versatile synthetic intermediates during the total synthesis of various mono- and oligosaccharide targets. The applicability of the developed protocol was successfully demonstrated on a range of carbohydrate substrates of various configurations and substitution patterns featuring functionalized aliphatic and aromatic aglycones. The protocol has shown excellent compatibility with the widely used O-anomeric protecting groups, prespacer aglycones, and thioglycoside glycosyl donors.

Diastereoselective Synthesis of Dispiro[Imidazothiazolotriazine-Pyrrolidin-Oxindoles] and Their Isomerization Pathways in Basic Medium.

Highly diastereoselective methods for the synthesis of two series of regioisomeric polynuclear dispyroheterocyclic compounds with five or six chiral centers, comprising moieties of pyrrolidinyloxindole and imidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine of linear structure or imidazo[4,5-e]thiazolo[2,3-c]-1,2,4-triazine of angular structure, have been developed on the basis of a [3+2] cycloaddition of azomethine ylides to functionalized imidazothiazolotriazines. Depending on the structure of the ethylenic component, cycloaddition proceeds as an anti-exo process for linear derivatives, while cycloaddition to angular ones resulted in a syn-endo diastereomer. Novel pathways of isomerization for the synthesized anti-exo products upon treatment with sodium alkoxides have been found, which resulted in two more series of diastereomeric dispiro[imidazothiazolotriazine-pyrrolidin-oxindoles] inaccessible with the direct cycloaddition reaction. For the first series, the inversion of the configuration of one stereocenter, i.e., C-4' atom of the pyrrolidine cycle, (epimerization) was established. For the second one, configuration of the obtained diastereomer formally corresponded to the syn-endo approach of the azomethine ylide in the case of cycloaddition to the ethylenic component.

Synthesis and Evaluation on the Fungicidal Activity of S-Alkyl Substituted Thioglycolurils.

A series of S-alkyl substituted thioglycolurils was prepared through the alkylation of corresponding thioglycolurils with halogenoalkanes and tested for their fungicidal activity against six phytopathogenic fungi from different taxonomic classes: Venturia inaequalis, Rhizoctonia solani, Fusarium oxysporum, Fusarium moniliforme, Bipolaris sorokiniana, and Sclerotinia sclerotiorum, and two pathogenic yeasts: Candida albicans and Cryptococcus neoformans var. grubii. A number of S-alkyl substituted thioglycolurils exhibited high activity against Venturia inaequalis and Rhizoctonia solani (85-100% mycelium growth inhibition), and moderate activity against other phytopathogens. S-Ethyl substituted thioglycolurils possessed a high activity against Candida albicans. Additionally, the hemolytic and cytotoxic properties of promising derivatives were determined using human red blood cells and human embryonic kidney cells, respectively. Two S-ethyl derivatives possessed both low cytotoxicity against normal human cells and high fungicidal activity against Candida albicans.

Synthesis of functionalized imidazo[4,5-e]thiazolo[3,2-b]triazines by condensation of imidazo[4,5-e]triazinethiones with DMAD or DEAD and rearrangement to imidazo[4,5-e]thiazolo[2,3-c]triazines.

Two series of functionalized imidazothiazolotriazine derivatives were synthesized via the condensation of imidazo[4,5-e]-1,2,4-triazine-3-thiones with acetylenedicarboxylic acid dimethyl and diethyl esters (DMAD and DEAD) and subsequent base-catalyzed rearrangement of the obtained imidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazines into regioisomeric imidazo[4,5-e]thiazolo[2,3-c]-1,2,4-triazine derivatives.

Catalyst-free regioselective acetylation of primary hydroxy groups in partially protected and unprotected thioglycosides with acetic acid.

Highly regioselective acetylation of primary hydroxy groups in thioglycoside derivatives with gluco- and galacto-configurations was achieved by treatment with aqueous or anhydrous acetic acid (60-100% AcOH) at elevated temperatures (80-118 °C), avoiding complex, costly and time-consuming manipulations with protective groups. Acetylation of both 4,6-O-benzylidene acetals and the corresponding diols as well as the unprotected tetraol with AcOH was shown to lead selectively to formation of 6-O-acetyl derivatives. For example, the treatment of phenyl 1-thio-ß-d-glucopyranoside with anhydrous AcOH at 80 °C for 24 h gave the corresponding 6-O-acetylated derivative in 47% yield (71% based on the reacted starting material) and unreacted starting tetraol in 34% yield, which can easily be recovered by silica gel chromatography and reused in further acetylation.

A Ring Contraction of 2,3-Di- O-Silylated Thiopyranosides To Give Thiofuranosides under Mildly Acidic Conditions.

A pyranose ring contraction of ethyl 1-thio-ß-d-galactopyranosides has been discovered that proceeds with retention of aglycon under mildly acidic conditions (aq TFA in CH2Cl2). Key factors for success of this rearrangement are the presence of bulky silyl (TIPS or TBDPS) substituents at both O-2 and O-3 and a free hydroxy group at C-4 (derivatives with acid-labile protective groups at O-4 will also engage in this reaction). The rearrangement cleanly proceeds for 2,3-di- O-TIPS derivatives with two hydroxy groups at C-4 and C-6, acid-labile TES groups at O-4 and O-6, or one acyl substituent (Bz, ClAc) at O-6. A possibility to switch the direction of the debenzylidenation reaction in 4,6- O-benzylidene-2,3-di- O-TIPS/TBDPS derivatives by the choice of an acid (TFA, which cleanly gives furanose, versus AcOH, which cleaves benzylidene acetal only) may present an advantage in the divergent synthesis of selectively protected glycosyl donors (either in furanose or pyranose form) useful for the synthesis of biologically important oligosaccharides.

The influence of substituents on the reactivity and cytotoxicity of imidazothiazolotriazinones.

A series of tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7(1H, 6H)-diones were synthesized via the reaction of imidazotriazinethiones and bromoacetic acid followed by condensation with isatins. Amidine skeletal rearrangement of 3,3a,9,9a-tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7 (1H, 6H)-diones into 1,3a,4,9a-tetrahydroimidazo[4,5-e]thiazolo[2,3-c]-1,2,4-triazine-2,8 (3H, 7H)-diones under KOH treatment has been studied. The influence of substituents at positions 1,3,3a,6,9a of imidazothiazolotriazine on the ability to undergo rearrangement was analyzed based on experimental data and theoretical calculations. Both imidazothiazolo[3,2-b]triazines and their rearrangement products were evaluated for their cytotoxic activity against rhabdomyosarcoma, A549, HCT116 and MCF7 human cancer cell lines by MTT assay. Among the derivatives, 1,3-diethyl-6-[1-(2-propyl)-2-oxoindolin-3-ylidene]-3,3a,9,9a-tetrahydroimidazo [4,5-e]thiazolo[3,2-b]-1,2,4-triazine-2,7(1H, 6H)-dione 4i was found to have the highest antiproliferative activity toward the tested cell lines (4i: [Formula: see text], 2.29, 0.47 and [Formula: see text], respectively). The [Formula: see text] value of compound 4i against normal human embryonic kidney cells HEK293 was [Formula: see text], which appeared to be 6-41-fold higher than [Formula: see text] values of 4i against human cancer cells.

Synthesis and biological evaluation of new substituted thioglycolurils, their analogues and derivatives.

A novel series of substituted N-aminothioglycolurils was synthesized by tandem hydrazone formation - ring contraction reaction of 3-thioxoperhydroimidazo[4,5-e]-1,2,4-triazin-6-ones with (E)-3-phenyl(furan-2-yl)acrylaldehyde derivatives. S-Alkyl substituted N-aminothioglycolurils were prepared through alkylation of corresponding thioglycolurils with iodoalkane or 4-chlorobenzylchloride. Methylthio group in S-methyl derivatives can be substituted with hydroxyl group in acid medium to give N-aminoglycolurils. Representative compounds were evaluated for their cytotoxic activity against RD, A549, HCT116 and MCF7 human cancer cell lines by MTT-assay and screened for their antifungal activity against phytopathogenic fungi using the mycelium growth inhibition method in vitro. Among the derivatives, 4-((E)-((E)-3-(2-Methoxyphenyl)allylidene)amino)-3-methyl-1-phenylthioglycoluril 8i was found to have the highest antiproliferative activity toward the RD and HCT116 cell lines (8i: IC50 = 0.02 and 0.012 µM, respectively), which exceeded cytotoxicity of reference drugs. 1,3-Diethyl-4-((E)-((E)-3-(2-methoxyphenyl)allylidene)amino)thioglycoluril 8l showed the most marked activity toward A549 cells (8l: IC50 = 0.61 µM) compared to reference drugs. The IC50 values of thioglycolurils 8i,l against normal human embryonic kidney cells HEK293 were 0.23 and 86.11 µM, respectively, exceeding the IC50 values of this compound toward the RD, HCT116 (8i) and A549 cells (8l) by one-two orders of magnitude. Experiments with annexin showed that compounds 8b,i,l induced apoptosis in Jurkat cells (acute T cell leukemia). Alkylthioderivatives 12a,13a displayed the strongest antifungal action against R. solani, F. oxysporum, and F. moniliforme exceeding those of triadimefon.