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A series of benzo[b]furan derivatives having a five-membered heterocyclic substituent at the 2-position were prepared from 2-(1-chloro-2-formylvinyl)benzo[b]furans (2) and 2-(4-alkylcarbamoylbuta-1,3-dienyl)benzo[b]furans. These 2-heterocyclic benzo[b]furans were evaluated for their cysteinyl leukotriene receptor (cysLT1, cysLT2) inhibitory activity. Several compounds showed moderate inhibition of calcium mobilization in HEK 293T-cysLT2 or CHO-cysLT1 cells.

Graphical abstract Preparation of novel (Z)-4-ylidenebenzo[b]furo[3,2-d][1,3]oxazines and their biological activities such as anti-osteoclastic bone resorption activity, antagonistic activity of the cysLT1 receptor and growth inhibitory activity for MIA PaCa-2 and MCF-7 are described., A reaction of 2-acetyl-3-acylaminobenzo[b]furans (9d–o) with Vilsmeier (VM) reagent afforded a mixture of (E)- and (Z)-{(E)-2-aralkenylbenzo[b]furo[3,2-d][1,3]oxazin-4-ylidene}acetaldehydes (5) with a characteristic exo-formylmethylene group on the oxazine ring. The Z-isomer was more stable than the E-isomer. The Z-isomers ((Z)-5) were reacted with phosphonate reagents under two different conditions to obtain various butadiene derivatives (12) containing benzo[b]furo[3,2-d][1,3]oxazine skeleton. Typical compounds (5 and 12) were evaluated for their anti-osteoclastic bone resorption activity, antagonistic activity for the cysLT1 receptor and growth inhibitory activity for MIA PaCa-2 and MCF-7. Compounds 12f and 12j showed potent anti-osteoclastic bone resorption activity comparable to E2 (17β-estradiol).

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.

The novel skeleton transformation reaction of 2a-substituted 2a,8b-dihydrobenzo[ B]cyclobuta[ D]pyran-3-one derivatives into 2-(2-substituted 2-oxoethyl)-2 H-1-benzopyran derivatives has been accomplished using Znl 2 in the presence of an organic base and water in excellent yields.

We found two novel skeleton rearrangement reactions. The one was the reaction from coumarin derivatives having an electron-withdrawing group at the 3-position with dimethylsulfoxonium methylide to cyclopenta[b]benzofuran derivatives. The other was the reaction from benzo[b]cyclobuta[d]pyran derivatives having an electron-withdrawing group at the 2a-position to tetrahydrodibenzofuran derivatives. Interestingly, the latter reaction proceeded stereoconvergently regardless of the stereochemistry at the 1-position in the cyclobutane compounds. Driving forces of these reactions would be attributable to release of the ring strain including in a cyclopropane ring and cyclobutane ring. These methodologies were applied to the total synthesis of linderol A, which is a constituent of Lindera umbellata (Lauraceae) and has a potent inhibitory activity on melanin biosynthesis, and the synthesis was performed in 14 steps, 34% overall yield. Furthermore, the uncertain absolute structure of linderol A was determined, and its asymmetric synthesis was also achieved.

Eleven 3-substituted isocoumarins and a benzylidenephthalide were synthesized through thermal cyclization reaction of delta- and gamma-ketoamides, respectively. Subsequent deprotection of the hydroxyl groups of the resulting isocoumarin and benzylidenephthalide compounds afforded thunberginols A, B, and F, respectively, which originated from the processed leaves of Hydrangea macrophylla SERINGE var. thunbergii MAKINO. The synthesized isocoumarins and thunberginols were evaluated for their anti-allergic activity, in which thunberginol B exhibited the highest inhibitory potency on the degranulation of RBL-2H3 cells induced by antigen. Structure-activity relationship studies were carried out to determine the necessary substituents on the 3-phenylisocoumarin skeleton for inhibitory activity.

The first asymmetric total synthesis of (-)-Linderol A, a potent inhibitor of melanin biosynthesis of cultured B-16 melanoma cells, has been achieved via two key reactions: a diastereoselective [2+2] photocycloaddition of a coumarin-3-carboxylate bearing a chiral auxiliary with 3-methyl-1-butene and a subsequent stereoconvergent transformation of the photoadducts with use of dimethylsulfoxonium methylide to afford a tetrahydrodibenzofuran derivative.

Reuse of chiral ruthenium catalyst in catalytic asymmetric transfer hydrogenation (CATH) has attracted attention from economic and environmental viewpoints, and reactions using ionic liquids (ILs) as solvent are recognized as one of the most useful methods for reuse of the catalyst. We synthesized (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (TsDPEN) derivatives with various ionic moieties, and investigated the effect of their structure with respect to catalytic ability and recyclability in CATH with ILs. Ligand 3a having an imidazolium group showed the best results, and significant differences were observed depending on the structure of the ionic moiety or the length of the alkyl chain connecting the ligand site and the ionic moiety. Among various prochiral ketones used as substrates at various cycles, 3a showed a relatively good result.

A novel oxazine ring formation method was established using the reaction of 2-acetyl-( E )-3-styrylcarbonylaminobenzo[ b ]furans ( 4 ) with Vilsmeier–Haack–Arnold reagent to afford ( E and Z )-(( E )-2-styrylbenzo[ b ]furo[3,2- d ][1,3]oxazin-4-ylideno)acetaldehydes ( 5 ). ( Z )-4-(8-Bromo-( E )-2-styrylbenzo[ b ]furo[3,2- d ][1,3]oxazin-4-ylideno)but-( E )-2-enoic acid ethyl ester ( 6b ), derived from ( Z )- 5a , showed significantly potent anti-osteoclastic bone resorption activity comparable to 17 β -estradiol (E 2 ).

Homonuclear Diels–Alder dimerization of various 5-ethenyl-2-phenylsulfanyl-1H-imidazoles provided a novel highly regio- and stereoselective route to the preparation of multifunctionalized 4,5,6,7-tetrahydrobenzimidazoles, which is the basic skeleton of ageliferin, a biologically active pyrrole-imidazole marine alkaloid. The reaction was applied to the synthesis of 12,12′-dimethylageliferin.

Reaction of 1-substituted 3-alkenyl-1 H -indoles with an equimolar amount of trifluoroacetic acid in dichloromethane gave cyclic dimers, 1,3- trans - N , N ′-disubstituted cyclopent[ b ]indoles, in 53–84% yields as sole products through an acid-mediated stereoselective cyclo -dimerization process. The structure of the cyclic dimer derived from 3-cyclopentylidenemethyl-1-methyl-1 H -indole was elucidated by X-ray crystallographic analysis.

Reaction of 1- tert -butoxycarbonyl-3-cyclopentylidenemethyl-1 H -indole with an excess of trifluoroacetic acid in dichloromethane at room temperature gave a cyclic dimer, 13-cyclopentyl-6,7,12,13-tetrahydrospiro[5 H -cyclohepta[1,2- b :4,5- b ′]diindole-6,1′-cyclopentane] in 73% yield as the sole product through a novel cyclo-dimerization process. Structure of the cyclic dimer derived from 5-bromo-1- t -butoxycarbonyl-3-cyclopentylidenemethyl-1 H -indole was elucidated by X-ray crystallographic analysis.

1,2a-Disubstituted benzo[b]cyclobuta[d]pyrans, which were prepared by photochemical [2+2] cycloaddition between coumarins and alkenes, were treated with two equivalents of dimethyl-sulfoxonium methylide. 1,3-Disubstitutedtetrahydrodibenzofurans having r-1,t-4a,t-9b stereochemistry were obtained stereoconver-gently regardless of the stereochemistry of the 1-position in the cyclobutane derivatives. This methodology was applied to the second-generation synthesis of (′)-linderol A, a melanin biosynthesis inhibitory active natural product.

Reaction of 2-(1-chloro-2,2-dimethylpropyl)-1-methyl-1H-irnidazoles with diethyl methylmalonate in the presence of NaH gave a normal SN product, 2-[(1,1-diethoxycarbonylethyl)-2,2-dimethylpropyl]-1-methyl-1H-imidazole (2a), and two tele-reaction products, 5-(1,1-diethoxycarbonylethyl)-1-methyl-2-(2,2-dimethylpropyl)-1H-imidazole (3a) and trans-4,5-di-(1,1-diethoxycarbonylethyl)-4,5-dihydro-1-methyl-2-(2,2-dimethylpropyl)-1H-imidazole (4a) in 5, 17 and 70% yields, respectively. The scope and mechanism of this reaction are discussed.

Novel 3-acetoacetylaminobenzo[b]furan derivatives having a modified triene system at the 3-position were synthesized starting with 3-aminobenzo[b]furans. The enol isomers, 3-[(3-hydroxybut-2-enonyl)amino]benzo[b]furans (), of the 3-acetoacetylaminobenzo[b]furans were obtained as stable isomers owing to formation of a hydrogen bonding between the enol hydroxyl group and the amidocarbonyl group. The planarity of the C-2 substituent through the C-3 side chain suggested the existence of a modified conjugational triene system in the enol compound. Cysteinyl leukotriene 1 and 2 receptor antagonistic activities for these compounds were evaluated. 2-(4-Cyanobenzoyl or ethoxycarbonyl)-3-[(2-cyano-3-hydroxybut-2-enonyl)amino]benzo[b]furans (, ) were moderately active.

Diels–Alder-type dimerization of various 5-ethenyl-2-phenylsulfanyl-1 H -imidazoles provided a novel highly regio- and stereoselective route to the preparation of multifunctionalized 4,5,6,7-tetrahydrobenzimidazoles, the basic skeleton of ageliferin, a biologically active pyrrole–imidazole marine alkaloid. The reaction was applied to the synthesis of 12,12′-dimethylageliferin.

The first total synthesis of naamine C and pyronaamidine, highly substituted and cytotoxic imidazole marine alkaloids of a certain kind of sponge, was achieved through an eight-step reaction starting from 1-methyl-2-phenylthio-1H-imidazole.

When the coumarins ( 4 ) having an electron-withdrawing group at the 3 position were treated with 2.4 equiv. of dimethylsulfoxonium methylide at room temperature in DMF or DMSO, novel tricyclic 2-substituted cyclopenta[b]benzofuran-3-ols ( 5 ) were obtained in moderate to good yields. The intermediates, 1a-substituted benzo[b]cyclopropa[d]pyran-2(1aH)-ones ( 3 ), of this tandem reaction were isolated and derived to the corresponding 2-substituted cyclopenta[b]benzofuran-3-ols ( 5 ) by treatment with 1.1 equiv. of dimethylsulfoxonium methylide.

1,3-Dialkyl-2,3-dihydro-2-imino-1H-imidazole derivatives are synthesized in 49–86% yield by treatment of 1,3-dialkyl-2-(phenylsulfanyl)imidazolium salts with primary carbamates or amides in the presence of a base such as LDA or NaH, and the first total synthesis of naamine B, a marine 2-imino-2,3-dimethyl-1,3-dihydro-1H-imidazole alkaloid, is achieved by application of this reaction as a key step.

Treatment of 1,3-dialkyl-2-(phenylthio)benzimidazolium salts 3 and 1,3-dialkyl-2-phenylthio-1H-imidazolium salts 7 with aq. K2CO3 gives 1,3-dialkyl-1,3-dihydrobenzimidazol-2-ones 4 and 1,3-dialkyl-1,3-dihydroimidazol-2-ones 8, respectively, in 22–94% yield. A regio-isomer 17 of kealiiquinone, a marine benzimidazole alkaloid, where the 4-methoxyphenyl group at the 4-position migrates to the 9-position, is synthesized by application of the reaction. Cytotoxity of 17 and kealiiquinone against 39 human cancer cells is evaluated. They have weak activity but a unique mechanism of action.

2-(1-Chloro-2,2-dimethylpropyl)-1-methyl-1 H -imidazole hydrochloride ( 2a ·HCl) was treated with an excess of N,N -dimethylamine at room temperature to give an abnormal addition product, 4,5-bis( N,N -dimethylamino)-1-methyl-2-(2,2-dimethylpropyl)-2-imidazoline ( 4a ), in 74.2% yield together with a normal S N 2 product, 2-(1- N,N -dimethylamino-2,2-dimethylpropyl)-1-methyl-1 H -imidazole ( 3a ), in 15.0% yield. The former might be evolved from a serial double nucleophilic addition of the secondary amine molecules to the imidazole nucleus, which has been generally considered as an electron-excessive and stable aromatic ring.

The first total synthesis of clathridine A (8), a marine imidazole alkaloid, was achieved by using a novel regioselective condensation as a key step, in which preclathridine A (2) was treated with 1-methylparabanic acid (11) in the presence of a silylating agent.

In the presence of samarium diiodide, 2-aryl and 2-heteroaryl cyclopropane-1, 1-dicarboxylic esters were readily dimerized to give 3, 4-disubstituted 1, 1, 6, 6-hexanetetracarboxylic esters as diastereomeric mixtures in moderate to good yields. The diastereomeric mixtures were separated by preparative HPLC and stereo-chemistries of the isolated meso and racemic compounds were determined on the basis of HPLC analysis on chiral stationary phases. Between the 1H-NMR spectra of the separated diastereomers, the characteristic differences in the chemical shifts of the C2-H (C5-H) signals were observed and explained based on the MOPAC calculation.

Trimethylsilylaion of 1, 2, 3-triazole regioselectively proceeded to give 2-trimethylsilyl-2H-1, 2, 3-triazole, which was treated with primary alkyl halides in the presence of tetrabutylammonium fluoride to give 1-alkyl-1H-1, 2, 3-triazoles as a sole product. 1-Methyl-5-substituted 1H-1, 2, 3-triazoles were prepared by alkylation of 5-lithio-1-methyl-1H-1, 2, 3-triazole, and 1-methyl-4-substituted 1H-1, 2, 3-triazoles were obtained by alkylaiton of 4-lithio-1-methyl-5-phenylthio-1H-1, 2, 3-triazole followed by reductive desulfurization.

Nortopsentins A-D, antifungal 1, 4-bisindolylimidazole marine alkaloids isolated from a sponge, were synthesized through palladium-catalyzed cross-coupling of 3-indolylboronic and 6-bromo-3-indolylboronic acids with halogenoimidazoles as the key reaction.

The first total synthesis of kealiiquinone 1, the marine alkaloid of a sponge, was achieved starting frum 5-[1-hydroxy-1-(3,4+dimethoxy-2-methoxymethoxyphenyl)methyl]-l-melhyl-2-phenyl-thio-1 H -imidazole (5).

Cyclic ketone O-trimethylsilylcyanohydrins (2) were prepared and converted to various compounds : α-hydroxyketones (3), dehydroxylated ketones (4), α, β-unsaturated ketones (9), tricyclic ketones (10), 1-ethoxycarbonyl-4-phenyl-1, 2, 4a, 5, 6, 7, 8, 8a-octahydro-2-naphthalenone (13), 1-phenylperhydroisocoumarin (18) and 1, 2, 3, 4, 4a, 10, 11, 11a-octahydro-5H-benzo[a, d]cyclohepten-10-one (20).

The cyclopropane ring in 2-substituted 1, 1-cyclopropanedicarboxylates was regioselectively opened by using samarium(II) diiodide (SmI2) in a hexamethylphosphoric triamide (HMPA)-tetrahydrofuran (THF) (1 : 10) system under mild and neutral conditions to give (2-substituted ethyl)malonates in moderate to good yields. The cyclopropane ring in 2-substituted cyclopropanecarboxylates or 2-substituted 3-(trimethylsilyl)cyclopropanecarboxylates was similarly cleaved regioselectively by using SmI2 in a HMPA-THF (1 : 1) system to give 4-arylbutyrates or 4-aryl-3-(trimethylsilyl)butyrates in 16-89% yields. The reaction mechanism of these ring-opening reactions is discussed.

(±)-8-Deisopropyladunctin B, the deisopropyl form of adunctin B, which was isolated from the leaves of Piper aduncum (Piperaceae) collected in Papua New Guinea, was synthesized in 0.77% overall yield in 17 steps from 5,7-dimethoxycoumarin-3-carboxylate. The key step was our original stereoconvergent skeleton transformation from 1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-one to 1,2,4a,9b-tetrahydrodibenzofuran-4-ol with dimethylsulfoxonium methylide.

Synthesis of 3-alkylamino-1, 4-naphthoquinone-2-carboxylic acid (2) was attempted. Although 3-(1-piperidinyl)-1, 4-naphthoquinone-2-carboxylic acid (2a) was not obtained, probably because of its instability, the esters (18a, b)of 2a could be prepared. 2-Alkylamino-3-hydroxymethyl-1, 4-naphthoquinones (9a-g) were photochemically cyclized to the 1, 4, 5, 10-tetrahydro-5, 10-2H-naphth[2, 3-d][1, 3]oxazines (19a-g), containing a novel heterocyclic ring system in moderate yields. Anti-bacterial activity of the prepared compounds was weak or insignificant.

The 4-position of the 1-methyl-1H-imidazole ring was lithiated by treatment of the corresponding 4-bromo derivatives with tert-butyllithium. This procedure was applied to synthesis of the left-hand part of pyronaamidine (1), which is a biologically interesting marine alkaloid.

In the presence of samarium diiodide (SmI2) in THF, chloromethyl sulfides reacted with carbonyl compounds to give β-hydroxythioethers under mild and neutral conditions in moderate to good yields.

1-(1-Alkoxyalkyl)-1H-1,2,4-triazoles (I) were prepared by treating various acetals with 1H-1,2,4-triazole in the presence of pyridinium p-toluenesulfonate . The alkoxy group of I was substituted with -NR 4 COR 3 group by treating with carboxamides to give various 1-(1-acylaminoalkyl)-1H-1,2,4-triazole in variable yields.

Pyrido[1,2-a] benzimidazole derivatives (12a and 19a) were synthesized in moderate yields via an intramolecular aldol-condensation of 2-acetyl-1-formylmethylbenzimidazole (11) and an intramolecular acylation of the acylimidzolide (18) prepared from 2-ethoxycarbonylmethyl-1-(2-carboxyethyl)-benzimidazole (17), respectively

Photochemical Fries rearrangement of 1-phenyl-2-pyrrolidone (1) proceeded smoothly in methanol especially in the presence of piperylene. Continuous photo-irradiation of 1 successfully was carried out to raise the yield by utilizing a reaction mixture-circulation system consisting of a spiral quartz cell, a pump, a uv light source and a column packed with appropriate absorbents for the Fries rearranged product (3) and pigments

The reactions of 2-halogenonaphthoquinones (5, 13, 14 and 15) and 2-methyl-1, 4-naphthoquinone (20; vitamin K3) with primary and secondary amines were examined. 1, 3-Dialkyl-1, 2, 3, 4-tetrahydrobenzo[g]quinazoline-5, 10-diones (9) were obtained in moderate yields by treating 20 with formaldehyde in primary amines. A plausible reaction path-way is also presented.

Synthesis of 3-alkylamino-1, 4-naphthoquinone-2-carboxylic acid (2) was attempted. Although 3-(1-piperidinyl)-1, 4-naphthoquinone-2-carboxylic acid (2a) was not obtained, probably because of its instability, the esters (18a, b)of 2a could be prepared. 2-Alkylamino-3-hydroxymethyl-1, 4-naphthoquinones (9a-g) were photochemically cyclized to the 1, 4, 5, 10-tetrahydro-5, 10-2H-naphth[2, 3-d][1, 3]oxazines (19a-g), containing a novel heterocyclic ring system in moderate yields. Anti-bacterial activity of the prepared compounds was weak or insignificant.

3-Ethoxycarbonylcoumarin ( 4 ) was treated with 2.4 equivalent of dimethylsulfoxonium methylide in DMF at room temperature to give a novel tricyclic product, ethyl (3 a R ∗ , 8 b S ∗ )- 3a,8b-dihydro-3-hydroxy -1H- cyclopenta [b] benzofuran-2-carboxylate ( 5 ), in 64% yield. This reaction could be applied to several 3-substituted coumarins.

Cyclopropane ring of 2- and 2,3-substituted cyclopropanecarboxylates (1) was regioselectively cleaved using SmI 2 -HMPA-THF system in the presence of tert-BuOH to give 4- and 3,4-substituted butyrates (2) in moderate to good yields

Cyclic ketone O-trimethylsilylcyanohydrins (2) were prepared and converted to various compounds : α-hydroxyketones (3), dehydroxylated ketones (4), α, β-unsaturated ketones (9), tricyclic ketones (10), 1-ethoxycarbonyl-4-phenyl-1, 2, 4a, 5, 6, 7, 8, 8a-octahydro-2-naphthalenone (13), 1-phenylperhydroisocoumarin (18) and 1, 2, 3, 4, 4a, 10, 11, 11a-octahydro-5H-benzo[a, d]cyclohepten-10-one (20).

The cyclopropane ring in 2-substituted 1, 1-cyclopropanedicarboxylates was regioselectively opened by using samarium(II) diiodide (SmI2) in a hexamethylphosphoric triamide (HMPA)-tetrahydrofuran (THF) (1 : 10) system under mild and neutral conditions to give (2-substituted ethyl)malonates in moderate to good yields. The cyclopropane ring in 2-substituted cyclopropanecarboxylates or 2-substituted 3-(trimethylsilyl)cyclopropanecarboxylates was similarly cleaved regioselectively by using SmI2 in a HMPA-THF (1 : 1) system to give 4-arylbutyrates or 4-aryl-3-(trimethylsilyl)butyrates in 16-89% yields. The reaction mechanism of these ring-opening reactions is discussed.

α-Keto amides were dimerized in the presence of SmI2 in THF to give substituted tartaric amides in moderate to good yields. Although the dimerization of the secondary keto amides did not proceed stereoselectively, racemic tartaric amides were produced exclusively in the case of the tertiary keto amides.