New chiral block for cyclopentanoids synthesis

Hydroxymethylation of bicyclic allylsilane, (3aR,6R,6aS)-3,3a,6,6a-tetrahydro-6-(trimethylsilyl)-cyclopenta[c]furan-1-one with formaldehyde by Prins reaction proceeds via S_E2' mechanism with the formation of anti-addition product. Some reactions of obtained (3aS,4S,6aR)-4-(hydroxymethyl)-3,3a,4,6a-tetrahydro-1H-cyclopenta[c]furan-1-one were investigated.     

A novel glyceryl ester (glyceryl dendryphiellate A), a trinor-eremophilane (dendryphiellin A1), and eremophilanes (dendryphiellin E1 and E2) from the marine deuteromycete Dendryphiella salina (SUTHERLAND) PUGH et NICOT

Continuing studies of the global extracts from cultures of the marine deuteromycete Dendryphiella salina have led to the isolation of novel compounds that add to the scarce list of marine fungal metabolites. Besides (22E)-ergosta-4.6,8(14),22-tetraen-3-one which, though known from basidiomycetes, was unknown in the sea, they are an unusual glyceryl ester, i.e. glycer-1-yl dendryphiellale A (= (+)-(2R)-2,3-dihydroxyprop-l-yl (6S,2E,4E)6-methylocta-2,4-dienoate; (+)- 1 ), a trinor-eremophilane, i.e. dendryphiellin A1 ( = (+)-(3R*,4E,6E)-7-{[(1R*,2S*,7R*,8aR*)-1,2,6,7,8,8a-hexahydro-7-hydroxy-1,8a-dimethyl-6-oxonaphthalen-2yl]oxycarbonyl}-3-methylhepta-4,6-dienoic acid; (+)- 11 ), and two eremophilanes, i.e. dendryphiellin El ( = (+)-(1R*, 2S*, 7S*,8aR*)-1,2,6,7,8,8a-hexahydro-1,8a-dimethyl-7-(1-methylethenyl)-6-oxonaphthalen-2-yl(6S,2E,4E)-6-methyl-octa-2,4-dienoate; (+)- 13 ) and dendryphiellin E2 ( = (+)-(1R*, 2S*, 8aR*)-1,2,6,7,8,8a-hexahydro-7-isopropyl-idene-1,8a-dimethyl-6-oxonaphthalen-2-yl (6S,2E,4E)-6-Methylocta-2,4-dienoate; (+)- 14 ). Absolute configurations have been established for (+)- 1 via total synthesis and for the acid portion of (+)- 13 and (+)- 14 via transesterification in NaOMe/MeOH which gave in both cases melhyl dendryphiellate A ((+)- 16 ) of known configuration and the free alcoholic moiety of (+)- 14 , i.e. (+)- 17 .     

Synthetic transformations of methylenelactones of eudesmanic type. Behavior of isoalantolactone under the conitions of heck reaction

By Heck reaction of isoalantolactone with aryl bromides or aryl iodides (3aR,4aS, 8aR,9aR,E)-3-arylmethylidene-8a-methyl-5-methylidenedecahydronaphtho[2,3-b]furan-2(3H)-ones and (4aS,8aR,9aS)-3-arylmethyl-8a-methyl-5-methylidene-4a,5,6,7,8,8a,9,9a-octahydronaphtho[2,3-b]furan-2(4H)-ones, products of the double bond shift, were synthesized. The yields of the arylation products depend on the nature of the catalytic system and on the structure of the aryl halide. The structures of (3aR,4aS,8aR,9aR,E)-3-(3,4-dimethoxybenzylidene)-8amethyl-5-methylidenedecahydronaphtho[2,3-b]furan-2(3H)-one and (4aS,8aR,9aS)-3-(2-methylsulfanylbenzyl)-8amethyl-5-methylidene-4a,5,6,7,8,8a,9,9a-octahydronaphtho[2,3-b]furan-2(4H)-one were proved by XRD analysis.     

Studies on ketene and its derivatives. CXI . Photoreaction of diketene with 2(1H)-quinolone derivatives

Photoreaction of diketene with 4-methyl-2(1H)-quinolone and 1,4-dimethyl-2(1H)-quinolone gave 2R*,2aR*,SbR*- and 2R*,2aS*8bS*-8b-methyl-3-oxo-1,2,2a,3,4,8b-hexahydrocyclobuta[c]quinoline-2-spiro-2′-(oxetan)-4′-one ( 6a and 6b ), and their 4-methyl derivatives 7a and 7b , respectively. Thermolysis of compounds 6 and 7 afforded 2aR*,8bS*-8b-methyl-2-methylene-3-oxo-1,2,2a,3,4,8b-hexahydrocyclobuta[c]quinoline ( 8 ) and its 4-methyl derivatives 9 , respectively. Similarly, photolysis of diketene and 4-acetoxy-2(1H)-quinolone gave 1R*,2aS*,8bS*- and 1R*,2aR*,8bR*-8b-acetoxy-3-oxo-1,2,2a,3,4,8b-hexahydrocyclobuta[c]-quinoline ( 11a and 11b ). Alcoholysis of compounds 11a and 11b with hydrogen chloride in methanol gave 1-hydroxy-1-(methoxycarbonyl)methylcyclobuta[c]quinoline derivative 12 and 13 which were transformed to 4-acetyl-3-methyl-2(1H)-quinolone ( 15 ) by further alcoholysis. Photoreaction of diketene with 2(1H)-quinolone derivatives gave the corresponding cyclobuta[c]quinoline spirooxetanone derivatives 18 and 23 , which, by thermolysis, were transformed to 2-methylenecyclobuta[c]quinoline 23 and 25 , respectively.     

Regioselectivity in the formation of norbornene-fused pyrazoles: preparation of 1-substituted derivatives of 4,5,6,7-tetrahydro-1H-4,7-methanoindazole

The structural characteristics of (±)-(exo,exo)-3-(hydroxymethylene)-5,6-(isopropylidenedioxy)bicyclo[2.2.1]heptan-2-one make the reactions between this β-diketone and hydrazines particularly interesting for elucidating the mechanism of pyrazole formation. The isolation and X-ray structure determination of two 5-hydroxy substituted Δ²-pyrazolines [(±)-(3aR*,4R*,5R*,6S*,7R*,7aR*)-7a-hydroxy-5,6-(isopropylidenedioxy)-3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-indazole] and [(±)-(3aS*,4R*,5R*,6S*,7R*,7aR*)-7a-hydroxy-5,6-(isopropylidene-dioxy)-1-phenyl-3a,4,5,6,7,7a-hexa-hydro-4,7-methano-1H-indazole] has been determinant for proposing a mechanism. Besides B3LYP/6-31G* calculations have been carried out on all intermediate dihydroxypyrazolidines and 5-hydroxypyrazolines. Finally, the annular tautomerism of the NH-methanotetrahydroindazoles has been studied both experimentally (¹³C NMR) and theoretically: the Mills-Nixon effect favours the 2H-tautomer.     

New Monoterpene-Substituted Dihydrochalcones from Piper aduncum

Five New unusual monoterpene-substituted dihydrochalcones, the adunctins A–E (1″S)-1-{2′-hydroxy-4′-methoxy-6′-[4″-methyl-1″-(1?-methylethyl)cyclohex-3″ -en-1″ -yloxy]phenyl}-3-phenylpropan-1-one ( 1 ), (5aR*,8R*,9aR*)-3-phenyl-1-[5′,8′,9′,9′a-tetrahydro-3′-hydroxy-1′-methoxy-8′-(1″-methylethyl)-5′-a-methyldibenzo-[b,d]furan-4′-yl]propan-1-one ( 2 ), (2′R*,4″S*)-1-{6′-hydroxy-4′-methoxy-4″-(1?-methylethyl)spiro[benzo[b]-furan-2′(3′H),1″ -cyclohex-2″ -en]-7′-yl}-3-phenylpropan-1-one ( 3 ), (2′R*,4″R*)-1-{6′-hydroxy-4′-methylethyl-4″-(1?-methylethyl)spiro[benzo[b]furan-2′(3′H),1″-cyclohex-2″-en]-7′-yl}-3-phenypropan-1-one ( 4 ), and (5′aR*,6′S*, 9′R*,9′aS*)-1-[5′a,6′,7′,8′,9′a-hexahydro-3′,6′-methoxy-6′-methyl-9′-(1″-methylethyl)dibenzo[b,d]-furan-4′-yl]-3-phenylpropan-1-one ( 5 ) were isolated from the leaves of Piper aduncum (Piperaceae) by preparative liquid chromatography. In addition, (?)-methyllindaretin ( 6 ), trans-phytol, and α-tocopherol ( = vitamin E) were also isolated and identified. The structures were elucidated by spectroscopic methods, including 1D- and 2D-NMR spectroscopy as well as single-crystal X-ray diffraction analysis. The antibacterial and cytotoxic potentials of the isolates were also investigated.     

Novel Trinor-eremophilanes (Dendryphiellin B,C, and D), Eremophilanes (Dendryphiellin E,F, and G), and Branched C9-Carboxylic Acids (Dendryphiellic Acid A and B) from the Marine Deuteromycete Dendryphiella salina (SUTHERLAND) PUGHet NICOT

Further investigation of global extracts from cultures of the marine deuteromycete Dendryphiella salina leads to the isolation of three novel trinor-eremophilanes esterified by branched C₉-carboxylic acids, dendryphiellin B (= (+)-(1R*,2S*,7R*,8aR*)-1,2,6,7,8,8a-hexahydro-7-hydroxy-1,8a-dimethyl-6-oxonaphthalen-2-yl (6R*, 2E, 4E)-6-hydroxy-6-methylocta-2,4-dienoate; (+)- 2 ), dendryphiellin C (=(+)-(1R*, 2S*, 7R*, 8aR*)-1,2,6,7,8,8a-hexa-hydro-7-hydroxy-1,8a-dimethyl-6-oxonaphthalen-2-yl (6S, 2E, 4E)-6-methylocta-2,4-dienoate; (+)- 3 )), and dendryphiellin D (=(+)-(1R*, 2S*, 7R*, 8aR*)-1,2,6,7(8,8a-hexahydro-7-hydroxy-1,8a-dimethyl-6-oxonaphthalen-2-yl (6R*,2E,4E)-6-(hydroxymethyl)octa-2,4-dienoate; (+)- 4 ). An intact eremophilane, dendryphiellin E ( 5 ), and its ethanolysis product dendryphiellin F whose absolute configuration is represented by structural formula (+)- 6 are also isolated from the above extracts. Dendryphiellin E exists as an open form 5a in equilibrium with a closed form 5b . A similar equilibrium exists between the open form 8a and the closed form 8b of a non-esterified eremophilane, dendryphiellin G ( 8 ), which is isolated too from the above extracts and proves structurally related to the cyclic portion of 5 . Finally, the free, branched C₉-carboxylic acids dendryphiellic acid A ((+)- 9 ) and B ((+)- 10 ) which correspond to side chains of the above esterified terpenes are also isolated from the above extracts.     

Synthesis of (−)- and (+)-8-fluoro-galanthamine

The synthesis of racemic 8-fluorogalanthamine and its separation into (−)- and (+)-8-fluorogalanthamine (= (4aS,6R,8aS)- and (4aR,6S,8aR)-1-fluoro-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol) is described.     

Enzymatic desymmetrization of meso cis-2,6- and cis,cis-2,4,6-substituted piperidines. Chemoenzymatic synthesis of (5S,9S)-(+)-indolizidine 209D

The stereoselective acylation of meso piperidines 3a,b by vinyl acetate (solvent and acyl donor) in the presence of Candida antarctica lipase gave the corresponding (2S,6R) and (2S,4R,6R) monoesters 2a,b in high enantiomeric purity. (5S,9S)-(+)-Indolizidine 209D was prepared in eight steps from (2S,6R)-2a.     

Novel cembranolides (Coralloidolide D and E) and a 3,7-Cyclized cembranolide (Coralloidolide C) from the mediterranean coral Alcyonium coralloides

The Mediterranean alcyonacean Alcyonium (= Parerytkropodium) coralhides (PALLAS, 1766) is shown to contain three novel diterpenes which are of biogenetic significance: the 3,7-cyclized cembranoid Coralloidolide C ( = (+)-(6R*, 7R*, 11S*, 12aS* 3aE)-7,8-epoxy-3,5,6,7,8,9,10,11,12,12a-decahydro-12a-hydroxy-11-isopropenyl-1,4-dimethyl-3-oxocyciopentacydoundecene-8,6-carbolactone; (?)- 3 ), the O-bridged diketonic cembranolide Coralloidolide D (= (+)-(1R*, 2S*, 3R*, 5R*, 12S*, 8Z)-2,5-epoxy-1-hydroxy-12-isopropenyl-5,9-dimethyl-7,10-dioxocyclotetradeca-8-ene-1,3-carbolactone; (+)- 4 ), and the diketonic epoxycembranolide coralloidolide E (=(+)-(1R*, 2R*, 3R*, 12S*, 5Z, 8Z)-1,2-epoxy-12-isopropenyl-5,9-dimethyl-7,10-dioxocyclotetra-deca-5,8-diene-1,3-carbolactone; (+)- 5 ), The latter in pyridine at r. t. undergoes a double bond shift from C(4) = C(5) to C(4) = C(18) to give the isomer (?)- 7 . Structural assignments are mainly based on ID and 2D NMR and MS spectral data. Either corailoidolide A ((?)- 1 ) or the hypothetic unsaturated 1,4-diketone 9 can be envisaged as the precursors of all coralloidolides.     

Studies on the Michael addition of naphthoquinones to sugar nitro olefins: first synthesis of polyhydroxylated hexahydro-11H-benzo[a]carbazole-5,6-diones and hexahydro-11bH-benzo[b]carbazole-6,11-diones

A strategy for the synthesis of the novel (6bR,7R,8S,9S,10S,10aR)-8-(benzyloxy)-7,9,10-trihydroxy-6b,7,8,9,10,10a-hexahydro-11H-benzo[a]carbazole-5,6-dione is reported. The key steps were the Michael addition of 2-hydroxy-1,4-naphthoquinone to 1-nitrocyclohexene or 3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-6-nitro-α-d-xylo-hex-5-enefuranose and the diastereoselective intramolecular Henry reaction of 3-O-benzyl-5,6-dideoxy-5-C-(3′-hydroxy-1′,4′-naphthoquinon-2′-yl)-1,2-O-isopropylidene-6-nitro-α-d-glucofuranose to give the key (1S,2S,3S,4R,5R,6R)-3-(benzyloxy)-1,2,4-trihydroxy-5-(3′-hydroxy-1′,4′-naphthoquinon-2′-yl)-6-nitrocyclohexane. When 2-hydroxy-1,4-naphthoquinone was replaced by (1,4-dimethoxynaphthalen-2-yl)lithium, the novel (1R,2S,3S,4R,4aS,11bS)-2-(benzyloxy)-1,3,4-trihydroxy-1,2,3,4,4a,5-hexahydro-11bH-benzo[b]carbazole-6,11-dione was obtained.     

Diastereoselective synthesis of new polyhydroxylated indolizidines from (l)-glutamic acid

A diastereoselective synthesis of two new swainsonine's analogues 1a and 1b with the piperidine ring fused to a phenyl nucleus at C6-C7, namely (1R, 2S, 10R, 10aR)-(+)-1,2,10-trihydroxy-1,2,3,5,10,10a-hexahydrobenzo[f] indolizine (1a) and (1S, 2R, 10R, 10aR)-(+)-1,2,10-trihydroxy-1, 2, 3, 5, 10, 10a-hexahydrobenzo[f] indolizine (1b), is described. Throughout this work, the effectiveness of the tricyclic indolizidine dione 5, readily available in three steps from the cheap l-glutamic acid, as an attractive platform for chemo- and stereodivergent transformations is illustrated. The key steps involved totally diastereoselective ketone reduction of compound 5 and catalytic cis-dihydroxylation of the unsaturated amide 10. The synthetic strategy also allowed for the diastereoselective synthesis of benzoanalogues of the 1,8a-di-epi-lentiginosine 3a ((1R, 2S, 10aR)-(+)-1,2-dihydroxy-1, 2, 3, 5, 10, 10a-hexahydrobenzo[f]indolizine) and 2,8a-di-epi-lentiginosine 3b ((1S, 2R, 10aR)-(+)-1,2-dihydroxy-1,2,3,5,10,10a-hexahydrobenzo[f]indolizine).     

New Sesquiterpenoids from Salvia castanea Diels f. tomentosa

Two new sesquiterpenoids, castanin A (= 4R*,5R*,5aS*,8S*,8aR*,8bR*)‐8‐formyl‐4,5,5a,6,7,8,8a,8b‐octahydro‐5,8b‐dihydroxy‐3,5a,8‐trimethyl‐2‐oxo‐2H‐indeno[4,5‐b]furan‐4‐yl acetate; 1 ) and castanin B (= 1aS*,6R*,6aS*,7aR*,9aR*)‐1a,2,6,6a,7a,8,9,9a‐octahydro‐1a,5,7a‐trimethylbisoxireno[4,5 : 8,9]cyclodeca[1,2‐b]furan‐6‐yl acetate; 2 ) were isolated from the aerial parts of Salvia castanea Diels f. tomentosa, together with two known compounds, oplophanone and 1β,6α‐dihydroxyeudesm‐4(14)‐ene. Their structures were elucidated by spectroscopic analyses and, in the case of 2 , also by X‐ray crystallography. Castanin A ( 1 ) represents a novel sesquiterpenoid, with a contracted ring A, derived from eudesmanolide. A possible biogenetic pathway is proposed.     

Traceless chirality transfer from a norbornene β-amino acid to pyrimido[2,1-a]isoindole enantiomers

The synthesis of two enantiomeric pairs of pyrimidoisoindoles 9a, 9b and 10a, 10b is reported. During a domino ring-closure reaction, followed by cycloreversion, the chirality of diendo-(?)-(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide [(?)-1] was successfully transfered to heterocycles (+)-9a, (+)-10a, (?)-9b, (?)-10b and (?)-10c.     

Furopyridines. XVIII. Photocycloaddition of furo[2,3-c]pyridin-7(6H)-one with acrylonitrile

The photocycloaddition of furo[2,3-c]pyridin-7(6H)-one ( 1 ) and its N-mefhyl derivative ( 1-Me ) to acrylonitrile has been studied. The structures of the photoadducts isolated by colum chromatography were determined by the nuclear magnetic resonance spectroscopy and single crystal X-ray analysis. The cyclo-addition of 1 afforded an adduct 2 at the carbonyl oxygen and 8-cyano-8,9-dihydrofuro[d]azocin-7(6H)-one ( 3 ), and the addition of 1-Me the N-methyl derivative 3-Me of 3 , (9S*)-9-cyano-6-methyl-3a,7a-dihydro-3a,7a-ethanofuro[2,3-c]pyridin-7(6H)-one ( 4 ), (2S*, 2aR*, 7bR*)- ( 5 ) and (1R*, 2aS*, 7bS*)-2-cyano-3-methyl-4-oxo-1,2,2a,3,4,7b-hexahydrocyclobuta[e]furo[2,3-c]pyridine ( 6 ).     

Enantioselective Synthesis of Cyclopentyltetrahydrofuran (Cp-THF), an Important High-Affinity P2-Ligand for HIV-1 Protease Inhibitors

A convenient optically active synthesis of (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[b]furan, a high-affinity nonpeptidyl ligand for HIV-1 protease inhibitor 2, is described. The synthesis utilizes commercially available (1R,5S)-(+)-2-oxabicyclo[3.3.0]oct-6-en-3-one as the starting material and oxymercuration or bromohydrin reaction as the key step. Enantiopure ligand was converted to protease inhibitor 2.     

Efficient synthesis and resolution of novel 2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b] furan-6(2H)-one by lipase Pseudomonas cepacia

Lipase Pseudomonas cepacia catalyzed acylation of (±)-2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b] furan-6(2H)-one using vinyl acetate as the acyl donor in acetone gave (−)-(R)-2-acetoxy-2-(methyl)-7,8-dihydro-1H-indeno[5,4-b] furan-6(2H)-one and (+)-(S)-2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b] furan-6(2H)-one with high enantiomeric excess. Enantiomerically pure 2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b] furan-6(2H)-one are useful intermediates for the preparation of Ramelteon, an FDA approved drug for the treatment of insomnia.     

Synthesis of tricyclic isoindoles and thiazolo[3,2-c][1,3]benzoxazines

The thermolysis of (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylic acids in Ac₂O led to novel 3-methylene-2,5-dioxo-3H,9bH-oxazolo[2,3-a]isoindoles and chiral (9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindoles were obtained on FVP. Starting from l-cysteine methyl ester (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazines were obtained as single stereoisomers. The thermolysis of (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazine-3-carboxylic acid in Ac₂O gave 5-acetyl-2-phenyl-2,3-dihydrothiazole. The structures of methyl (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylate 1a and methyl (2R,4R)-N-chlorocarbonyl-2-(2-hydroxyphenyl)thiazolidine-4-carboxylate 9 were determined by X-ray crystallography.     

Perhydro-1,3-benzoxazines derived from (−)-8-aminomenthol as ligands for the catalytic enantioselective addition of diethylzinc to aldehydes

The catalytic potency of a series of perhydro-1,3-benzoxazines prepared from (?)-8-aminomenthol was examined in the enantioselective addition of diethylzinc to aldehydes. When (2R,3S,3aS,4aR,6R,8aS)-2-isopropyl-6,9,9-trimethyl-3-phenyldecahydro-4aH-pyrrolo[2,1-b][1,3]benzoxazin-3-ol 7b was used as a chiral ligand, 1-substituted propanols with an (R)-configuration were obtained in high yields and enantiomeric excesses up to >99%. The catalyst can be recovered and used without any loss in its activity.     

Reactions of N- and C-alkenylanilines: IX. Synthesis, oxidation, and nitration of some 7-methyl-1,3a,4,8b-tetrahydrocyclopenta[b]indoles

Heating of 4-acyl-3-iodo-7-methyl-1,2,3,3a,4,8b-hexahydrocyclopenta[b]indoles in piperidine gave 4-acyl-7-methyl-1,3a,4,8b-tetrahydrocyclopenta[b]indoles which were oxidized with KMnO4 to obtain the corresponding 4-acyl-7-methyl-1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole-1,2-diols. Oxidation of 4-acyl-7-methyl-1,3a,4,8b-tetrahydrocyclopenta[b]indoles at the olefinic double bond with hydrogen peroxide in acetonitrile in the presence of formic acid afforded stereoisomeric epoxides with cis and trans orientation of the nitrogen-containing and oxirane rings. Nitration with a mixture of ammonium nitrate and trifluoroacetic anhydride produced 5-nitro derivatives. The structure of 1-{(1aR*,1bR*,6bS*,7aS*)-5-methyl-1a,1b,2,6b,7,7ahexahydrooxireno[4,5]cyclopenta[1,2-b]indol-2-yl}ethanone was determined by X-ray analysis.