Synthesis, structural revision, and biological activities of 4′-chloroaurone, a metabolite of marine brown alga Spatoglossum variabile

4′-Chloroaurone (1a), the only aurone reported from a marine source, Spatoglossum variabile was synthesized from 2-hydroxyacetophenone along with six structural analogs. The products obtained were Z-isomers and these were converted into E-isomers by photoisomerization. The E and Z isomers of aurones showed distinct proton and carbon chemical shifts. However, the spectroscopic data of either Z-4′-chloroaurone (1a) or its E-isomer (2a) did not match with those reported for the natural product and thus requires revision of the structure assigned. The proton NMR spectroscopic data reported for the natural product matches with those reported for a known isocoumarin (5). The synthesized E and Z aurones were evaluated for their antioxidant and antibacterial activities. The aurone, Z-2-[(3,4-dihydroxyphenyl)methylene]benzo[b]furan-3-one exhibited significant antioxidant activity. Interestingly, Z-aurones are active against Gram-positive and Gram-negative bacteria, whereas the corresponding E-aurones were inactive.     

Five novel norcembranoids from Sinularia leptoclados and S. parva

Three new norcembrane-based diterpenoids, leptocladolides A (1), B (4) and C (5), along with five known metabolites 6-10, have been isolated from the dichloromethane extract of a Taiwanese soft coral Sinularia leptoclados. Furthermore, a chemical investigation on the dichloromethane extract of S. parva has resulted in the isolation of two new related isomers, 1-epi-leptocladolide A (2) and 7E-leptocladolide A (3), in addition to 1 and 7. The structures of new metabolites 1-5 were elucidated on the basis of extensive spectroscopic analyses and their relative stereochemistries were determined by NOESY experiments. The new metabolites 1 and 3 have been shown to exhibit significant cytotoxic activity against KB and Hepa59T/VGH cancer cell lines.     

Asymmetric synthetic study of macrolactin analogues

We designed two aromatic analogues 1a and 1b of macrolactin A with expectation of enhancing biological activity and metabolical stability. As a result of retrosynthetic analysis of these compounds 1a-b, two synthetic strategies have been examined. The first strategy includes the enantioselective addition of nonadienyl anion, derived from 3, to aldehyde 4 as a key step. The second one includes epimerization of ynone 7 to (E,E)-conjugated dienone 31 and subsequent diastereoselective hydride-reduction of 31. Although the former route furnished no desired target, the latter one was revealed to work well for the synthesis of 1. Unfortunately, the aimed (2Z,4E)-analogue 1a could not be synthesized due to an epimerization of the (2Z)-olefin into the (2E)-olefin. However, these methods could be applied to the total asymmetric synthesis of the (2E,4E)-analogue 1b. Overall, control of all of the four stereocenters was achieved by means of asymmetric and diastereoselective reactions without using any chiral natural sources.     

Four new ginkgolic acids from Ginkgo biloba

Four new compounds, 2-hydroxy-6-(12′-hydroxyheptadec-13′(E)-en-1-yl)benzoic acid (1), 2-hydroxy-6-(13′-hydroxyheptadec-11′(E)-en-1-yl)benzoic acid (2), 2-hydroxy-6-(10′-hydroxypentadec-11′(E)-en-1-yl)benzoic acid (3), and 2-hydroxy-6-(11′-hydroxypentadec-9′(E)-en-1-yl)benzoic acid (4) were isolated from the leaves of Ginkgo biloba and the structures of new ginkgolic acids were deduced on the basis of spectroscopic methods and chemical means. Compounds 1 and 2, and 3 and 4 examined as an inseparable mixture of hydroxyl and double bond positional isomers, were ultimately defined by total synthesis. Compounds 1–4 showed moderate lipid droplets accumulation inhibitory activity on mouse pre-adipocyte cell line, MC3T3-G2/PA6.     

Base-catalyzed stereoselective intermolecular addition of imidazoles onto alkynes: an easy access to imidazolyl enamines

An efficient transition metal-free approach for the regio- and stereoselective addition of imidazoles 1a–f onto alkynes 2a–l to provide the Z- and E isomers of imidazolyl enamines 3a–q and 4a–d using catalytic amount of KOH is described. Stereoselectivity of the addition products (Z and E isomer) was found to be dependent upon time. Competitive experiments show that imidazole is less reactive than pyrrole and more reactive than aniline towards hydroamination.     

Synthesis of new compounds containing the 2,3-dihydro[1,4]dioxino[2,3-b]pyridine heterocyclic system as a substructure

2,3-Dihydro-spiro[1,4]dioxino[2,3-b]pyridine-3,3′-pyrrolidine (8A) and 2,3-dihydro-spiro[1,4]dioxino[2,3-b]pyridine-3,4′-piperidine (9A) have been synthesized from 2-chloro-3-pyridinol. The corresponding 2,3′ (8B) and 2,4′ (9B) isomers were obtained via the Smiles rearrangement, while 9B was also selectively synthesized from 2-nitro-3-pyridinol. The separation of the isomers A and B under the sulfamide form was carried out by flash column chromatography. Subsequent transformations of the corresponding dioxinopyridine derivatives were described.     

An efficient synthesis of (E)-(2-arylpyrazino[1,2-a]pyrimidine-4-ylidene)acetonitriles and cyanomethyl appended pyrimidines

A series of (E)-(2-arylpyrazino[1,2-a]pyrimidine-4-ylidene)acetonitriles 5a-j and aryl/heteroaryl tethered pyrimidin-4-yl acetonitriles 6a-e has been synthesized in excellent yields through base catalyzed ring transformation of suitably functionalized 2H-pyran-2-ones 3 using 2-aminopyrazine 4a and arylamidinium salts 4b, separately.     

Convenient synthesis of 3-fluoro-4,5-diphenylfuran-2(5H)-one from benzoin ethers : Novel and efficient Z-E isomerisation and cyclisation of 2-fluoroalkenoate precursors, substitution of vinylic fluorine

Mixtures of ethyl (E)- and (Z)-4-alkoxy-2-fluoro-3,4-diphenylbut-2-enoates (6-8) prepared from benzoin ethers and ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate were transformed in high yields to the target 3-fluoro-4,5-diphenylfuran-2(5H)-one (14) using bromine in tetrachloromethane at room temperature. The non-cyclisable Z-isomers 6b-8b were gradually isomerised to the cyclisable E-isomers 6a-8a during the process. The reaction of the (E)-butenoates 6a-8a with boron trifluoride led to furanone 14, while in Z-isomers 6b-8b both alkoxy group and vinylic fluorine were substituted with bromine during the reaction. Mechanisms for both complex reactions have been proposed. Furanone 14 was transformed to 2-[tert-butyl(dimethyl)silyloxy]-3-fluoro-4,5-diphenylfuran (18) as a novel building block.     

Novel antifungal polyene amides from the myxobacterium Cystobacter fuscus: isolation, antifungal activity and absolute structure determination

Three new unstable metabolites, (6E,10Z)-2′-O-methylmyxalamide D (1), 2′-O-methylmyxalamide D (2) and (6E)-2′-O-methylmyxalamide D (3) were isolated from the myxobacterium Cystobacter fuscus. The planar structures were elucidated by spectroscopic analyses to be geometrical isomers of a polyene amide related to a myxobacterial metabolite, myxalamide D (4). Their absolute stereochemistry was determined by synthesis of degradation products. Antifungal activities of 1-3 as well as their acetates were evaluated against the phythopathogenic fungus Phythopthora capsici.     

Highly stereoselective synthesis of para-substituted (E)-N-styrylcarbazoles via sequential silylative coupling-Hiyama coupling reaction

A series of new para-substituted (E)-(N)-styrylcarbazoles, i.e., eight (E)-9-[2-(aryl)ethenyl]-9H-carbazoles (5-12) and 1,4-bis[(E)-2-(9H-carbazol-9-yl)vinyl]benzene (13), have been synthesized in high yield and stereoselectively by a sequential silylative coupling-Hiyama coupling reaction, i.e., coupling of commercially available 9-vinylcarbazole with vinyltriethoxysilane or divinyltetramethyldisiloxane in the presence of [RuHCl(CO)(PCy₃)₂] (I), followed by Pd (II) catalyzed cross-coupling with para-substituted iodobenzenes.The tandem procedure has facilitated the synthesis of 13. X-ray structures of the intermediate silylvinylcarbazole (4), as well as products 12 and 13 have been obtained.     

Ultrasound-assisted convenient synthesis of hypolipidemic active natural methoxylated (E)-arylalkenes and arylalkanones

An ultrasound-assisted convenient method was developed for the conversion of toxic methoxylated cis-isomer of arylalkenes into its hypolipidemic active trans-isomer. Treatment of cis-isomer or mixture of all three isomers (1a-1j) with ammonium formate and 10% Pd/C gave arylalkanes (2a-2j), which upon oxidation with DDQ in anhydrous dioxane containing a little amount of silica gel, provided (E)-arylalkenes (3a-3g) in 42-72% yield depending upon the substituents attached at the aryl ring. The same method, upon addition of a few drops of water, provided hypolipidemic active arylalkanones (3h-3j) in 59-65% yield.     

Synthesis of Closo-1,7-Carboranyl Alkyl Amines

Of the three closo-carborane isomers (C₂B₁₀H₁₂), closo-1,2-carborane has been used most widely in the synthesis of carboranyl amines. However, closo-1,2-carboranes are prone to deboronation to nido-7,8-carborane under various conditions including attack by basic amino groups. In order to overcome this problem, closo-1,7-carboranyl ethyl-, propyl-, and butylamine were synthesized, which should be more stable towards basic deboronation than their closo-1,2-carboranyl counterparts. These closo-1,7-carboranyl amines (5, 18 and 19) were synthesized using two different methods, both starting from the corresponding closo-1,7-carboranyl alkyl iodides (3, 14 and 15). One of the carboranyl alkyl amine (5) was conjugated with folic acid to form a closo-1,7-carborane-folic acid bioconjugate (20).     

Synthesis, structure, electrochemical properties, cytotoxic effects and antioxidant activity of 5-amino-8-methyl-4H-benzopyran-4-one and its copper(II) complexes

The chromone derivative 5-amino-8-methyl-4H-benzopyran-4-one (ligand) (1) has been used to obtain a series of Cu(II) complexes 2-4 as potential anticancer compounds. The molecular structures of ligand 1 and its Cu(II) complex 3 have been determined by X-ray crystallography. The cytotoxicity of all obtained compounds has been evaluated on melanoma A375 cell line. The ability of compounds 1-4 to take part in redox reactions and their antioxidant activity have been studied.     

An efficient microwave assisted synthesis of novel class of Rhodanine derivatives as potential HIV-1 and JSP-1 inhibitors

(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one (7a-q) derivatives have been synthesized by the condensation reaction of 3-phenyl-2-thioxothiazolidin-4-ones (3a-h) with suitably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehyde (6a-d) under microwave condition. The thioxothiazolidine-4-ones were prepared from the corresponding aromatic amines (1a-e) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes (6a-h) were synthesized from the corresponding acid chlorides (5a-d) using HSnBu₃.     

Microwave assisted synthesis of novel imidazo [2,1-b]thiazole derivative attached to quinoxalinones

3-(6-Phenylimidazo[2,1-b]thiazol-5-yl)quinoxalin-2(1H)-ones (qunoxalinone) (6a-q) have been synthesized by the reaction of ethyl 2-oxo-2-(6-phenylimidazo[2,1-b]thiazol-5-yl)acetates (4a-e) with suitably substituted o-phenylenediamines (5a-f) under microwave heating. The ethyl 2-oxo-2-(6-phenylimidazo[2,1-b]thiazol-5-yl)acetates (4a-e) were prepared by the reaction of 6-phenylimidazo[2,1-b]thiazoles (3a-e) with ethyl chlorooxoacetate in refluxing 1,4-dioxane whereas the thiazoles (3a-e) were synthesized by the reaction of 2-bromo-1-phenylethanones (2a-e) with thiazol-2-amine in refluxing acetone.     

A novel transformation of 1-exo-substituted 2a-aroyl-1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-ones with sulfoxonium ylide to highly strained 2a-(1-arylethenyl)-1,2,2a,7b-tetrahydrocyclobuta[b]benzofurans

When 1-substituted 2a-aroyl-1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-ones (1) were treated with dimethylsulfoxonium methylide, 1-endo isomers (endo-1) gave 1-substituted 3-aroyl-1,2,4a,9b-tetrahydrodibenzofuran-4-ols (2) exclusively as expected. On the other hand, 1-exo isomers (exo-1) underwent a novel transformation to 1-substituted 2a-(1-arylethenyl)-1,2,2a,7b-tetrahydrocyclobuta[b]benzofurans (3), together with 2.     

Studies on the Suzuki reaction on methyl 1-(2-bromoaryl)-5-oxo-3-aryl/heteroaryl-pyrrolidin-2-carboxylate derivatives: synthesis of N-aryl modified monocyclic γ-lactam derivatives in search for newer antibacterial agents

A large number of novel N-aryl modified monocyclic γ-lactam derivatives have been prepared via Pd(0) catalyzed heteroarylation in the N-aryl part of (±) cis and (±) trans γ-lactam carboxylate derivatives 3(a–f) and 6(a–f), respectively, with furan-2-boronic acid and thiophen-2-boronic acid. (±) cis Methyl 1-(2-bromoaryl)-5-oxo-3-aryl/heteroarylpyrrolidin-2-carboxylate derivatives 3(a–f), were prepared in good yields from 1(a–f) via hydrolysis, stereoselective decarboxylation, followed by esterification. Corresponding trans isomers 6(a–f) were prepared by the standard method already reported by us.     

Bioactive butenolides from Streptomyces antibioticus TÜ 99: absolute configurations and synthesis of analogs

The four furanones (butenolides) 1-4, which had been isolated from the fermentation broth of Streptomyces antibioticus TÜ 99 and in preliminary tests had been shown to be biologically active, were synthesized by reaction of the readily available furanones 9 or 16 with 2-methylpropanal or 2-methylbutanal. In addition, a series of analogs was prepared in a similar way from 16 using different aldehydes. The hitherto unknown absolute configurations of the natural products 1-4 as well as those of all the analogs prepared were determined with Mosher's NMR method and/or X-ray crystallography. Some of the compounds synthesized proved to be active in the quorum sensing system of Chromobacterium violaceum.     

The stereoselective synthesis of (E)-octafluoro-1,3,5-hexatriene and (3E,5E,7E)-dodecafluoro-1,3,5,7,9-decapentaene

(E)-(1,2-Difluoro-1,2-ethenediyl)bis[tributylstannane], 3, readily undergoes a Pd(PPh₃)₄/CuI-catalyzed cross-coupling reaction with iodotrifluoroethene to yield (E)-octafluoro-1,3,5-hexatriene, 4, in high isomeric purity. (1Z,3E,5Z)-(1,2,3,4,5,6-Hexafluoro-1,3,5-hexenetriyl)bis[tributylstannane], 7, was sequentially prepared from (1Z,3E,5Z)-(1,2,3,4,5,6-hexafluoro-1,3,5-hexenetriyl)bis[triethylsilane], 5, which was prepared via a Pd(PPh₃)₄/CuI-catalyzed cross-coupling reaction of 3 with (E)-1,2-difluoro-1-iodo-2-triethylsilylethene, 6. Pd(PPh₃)₄/CuI cross-coupling of 7 with iodotrifluoroethene gave (3E,5E,7E)-dodecafluoro-1,3,5,7,9-decapentaene, 8.     

Facile synthesis of (Z)- and (E)-3-allylidene-β-lactams via thermal β-elimination of trans-3-allyl-3-sulfinyl-β-lactams

A competent synthetic route for the synthesis of novel (Z)- and (E)-3-allylidene-β-lactams is described. The strategy involves oxidation of trans-3-allyl-3-phenylthio-β-lactams 1 using sodium metaperiodate (NaIO₄) to diastereomeric trans-3-allyl-3-phenylsulfinyl-β-lactams 2 and 3, which further undergo thermal β-elimination in refluxing carbon tetrachloride to furnish (Z)- and (E)-3-allylidene-β-lactams 5 and 6 in good to excellent yields. The molecular structure of 3b has been established with the help of single crystal X-ray analysis.