Total synthesis and analgesic activity of 6-fluoroindan-1-carboxylic acid

6-Fluoroindan-1-carboxylic acid (4) was conveniently synthesised from 3-fluorobenzaldehyde in six steps. The structure of this new compound and three other intermediates, 3-fluorophenylcyanoethylacrylate (1), 3-fluorophenyl succinic acid (2) and 6-fluoro-3-oxo-indan-1-carboxylic acid (3) was elucidated by comprehensive spectral data analyses. The analgesic activity of compounds 3 and 4 was assessed by the acetic acid induced writhing in Swiss albino mice.     

Synthesis and evaluation of fully (5-amidoisophthalic acid)-functionalised polyacrylamides as selective inhibitors of the beta crystal polymorph of l-glutamic acid

Poly-N-5-acrylamidoisophthalic acid (4), poly-N-(5-(N′-(3,5-dicarboxyphenyl)carbamoyl)pentyl)acrylamide (10a) and poly-N-(11-(N′-(3,5-dicarboxyphenyl)carbamoyl)undecyl)acrylamide (10b) were prepared and assessed as polymorph-selective crystallization inhibitors of the stable β form of l-glutamic acid. Polymerization was carried out as the final step in the preparation of 10a and 10b to ensure the preparation of fully functionalized polymers. Polymers 4, 10a and 10b were effective as complete inhibitors of the stable β form of l-glutamic acid in quantities of 0.5% w/w or greater, whereas the corresponding ‘monomeric’ additives 2 and 11 required quantities of 3% or greater to completely inhibit the β form, demonstrating a cooperative binding effect by the polymeric additives. Within the series of polymers 4, 10a and 10b, polymer 10a, which features a short tethering chain, was the most effective.     

Novel phthalocyanines bearing four 4-phenyloxyacetic acid functionalities

Metal-free (2) and Co(II), Zn(II), Ni(II), Cu(II) metallophthalocyanines (2a–d) with four 4-phenyloxyacetic acid groups on the periphery were prepared by cyclotetramerization of new p-(3,4-dicyanophenoxy)phenylacetic acid (1) and the corresponding divalent metal salts. Further reactions of these products with thionylchloride and then benzylamine in tetrahydrofuran, and octanol in pyridine gave amide (3, 3a–d) and ester (4, 4a–d) derivatives, respectively. The new compounds have been characterized by elemental analyses, IR, UV–Vis, mass and ¹H NMR spectroscopy. The redox properties of compounds 2 and 2a–d were identified by cyclic voltammetry.     

On the relative stereochemistry of atomaric acid and related compounds

The stereochemistry at C-3 of the known compounds atomaric acid 2a, 5′a-desmethyl-5′-acetylatomaric acid 4a, and stypoquinonic acid 5a is revised to 2, 4, and 5 on the basis of a careful study of 2D NOESY experiments and also from comparison of their ¹H and ¹³C chemical shifts with those of the related metabolites 6 and 7 isolated from Stypopodium zonale. Compound 7 is a novel unusually functionalized 1-keto-5′a-desmethyl atomaric acid derivative whose structure and stereochemistry were determined by spectroscopic means.     

Carbonyl complexes of manganese, rhenium and molybdenum with 2-pyridylimino acid ligands

[MBr(CO)₃{κ²(N,O)-pyca}] [M = Mn(1a), Re(1b), pyca = pyridine-2-carboxaldehyde] and [MoCl(η³-C₃H₄Me-2)(CO)₂{κ²(N,O)-pyca}] (1c) react with aminoacid β-alanine to give the corresponding iminopyridine complexes 2a-2c. The same method affords the iminopyridine derivatives from γ-aminobutyric acid (GABA) (3a-3c) and 3-aminobenzoic acid (4a-4c). For complexes 2a-2c, 3a, 3c and 4a, the solid state structures have been determined by X-ray crystallography, revealing interesting differences in their hydrogen-bonding patterns in solid state.     

Synthesis of a new family of protected 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid derivatives with thioctic acid pending arms

The synthesis and characterization of a new family of ester protected N-substituted [1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (H3DO3A) derivatives containing a pendant thioctic acid (α lipoic acid, LA) are reported. These compounds (DO3A^tBu-NLA, DO3A^tBu-NMeNLA, and DO3A^tBu-NEtNLA) are suitable for the functionalization of gold surfaces with rare-earth complexes.     

Solid-phase synthesis of 2-cyanoquinazolin-4(3H)-one and 2,3-dihydrooxazolo[2,3-b]quinazolin-5-one derivatives utilizing resin-bound anthranilic acid derivatives

We were able to obtain 2-cyanoquinazolin-4(3H)-ones 11 in 35-60% four-step overall isolated yields and 2,3-dihydrooxazolo[2,3-b]quinazolin-5-ones 12 in 20-71% four-step overall isolated yields utilizing polymer-bound anthranilic acid derivatives 1, and 6-amino-2-cyanoquinazolin-4(3H)-ones 19 in 30-44% six-step overall isolated yields making use of anthranilic acid derivative resin 2 via dithiazole resins 10 and 17. The reactions on solid phase were monitored by single bead ATR-FTIR spectroscopic method.     

Efficient synthesis of morolic acid and related triterpenes starting from betulin

Morolic acid (1) is a naturally occurring pentacyclic triterpene whose derivatives exhibit promising anti-HIV and other biological activities. An efficient synthesis of 1 has been accomplished in 11 steps with a total yield of 24% starting from betulin. Some related natural triterpenes including moradiol (4), acridocarpusic acid D (5), acridocarpusic acid E (6), and moronic aldehyde (7) have also been synthesized. Biological assay results showed that 1, 5, and 6 exhibited moderate inhibitory activity against glycogen phosphorylase.     

Syntheses and crystal structures of diorganotin (IV) moieties with 3-hydroxy-2-pyridinecarboxylic acid

A series of new organotin (IV) complexes with 3-hydroxy-2-pyridinecarboxylic acid (3-OH-2-picH) of two types: R₂SnCl(3-OH-2-pic) (I) (R = Me 1, n-Bu 2, Ph 3, PhCH₂4) and R₂ Sn(3-OH-2-pic)₂ (II) (R = Me 5, n-Bu 6, Ph 7, PhCH₂8)have been synthesized by reactions of diorganotin (IV) dichloride with 3-hydroxy-2-pyridinecarboxylic acid in the presence of sodium ethoxide. All complexes are characterized by elemental analyses, IR spectra and NMR spectra analyses. Among them, complexes 1, 5, 6 and 7 are also characterized by X-ray crystallography diffraction analyses. Complex 1 is a 1D polymeric chain with six-coordinate tin atoms and the packing of complex 1 is stabilized by the C-H?Cl intermolecular weak interactions, thus a 2D network of 1 is formed. Complex 5 is also a 1D polymeric chain with seven-coordinate tin atoms. Complex 6 is a zigzag polymeric chain linked by Sn?O intermolecular weak interactions. Complex 7 is a monomeric complex with distorted octahedral geometry.     

Spontaneous proton-transfer copolymerization of 2-methyl-2-oxazoline with itaconic acid

Copolymerization of two monomers, 2-methyl-2-oxazoline (1) and itaconic acid (2) was carried out. The copolymerization proceeded spontaneously in 1:1 monomer feed ratio to give 2:1 copolymer 3. The mechanism for the production of such a 2:1 copolymer was explained by the in situ formation of monomer 5 from 1 and 2. Then, the propagation proceeded between 5 and 1 via zwitterionic intermediates. When the ratio of 1 in the feed was higher, the homopropagation of 1 took place.     

Synthesis of 12-deoxyroyleanone, cryptoquinone, 11,14-dihydroxy-8,11,13-abietatrien-7-one, and related derivatives from dehydroabietic acid

Naturally occurring abietane quinones and hydroquinone, namely, 12-deoxyroyleanone (1a), cryptoquinone (4a), and 11,14-dihydroxyabieta-8,11,13-trien-7-one (5a), together with the epimers of tryptoquinones D (2) and F (3), were first synthesized from dehydroabietic acid (6).     

Synthesis and conformational analysis of 3-hydroxypipecolic acid analogs via CSI-mediated stereoselective amination

A short and efficient stereoselective synthetic approach toward substituted piperidines, involving (2S,3S)-3-hydroxypipecolic acid 1, (2R,3S)-3-hydroxypipecolic acid 3, and their acid-reduced analogs 2 and 4, has been developed. The requisite anti- and syn-1,2-amino alcohols 11 and 12 for the preparation of title four piperidine analogs 1-4 were synthesized via the regioselective and diastereoselective amination of anti- and syn-1,2-dibenzyl ethers 13 and 14 using chlorosulfonyl isocyanate (CSI). As a result, reaction of anti-1,2-dibenzyl ether 13 with CSI afforded exclusively the anti-1,2-amino alcohol 11 with the diastereoselectivity of 49:1 in toluene at −78 °C and syn-isomer 14 gave the syn-1,2-amino alcohol 12 as the major product with the diastereoselectivity of 12:1 in hexane at −78 °C. The result of these reactions could be explained by the neighboring group effect leading to retention of stereochemistry. In addition, conformational changes of trans-piperidine intermediate 9 in terms of the nature of N-protecting groups are described. The conformations of 9 and 24-28 were confirmed by ¹H NMR analysis and NOE correlation. Furthermore, the conformations of piperidines 18 and 23 with hydroxyl methyl substituent at C-2 were investigated by NMR spectroscopy.     

A quinoline-based tripodal fluororeceptor for citric acid

The quinoline-based tripodal fluororeceptor 1 has been designed and synthesized for the detection of citric acid in less polar solvents. Receptor 1 shows monomer emission quenching followed by excimer emission upon hydrogen bond-mediated complexation of citric acid. In comparison, receptor 2, in presence of the same acid, gives rise to a decrease in the monomer emission of the naphthyl moiety without showing any peak for the excimer. Receptor 1 is found to bind citric acid more strongly than receptor 2 in CHCl₃.     

Addition of diphenylphosphinodithioic acid and thioacetic acid with vinylidenecyclopropanes: reversed regioselectivities

The reaction of vinylidenecyclopropanes 1 with diphenylphosphinodithioic acid produces the adducts 3 in good to high yields in toluene upon heating at 100 °C within 1 h, whereas adducts 5 are obtained in excellent yields in reversed regioselectivity from the reaction of 1 with thioacetic acid under identical conditions. The radical reaction processes have been discussed on the basis of deuterium labeling experiment and the control experiments in the presence of radical inhibitors (TEMPO and BHT) or a proton scavenger (DTBMP).     

Highly emissive triphenylamine based fluorophores for detection of picric acid

Triphenylamine based, dumbbell shaped, highly fluorescent compound 1 was designed and synthesized. Compound 1 showed blue emission with quantum efficiency as high as 0.78 in benzene solution. Compound 1 showed turn-off sensitivity to picric acid, which is a common constituent of many powerful explosives and unavoidable environmental threats. The turn-off sensitivity to picric acid is attributed to the excited state charge transfer from compound 1 to picric acid. Compound 1 selectively senses picric acid with a detection limit of ∼400 ppb.     

Convenient synthesis of 3,3,3-trifluoropropanoic acid by hydrolytic oxidation of 3,3,3-trifluoropropanal dimethyl acetal

A convenient and efficient method for preparing 3,3,3-trifluoropropanoic acid (1) is reported. The starting material is 1-chloro-3,3,3-trifluoropropene (2) that can be easily transformed into 3,3,3-trifluoropropanal dimethyl acetal (4) on treatment with methanol and KOH followed by acid-catalyzed addition of methanol. Direct transformation of 4 into 1 was efficiently achieved with 30% aqueous hydrogen peroxide (4.0 equiv.) in the presence of FeCl₃ (0.025 equiv.) and hydrochloric acid (0.5 equiv.).     

Synthesis and pharmacological evaluation of potential metabolites of the potassium-competitive acid blocker BYK 405879

Four potential metabolites of the potassium-competitive acid blocker BYK 405879 (1) were synthesized which might be formed in vivo by enzymatic oxidation of the pyran moiety or the methyl groups attached to the (hetero) aromatic system. In all cases, the oxidation of the parent compound 1 was accompanied by a significant loss of pharmacological activity and by a decrease in lipophilicity. The target compounds 6, 14, 20, and 21 constitute valuable tool substances for the investigation of the metabolic fate of BYK 405879 (1).     

Dimethylthallium(III) complexes with picolinic acid and its hydroxyl derivatives

The reaction of dimethylthallium(III) hydroxide with picolinic acid (Hpic), 3-hydroxypicolinic acid (H₂3hpic) and 6-hydroxypicolinic acid (H₂6hpic) in an aqueous/methanol mixture afforded the complexes [TlMe₂(pic)] (1), [TlMe₂(H3hpic)] (2) and [TlMe₂(H6hpic)] (3), respectively. Complex 3′, [NaTlMe₂(6hpic)₂]_n, was obtained as a minor product from a methanolic solution of 3. Compounds 1–3 were characterized by IR and Raman spectroscopy and, in the cases of 1, 2 and 3′, by single-crystal X-ray diffraction. Complex 3′ is the first example of an H6hpic⁻ heterobimetallic compound to be isolated. The ¹H and ¹³C NMR spectra of 1 and 2 are also discussed.     

Synthesis of arotinoid acid and temarotene using mixed (Z)-1,2-bis(organylchalcogene)-1-alkene as precursor

An efficient and novel total synthesis of the two bioactive retinoids temarotene and arotinoid acid (TTNPB) is described. The key steps in this process include the regio and stereoselective hydrotelluration of thioacetylene 9 and Te/Li transmetalation of mixed (Z)-1,2-bis(organylchalcogene)-1-alkene (Z)-3. The subsequent reaction involving the β-phenylthio vinyl lithiated intermediate 10 with dimethyl sulfate gave the (E)-vinyl sulfide 11. The Ni⁺² cross-coupling of 11 with the corresponding phenylzinc bromide and p-oxazoline phenylzinc bromide 12 afforded the respective temarotene 2 and retinoid-oxazoline substituted 13. Finally, compound 13 was deprotected with HCl to furnish arotinoid acid (TTNPB) 1.     

Chemoenzymatic total syntheses of the linear triquinane-type natural products (+)-hirsutic acid and (−)-complicatic acid from toluene

Total syntheses of title natural products, 1 and 2, have been achieved using the cis-1,2-dihydrocatechol 7 as starting material. Compound 7 is readily obtained in large quantity and enantiomerically pure form through the whole-cell biotransformation of toluene using the genetically engineered micro-organism Escherichia coli JM109 (pDTG601) that over-expresses the enzyme toluene dioxygenase (TDO). Three key chemical steps were employed in these syntheses, the first of which was a high-pressure-promoted Diels-Alder cycloaddition reaction between diene 8 and cyclopentenone to give adduct 9. The second key step was the photochemically promoted oxa-di-π-methane rearrangement of the bicyclo[2.2.2]octenone derivative, 18, of 9 to give 20 while the third key step was the reductive cleavage of the last compound so as to afford the linear triquinane 22. Elaboration of compound 22 to targets 1 and 2 followed conventional and/or established procedures. Single-crystal X-ray analyses were carried out on compounds 10-13, 15, 18, 24, and 34.