Synthesis of (S)-(—)-Vertinolide

(S)-(?)-Vertinolide 1 was synthesized via the tetronic acid derivative 6 from (S)-(?)-tetrahydro-2-methyl-5-oxo-2-furancarboxylic acid 3. (±)-Vertinolide was also synthesized from (±)-3.     

Total Synthesis of ( + )-Methyl Phaseates

( ± )-Methyl phaseates were synthesized from ( ± )-4-(6′-acetoxymethyl-2 ′,6′-dimethyl-1′-cyclohexen-1′-y1)-but-3-en-2-one (20), which was prepared from a useful terpenoid building block, ( ± )-2-hydroxymethyl-2,6-dimethyl-1-cyclohexanone (11a and 11b). Photooxidation of the cyclohexadiene intermediate (22), followed by alkaline hydrolysis and methylation, gave four stereoisomers of ( ± )-methyl phaseates: (2Z,4E)-cis form (2), (2E,4E)-cis form (24), (2Z,4E)-trans form (25) and (2E,4E)-trans form (26).     

Ferulic acid dehydrodimers from wheat bran: isolation,purification and antioxidant properties of 8-0-4-diferulic acid

Summary

Wheat bran contains several ester-linked dehydrodimers of ferulic acid, which were detected and quantified after sequential alkaline hydrolysis. The major dimers released were: trans-5-[(E)-2-carboxyvinyl]-2-(4-hydroxy-3-methoxy-phenyl)-7-methoxy-2,3-dihydrobenzofuran-3-carboxylic acid (5–8-BendiFA), (Z)-β-(4-[(E)-2-carboxyvinyl]-2-methoxy-phenoxy)-4-hydroxy-3-methoxycinnamic acid (8-O-4-diFA) and (E,E)-4,4′-dihydroxy-5,5′-dimethoxy-3,3′-bicinnamic acid (5–5-diFA). trans-7-hydroxy-1-(4-hydroxy-3methoxyphenyl)-6-methoxy-1,2-dihydro-naphthalene-2,3-dicarboxylic acid (8–8-diFA cyclic form) and 4,4′-dihydroxy-3,3′-dimethoxy-β,β'-bicinnamic acid (8–8-diFA non cyclic form) were not detected. One of the most abundant dimers, 8-O-4-diFA, was purified from de-starched wheat bran after alkaline hydrolysis and preparative HPLC. The resultant product was identical to the chemically synthesised 8-O-4-dimer by TLC and HPLC as confirmed by ¹H-NMR and mass spectrometry. The absorption maxima and absorption coefficients for the synthetic compound in ethanol were: λ_max: 323 nm, λ_min: 258 nm, ε_λmax (M^?1cm^?1): 24800 ± 2100 and ε₂₈₀ (M^?1cm^?1): 19700 ± 1100. The antioxidant properties of 8-O-4-diFA were assessed using: (a) inhibition of ascorbate/iron-induced peroxidation of phosphatidylcholine liposomes and; (b) scavenging of the radical cation of 2,2′-azinobis (3-ethyl-benzothiazoline-6-sulphonate) (ABTS) relative to the water-soluble vitamin E analogue, Trolox C. The 8-O-4-diFA was a better antioxidant than ferulic acid in both lipid and aqueous phases. This is the first report of the antioxidant activity of a natural diferulate obtained from a plant.     

Enantiotopically Selective Oxidation of 1,5-Diols with Gluconobacters Preparation of (S)-Mevalonolactone

(±)-(2Z,4E)-α-Ionylideneacetic acid (2) was enantioselectively oxidized to (?)-(l′S)-(2Z,4E)-4′-hydroxy-α-ionylideneacetic acid (3), (+)-(1′R)-(2Z,4E)-4′-oxo-α-ionylideneacetic acid (4) and (+)-abscisic acid (ABA) (1) by Cercospora cruenta IFO 6164, which can produce (+)-ABA and (+)-4′-oxo-α-acid 4. This metabolism was confirmed by the incorporation of radioactivity from (±)-(2-¹⁴C)-(2Z,4E)-α-acid 2 into three metabolites. (?)-4′-Hydroxy-α-acid 3 was a diastereoisomeric mixture consisting of major 1′,4′-trance-4′-hydroxy-α-acid 3a and minor 1′,4′-cis-4′-hydroxy-α-acid 3b. These structures, 3a and 3b, were confirmed by ¹³C-NMR and ¹H-NMR analysis. Also, the enantioselectivity of the microbial oxidation was reexamined by using optically pure α-acid (+)-2 and (?)-2, as the substrates.     

Protective Group-Free Syntheses of (±)-Frontalin, (±)-endo-Brevicomin, (±)-exo-Brevicomin,and (±)-3,4-Dehydro-exo-brevicomin: Racemic Pheromones with a 6,8-Dioxabicyclo[3.2.1]octane Ring

Protective group-free syntheses of four racemic pheromones with a 6,8-dioxabicyclo[3.2.1]octane ring were achieved in five or six steps from commercially available (±)-3-butyn-2-ol (6) and 2-alkenyl halides or 2-alken-1-ol by employing Lewis acid-catalyzed acetalization of δ, ε-epoxy ketones as the key reaction. (±)-Frontalin (1) was prepared in a 25% overall yield in five steps from methallyl chloride (5a), (±)-endo-brevicomin (2) was prepared in a 23% overall yield in five steps from (E)-2-pentenyl bromide (5b), and (±)-exo-brevicomin (3) and (±)-3,4-dehydro-exo-brevicomin (4) were both prepared in a 4% overall yield in six steps based on (Z)-2-penten-1-ol (12).     

Conversion of (2Z,4E)-5-(1′,2′-epoxy-2′,6′,6′-trimethylcyclohexyl)-3-methyl-2,4-pentadienoic acid to xanthoxin acid by Cercospora cruenta, a fungus producing (+)-abscisic acid

(±)-(2Z,4E)-5-(1′,2′-epoxy-2′,6′,6′-trimethylcyclohexyl)-3-methyl-2,4-pentadienoic acid was metabolized by Cercospora cruenta, which has the ability to produce (+)-abscisic acid (ABA), to give (±)-(2Z,4E)-xanthoxin acid, (±)-(2Z,4E)-5′-hydroxy-1′,2′-epoxy-1′,2′-dihydro-β-ionylideneacetic acid, (±)-1′,2′-epoxy-1′,2′-dihydro-β-ionone and trace amounts of ABA.     

Lipases catalyzed enantioselective hydrolysis of (R,S)-methyl 1,4-benzodioxan-2-carboxylate intermediate for (S)-doxazosin mesylate

(S)-1,4-benzodioxan-2-carboxylic acid-1 is used as starting compound for the production of the more effective (S) enantiomer of the drug doxazosin mesylate. The catalytic ability of some commercial lipases for preparations of (S) enantiomer of 1 from (±) methyl 1,4-benzodioxin-2-carboxylate-2 is reported. Lipases from bacterial sources were more successful in resolving the ester than those from the yeast lipases. About 85% enantiomerically pure ester was achieved by lipase from alcaligenes sp.     

Constituents with tyrosinase inhibitory activities from branches of Ficus erecta var. sieboldii King

Phytochemical investigation of the branches of Ficus erecta var. sieboldii King resulted in the isolation of eight constituents: p-hydroxybenzoic acid (1), methyl p-hydroxybenzoate (2), vanillic acid (3), methyl vanillate (4), syringic acid (5), β-sitosterol (6), α-amyrin acetate (7), and ethyl linoleate (8). Their chemical structures were identified via spectroscopic means as well as by comparing their data with literature values. Studies on tyrosinase inhibition activities were conducted for the isolated compounds. Among them, p-hydroxybenzoic acid (1) and methyl p-hydroxybenzoate (2) were identified as active tyrosinase inhibitors with IC₅₀ values of 0.98?±?0.042 and 0.66?±?0.025?mM, respectively, showing comparable activities to that of arbutin (IC₅₀?=?0.32?±?0.015?mM), a standard control. Inhibition kinetics, as analyzed by Lineweaver-Burk plots, indicated that compounds 1 and 2 were competitive inhibitors of diphenolase of mushroom tyrosinase. Notably, isolated compounds 1–8 were reported for the first time as constituents of F. erecta.     

The synthesis of (Z)-4-oxo-4-(arylamino)but-2-enoic acids derivatives and determination of their inhibition properties against human carbonic anhydrase I and II isoenzymes

The synthesis of (Z)-4-oxo-4-(arylamino)but-2-enoic acid (4) derivatives containing structural characteristics that can be used for the synthesis of several active molecules, is presented. Some of the butenoic acid derivatives (4a, 4c, 4e, 4i, 4j, 4k) are synthesized following literature procedures and at the end of the reaction. In addition, structures of all synthesized derivatives (4a–4m) were determined by ¹H-NMR, ¹³C-NMR and IR spectroscopy. Carbonic anhydrase is a metalloenzyme involved in many crucial physiologic processes as it catalyzes a simple but fundamental reaction, the reversible hydration of carbon dioxide to bicarbonate and protons. Significant results were obtained by evaluating the enzyme inhibitory activities of these derivatives against human carbonic anhydrase hCA I and II isoenzymes (hCA I and II). Butenoic acid derivatives (4a–4m) strongly inhibited hCA I and II with K_is in the low nanomolar range of 1.85?±?0.58 to 5.04?±?1.46?nM against hCA I and in the range of 2.01?±?0.52 to 2.94?±?1.31?nM against hCA II.     

Preparation of Aroma Compounds by Microbial Transformation of Isophorone with Aspergillus niger

( ± )-cis-γ-Irone (1a), ( ± )-cis-dihydro-γ-irone (2a) and their trans- isomers (1b, 2b) were synthesized via 3,3-(Claisen) or 2,3-sigmatropic rearrangement of 1-hydroxymethyl-3,3,4- trimethyl-1-cyclo he xene (8) derivatives as each key step.     

Microbial Allyl Rearrangement and Resolution of Acetates of Unsaturated Cyclic Terpene Alchols by Pseudomonas sp. NOF-5 Strain

Microbial hydrolysis of the acetates of unsaturated cyclic terpene alcohols by Pseudomonas sp. NOF-5 isolated from soil was investigated. (±)-trans-Carveyl acetate ((±)-trans-3) was enantio-selectively hydrolyzed with NOF-5 strain to give ( – )-trans-carveol (( – )-trans-2 of 86.6% optical purity). However, the hydrolysis of (±)-cis-3 was less enantioselective, while (±)-piperitylacetate ((±)-6, a cis and trans mixture) was hydrolyzed to give the ( – )-trans- and ( – )-cis-piperitols (( – )- trans-5 and ( – )-cis-5) in a poor optical yield. In this case, other tert-alcohols, ( + )-trans- and ( – )- ds-2-p-menthen-1-ols ((±)-trans-7 and ( – )-cis-7), were also produced. Furthermore, microbial and enzymic allyl rearrangements of ( + )-trans-6 and ( – )-trans-verbenylacetate (( – )-trans-11) were studied. Biological treatment of (+)-trans-6 and ( – )-trans-11 with NOF-5 or its esterase gave (+)-trans- and (-)-cis-1 and ( + )-cis-3-pinen-2-ol (( + )-cis-12), respectively.     

Effective Cytochrome P450 (CYP) Inhibitors Isolated from Tarragon (Artemisia dracunculus)

Two effective cytochrome P450 (CYP) inhibitors were isolated from tarragon, Artemisia dracunculus. Their structures were spectroscopically identified as 2E,4E-undeca-2,4-diene-8,10-diynoic acid isobutylamide (1) and 2E,4E-undeca-2,4-diene-8,10-diynoic acid piperidide (2). Both compounds had dose-dependent inhibitory effects on CYP3A4 activity with IC₅₀ values of 10.0 ± 1.3 µM for compound 1 and 3.3 ± 0.2 µM for compound 2, and exhibited mechanism-based inhibition. This is the first reported isolation of effective CYP inhibitors from tarragon (Artemisia dracunculus) purchased from a Japanese market.     

Studies on Chrysanthemic Acid

Synthesis of (±)-trans-chrysanthemic acid from (±)-1′-hydroxydihydro-trans-chrysanthemic acid by the dehydration with p-toluene-sulfonic acid was attempted. However, the attempt was found to be unsuccessful giving a compound believed to be methyl methyl 2,6 dimethylhepta-3.6-diene-5-carboxylate upon dehydration.

A cleavage upon cyclopropane ring was confirmed by deriving the acid obtained by the hydrolysis of the above ester to already known 2,6-dimethyl-heptane-5-carboxylic acid.

Analogous mode of dehydration and cleavage upon the ester of (±)-2,2-dimethyl-3-trans-hydroxylbenzyl-cyclopropane-l-carboxylic acid was also observed to give 1-phenyl-4-methyl-penta-1,3-diene-3-carboxylic acid. On the other hand, (±)-trans-caronic acid being derived to (±)-1′-oxo-2′-hydroxy-dihydro-trans-chrysanthemic acid, the synthesis of (±)-trans-chrysanthemic acid from (±)-trans-caronic acid became possible using (±)-1′-oxo-2′-hydroxy-dihydro-trans-chrysanthemic acid as a relay substance.     

Insecticidal activity of pyrrolizine derivatives isolated fromStreptomyces griseus

Mixtures of 5,6,7,7a-tetrahydro-3H-pyrrolizin-3-one (1) and 5,6,7,7a-tetrahydro-3H-pyrrolizin-7a-ol-3-one (2) isolated from shaken cultures ofStreptomyces griseus exhibited contact killing effects on larvae ofLeptinotarsa decemlineata andAedes aegypti comparable with those of macrotetrolides and the commercial bioinsecticide Bactoculicid, respectively.Galleria mellonella (caterpillars),Anagasta kühniella andTetranychus urticae were insensitive to this action.     

Asymmetric Hydrolysis of (±)-1-Acetoxy-2,3-dichloropropane with Enzymes and Microorganisms

Enzymes and microorganisms were screened for the enantioselective hydrolysis of (±)-1-acetoxy-2,3-dichloropropane (1) which is convertible to epichlorohydrin. Pancreatin and steapsin from hog pancreas were found to hydrolyze (±)-1 asymmetrically to give (S)-1 of 90% enantiomeric excess (e.e.). From (S)-1 was synthesized the optically pure (S)-isomer of propranolol[1-isopropylamino-3-(1-naphthoxy)-2-propanol], one of the typical β-adrenergic blocking agents.     

Design,synthesis, and urease inhibition studies of some 1,3,4-oxadiazoles and 1,2,4-triazoles derived from mandelic acid

Some new structural type inhibitors of urease, i.e. 2,5-disubstituted-1,3,4-oxadiazoles (4a–e) and 4,5-disubstituted-1,2,4-triazole-3-thiones (5a–e) were synthesized in two steps from mandelic acid hydrazides (2a–e) and aryl isothiocyantes. The hydrazides in turn were synthesized from mandelic acid via esterification. Compounds 4a–e and 5a–e were evaluated against jack bean urease. Compounds 4d, 5b, and 5d were found to be more potent, with IC₅₀ values of 16.1?±?0.12?µM, 18.9?±?0.188?µM, and 16.7?±?0.178?µM, respectively, when compared to the standard (thiourea; IC₅₀?=?21.0?±?0.011?µM). These compounds may be subjected to further investigations for the development of antiulcer drugs.     

Relationship between Stereoisomerism and Biological Activity of Pyrethroids

(+)-trans-Homochrysanthemic acid, when boiled in dilute sulfuric acid, gives (+)-trans-ε-hydroxy-dihydrohomochrysanthemic acid, m.p. 176–7°, together with (+)-δ, δ-dimethyl-γ-isobutenyl-δ-valerolactone. The formation of optically active lactone from (+)-trans-homochrysanthemic acid provides another cogent evidence for the structure of the lactone previously deduced on the racemic compound.

The Arndt-Eistert reaction of the homo-acids give further higher homologues such as (±)-,(+)-trans-β-(3-isobutenyl-2, 2-dimethylcyclopropane-1)-propionic acids and (±)-cis-3-isobutenyl-2, 2 dimethylcyclobutane-1-acetic acid. Both trans-acids, in boiling dilute sulfuric acid, give the same (±)-γ-(1′, 1′, 4′-trimethyl-pent-2′-enyl)-butyrolactone together with the corresponding hydroxy-acids, optically inactive and active, respectively.

Complete resolution of (±)-trans-homochrysanthemic acid and (±)-trans-β-(3-isobutenyl-2, 2-dimethycyclopropane-1)-propionic acid was achieved by means of optically active α-phenylethylamine.     

Synthesis of ( ± )-Methyl Epijasmonate and ( ± )-Methyl Cucurbate

A novel synthesis of ( ± )-methyl epijasomonate (2) and the first synthesis of ( ± )-methyl cucurbate (4) were achieved starting from 2-allylcyclohexane-1,3-dione (8). The synthetic epimer 2 had a stronger jasmin flavor than the trans-isomer 1 with 95% purity.     

PTP1B inhibitory activity of kaurane diterpenes isolated from Siegesbeckia glabrescens

Protein tyrosine phosphatase 1B (PTP1B) is considered as a therapeutic target for the treatment of diabetes and obesity. In our preliminary screening study, a MeOH extract of the aerial part of Siegesbeckia glabrescens was found to inhibit PTP1B activity at 30 μg/mL. Bioassay‐guided fractionation led to the isolation of two active diterpenes, ent-16βH,17-isobutyryloxy-kauran-19-oic acid (1) and ent-16βH,17-acetoxy-18-isobutyryloxy-kauran-19-oic acid (2), along with ent-16βH,17-hydroxy-kauran-19-oic acid (3). Compounds 1 and 2 inhibited the PTP1B activity with IC₅₀ values of 8.7 ± 0.9 and 30.6 ± 2.1 μM, respectively. Kinetic studies suggest that both 1 and 2 are non-competitive inhibitors of PTP1B. However, compound 3 substituted with a hydroxyl group at C-17 in kaurane-type showed no inhibitory effects towards PTP1B.     

PTP1B inhibitory effects of tridepside and related metabolites isolated from the Antarctic lichen Umbilicaria antarctica

The selective inhibition of PTP1B has been widely recognized as a potential drug target for the treatment of type 2 diabetes and obesity. In the course of screening for PTP1B inhibitory natural products, the MeOH extract of the dried sample of the Antarctic lichen Umbilicaria antarctica was found to exhibit significant inhibitory effect, and the bioassay-guided fractionation and purification afforded three related lichen metabolites 1-3. Compounds 1-3 were identified as gyrophoric acid (1), lecanoric acid (2), and methyl orsellinate (3) mainly by analysis of NMR and MS data. These compounds inhibited PTP1B activity with 50% inhibitory concentration values of 3.6 ± 0.04 μM, 31 ± 2.7 μM, and 277 ± 8.6 μM, respectively. Furthermore, the kinetic analysis of PTP1B inhibition by compound 1 suggested that the compound inhibited PTP1B activity in a non-competitive manner.