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.     

Transformations of hispanolone. Novel Michael adducts with in planta activity against rice blast

Two novel Michael adducts 9α-cyano-15,16-epoxy-7β-hydroxylabda-13(16),14-dien-6-one (2) and 9α-cyano-15,16-epoxy-7-hydroxylabda-7,13(16),14-trien-6-one (3) and the reduction product of 2, 9α-cyano-15,16-epoxy-6β,7β-dihydroxylabda-13(16),14-diene (4), were synthesized from the naturally occurring labdane diterpene hispanolone (1). Compounds 2-4 exhibited in planta activity against the pathogenic rice blast fungus Magnaporthe grisea.     

Rearrangement of allylic azide and phenylthio groups of 3′-azido- or 3′-phenylthio-4′,5′-didehydro-5′-deoxyarabinofuranosyluridines

The reversible intramolecular [3,3]-sigmatropic rearrangement between 1-(3-azido-3,5-dideoxy-β-d-threo-pent-4-enofuranosyl)uracil (3) and 1-(5-azido-3,5-dideoxy-β-d-glycero-pent-4-enofuranosyl)uracil (4) and irreversible radical rearrangement of 1-(3,5-dideoxy-3-phenylthio-β-d-threo-pent-4-enofuranosyl)uracil (5) and 1-[3,5-dideoxy-3-(4-tolyl)thio-β-d-threo-pent-4-enofuranosyl]uracil (7) into 1-(3,5-dideoxy-5-phenylthio-β-l-glycero-pent-4-enofuranosyl)uracil (6) and 1-[3,5-dideoxy-5-(4-tolyl)thio-β-l-glycero-pent-3-enofuranosyl]uracil (8) were attained at room temperature.     

Two novel 9,11-seco-11-norabietanes from the roots of Taiwania cryptomerioides

Two novel 9,11-seco-11-norabietanes, namely taiwanlactones A (1) and B (2), together with 3β-hydroxysugiol (3) and 6α-hydroxysugiol (4), were isolated from the roots of Taiwania cryptomerioides. Their structures were elucidated through spectral studies. The absolute configuration of 1 was elucidated by a modified Mosher’s method. The biotransformation mechanisms of 1 and 2 were proposed.     

Interesting transformations of naturally occurring cassane diterpenoids and bioevaluation of the products

Two cassane diterpenoids, pulcharrin G (1) and 6β-cinnamoyl-7β-hydroxy-voucapen-5-α-ol (2), the constituents of Caesalpinia pulcherrima, were treated with BF₃·OEt₂ to furnish two olefinic products 3 and 4, respectively. The products were formed by elimination of water and migration of a methyl group from C-4 to C-5. The cytotoxic and antimicrobial activities of 3 and 4 were examined.     

First cross-coupling reactions on halogenated 1H-1,2,4-triazole nucleosides

The halogenated 1H-1,2,4-triazole glycosides 6-10 were synthesized by BF₃-activated glycosylation of 3(5)-chloro-1,2,4-triazole (2), 3,5-dichloro-1,2,4-triazole (3), 3,5-dibromo-1,2,4-triazole (4), and 3(5)-bromo-5(3)-chloro-1,2,4-triazole (5) with 1,2,3,4-tetra-O-pivaloyl-β-d-xylopyranose (1). The β-anomeric major products 3-chloro-1-(2,3,4-tri-O-pivaloyl-β-d-xylopyranosyl)-1,2,4-triazole (6β), 3,5-dichloro-1-(2,3,4-tri-O-pivaloyl-β-d-xylopyranosyl)-1,2,4-triazole (7β), and 3,5-dibromo-1-(2,3,4-tri-O-pivaloyl-β-d-xylopyranosyl)-1,2,4-triazole (8β) were used as starting materials for transition metal catalyzed C-C-coupling reactions. Arylations of the triazole ring of 7β, and 8β were successful in 5-position with phenylboronic acid, 4-vinylphenylboronic acid, and 4-methoxyphenylboronic acid, respectively, under Suzuki cross-coupling conditions (products 11-17). Moreover, a Cu-catalyzed perfluoroalkylation of 8β is reported with 1-iodo-perfluorohexane yielding 3-perfluorohexyl-1-(2,3,4-tri-O-pivaloyl-β-d-xylopyranosyl)-1,2,4-triazole (18). Compound 18 was depivaloylated to the trihydroxy derivative 19. The copper-mediated reaction of 8β with Rupert's reagent gave the bis(3-bromo-1-(2,3,4-tri-O-pivaloyl-β-d-xylopyranosyl)-1,2,4-triazol-5-yl) (20).     

Syntheses and bioactivities of tricyclic pyrones

In search of compounds that ameliorate the toxicity of amyloid-β (Aβ) peptides, new derivatives of tricyclic pyrones (1-7) were synthesized and their biological activities evaluated. The carboxylic ester and amide derivatives 1-4 were synthesized from a selective carboxylation of C3 methyl of (5aS,7S)-{7-Isopropenyl-3-methyl-1H,7H-5a,6,8,9-tetrahydro-1-oxopyrano[4,3-b][1]benzopyran (8) with LDA followed by benzyl chloroformate or carbon dioxide to provide ester 1 and carboxylic acid 9, respectively. Three isomeric tricyclic pyrone, 5-7, containing adenine moiety at C7 side chain were synthesized from the alkylation of mesylate 13 with adenine, and displacement of chloropurine 15 with amine 14. Although C3-benzyloxycarbonylmethyl analogs 1-3 have marginal ACAT and CETP activities, their modified aspartate analog 4 and C3-methyl-C7-(N3-adeninyl)-2-propyl analog 6 show a significant effect in protecting against neuron-cell death from the toxicity of intracellular accumulation of Aβ or Aβ-containing C-terminal fragments (CTF) of amyloid β precursor protein (APP). N9-Adenine analog 5 is 20-fold less effective than N3-adenine derivative 6 in the protection of neuron-cell death induced by Aβ, while N10-adenine analog 7 was inactive. As a result of this study, compounds 4 and 6 will well serve as lead compounds for further studies of the mechanism of action of Aβ-and CTF-induced neuron-cell death, studies which should enhance the future development of new drugs for the prevention and treatment of AD.     

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.     

Synthesis of imidazo[5,1-b]thiazoles or spiro-β-lactams by reaction of imines with mesoionic compounds or ketenes generated from N-acyl-thiazolidine-2-carboxylic acids

New mesoionic compounds (2H, 3H-thiazolo[3,2-c]oxazol-7-ones) (β) or ketenes ((3-acyl-1,3-thiazolidin-2-ylidene)methanone) (β′) were generated from N-acetyl and N-benzoyl-thiazolidine-2-carboxylic acids (7a,b) using different methods, and their reactivity towards N-(phenylmethylene)benzenesulfonamide (2) and N-(phenylmethylene)aniline (3) was tested. When (7a,b) were treated with (2) and acetic anhydride in refluxing toluene solution, only imidazo[5,1-b]thiazoles (8a,b) were obtained from the mesoionic compound intermediates (β). When the ketene intermediates (β′) were generated from (7a,b) by means of Mukaiyama's reagent, only spiro-β-lactams (9a,b) were isolated.     

Cyclooxygenase-2 enzyme inhibitory withanolides from Withania somnifera leaves

Four novel withanolide glycosides and a withanolide have been isolated from the leaves of Withania somnifera. The structures of the novel compounds were elucidated as physagulin D (1→6)-β-d-glucopyranosyl-(1→4)-β-d-glucopyranoside (1), 27-O-β-d-glucopyranosyl physagulin D (2), 27-O-β-d-glucopyranosyl viscosalactone B (3), 4,16-dihydroxy-5β, 6β-epoxyphysagulin D (4), and 4-(1-hydroxy-2,2-dimethylcyclo-propanone)-2,3-dihydrowithaferin A (5) on the basis of 1D-, 2D NMR and MS spectral data. In addition, seven known withanolides withaferin A (6), 2,3-dihydrowithaferin A (7), viscosalactone B (8), 27-desoxy-24,25-dihydrowithaferin A (9), sitoindoside IX (10), physagulin D (11), and withanoside IV (12) were isolated. These withanolides were assayed to determine their ability to inhibit cycloxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes and lipid peroxidation. The withanolides tested, except compound 9, showed selective COX-2 enzyme inhibition ranging from 9 to 40% at 100 μg/ml. Compounds 4, 10 and 11 also inhibited lipid peroxidation by 40, 44 and 55%, respectively. The inhibition of COX-2 enzyme by withanolides is reported here for the first time.     

β,β-Difluoro analogs of α-oxo-β-phenylpropionic acid and phenylalanine

A simple three-step procedure converted the readily accessible (2-bromo-1,1-difluoroethyl)arenes (2) into α-aryl-α,α-difluoroacetaldehydes (1). Subsequent hydrocyanation, hydrolysis, oxidation and again hydrolysis afforded β-aryl-β,β-difluoro-α-oxopropionic acids (3). Reductive amination transformed the oxoacids 3 into a separable mixture of α-hydroxyacids 11 and racemic β,β-difluoro-β-phenylalanine derivatives (4). Enantiomerically pure β,β-difluorophenylalanine (l-4a) was obtained when α,α-difluoro-α-phenylacet-aldehyde (1a) was condensed with homochiral 1-phenylethylamine, hydrogen cyanide added to the resulting imine, the diastereomeric mixture thus produced hydrolyzed to the carboxamides (15) which were found to be separable by fractional crystallization or chromatography. The pK_a values of the β-aryl-β,β-difluoroalanines (4) were measured and biological profile of the latter probed. 3-(4-Chlorophenyl)-3,3-difluoro-2-oxopropionic acid (4c) proved to be a potent (K_i 27 μM) and selective inhibitor of arogenate dehydratase, a key enzyme catalyzing the last step of the phenylalanine biosynthesis.     

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.     

Polyhydroxylated pyrrolidines: synthesis from d-fructose of new tri-orthogonally protected 2,5-dideoxy-2,5-iminohexitols

The readily available 3-O-benzyl-1,2-O-isopropylidene-β-d-fructopyranose (2) was transformed into its 5-O- (3) and 4-O-benzoyl (4) derivative. Compound 4 was straightforwardly transformed into 5-azido-4-O-benzoyl-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-d-fructopyranose (7) via the corresponding 5-deoxy-5-iodo-α-l-sorbopyranose derivative 6. Cleavage of the acetonide in 7 to give 8, followed by regioselective 1-O-silylation to 9 and subsequent catalytic hydrogenation gave a mixture of (2S,3R,4R,5R)- (10) and (2R,3R,4R,5R)-4-benzoyloxy-3-benzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (12) that was resolved after chemoselective N-protection as their Cbz derivatives 11 and 1a, respectively. Stereochemistry of 11 and 1a could be determined after total deprotection of 11 to the well known DGDP (13). Compound 2 was similarly transformed into the tri-orthogonally protected DGDP derivative 18.     

Tetracyclic 1,6-methano-[10]annulenes a novel class of steroidal annulenes

Reaction of 19-hydroxyandrosta-4,6-diene-3,17-dione (8b) and the corresponding Δ⁷-compound (8c) with diethyl-(2-chloro-1,1,2-trifluoroethyl)-amine affords 5β,19-cyclo-Δ^1,6- and 5β,19-cyclo-Δ^1,7-3-ketones (4b) and (4c) respectively. Solvolysis experiments with the 19-tosylates of the 19-hydroxy-Δ^4,6- and Δ^4,7-3-ketones (8b) and 8c) are described as alternate approaches to (4b) and (4c). Exposure of 5β,19-cyclo compounds (4b) and (4c) to acetic anhydride-acetic acid-p-toluenesulfonic acid yields the respective 3-acetoxycycloheptatrienes (5a) and (6a). The latter substance (6a) is converted into the novel tetracyclic 1,6-methano-[10]annulene (2a) on exposure to N-bromosuccinimide in boiling carbon tetrachloride. Synthesis of the corresponding 3-methoxy- and 3-desoxy-1,6-methano-[10]annulenes (2b) and (2c) are also described. The NMR spectra of (2a), (2b) and (2c) and related intermediates are discussed.     

The microbiological transformation of steroidal saponins by Curvularia lunata

The microbiological transformation of polyphyllin I (compound I), polyphyllin III (compound II), polyphyllin V (compound III) and polyphyllin VI (compound IV) by Curvularia lunata into their corresponding subsaponins, for example, diosgenin-3-O-α-l-arabinofuranosyl (1→4)-β-d-glucopyranoside (compound V), diosgenin-3-O-α-l-rhamnopyranosyl (1→4)-β-d-glucopyranoside (compound VI), diosgenin-3-O-β-d-glucopyranoside (compound VII) and pennogenin-3-O-β-d-glucopyranoside (compound VIII), were studied in this paper. Curvularia lunata is able to hydrolyze terminal rhamnosyls that are linked by 1→2 C- bond to sugar residues of steroidal saponins at C-3 position with high activity and regioselectivity.     

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.     

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.     

Combined biotransformations of 4(20),11-taxadienes

Taxuyunnanine C (1) and its analogs (2 and 3), the C-14 oxygenated 4(20), 11-taxadienes from callus cultures of Taxus sp., were regio- and stereo-selectively hydroxylated at the 7β position by a fungus, Abisidia coerulea IFO 4011, and it was interesting that the longer the alkyl chain of the acyloxyl group at C-14 became, the higher the yield of 7β-hydroxylated product was. Besides the three 7β-hydroxylated products (5, 9, 17), other nine new products (7, 11, 12, 14, 15, 16, 18, 20 and 21) and six known products (4, 6, 8, 10, 13 and 19) were obtained. Subsequently, the acetylated derivatives (24 and 27) of 7β-and 9α-hydroxylated products of 1 were regio- and stereo-specifically hydroxylated at the 9α position by Ginkgo cells and 7β position by A. coerulea, respectively. Thus, the two specific oxidations have been combined. These bioconversions would provide not only valuable intermediates for the semi-synthesis of paclitaxel or other bioactive taxoids from 1 and its analogs, but also some useful hints for the biosynthetic pathway of taxoid in the natural Taxus plant.     

New synthesis of glycolipid immunostimulants RC-529 and CRX-524

An efficient and scalable synthesis of the potent vaccine adjuvant RC-529 (3) and TLR4 agonist CRX-524 (4) is described in eight steps from 1,3,4,6-tetra-O-acetyl-2-amino-2-benzyloxycarbonyl-2-deoxy-β-d-glucopyranose (10c) in ca. 25% overall yield. The synthesis features the strategic use of the N-Cbz group for β-glycosylation and the selective N,N,O-triacylation of common advanced intermediate 15 with (R)-3-tetradecanoyloxy or decanoyloxytetradecanoic acid (8, 9) late in the synthesis. A new method for preparing and enhancing the enantiopurity of (R)-3-hydroxytetradecanoic acid (6), a key component of 3 and 4 as well as bacterial lipid A, is also described.     

Enantioselective alkylation and protonation of prochiral enolates in the asymmetric synthesis of β-amino acids

Achiral 1-benzoyl-3-methylperhydropyrimidin-4-one (1) was deemed a useful, potential precursor for the enantioselective synthesis of α-substituted β-amino acids. Pyrimidinone 1 was prepared from inexpensive β-aminopropanoic acid in 62% overall yield. Prochiral enolate derivative 1 -Li was alkylated in good yield and moderate enantioselectivity in the presence of chiral amines (S)-8, (S,S)-9, (S,S)-10, or (−)-sparteine. The enantioselectivity of the alkylation process is highest in toluene as the solvent and in the presence of lithium bromide as additive. The racemic alkylated derivatives 2 and 3 were readily metallated with LDA to give prochiral enolates 2-Li and 3-Li, that were reprotonated with novel chiral phenolic acids (S)-11, (S,S)-12, (S)-13, and (S,S)-14 in moderate enantioselectivity in the case of 2-Li and good enantioselectivity in the case of 3-Li. The acid (6N HCl) hydrolysis of enantioenriched 2 and 3 proceeded in good yield and without racemization to afford α-alkyl-β-amino acids 4 and 5, respectively.