Stereoselective synthesis and moulting activity of 2,3-diepi-20-hydroxyecdysone and 2,3-diepi-5α-20-hydroxyecdysone

The ecdysteroid analogues 2,3-diepi-20-hydroxyecdysone and 2,3-diepi-5α-20-hydroxyecdysone have been synthesized from the readily available ecdysteroid, 20-hydroxyecdysone, and moulting activity has been determined using the Musca bioassay. As expected, the 2,3-diepi-analogue was less active than the parent ecdysteroid, 20-hydroxyecdysone. However, the 2,3-diepi-5α-analogue, which was expected to be inactive in the assay, exhibited moulting activity though it was approximately 1.5-fold less active than its 5β-analogue. The activity of the 5α-analogue could possibly result from the ability of this compound to bind to the ecdysteroid receptor. Alternatively, a possible in vivo C-5 epimerization of the 2,3-diepi-5α-analogue to the corresponding 5β-analogue could account for its activity.     

Synthesis of unnatural 2- and 3-deoxyfuranose analogues

This Letter describes the synthesis of two racemic analogues of unnatural 3′-deoxy and 2′-deoxy sugars, where a phosphorus atom replaces the carbon atom in the 2′- or 3′-position. Two methods of four- and 5-steps were developed affording these new unnatural sugar analogues.     

Robust synthesis of enantiopure cyclohexenyl analogues of 2/3-deoxyribose sugars as carbocyclic nucleoside precursors

An expedient synthesis of 2-deoxy (10) and 3-deoxy (11) cyclohexenyl analogues of 2-deoxy and 3-deoxy-d-ribose sugar from commercially available starting materials is reported. Highly efficient enzymatic resolution of the key compound 10 is described using lipase under hydrolytic conditions. The robust methodology applied here will be useful to synthesize cyclohexenyl nucleosides, which possess potent antiviral activity and are capable of gene silencing via RNAi or antisense applications.     

Stereoselective synthesis and moulting activity of integristerone A and analogues

Integristerone A, a rare ecdysteroid of plant origin, has been synthesized from 20-hydroxyecdysone with 2-deoxy-1,2-didehydro-20-hydroxyecdysone as the key intermediate, followed by stereoselective asymmetric dihydroxylation. The analogues 1,2-di-epi-integristerone A and 1,2-di-epi-5α-integristerone A have also been synthesized. Integristerone A exhibited approximately 9-fold lower moulting activity than the parent 20-hydroxyecdysone in the Musca domestica bioassay, indicating that the presence of a 1β-hydroxyl group resulted in a decrease in activity. As expected, the 1,2-di-epi-5α-analogue was inactive in this assay.     

Synthesis of unnatural 3′-phospha-2′-deoxyfuranose nucleoside analogues

This Letter describes the synthesis of racemic analogues of unnatural 2′-deoxy nucleoside with a phosphorus atom replacing the carbon atom in the 3′-position. A seven-step sequence was developed in racemic series to afford unnatural 3′-phospha-2′-deoxyfuranose nucleosides. The phospha nucleoside analogues were tested against HCV, but did not show any antiviral activity at a 10 μM maximum concentration used for the inhibition assays of analogues 2-T, 2-C and 4-Tα.     

Highly diastereoselective chemoenzymatic synthesis of (2′R)- and (2′S)-2′-deoxy[2′-H]guanosines

In an effort to develop an efficient synthetic method of highly diastereoselective (2′R)- and (2′S)-2′-deoxy[2′-²H]guanosines, chemoenzymatic conversion was investigated. The synthesis of (2′R > 98% de)-2′-deoxy[2′-²H]guanosine was achieved by biological transdeoxyribosylation using (2′R > 98% de)-2′-deoxy[2′-²H]uridine, 2,6-diaminopurine, and Enterobacter aerogenes AJ-11125, followed by treatment with adenosine deaminase. (2′S > 98% de)-2′-Deoxy[2′-²H]guanosine was synthesized from (2′S > 98% de)-2′-deoxy[2′-²H]uridine and 2,6-diaminopurine using thymidine phosphorylase and purine nucleoside phosphorylase instead of E. aerogenes AJ-11125.     

A new convenient synthesis of N-acyl-2-(dimethoxyphosphoryl)glycinates

Easily accessible N-acyl-2-triphenylphosphonioglycinate tetrafluoroborates react smoothly with trimethylphosphite in the presence of methyltriphenylphosphonium iodide to give N-acyl-2-(dimethoxyphosphoryl)glycinates in good or very good yields. The dimethoxyphosphorylglycinates may be isolated by column chromatography, or used directly for the Wadsworth-Emmons synthesis of α,β-dehydro-α-amino acids in a one-pot procedure without purification.     

The synthesis of β-heteroarylamino-α,β-dehydro-α-amino acid and β-heteroarylamino-α-amino acid derivatives

From heteroarylaminomethyleneoxazolones 4 , obtained from N-heteroarylformamidines 2 and 2-phenyl-5-oxo-4,5-dihydro-1,3-oxazole ( 3 ), the following β-heteroarylamino-α,β-dehydro-α-amino acid derivatives were prepared: methyl 8 and ethyl esters 9 , amides 10 and 11 , hydrazides 12 , and azides 15 . By catalytic hydrogenation the compounds 4 were converted into β-heteroarylamino substituted amides 18 and β-heteroarylamino-α-amino acids 20 .     

Transformations of isomeric naphthopyranones. The synthesis of substituted β-naphthyl-α,β-dehydro-α-amino acid derivatives

The opening of the pyranone ring in 2H-naphtho[1,2-b]pyran-2-one derivative (1) and 3H-naphtho[2,1-b]-pyran-3-one derivatives 8 and 20 with nucleophiles afforded 3-(naphthyl-1)- and 3-(naphthyl-2)propenoates (substituted β-naphthyl-α,β-dehydro-α-amino acid derivatives) 7, 13, 14, 15, 24 , and 35 .     

Base promoted facile route to functionalized benzo[b][1,8]naphthyridin-2-(1H)-ones from N-benzyl-N-(3-cyanoquinolin-2-yl)acetamides

A facile synthesis of 4-amino-N-benzylbenzo[b][1,8]naphthyridin-2(1H)-ones 3 is described from N-benzyl-N-(3-cyanoquinolin-2-yl)acetamides 2 with t-BuOK in excellent yields in mild conditions. These reactions proceeded at room temperature under aerobic atmosphere in very short period. The cyclization reactions were also extended with N-alkyl amino acetamide analogues affording the products in good yields.     

The synthesis of β-heteroarylamino-α,β-dehydro-α-amino acid derivatives via thiazolones

2-Alkoxy-4-heteroarylaminomethylene-5(4H)-thiazolones 4 were converted with various nucleophiles into β-heteroarylamino-α,β-dehydro-α-amino acid derivatives 11, 14, 15, 16, 17, 18 , and 19 . Reduction of 4 with sodium borohydride in ethanol saturated with gaseous ammonia afforded the corresponding β-heteroaryl-amino substituted alanyl amides 20 . Thiazoledione derivative 7a was transformed with sodium methoxide in methanol into 1-(4,6-dimethylpyrimidinyl-2)-4-mercaptocarbonylimidazol-2(3H)-one ( 8a ).     

Thermodynamics of complexes between nucleobase-modified β-cyclodextrins and bile salts

The binding of three nucleobase-modified β-CDs, (i.e., mono(6-ade-6-deoxy)-β-CD 2, mono(6-thy-6-deoxy)-β-CD 3, and mono(6-ura-6-deoxy)-β-CD 4) with four bile salts (deoxycholate, DCA; cholate, CA; glycocholate, GCA; and taurocholate, TCA) were investigated by means of circular dichroism, 2D NMR spectroscopy and calorimetric titration. The results show the binding of host 2 with bile salts is weaker and different from hosts 3 and 4. Enthalpy changes between hosts 2–4 and bile salts are much more favorable than those of native β-CD 1, whereas the entropy changes are unfavorable.     

Synthesis of Modified Di- and Trisaccharide Fragments of N-Glycoproteins

Abstract

The syntheses of several analogues of disaccharide Manot(1→6)Mana-OCH₃ (1) and of trisaccharide Mana(1→6)[Mana(1→3)]Mana-OCH₃ (2) are reported. The syntheses are described of the diastereomeric 6-methyl derivatives 9a and 9b, which are representatives of fixed conformations of disaccharide 1. The syntheses of the 2-amino-2-deoxy analogues 15 and 17 and the synthesis of the 2-fluoro-2-deoxy analogue 28 are also reported.     

Modellreaktionen zur Biosynthese von Verbindungen der Damascon-Reihe und ihre präparative Anwendung

We report a new general synthesis of damascones. In the presence of acids, 7, 8-dehydro-β-ionole ( 10 ) or the related diols 11 are converted into a mixture of β-damascone ( 2 ) and the 7, 8-dehydrotheaspiranes ( 19 ). In the same way the 6-hydroxy-7, 8-dehydro-α-ionoles 12 are transformed into a mixture of β-damascenone ( 3 ) and the 8-oxatheaspiranes ( 20 ). The reaction Provides access to damascone derivatives 4 – 7 which have been found in nature. These synthetic experiments lend support to our hypotheses concerning the biogenesis of damascones from suitable carotenoids or their metabolites.     

Synthesis of stable and cell-type selective analogues of cyclic ADP-ribose, a Ca(2+)-mobilizing second messenger. Structure--activity relationship of the N1-ribose moiety

We previously developed cyclic ADP-carbocyclic ribose (cADPcR, 2) as a stable mimic of cyclic ADP-ribose (cADPR, 1), a Ca(2+)-mobilizing second messenger. A series of the N1-ribose modified cADPcR analogues, designed as novel stable mimics of cADPR, which were the 2"-deoxy analogue 3, the 3"-deoxy analogue 4, the 3"-deoxy-2"-O-(methoxymethyl) analogue 5, the 3"-O-methyl analogue 6, the 2",3"-dideoxy analogue 7, and the 2",3"-dideoxydidehydro analogue 8, were successfully synthesized using the key intramolecular condensation reaction with phenylthiophosphate-type substrates. We investigated the conformations of these analogues and of cADPR and found that steric repulsion between both the adenine and N9-ribose moieties and between the adenine and N1-ribose moieties was a determinant of the conformation. The Ca(2+)-mobilizing effects were evaluated systematically using three different biological systems, i.e., sea urchin eggs, NG108-15 neuronal cells, and Jurkat T-lymphocytes. The relative potency of Ca(2+)-mobilization by these cADPR analogues varies depending on the cell-type used: e.g., 3"-deoxy-cADPcR (4) > cADPcR (2) > cADPR (1) in sea urchin eggs; cADPR (1) > cADPcR (2) approximately 3"-deoxy-cADPcR (4) in T-cells; and cADPcR (2) > cADPR (1) > 3"-deoxy-cADPcR (4) in neuronal cells, respectively. These indicated that the target proteins and/or the mechanism of action of cADPR in sea urchin eggs, T-cells, and neuronal cells are different. Thus, this study represents an entry to cell-type selective cADPR analogues, which can be used as biological tools and/or novel drug leads.     

A simple and efficient method for the synthesis of highly substituted imidazoles using 3-aroylquinoxalin-2(1H)-ones

3-Aroylquinoxalin-2(1H)-ones were found to be hetero analogues of α-diketones for the efficient, one-pot, three component synthesis of 2,4,5-trisubstituted imidazoles and imidazo[1,5-a]quinoxalin-4(5H)-ones in boiling methanol. The key advantages of this process are high yields, ready availability and low cost of 3-aroylquinoxalin-2(1H)-ones and easy work-up and separation of the products by non-chromatographic methods. Furthermore, the presence of an ortho-iminoanilide fragment at position 4 of the imidazoles obtained has made it possible to produce 2-(imidazol-4-yl)benzimidazoles in almost quantitative yields.     

Novel recoverable catalysts for asymmetric transfer hydrogenation

9-Amino(9-deoxy)epiquinine and 9-amino(9-deoxy)epicinchonine were applied in asymmetric transfer hydrogenation of aromatic ketones in both iridium and rhodium catalytic systems using i-propanol as the hydrogen source. Good to excellent conversions and enantioselectivities were observed with a variety of aromatic ketones. Moreover, the Ir complex and Rh complex of 9-amino(9-deoxy)cinchonine were recovered in high yields with dilute hydrochloric acid. The enantioselectivity of 1-phenylethanol was nearly maintained after six cycles.     

Microwave-assisted palladium-catalyzed cross-coupling reactions between pyranoid glycals and aryl bromides. Synthesis of 2′-deoxy C-aryl-β-glycopyranosides

Under microwave irradiation, perbenzylated pyranoid glycals were coupled with aryl bromides in the presence of 5% mol palladium(II) acetate in dimethylformamide to produce 2′,3′-unsaturated C-aryl-α-glycopyranosides in a rapid and stereospecific manner. The synthetic applicability of the method was further demonstrated by converting the resulting C-aryl glycosides to 2′-deoxy C-aryl-β-glycopyranosides through oxidation mediated by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) and stereoselective reduction.     

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.     

Domino Vilsmeier-Haack/ring closure sequences: a facile synthesis of 3-chlorobenzo[b]thiophene-2-carbaldehydes

Vilsmeier’s reagent treatment of substituted diphenacyl sulfides or diphenacyl disulfides has led to the formation of a series of benzfused 3-chlorothiophene-2-carbaldehydes by a Domino Vilsmeier-Haack reaction/ring closure sequence, opening a new route for the synthesis of 3-chlorobenzo[b]thiophene-2-carbaldehydes and their benzfused analogues. A plausible mechanism has been proposed.