Synthesis and structural studies of C-5 aryl- and C-6 alkyl-substituted pyrimidine derivatives

C-5 and C-6 disubstituted pyrimidine derivatives 2–7 were synthesized. Introduction of the aryl rings at C-5 of pyrimidine moiety in 5 and 6 was performed using palladium-catalyzed Stille cross-coupling reaction. The novel C-6 fluorophenylalkylated 5-phenylpyrimidine derivative (7) was prepared by lithiation of 5-phenylpyrimidine (6) and subsequent reaction of thus obtained organolithium intermediate with p-fluoroacetophenone. The structures of 3, 4 and 6 were determined by X-ray crystal structure analysis. Both methoxy groups in these structures adopt a synperiplanar conformation with respect to the N1 and N3 atoms of the pyrimidine ring. The molecules of 3 and 4 are linked through weak Br···Br interactions into zig-zag chains. The molecules of 6 are assembled into layers by one C–H···O hydrogen bond, C–H···π and aromatic π···π stacking interactions.     

Synthesis of the fully functionalized nine-membered diyne core of the C-1027 chromophore

We report the synthesis of the fully functionalized seco-acid of the C-1027 chromophore. The key reaction is a LiN(TMS)₂/CeCl₃-promoted acetylide-aldehyde condensation to construct the highly strained nine-membered diyne. Appropriate functionalization of the substrates significantly affects the yield of the cyclization. The present findings will be the basis of further studies toward the total synthesis of the C-1027 chromophore.     

C- and N-Substituted Phosphorus(III) Derivatives of Azomethines

Abstract

The reactions of halogenides of P(III) acids with lithium derivatives of azomethines depending on the substituents at the phosphorus atom, the structure of azomethines and conditions of the reaction were studied. A method for synthesizing tile C- and N-phorphorus(III) substituted azomethines was proposed:     

General and Green Synthesis of C-6 Sulfonylmethyl 4-Aryl-3,4-dihydropyrimidinones in Water

A simple, inexpensive, and green reaction permitting the synthesis of new C-6 arylsulfonylmethyl 4-aryl-3,4-dihydropyrimidinones in water by S-alkylation of 6-bromomethyl 3,4-dihydropyrimidinones 2 with benzenesulfinic acid anions 3 is reported. The required 6-bromomethyldihydropyrimidone precursors 2 were readily prepared using an organic solid brominating reagent.     

[4+3] Cycloaddition of C-3 substituted furans. Stereoselectivity induced by coordination effects

Several C-3 substituted furans with chelating groups have been reacted with 2,3-dibromo-3-pentanone in the presence of a reducing metal, resulting in the formation of [4+3]-cycloadducts with complete cis-trans and endo-exo diastereoselectivity and in excellent yield. A certain variability of the conversion and reaction yield could be observed, when changing the reaction conditions, but in all cases the stereoselectivity was complete, compared to that of C-3 substituted furans with non-chelating groups. Also, a general method of assignment of stereochemistry of cycloadducts has been established by NMR, considering diagnostic patterns of signals with different multiplicity and chemical shifts depending on the stereochemistry of diastereomeric cycloadducts.     

Synthesis of Sialic Acid Analogues with the Oxime Group at C-4 Or C-5 of KDN 1

Abstract

The readily available methyl (methyl 3-deoxy-5,8:7,9-di-O-isopropylidene-β-D-glycero-D-galacto-2-nonulopyranosid)onate (7) was converted in five synthetic steps into methyl (methyl 4-acetamido-3,4-dideoxy-β-D-glycero-D-talo-2-nonulopyranosid)onate (11). Selective protection of the C-4, C-7, C-8 and C-9 hydroxy groups of methyl (methyl 3-deoxy-8,9-O-isopropylidene-β-D-glycero-D-galacto-2-nonulpyranosid)onate (2) followed by oxidation of the C-5 hydroxy group and then its oximination gave 5-hydroxyimino derivatives (15 and 16).

     

Synthesis, structure, and biological evaluation of C-2 sulfonamido pyrimidine nucleosides

The C-2 sulfonamido pyrimidine nucleosides were prepared by opening the 2,2′- or 2,3′-bond in anhydronucleosides under nucleophilic attack of sulfonamide anions. Reaction of the sodium salt of p-toluenesulfonamide or 2-(aminosulfonyl)-N,N-dimethylnicotinamide with 2,2′-anhydro-1-(β-d-arabinofuranosyl)cytosine gave the C-2 sulfonamido derivatives in excellent yields. Ring opening of the less reactive 2,2′-anhydrouridine and 2,3′-anhydrothymidine could be accomplished with DBU/CH₃CN activation of p-toluenesulfonamide, giving moderate yields for C-2 sulfonamido derivatives. The action of acetic acid or ZnBr₂/CH₂Cl₂ on 5-methyl-N²-tosyl-1-(2-deoxy-5-O-trityl-β-d-threo-pentofuranosyl)isocytosine led to the cleavage of both the protection group and the nucleoside bond, yielding 5-methyl-N²-tosylisocytosine as the major product. Structures of the prepared C-2 sulfonamido nucleosides were confirmed by the 1D and 2D NMR experiments, and X-ray structural analysis of 4-imino-N²-tosylamino-1-(β-d-arabinofuranosyl)pyrimidine. Both methods confirmed β-configuration and anti-conformation of the 2-sulfonamido nucleosides. The investigated compounds displayed moderate inhibition of tumor cell growth in vitro, as determined by the MTT assay using six different human tumor cell lines.     

The Role of the C-3 Substituent in the Asymmetric Dihydroxylation of Hexo-5-Enofuranosides

ABSTRACT

Asymmetric dihydroxylation of vinyl furanosides 1-6 by use of OsO₄, AD-mix-α® and β® is described yielding the corresponding hexofuranose sugars. Vinyl furanosides 2 and 3, with an ester group at C-3, and vinyl manno furanoside 5 on asymmetric dihydroxylation with AD-mix α® exhibited high R diastereoselectivity at C-5. Reversal in diastereoselectivity at C-5 was observed for the 3-deoxy vinyl furanoside 6 giving furanosaccharide 6S with the S configuration at C-5.     

A highly efficient synthesis of the C-13 side-chain of taxol using Shibasaki's asymmetric Henry reaction

The synthesis of the C-13 side-chain of taxol has been achieved using Shibasaki's asymmetric Henry reaction catalyzed by an optically active rare earth lanthanum-(R)-binaphthol complex.     

Unexpected Reactivity of Ethyl 2-(Diethylphosphono)Propionate Toward 2,2-Disubstituted-1,3-cyclopentanediones

Abstract

A Horner-Wadsworth-Emmons reagent-ethyl 2-(diethylphosphono)propionate in the reaction with 2,2-disubstituted-1,3-cyclopentanediones, results in 4-oxohexanoic acid ethyl ester derivative up to 90% isolated yield. ³¹P-¹³C- and ¹H-NMR study of the intermediates of the reaction involving the ethyl 2-(diethylphosphono)propionate was accomplished.     

Assessing the Molecular Targets and Mode of Action of Furanone C-30 on Pseudomonas aeruginosa Quorum Sensing

Quorum sensing (QS), a sophisticated system of bacterial communication that depends on population density, is employed by many pathogenic bacteria to regulate virulence. In view of the current reality of antibiotic resistance, it is expected that interfering with QS can address bacterial pathogenicity without stimulating the incidence of resistance. Thus, harnessing QS inhibitors has been considered a promising approach to overriding bacterial infections and combating antibiotic resistance that has become a major threat to public healthcare around the globe. Pseudomonas aeruginosa is one of the most frequent multidrug-resistant bacteria that utilize QS to control virulence. Many natural compounds, including furanones, have demonstrated strong inhibitory effects on several pathogens via blocking or attenuating QS. While the natural furanones show no activity against P. aeruginosa, furanone C-30, a brominated derivative of natural furanone compounds, has been reported to be a potent inhibitor of the QS system of the notorious opportunistic pathogen. In the present study, we assess the molecular targets and mode of action of furanone C-30 on P. aeruginosa QS system. Our results suggest that furanone C-30 binds to LasR at the ligand-binding site but fails to establish interactions with the residues crucial for the protein’s productive conformational changes and folding, thus rendering the protein dysfunctional. We also show that furanone C-30 inhibits RhlR, independent of LasR, suggesting a complex mechanism for the agent beyond what is known to date.     

Simultaneous determination of Cr(III) and Cr(VI) with prechelation of Cr(III) using phthalate by ion interaction chromatography with a C-18 column

Ion interaction chromatography has been successfully used for the simultaneous determination of Cr(III) and Cr(VI) in waste water. A C-18 column which had been dynamically coated with octylamine was used for the separation of Cr(III) and Cr(VI) based on anionic interaction. Cr(III) was chelated with potassium hydrogen phthalate (KHP) before injecting into the column since the Cr(III) did not exist in an anionic form like the Cr(VI) (Cr₂O₇²⁻) presented at the optimum condition. The analytes were detected at 200 nm and linear relationship between absorption with the concentration of Cr(III) or Cr(VI) was 0.1-50 mg/L. Most of the interested interferences including alkali metals, heavy metals and organic materials have no significant effect on Cr(III)-KHP complexation and Cr(VI) stability, only NH₄⁺ and ascorbic acid yielded the serious effect on the Cr(VI) stability. The relative standard deviations calculated from both of peak area and retention time were 0.75-2.20%. The sensitivity of the method at the level concentration of sub mg/L enabled the simultaneous determination of Cr(III) and Cr(VI) contents in waste water samples without any special sample preparation step.     

Retention Characteristics of Co+3, Fe+3, and Cu+2 4-(2-Pyridylazo)Resorcinol (PAR) Complexes on C-18 and Amino Silica Packings

Abstract

Chloroform extraction of Co-PAR, Fe-PAR, and Cu-PAR complexes in a pH 6.5 phosphate buffer implied the first two species were primarily monoanions, but the latter was a dianion. Examination of the literature and retention data of these complexes on C-18 and amino columns confirmed the more anionic nature of Cu-PAR. The Co⁺³ and Cu⁺² complexes were slightly resolved from each other, but the Fe⁺³ complex was retained longer on the C-18 silica. In contrast, the Co⁺³ and Fe⁺³ complexes were not resolved, but the Cu⁺² complex was well-retained on the weak anion exchange amino silica column. Use of short amino and C-18 columns in series provided a good separation of all three complexes. Detection of the metal complexes at 546 nm instead of 254 nm avoided interference by PAR and good detection limits were still maintained.     

Synthesis of New Brassinosteroid 24-Norcholane Type Analogs Conjugated in C-3 with Benzoate Groups

The metabolism of brassinosteroid leads to structural modifications in the ring skeleton or the side alkyl chain. The esterification and glycosylation at C-3 are the most common metabolic pathways, and it has been suggested that conjugate brassinosteroids are less active or inactive. In this way, plants regulate the content of active brassinosteroids. In this work, the synthesis of brassinosteroid 24-norcholane type analogs conjugated at C-3 with benzoate groups, carrying electron donor and electron attractant substituents on the aromatic ring, is described. Additionally, their growth-promoting activities were evaluated using the Rice Lamina Inclination Test (RLIT) and compared with that exhibited by brassinolide (used as positive control) and non-conjugated analogs. The results indicate that at the lowest tested concentrations (10⁻⁸–10⁻⁷ M), all analogs conjugated at C-3 exhibit similar or higher activities than brassinolide, and the diasteroisomers with S configuration at C-22 are the more active ones. Increasing concentration (10⁻⁶ M) reduces the biological activities of analogs as compared to brassinolide.     

High Performance Liquid Chromatography of Zinc and Copper Pheophytins

Abstract

The zinc or copper chelates of pheophytins a and b were formed and separated on a reversed-phase C-18 column. Allomerized products were produced readily during the chelation reaction. Resolution of the allomerized compounds from the non-allomerized chelates was achieved using a gradient elution technique. Compound identification was facilitated by monitoring the column eluate at both 436 and 658 nm. The method allowed for isolation of individual pigments for further study.     

THE SYNTHESIS OF SOME C-4 AND C-9 SUBSTITUTED DERIVATIVES OF KDN2EN METHYL ESTER

The synthesis of a number of C-4 and C-9 substituted derivatives of KDN2en methyl ester 2 is reported. 9-Deoxy-9-iodo, 9-azido-9-deoxy and 9-O-methyl derivatives of 2(compounds 5, 7and 9) were prepared from the corresponding 9-O-tosylate, methyl 2,6-anhydro-3-deoxy-9-O-p-toluenesulfonyl-D-glycero-D-galacto-non-2-enonate (3). These compounds have been fully characterised as the peracetates 6, 8 and 10. Treatment of 3 with KSAc gave the 9-thioacetyl derivative which was isolated as the peracetate 11. 4-C-Ethenyl-4-deoxy (14), 4-C-phenyl-4-deoxy (15) and 4-C-[1-(methoxycarbonyl)ethenyl]-4-deoxy (16) derivatives of 2were prepared via the palladium-catalysed coupling of the 4-epi-chloride, methyl 5,7,8,9-tetra-O-acetyl-2,6-anhydro-4-chloro-3,4-dideoxy-D-glycero-D-talo-non-2-enonate (12) with the appropriate organostannanes.     

Hydrogen atom transfer methodology for the synthesis of C-22, C-23, and C-25 stereoisomers of cephalostatin north 1 side chain from spirostan sapogenins

A simple synthesis of all eight C-22, C-23, and C-25 diastereoisomers of the cephalostatin north 1 side chain has been accomplished from (25R)-5α-spirostan-3β-ol (tigogenin). The synthesis involves selective hydroxylations at C-23 and C-25 and reductive opening of the 1,6-dioxaspiro[4.5]decane spirostan system to give a conveniently protected 5α-furostan-3β,23,25,26-tetrol. The construction of the required 1,6-dioxaspiro[4.4]nonane system entailed an intramolecular hydrogen abstraction reaction promoted by the C-25 alkoxyl radical as the key step. Acid-catalyzed isomerization of the spiroketal unit suggested that 22R isomers are the thermodynamic products while the 22S isomers are the result of kinetic control. The acid-catalyzed equilibrium between 1,6-dioxaspiro[4.4]nonane and 1,6-dioxaspiro[4.5]decane systems was also studied. In the 1,6-dioxaspiro[4.4]nonane units, the observed ³J_23,24 coupling constants suggest that the five-membered puckered ring-F undergoes substantial conformational changes on going from 22S to 22R isomers.     

Route selection in the synthesis of C-4 and C-6 substituted thienopyrimidines

Three different routes have been investigated for the preparation of 6-aryl-N-(1-arylethyl)thienopyrimidin-4-amines. First the possibilities of selective Suzuki reactions on 6-bromo-4-chlorothienopyrimidine were investigated. The preference for mono arylation at C-6 could be increased, in the case of Pd(PPh₃)₄ catalysis, by reducing the water content of the reaction, or by using less electron rich Pd-ligands. The highest selectivity was obtained with Pd(OAc)₂ or Pd₂(dba)₃, while reactions with the more electron rich Pd(PPh₃)₄ and especially XPhos gave a lower mono- to dicoupled product ratio. Secondly, two alternative strategies avoiding this selectivity issue were tested. Suzuki reaction on C-6 of 6-bromothienopyrimidin-4(3H)-one (three examples) proceeded in 70-89% yield using Pd(PPh₃)₄ in dioxane/water. Similar conditions on 4-amino-6-bromo-thienopyrimidine (eight examples) gave 67-95% yield. The reaction could be performed with boronic acids containing nonprotected phenolic groups in the ortho, meta and para positions. By prolonging the reaction time, coupling with sterically crowded arylboronic acids was also efficient. Diarylation of 6-bromo-4-chlorothienopyrimidine gave the corresponding 4,6-diarylated derivatives in 71-80% yield depending on the nature of the arylboronic acid.     

Relative stereochemical assignment of C-33 and C-35 in the antibiotic gladiolin

Gladiolin is a macrolide antibiotic isolated from Burkholderia gladioli BCC0238 with promising activity against Mycobacterium tuberculosis, including several multidrug resistant strains. The configuration of all but one of the stereogenic centers of gladiolin has previously been elucidated using a combination of NOESY NMR experiments and predictive sequence analysis of the polyketide synthase responsible for its assembly. However, it was not possible to assign the configuration of the C-35 methyl group using such methods. Here we report the synthesis of C-33/C-35-syn and C-33/C-35-anti mimics of the C-30 to C-38 fragment of gladiolin from (R) and (S)-citronellol, respectively. Comparison of HSQC NMR data for the mimics and the natural product showed that the C-35 methyl is anti to the C-33 hydroxyl group, indicating that gladiolin has the 35S configuration.     

Synthetic Studies Towards Taxol Analogs: Chemoselective Cleavage of C-5 Cinnamoyl Group in Taxane Group of Diterpenoids with Hydroxylamine

Taxane group of diterpenoids 2 and 3 which possess cinnamoyl moiety at C-5 position underwent selective cleavage to C-5 hydroxy compounds 4 and 5 on treatment with hydroxylamine. The resulting compounds were characterised based on their spectral data.