Specific oxidation of C-14 oxygenated 4(20),11-taxadienes by microbial transformation

Three C-14 oxygenated taxanes, 2α,5α,10β,14β-tetraacetoxytaxa-4(20),11-diene (1), 2α,5α,10β-triacetoxy-14β-(2-methylbutyryloxy)taxa-4(20),11-diene (2), and yunanaxane (3), major products of callus cultures of Taxus spp., were regio- and stereoselectively hydroxylated at the 7β position by a fungus, Absidia coerulea IFO 4011. Intriguingly, when 1 was co-administered with β-cyclodextrin and incubated with the fungus cell cultures, three other compounds 5α,9α,10β,13α-tetraacetoxytaxa-4(20),11-dien-14β-ol (7), 5α,9α,10β,13α-tetraacetoxytaxa-4(20),11-dien-1β-ol (8) and 5α,9α,10β,13α-tetraacetoxy-11(15→1) abeotaxa-4(20),11-dien-15-ol (9) were obtained.     

Biotransformation of triptolide by Cunninghamella blakesleana

Biotransformation of triptolide 1 by Cunninghamella blakesleana (AS 3.970) was carried out. Seven biotransformation products were obtained and four of them were characterized as new compounds. On the basis of their NMR and mass spectral data, their structures were characterized as 5α-hydroxytriptolide 2, 1β-hydroxytriptolide 3, triptodiolide 4, 16-hydroxytriptolide 5, triptolidenol 6, 19α-hydroxytriptolide 7 and 19β-hydroxytriptolide 8. All the new transformed products (2, 3, 7 and 8) were found to exhibit potent in vitro cytotoxicity against some human tumor cell lines.     

Synthesis of (4R,15R,16R,21S)- and (4R,15S,16S,21S)-rollicosin

A convergent synthesis of (4R,15R,16R,21S)-rollicosin (1) and (4R,15S,16S,21S)-rollicosin (2) was accomplished. Hydroxy lactone 6a and/or 6b were synthesized from 4-pentyn-1-ol, and α,β-unsaturated lactone 7 was synthesized from γ-lactone 8 and 5-hexen-1-ol. Inhibitory activity of these compounds was examined with bovine heart mitochondrial complex I.     

Synthesis of the aglycone of 26-O-deacetyl pavoninin-5

The aglycone of 26-O-deacetyl pavoninin-5, (25R)-cholest-5-en-3β,15α,26-triol, 5a, was synthesized in 10 steps in 17% overall yield from diosgenin, 3. Removing mercury from the Clemmensen reduction of diosgenin 3, gave a higher yield of (25R)-cholest-5-en-3β,16β,26-triol, 4, by a method, that is also more environmentally friendly. Attempted methods for the transposition of the C-16β hydroxyl to the 15α position are described. A successful method for this transposition via the 15α-hydroxy-16-ketone, 13, using the Barton deoxygenation reaction on the 16-alcohol, 15, is reported.     

Autoxidation of isotachysterol

Isotachysterol, the acid-catalyzed isomerization product of vitamin D₃, produces seven previously unknown oxygenation products in a self-initiated autoxidation reaction under atmospheric oxygen in the dark at ambient temperature. They are (5R)-5,10-epoxy-9,10-secocholesta-6,8(14)-dien-3β-ol (6a), (5S)-5,10-epoxy-9,10-secocholesta-6,8(14)-dien-3β-ol (6b), (10R)-9,10-secocholesta-5,7,14-trien-3β,10-diol (7a), (10S)-9,10-secocholesta-5,7,14-trien-3β,10-diol (7b), (7R,10R)-7,10-epoxy-9,10-secocholesta-5,8(14)-dien-3β-ol (8), 5,10-epidioxyisotachysterol (9) and 3,10-epoxy-5-oxo-5,10-seco-9,10-secocholesta-6,8(14)-dien-10-ol (10). The formation of these products is explained in terms of free radical peroxidation chemistry.     

Solvent-free reactions of N,N′-thiocarbonyldiimidazole with ferrocenylcarbinols

The efficient and simple routes for the synthesis of various ferrocenyl derivatives from ferrocenylcarbinols and N,N′-thiocarbonyldiimidazole (TCDI) are described. It involves grinding the two substrates in a Pyrex tube with a glass rod at room temperature. The reaction of ferrocenylmethanol (1a) provided S,S-bis(ferrocenylmethyl)dithiocarbonate (1b), whose crystal structure and a plausible mechanism for its formation are also reported. The reaction of 1-ferrocenyl-1-phenylmethanol (2a) and 1-ferrocenylbutanol (2b) gave the products 2c and 2d, respectively. The reaction of ω-ferrocenyl alcohols 4-ferrocenylphenol (3a) and 6-ferrocenylhexan-1-ol (3b) yielded the products 3c and 3d, respectively. Reaction of 1,1′-ferrocenedimethanol (3e) afforded 3f in moderate yield, and by contrast, it was not similar to 1b. Reaction of [4-(trifluoromethyl)phenyl]methanol (4a) provided the thiocarbonate 4b in good yield.     

New antitumor sesquiterpenoids from Santalum album of Indian origin

Three new campherenane-type (1, 4, 7) and three new santalane-type (9, 11, 12) sesquiterpenoids, and two aromatic glycosides (21, 22) together with 12 known metabolites including α,β-santalols (14, 18), (E)-α,β-santalals (15, 19), α,β-santaldiols (16, 20), α-santalenoic acid (17), and vanillic acid 4-O-neohesperidoside were isolated from Santalum album chips of Indian origin. The structures of the new compounds, including absolute configurations, were elucidated by 1D- and 2D-NMR spectroscopic and chemical methods. The antitumor promoting activity of these isolates along with several neolignans previously isolated from the same source was evaluated for both in vitro Epstein-Barr virus early antigen (EBV-EA) activation and in vivo two-stage carcinogenesis assays. Among them, compound 1 exhibited a potent inhibitory effect on EBV-EA activation, and also strongly suppressed two-stage carcinogenesis on mouse skin.     

First stereoselective total synthesis of triumfettamide

The first total synthesis of triumfettamide (1) is described. The asymmetric syntheses of two highly functionalized units—α-hydroxylated C17 monounsaturated fatty acid unit (2) and C26 phytosphingosine (3) have been accomplished involving Sharpless asymmetric dihydroxylation, Sharpless kinetic resolution, regioselective epoxide opening, regioselective DIBAL-H reduction of acetal, Wittig olefination as the key steps. Finally N-acylation of phytosphingosine 3 with (2R,6Z)-2-hydroxy-6-heptadecenoic acid 2 followed by DDQ deprotection of PMB, provided target compound 1.     

Sesquiterpenoids from Ligularia virgaurea spp. oligocephala

Four novel eremophilane-type sesquiterpene lactones, 6β,10α-dihydroxy-1-oxoeremophila-7(11),8(9)-dien-12,8-olide (1), 6β-acetyl-2-oxoeremophila-1(10),7(11), 8(9)-trien-12,8-olide (2), 6β,8β-diacetyl-2-oxoeremophila-1(10),7(11)-dien-12,8-olide (3), dimeric eremophilane ligulolide B (5), and known sesquiterpenoid, 6β,8α-diacetyleremophila-1(10),7(11)-dien-12,8-olide (4), were isolated from an extract of the whole plant of Ligularia virgaurea spp. oligocephala. The structure of 1 was confirmed by NMR spectra and single crystal X-ray crystallography investigation, as well as 2, 3, and 5 were elucidated by spectroscopic methods including 1D and 2D NMR spectra. A discussion of biogenesis of 5 was described. Cytotoxicities of compound 1 were measured in vitro against selected cancer cells human promyelocytic leukemia (HL-60), human ovarian (HO-8910) and human lung epithehial (A-549).     

Cytotoxic cembranoids from the Red Sea soft coral, Sarcophyton auritum

Chemical investigation of the Red Sea soft coral Sarcophyton auritum led to the isolation and structure elucidation of two new diterpene cembranoids; 2-epi-sarcophine (2) and (1R,2E,4S,6E,8R,11R,12R)-2,6-cembradiene-4,8,11,12-tetrol (4), as well as two known diterpene cembranoids, reported for the first time from this species, namely sarcophine (1) and (+)-7α,8β-dihydroxydeepoxysarcophine (3). Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR and HRMS. The isolated cembranoids were found to display high cytotoxicity against HepG2 (liver cancer cell line) and MCF-7 (breast cancer cell line).     

Total synthesis of apigenin 7,4′-di-O-β-glucopyranoside, a component of blue flower pigment of Salvia patens, and seven chiral analogues

We have succeeded in the first total synthesis of apigenin 7,4′-di-O-β-d-glucopyranoside (1a), a component of blue pigment, protodelphin, from naringenin (2). Glycosylation of 2 according to Koenigs-Knorr reaction provided a monoglucoside 4a in 80% yield, and this was followed by DDQ oxidation to give apigenin 7-O-glucoside (12a). Further glycosylation of 4′-OH of 12a with 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl fluoride (5a) was achieved using a Lewis acid-and-base promotion system (BF₃·Et₂O, 2,6-di-tert-butyl-4-methylpyridine, and 1,1,3,3-tetramethylguanidine) in 70% yield, and subsequent deprotection produced 1a. Synthesis of three other chiral isomers of 1a, with replacement of d-glucose at 7 and/or 4′-OH by l-glucose (1b-d), and four chiral isomers of apigenin 7-O-β-glucosides (6a,b) and 4′-O-β-glucosides (7a,b) also proved possible.     

Simple preparation of phenylpropenoid β-d-glucopyranoside congeners by Mizoroki-Heck type reaction using organoboron reagents

Palladium(II)-catalyzed carbon-carbon bond formation between allyl 2,3,4,6-tetra-O-acetyl-β-d-glucopyranoside (3) and arylboronic acid congeners gave the corresponding cinnamyl 2,3,4,6-tetra-O-acetyl- β-d-glucopyranosides (4a-m) in good yield. Among them, coupling products 4a-m were converted to not only the naturally occurring phenylpropenoid β-d-glucopyranoside analogues (1a-e) but also the unnaturally ones (1f-m).     

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.     

New oxindole and indole alkaloids from Gelsemium rankinii

Six new humantenine-type (1-6) and two new gelsemine-type (7, 8) oxindole alkaloids and one new indole alkaloid (9) were isolated from the leaves and branches of Gelsemium rankinii. The structures of the new alkaloids were determined by spectroscopic analyses. Among them, 6-hydroxyhumantenine (5) is the first example of a Gelsemium alkaloid with an oxygen function at C-6 position, and is a plausible biogenetic precursor of gelsemine-type alkaloids.     

Separation and identification of three epimeric pairs of new C-glucosyl anthrones from Rumex dentatus by on-line high performance liquid chromatography–circular dichroism analysis

Six C-glucosyl anthrones were characterized as three pairs of epimers by on-line high performance liquid chromatography–circular dichroism (HPLC–CD) analysis and isolated from the roots of Rumex dentatus by column chromatography. Their structures were elucidated by mass spectrometry, nuclear magnetic spectroscopy and HPLC–CD analysis. They are 10R-C-β-d-glucosyl-10-hydroxyemodin-9-anthrone (rumejaposide E, 1) and 10S-C-β-d-glucosyl-10-hydroxyemodin-9-anthrone (rumejaposide F, 2), 10R-C-β-d-glucosylemodin-9-anthrone (rumejaposide G, 3) and 10S-C-β-d-glucosylemodin-9-anthrone (rumejaposide H, 4), 10S-C-β-d-glucosyl-10-hydroxychrysophanol-9-anthrone (cassialoin, 5) and 10R-C-β-d-glucosyl-10-hydroxychrysophanol-9-anthrone (rumejaposide I, 6). Rumejaposides F–I (2–4 and 6) were new C-glucosyl anthrones. Rumejaposide E (1) and cassialoin (5) were isolated for the first time in Rumex plants. On-line HPLC–UV–CD analysis was a useful tool for structure elucidating epimeric C-glycosides anthrones 3–6 because of the poor stability of the pure isomers (3 and 4) and the minute quantity of 5 and 6 in the mixture.     

Bis-spiro-azaphilones and azaphilones from the fungi Chaetomium cochliodes VTh01 and C. cochliodes CTh05

Four new dimeric spiro-azaplilones, cochliodones A-D (1-4), two new azaphliones, chaetoviridines E and F (5 and 6), a new epi-chaetoviridin A (7), together with five known compounds, chaetoviridin A (8), ergosterol (9), chaetochalasin A (10), 24(R)-5α,8α-epidioxyergosta-6-22-diene-3β-ol (11), and ergosterol-β-d-glucoside (12) were isolated from the fungi Chaetomium cochliodes VTh01 and C. cochliodes CTh05. Structures and stereochemistry of the atropisomers 1-3 were determined by single-crystal X-ray diffraction analysis. Compounds 5, 10, and 11 exhibited antimalarial activity against Plasmodium falciparum, while 3, 5, 6, 10, and 11 showed antimycobacterial activity against Mycobacterium tuberculosis. In addition, 5 and 6 also showed cytotoxicity against the KB, BC1, and NCI-H187 cell lines.     

Highly stereoselective synthesis of novel trans-thiophenylene-silylene-vinylene-arylene molecular and macromolecular compounds

Novel stereoregular molecular compounds 8-13 containing thiophenylene-silylene-vinylene-phenylene units have been synthesised via highly effective silylative coupling of styrene and 1,4-divinylbenzene (7) with respective vinylsilylthiophenes (3, 4) and bis(vinylsilyl)thiophenes (5, 6) catalyzed by RuHClCO(PCy₃)₂. Respective copolymers (14, 15) were produced via silylative copolycondensation of 5 and 6 with 7. All products were isolated and characterised by NMR, MS, HRMS and two of them 10 and 11 by X-ray method. Catalytic study as well as stoichiometric reactions of Ru-H (1) with 2-(vinylsilyl)thiophene (3) and Ru-Si (16) with styrene confirmed the mechanism of the silylative coupling olefins with vinylsilicon compounds.     

N-Arylmethyl-7-azabicyclo[2.2.1]heptane derivatives: synthesis and reaction mechanisms

N-Arylmethyl-7-azabicyclo[2.2.1]heptane (I) derivatives have been synthesized by deprotection of N-protected, N-(arylmethyl)cyclohex-3-enamines, bromination of the resulting secondary cyclohex-3-enamines, followed by base-promoted cyclization (route a), or by bromination of N-protected, N-(arylmethyl)cyclohex-3-enamines followed by deprotection and base-mediated cyclization (route b). In these protocols we have observed that the bromination of the key intermediates (12, 13, and 19) is stereoselective leading to major trans-3-cis-4-dibromides (14, 17, and 20), whose mild base-mediated heterocyclization (on compound 14), or the two-step acid hydrolysis plus base-promoted cyclization (on compounds 17 and 20), gave products 6 and 7 in good yield. A mechanistic investigation using DFT has been carried out to explain the results observed in this work.     

Stabilization of (N-methyleneamino)imidoylketenes: synthesis of dipyrazolo[1,2-a;1′,2′-d][1,2,4,5]tetrazines

Thermolysis of substituted methyl 1-methyleneamino-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates 2a,b led to substituted dimethyl 3,9-dioxo-1,5,7,11-tetrahydro-1H,7H-dipyrazolo[1,2-a;1′,2′-d][1,2,4,5]tetrazine-1,7-dicarboxylates 4a,b and methyl 2,5-dihydro-5-oxo-1H-pyrazole-3-carboxylates 5a,b as minor products. The structure of compound 4a was determined by X-ray crystallography. The proposed mechanism of this conversion includes generation of (N-methyleneamino)imidoylketenes 6a,b and its intramolecular transformation to azomethine imines—5-oxo-2,5-dihydropyrazole-1-methylium-2-ides 7a,b, which undergo dimerization in head-to-tail manner yielding products 4a,b and partially hydrolyse to compounds 5a,b.     

Synthesis of arylated highly congested indans using a domino sequence

A novel and efficient regioselective synthesis of various arylated highly congested 7-aryl-5-methylsulfanylindan-4-carbonitriles (3a-f), methyl 7-aryl-5-methylsulfanylindan-4-carboxylates (10a-e) and 7-aryl-5-methylsulfanylindan-4-carboxylic acids (11a-e) through base-catalyzed reaction of 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (1a-f) and methyl 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylates (9a-e) by cyclopentanone (2) has been delineated. The synthetic potential of 2-pyranone was explored further to generate molecular diversity using 6-aryl-4-sec-amino-2-oxo-2H-pyran-3-carbonitriles (7a-h), 5,6-diaryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (5a,b) and methyl 5,6-diaryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylates (12a,b) as precursors for the ring transformation by cyclopentanone to assess the effects of substituents on the course of the reaction to obtain highly congested indans, 6,7-diaryl-5-methylsulfanylindan-4-carbonitriles (6a,b), 7-aryl-5-(piperidin-1-yl)indan-4-carbonitriles (8a-h) and methyl 6,7-diaryl-5-methylsulfanylindan-4-carboxylates (13a,b).