Chemoenzymatic syntheses of naturally occurring β-glucosides

Enzymatic glycosidation of the various kinds of primary alcohols 5, 7, 9, 11, 13 and 15 and 4-nitrophenyl-β-d-glucopyranoside 4 using β-glucosidase from almonds gave stereoselectively β-d-glucosides 6, 8, 10, 12, 14 and 16 including the naturally occurring β-glucosides in moderate yield. Among them, the β-glucosides 6, 8 and 10 were converted to the cyanoglycosides, rhodiocyanoside A 20a, osmaronin 24a and sutherlandin 29, respectively.     

Some electrophilic reactivity studies of di-(2-indolyl)dibenzofurans and di-(2-indolyl)carbazoles

3,6-Bis-(2-indolyl)dibenzofurans 1,2, and carbazoles 3–6 underwent a range of electrophilic substitution reactions to produce formyl indoles 7–12, biindolyls 24–28 and 33–34, glyoxylamides 40–42, and amides 48.     

Resolution of 1-arylalkylamines with 3-O-hydrogen phthalate glucofuranose derivatives: role of steric bulk in a family of resolving agents

The development of three new acidic resolving agents which are hydrogen phthalates of 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose 1, 1,2:5,6-di-O-cyclohexylidene-α-d-glucofuranose 2 and 1,2-O-cyclohexylidene-5,6-O-diphenylmethylidene-α-d-glucofuranose 3 is shown for the resolution of 1-arylalkylamines 7a–k. The salts between 1, 2 and (RS)-1-arylalkylamines 7a–k selectively crystallize 1·(S) 7a–j and 2·(S) 7a–h salts, allowing us to recover the corresponding bases (S) 7a–j and (S) 7a–h, respectively, in good yield and enantiomeric excess (73–95% ee). Whereas, the salts between 3 and (RS)-1-arylalkylamines 7a–c,g–i,k selectively crystallize 3·(S)-7a–c,g–i salts to recover the corresponding bases (S)-7a–c,g–i in poor enantiomeric excess (4–35% ee). The difference between the resolving ability of 1 and 2 for 1-arylalkylamines 7a–h is very slight, but there is considerable difference compared to ortho-substituted 1-arylalkylamines 7i and 7j. The role of substituents on a family of resolving agents 1, 2 and 3 is also discussed to interpret their resolving ability.     

Schwefelheterocyclen durch dithiocarboxylierung von Benzoylacetonitril

Disodium salt 2 reacts with hydrogen peroxide to give 1,2,4-trithiolane 3, whereas treatment with methyl chloroformate yields 1,3-dithietane 4. Adding diluted NaOH to 3 leads to a mixture of an isothiazole 7 and 4. By chlorination of 2 isothiazole 8 is available. S-amination of 2 or 9 and following cyclization gives the isothiazoles 10 and 12, respectively. 3-Mercapto-acrylonitrile 14 reacts with quinones to condensed oxathioles 16 or 17.     

Hydroboration d'aziridudines èthylèniques synthése d'aza-1 bicyclo[n, 1, 0]alcanes

Hydroboration of aziridines having a β or γ-double bond 3b, 3c, 4b, 7c and 8 yields after oxidation, the expected hydroxy aziridines 11b, 11c, 12b, 13 and 14, which were cyclized by reaction with PPh₃/Br₂ to give 1-aza bicyclo[n, 1, 0]alkanes 23b, 24b, 25c, 26 and 27. The hydroboration of 2-vinyl aziridines 3a, 4a and 7a give _Z-allylic amines 16aZ, 17aZ and 18Z. The use of 9-BBN or of 2-vinyl substituted aziridines provides the β-hydroxy aziridines 19, 20 and 21.     

The synthesis of annulated pyridazines by cycloaddition of azodicarboxylates to vinyl heterocycles

Reaction between 2-vinyl pyridine and azodicarboxylates 2 or 5 gives N,N'-disubstituted tetrahydropyrido[3,2-c]pyridazines 3 and 6, and dihydro-3H-pyrido[1,2-c]triazines 4 and 7; 2-(prop-1-en-1-yl)-pyridine 8 gives hydropyridopyridazines 10 and 11 but 2-(prop-1-en-2-yl)pyridine 9 gives mainly the ‘ene’ addition product 12. From 4-vinyl-pyridine and esters 2 or 5 diesters of tetrahydropyrido[3,4-c]pyridazine-1,2-dicarboxylic acid, 25 and 26 are obtained, and from 2-methyl-5-vinylpyridine both possible cyclisation products, the tetrahydro-pyrido[2,3-c]pyridazines 33 and 36, and -pyrido[4,3-c]pyridazines 34 and 37. The di-t-butyl esters 6, 11, 26, and 37 are quantitatively decarbalkoxylated in TFA, giving tetrahydropyridopyridazines 16, 18, 27, and 41; of these, the first three were oxidized to give pyrido[2,3-c]-pyridazine 15, its 3-methyl derivative 19, and pyrido[3,4-c]pyridazine 28 respectively. A dihydropyrido[4,3-c]-pyridazine 42 was obtained from compound 41. Thieno[2,3-c]-pyridazine 48 has been similarly prepared from 2-vinylthiophen, but 2-(prop-1-en-2-yl)thiophen gave an ene addition compound 51 and a dihydrothienopyridazine 50. Reactions with other vinylpyridines, and with vinylfurans, were unsuccessful.     

Approach to the perhydroisoindole system in cytochalasin B

The synthesis of the perhydroisoindole systems 17a, b, 22 and 23 is described using the following sequence of reactions. Diels-Alder cycloaddition of silyloxydienes 4 with methyl acrylate leads, after methanolysis, to cyclohexenonecarboxylates 6, subsequent acetalization and epoxidation of the α,β-unsaturated esters 7 yields the epoxy esters 8 and 9. Conversion of these esters into acyl chlorides 11, via the sodium salts 10, and subsequent treatment with an amine component (phenylalanine methyl ester, diethyl aminomalonate and ethyl 2-amino benzoyl-acetate) produces the epoxy carbonamides 12, 15 and 18, respectively. These epoxy amides are subjected to acid-catalyzed hydrolysis to give the cyclohexenonecarbonamides 13, 16 and 19, respectively. Subsequent ring-closure of the amides 16 and 19 with base leads to the perhydroisoindole derivatives 17a, b and 22, respectively. The formation of 22 proceeds via a concomitant benzoyl transfer reaction. The amide 13 failed to ring-close. A by-product of the acid treatment of 18 is 21 which with base undergoes a benzoyl transfer to perhydroisoindole 23. The structures of the products 9a, 22 and 23 were ascertained by means of an X-ray analysis.     

New mycotoxins from the scale insect fungus Aschersonia coffeae Henn. BCC 28712

Nine new mycotoxins; five xanthones 1–5, hydroxanthone 6, and three anthraquinones 7–9, together with nine known compounds; sterigmatocystin (10), demethylsterigmatocystin (11), dihydrodemethylsterigmatocystin (12), sterigmatin (13), austocystin F (14), averufin (15), aflatoxin B1, paeciloquinone A, and zeorin, were isolated from the scale insect fungus Aschersonia coffeae Henn. BCC 28712. The structures of these compounds were elucidated using NMR spectroscopic and MS spectrometric analyses. Compounds 1–3 and 6–9 displayed cytotoxic activity while the xanthone 2 and anthraquinones 8 and 9 also showed antimalarial activity.     

Search for a simpler synthetic model system for intramolecular 1,3-dipolar cycloaddition to the 5,6-double bond of a pyrimidine nucleoside

In search for a simpler model system for the study of intramolecular thermal reactions between the base and 5'-functionalized sugar moiety in nucleosides, 1-(3-azidopropyl)uracil (2), 1-(4-azidobutyl) pyrimidines (12 and 13) and 1-(5-azidopentyl)-uracil (14) was synthesized through the corresponding ω-benzoyloxy-(6,7 and 8) and ω-hydroxyalkyl-pyrimidines (9,10 and 11). Heating 2 gave 1,N⁶-trimethylene-6-aminouracil (4), while heating 12 and 13 gave N¹-C₆ cleaved addition products. 15 and 16, respectively. 15 was regiospecifically transformed to 1,2,3-triazole derivatives, 17,18 and 19. Heating 1-(4-azidobutyl)-5-bromouracil (20) yielded 3,9-tetramethylene-8-azaxanthine (22). 9 with NBA gave 1,0⁶-tetramethylene-5-bromo-6-hydroxy-5,6-dihydrouracil (24) and the 5-brominated analog of 9 (25). The 4-functionalized butyl side chain proved to serve as a substitute for the 5'-functionalized sugar moiety in pyrimidine ribonucleosides.     

Synthese und reaktionen von di(benzthiazol-2-yl)- und di(benzoxazol-2-yl)methylgerman

Reaction of benzthiazol-2-yl and benzoxazol-2-yl-trimethylstannane with methyltrichlorogermane leads to the mono-, bis- and tris-heterocyclic substituted germanes RGe(Me)Cl₂, R₂Ge(Me)Cl, R₃GeMe (2, 3, 4: R = benzthiazol-2-yl; 6, 7, 8: R = benzoxazol-2-yl), which exist in a mobile equilibrium. From the chlorogermanes 2, 3 and 6, 7 the corresponding germanes 9, 10 and 11, 12 can be obtained by reaction with trimethylstannane. From the germane 10 the mono- and bis-N-methylated salts 15 and 17 can be synthesized. The compounds 10, 12 and 15 easily decompose by α-elimination reactions. The salt 17 can be regarded as a suitable model substance for the synthesis of a germacyanine dye.     

Thio-acids—V : Some reactions of 3-oxo-1,2-dithioles

Diphenyldiazomethane with compound (1) gave dibenzoyl, while 2 and 3 gave the corresponding 3-oxo(2H)thiophenes 5. With copper-bronze 1 gave 2,2′-di-(thiobenzoate) (4), while 2 gave 2,7-diphenylthiepin (6a) and 2,5-diphenylthiophene (7a), but 3 gave only 2,5-di-(p-methoxyphenyl)thiophene (7b). With Grignard reagents 1 gave the corresponding methanol derivative 14, while 2 gave the thiobenzoylethylenes 13a and b, but 3 gave 2,7-di-(p - methoxyphenyl) - 4,4,5,5- tetraphenyl(4H)thiepin (15). The reaction mechanisms are discussed.     

Reactions retrodieniques—IX: Synthese par thermolyse eclair et etude d'enamines primaires instables

Ethenamine 1 and its methyl derivatives 2–7 have been synthesized from the adducts 8–14 by a retro-Diels-Alder reaction under flash thermolytic conditions. The primary enamines 1–4 have been identified (IR, ¹H and ¹³C NMR) in a pure state at ?80°; at the same temperature, the enamines 5–7, less stable, are already accompanied by their tautomeric imines 33 or 34. When warmed up to room temperature, the enamines 1–7 lead, following to their substitution, either to nitrogen heterocycles (30, 42) or to acyclic azadienes (35–37, 39, 40).     

Homo-Diels-Alder and ene reactions of phosphaalkynes

Cycloalka-1,3-dienes 1 and 6 react with phosphaalkynes 2 to form the bicyclic systems 3 and 7 containing λ³σ²-phosphorus atoms. Products 3 and 7 react with a further equivalent of 2 to furnish the tetracycles 4 and 8 by way of a previously unknown homo-Diels-Alder reaction. The ene reaction 9 + 2 → 10 defines the limits of the cycloaddition process.     

Studies on organophosphorus compounds: Thiation of 3,1-benzoxathian-4-ones. New routes to 1,2-benzisothiazole-3(2H)-thiones and 3H-1,2-benzodithiol-3-imines

3,1-Benzoxathian-4-ones, 2, when heated with 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2, 4-disulfide, 1, or with P₄S₁₀ give one or more of the following products 3,1-benzoxathian-4-thione, 3, 1,3-benzodithian-4-one, 4, 1,3-benzodithian-4-thione, 5, and 3H-1,2-benzodithiole-3-thione, 6. Compounds 2, when heated with primary and secondary amines and with hydrazines, give 2-mercaptobenzamides, 7, and 2-mercaptobenzohydrazides, 8, or their corresponding disulfides, 7' and 8'. 3H-1, 2-Benzodithiol-3-immes, which are in equilibrium with 1,2-benzisothiazole-3(2H)-thiones, (9A ? 9B), are prepared by two new routes (a) by allowing 3 or 5 to react with primary amines or hydrazines, (b) by allowing 7, 8, 7' or 8' to react with 1.     

The structures of macbecin I and II : New antitumor antibiotics

Macbecin I 1, C₃₀H₄₂N₂O₈, and macbecin II 2, C₃₀H₄₄N₂O₈, were shown to be 2,6-disubstituted benzoquinone and hydroquinone derivatives by an oxidation-reduction relationship, UV. ¹H and ¹³C NMR spectra. Alkaline methanolysis of 1 gave a 2-aminobenzoquinone derivative 5, suggesting an ansa-structure for 1, and acid hydrolysis of 1 gave decarbamoyl products 9,10 and 11, indicative of the location of carbamoyloxy group in allylic position. Spin decoupling studies on 1,3 and 5clarified the partial structures [A], [B], [C] and [D]. From their mutual disposition two structures 1a and 1b, were proposed out of which 1a has been selected for the structure of 1 on the basis of the structure of oxidative degradation product 12. X-Ray analysis of the bromoacetyl derivative of 1 confirmed the above proposed structure and determined the absolute stereochemistry of 1 and 2.     

Structural elucidation,antioxidant and hepatoprotective activities of chemical composition from Jinsi Huangju (Chrysanthemum morifolium) flowers

Six new compounds (huangjusus A-F), including three caffeic acid glycosides (1–3), one quinic acid derivative (4), one dihydroflavone glycoside (11) and one monoterpene (31), together with thirty-eight known compounds (5–10, 12–30, 32–44), were obtained from “Jinsi Huangju” (Chrysanthemum morifolium Ramat.) flowers. Their structures were elucidated on the basis of the data obtained from different spectroscopic techniques. Among these compounds, five new (1–4 and 11) and ten known (5–9, 12, 13, 17, 40, and 42) compounds demonstrated significant 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging effects with IC₅₀ values of 4.22–19.90 μM. Furthermore, three new compounds (1, 11, and 31) and seven known compounds (13, 19, 21, 29, 30, 39, and 41) exhibited potent hepatoprotective activities against N-acetyl-p-aminophenol (APAP)-induced toxicity in HepG2 cells with the cell survival rates of 61.53 %, 63.55 %, 60.01 %, 63.05 %, 59.75 %, 59.15 %, 61.07 %, 62.72 %, 58.86 %, and 58.76 % (positive control bicyclol, 58.41 %), respectively, at a concentration of 10 μM. These results indicate the potency of the flowers against radicals and in hepatoprotections.     

9(11)-Secoestra-11,17-dioic acids and related compounds

While hydrogenations of 2b furnished a mixture in which the rac 14α isomer 8b predominated, the rac lactone 6 was hydrogenolyzed to give the rac 14β diacid 9a. Clemmensen reduction of 6 gave the rac 14α tetrahydro compound 7a. Another route to 8 involved conversion of the d-ketoacid 11b into 23b via the cyanolactone 20b or the amidolactone 21b. Base-catalyzed elimination at 206° yielded the Δ¹⁶ diester 27 which was hydrogenated to 8c. An analogous conversion was also carried out in the ring B reduced series 13 → 20a + 21a → 23a → 25a → 26. In the 14β series, using the same sequence of reactions, the rac ketoacid 10a was transformed into the rac lactone ester 29. In distinction from the 14α series, treatment with alkali at 206° gave only partial elimination, the double bond migrating to the 14,15 position to furnish 2. Evidence is presented that amides of the ketoacid 13a exist in the hydroxylactam form 30 and can be readily O-alkylated to furnish 22. Attempts to aromatize ring B of 13a with DDQ led to lactones 15 and 16, while reaction of the ester 13b with DDQ gave the pentaene 17 and the hexaene 18, establishing that dehydrogenation proceeded stepwise in the sequence Δ⁸, Δ¹⁴ and finally Δ⁶.     

Chemo-, stereo- and regioselective hydrogenolysis of carbohydrate benzylidene acetals. Synthesis of benzyl ethers of benzyl α-d-, methyl β-D-mannopyranosides and benzyl α-D-rhamnopyranoside by ring cleavage of benzylidene derivatives with the LiAlH4-AlCl3 reagent

Treatment of benzyl α-(1) and methyl β-d-mannopyranoside (2) with α,α-dimethoxytoluene gave the exo and endo isomers (3,5 and 4,6) of the dibenzylidene derivatives of 1 and 2. Hydrogenolysis of the exo isomers (3 and 5) with a molar equivalent of AlH₂Cl gave the 3-0-benzyl-4,6-0-benzylidene derivatives (7 and 21), whereas the endo isomers (4 and 6) gave the 2-0-benzyl-4,6-0-benzylidene compounds (8 and 22). The 2-0-allyl ether 9 of 7, the 3-0-allyl derivative (10) of 8 and compounds 21 and 22 were treated with an additional molar equivalent of AlH₂Cl at reflux and the products were the 4-0-benzyl-6-hydroxyl derivatives (11, 12, 23 and 24), whereas in the case of 22 the 6-0-benzyl-4-hydroxyl isomer (25) was also isolated. By deallylation of 11 and 12, 3,4-(13) and 2,4-di-0-benzyl (14) ethers of 1 were prepared. Tosylation of 11 and 12, and subsequent reduction of the products (15 and 16) made possible the preparation of the partially protected benzyl α-d-rhamnopyranoside derivatives (17–20). The structures of the compounds synthesized were characterized by ¹H and ¹³C NMR spectroscopic investigation and by chemical methods.     

Cytotoxic and anti-inflammatory diterpenoids from the Dongsha Atoll soft coral Sinularia flexibilis

Seven new diterpenoids, namely, flexibilisolides C–G (1–5), flexibilisin C (6), and a novel 11,12-secoflexibillin (7), along with seven known compounds, 8–14, were isolated from the Dongsha Atoll soft coral Sinularia flexibilis. The structures of the new metabolites were elucidated by extensive spectroscopic analysis and comparison of the NMR data with those of known analogues. Compounds 1, 8, and 11 were shown to exhibit moderate cytotoxic activity against HeLa and B16 cancer cell lines, and compound 10 was found to exhibit more potent cytotoxic activity against SK-Hep1 and B16 cancer cell lines. Moreover, compounds 1, 2, 8, 9, and 11–14 could significantly inhibit the accumulation of the pro-inflammatory iNOS protein and 1, 8, 11, and 14 could reduce the accumulation of COX-2 protein in LPS-stimulated RAW264.7 macrophage cells.     

Remote halogenation: Some model studies and specific degradation of the cholesterol,sitosterol, and campesterol side chain

1) Two high-yield procedures for the conversion of 1 to 4 are reported. 2) 11 was degraded to 34 in good overall yield via 17, 20, 26, 31, 29, and 30. Similarly, 34 was obtained from 12 and 13.