3-Oxyanthranilic acid derivatives from Actinomadura sp. BCC27169

Eight new compounds including 9′-[2-amino-3-(4″-O-methyl-α-rhamnopyranosyloxy) phenyl]nonanoic acid (1), 9′-[2-amino-3-(4″-O-methyl-α-ribopyranosyloxy)phenyl] nonanoic acid (2), 11′-[2-amino-3-(4″-O-methyl-α-rhamnopyranosyloxy)phenyl]undecanoic acid (3), 11′-[2-amino-3-(4″-O-methyl-α-ribopyranosyloxy)phenyl]undecanoic acid (4), 8-(4′-O-methyl-α-rhamnopyranosyloxy)-3,4-dihydroquinolin-2(1H)-one (5), 8-(4′-O-methyl-α-ribopyranosyloxy)-3,4-dihydroquinolin-2(1H)-one (6), 8-(4′-O-methyl-α-rhamnopyranosyloxy)-2-methyquinoline (7), and 8-(4′-O-methyl-α-ribopyranosyloxy)-2-methylquinoline (8) were isolated from Actinomadura sp. BCC27169. The chemical structures of these compounds were determined based on NMR and high-resolution mass spectroscopy. The absolute configurations of these monosaccharides were revealed by the hydrolysis of compounds 7 and 8. Compounds 3 and 8 exhibited antitubercular activity at MIC 50 μg/mL. Only compound 3 showed cytotoxicity against KB cell at IC₅₀ 18.63 μg/mL, while other isolated compounds were inactive at tested maximum concentration (50 μg/mL).     

Synthesis of 4-substituted azepino[3,4-b]indole-1,5-diones

Mono- or dibromo derivatives 2 and 3 were prepared by an efficient two-step route from 10-methyl-azepino[3,4-b]indole-1,5-dione 1. Elimination reaction on 2 gave access to 4-bromo-10-methyl-2H,10H-azepino[3,4-b]indole-1,5-diones 4. Finally, 4-substituted 10-methyl-2H,10H-azepino[3,4-b]indole-1,5-diones 6-14 were synthesised in good yields from 4 via palladium-mediated cross-coupling reactions.     

Substituent dependent regioselective synthesis of pyranopyrandiones and 1,2-teraryls from 2H-pyran-2-ones

The one-pot substituent-directed regioselective synthesis of 1,7-diaryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-diones 3 as the major and 3,4-diaryl-2-methyl-6-methylsulfanylbenzonitriles 4 as the minor products has been delineated through ring transformation of suitably functionalized 2H-pyran-2-ones 1 with aryl acetones 2. Under similar reaction conditions, 6-aryl-4-sec-amino-2H-pyran-2-ones 5 led, regioselectively, to 3,4-diaryl-2-methyl-6-sec-aminobenzonitriles 6.     

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).     

Substituent-induced regioselective synthesis of 1,2-teraryls and pyrano[3,4-c]pyran-4,5-diones from 2H-pyran-2-ones

Substituent-controlled regioselective synthesis of highly functionalized 1,2-teraryls 3a-k has been achieved through ring transformation of 6-aryl-4-(pyrrolidin-1-yl/piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles 1a-g by aryl acetones 2a-c in the presence of powdered KOH in DMF in very good yield. Under similar reaction conditions, 6-aryl-4-methylsulfanyl-2H-pyran-2-ones 5a-f afforded 1,7-diaryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-diones 6a-j as major products and 3,4-diaryl-2-methyl-6-methylsulfanylbenzonitriles as minor constituents 7a-j.     

Three-component synthesis of 5:6 and 6:6 fused pyrimidines using KF-alumina as a catalyst

A series of fused pyrimidine derivatives were synthesized by the three-component reaction of an aryl aldehyde, urea, or guanidine in ethyl alcohol/dioxane in presence of 1-methyl-1H-pyrrol-2(3H)-one 1, 1-methylpiperidin-2-one 2, 1-methylindolin-2-one 3, or 1,3-dimethyl-dihydropyrimidine-2,4-dione 9 at 80 °C catalyzed by KF-Al₂O₃. For example, when 1-methyl-1H-pyrrol-2(3H)-one 1, arylaldehyde 4, and urea 5 were treated with KF-Al₂O₃ in ethyl alcohol at 80 °C for 3-5 h, we obtained pyrrolo[2,3-d]pyrimidine derivatives in good yield.     

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.     

Base dependent purported synthesis of congested 2-aminobenzylamines and tetrahydro-2-oxoquinazolines from 2-pyranones

An expeditious and concise synthesis of highly congested 2-amino-3-aminomethyl-5-methylsulfanyl/-sec-aminobiphenyl-4-carbonitrile 4 and 1-tert-butoxycarbonyl-6-sec-amino-8-aryl-5-cyano-2-oxo-1,2,3,4-tetrahydroquinazoline 5 has been delineated through base catalyzed ring transformation of 6-aryl-4-methylsulfanyl/-sec-amino-2H-pyran-2-one-3-carbonitrile 1 with 1,3-bis(tert-butoxycarbonylamino)-2-propanone 2, followed by TFA catalyzed hydrolysis of the intermediate [3-tert-butoxycarbonylaminomethyl-4-cyano-5-methylsulfanyl/-sec-aminobiphenyl-2-yl]carbamic acid tert-butyl ester 3 in moderate yield. The mechanism of formation of 5 has been established through isolation and transformation of the intermediate 3 to the 1-tert-butoxycarbonyl-6-sec-amino-8-aryl-5-cyano-2-oxo-1,2,3,4-tetrahydroquinazoline.     

Synthesis of novel photolabile glycosides from methyl 4,6-O-(o-nitro)benzylidene-α-d-glycopyranosides

Novel photolabile sugar derivatives bearing a 4- or 6-O-(o-nitro)benzyl group have been prepared from the corresponding methyl 4,6-O-(o-nitro)benzylidene α-d-glycopyranosides. Regioselective cleavage with BF₃·Et₂O/Et₃SiH led to the methyl 6-O-(o-nitro)benzyl gluco- and manno-α-d-glycopyranosides 3 and 6. Inversion of configuration at 4-OH position of gluco and manno derivatives offered the otherwise inaccessible methyl 6-O-(o-nitro)benzyl galacto- and talo-α-d-glycopyranosides 4, 5, and 7. Careful reaction with PhBCl₂/Et₃SiH (3 equiv of reagents, 10 min at −78 °C) led to the desired methyl 4-O-(o-nitro)benzyl gluco- and manno-α-d-glycopyranosides 8 and 9 in very good yield. However, prolonged reaction with 6 equiv of PhBCl₂/Et₃SiH transformed the methyl 4,6-O-(o-nitro)benzylidene α-d-glucopyranoside 11 into the reduced d-glucitol derivative 15. Oxidative cleavage of 5,6-diol function of 15 gave the corresponding photolabile l-xylose 17. The photolabile glucosides 3 and 8 have been further transformed into the photolabile α-C-allyl d-glucopyranosides 20 and 22.     

A novel strategy for the expeditious synthesis of aryl-tethered highly congested 2-hydroxybenzyl alcohols from 2-pyranones

An efficient and simple synthesis of highly congested 2-benzyloxy-3-benzyloxymethyl-5-sec-aminobiphenyl-4-carbonitriles 3a-e has been delineated through base catalyzed ring transformation of 6-aryl-4-sec-amino-2H-pyran-2-one-3-carbonitriles 1 by 1,3-bisbenzyloxypropan-2-one 2. Debenzylation of both the O-benzyl groups of 3a-e with boron trichloride provided the corresponding diols, 2-hydroxy-3-hydroxymethyl -5-sec-aminobiphenyl-4-carbonitriles 4a-e in very good yields.     

Stereoselective synthesis of 4-C-methyl-2,3,5-tri-O-benzyl-d-ribofuranose and 4-C-methyl-2,3,5-tri-O-benzyl-l-lyxofuranose

Sugar intermediates 4-C-methyl-2,3,5-tri-O-benzyl-d-ribofuranose (8b) and 4-C-methyl-2,3,5-tri-O-benzyl-l-lyxofuranose (8a) were synthesized by addition of alkylithium reagents to pentanones 3a,b. The nucleophilic additions proceeded with good stereoselectivity and good yields to give the titled compounds in four steps from perbenzylated methyl d-ribofuranoside and methyl 5′-deoxy-d-ribofuranoside.     

Concise and practical route to tri- and tetra-hydroxy seven-membered iminocyclitols as glycosidase inhibitors from d-(+)-glucurono-γ-lactone

An efficient and short total synthesis of tetrahydroxy-1c and trihydroxy-azepane 1d is reported in 72% and 57% overall yields, respectively, from d-(+)-glucurono-γ-lactone. Thus, d-glucuronolactone 2 on acetonide protection, DIBAL-H reduction and one-pot intermolecular reductive amination followed by -NCbz protection afforded 6-(N-benzyl-N-benzyloxycarbonyl) amino-6-deoxy-1,2-O-isopropylidene-α-d-gluco-1,4-furanose 5a. 1,2-Acetonide hydrolysis in 5a and Pd-mediated intramolecular reductive aminocyclization afforded tetrahydroxyazepane 1c. An analogous pathway with 5-deoxy-1,2-O-isopropylidene-α-d-glucurono-6,3-lactone 3b gave trihydroxy-azepane 1d. Glycosidase inhibitory activity of 1c/1d was studied and 1d was found to be potent inhibitor of α-mannosidase and β-galactosidase.     

Polyhydroxylated pyrrolidines. Part 4: Synthesis from d-fructose of protected 2,5-dideoxy-2,5-imino-d-galactitol derivatives

The readily available 3-O-benzoyl-4-O-benzyl-1,2-O-isopropylidene-5-O-methanesulfonyl-β-d-fructopyranose (5) was straightforwardly transformed into its d-psico epimer (8), after O-debenzoylation followed by oxidation and reduction, which caused the inversion of the configuration at C(3). Compound 8 was treated with lithium azide yielding 5-azido-4-O-benzyl-5-deoxy-1,2-O-isopropylidene-α-l-tagatopyranose (9) that was transformed into the related 3,4-di-O-benzyl derivative 10. Cleavage of the acetonide in 10 to give 11, followed by regioselective 1-O-pivaloylation to 12 and subsequent catalytic hydrogenation gave (2R,3S,4R,5S)-3,4-dibenzyloxy-2,5-bis(hydroxymethyl)-2′-O-pivaloylpyrrolidine (13). Stereochemistry of 13 could be determined after O-deacylation to the symmetric pyrrolidine 14. Total deprotection of 14 gave 2,5-imino-2,5-dideoxy-d-galactitol (15, DGADP).     

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.     

Stereo-controlled approach to pyrrolidine iminosugar C-glycosides and 1,4-dideoxy-1,4-imino-l-allitol using a d-mannose-derived cyclic nitrone

Intramolecular N-alkylation of 2,3-O-isopropylidene-5-O-methanesulfonyl-6-O-t-butyldimethylsilyl-d-mannofuranose-oxime 7 afforded a five-membered cyclic nitrone 9, which on N-O bond reductive cleavage followed by deprotection of -OTBS and acetonide functionalities gave 1,4-dideoxy-1,4-imino-l-allitol (DIA) 3. Addition of allylmagnesium chloride to nitrone 9 afforded α-allylated product 10a in high diastereoselectivity providing an easy entry to N-hydroxy-C1-α-allyl-substituted pyrrolidine iminosugar 4a after removal of protecting group, while N-O bond reductive cleavage in 10a afforded C1-α-allyl-pyrrolidine iminosugar 4b.     

Palladium mediated synthesis of isoindolinones and isoquinolinones

The palladium-catalyzed reactions of 2-iodo-N-substituted benzamides 5-10 with acrylic esters 11-14 led to N-substituted-3-alkylisoindolinone esters 15-22 in good yields. The esters of isoindolinones 15-22 underwent hydrolysis reactions yielding the N-aryl-1,2,3,4-tetrahydro-1-oxoisoquinoline-3-carboxylic acid 26-31 in good yields.     

A new method for the synthesis of carba-sugar enones (gabosines) using a mercury(II)-mediated opening of 4,5-cyclopropanated pyranosides as the key-step

The stereoselective transformation of the cyclopropyl derivative 2, stereoselectively obtained with the Simmons-Smith reaction of methyl 2,6-di-O-benzyl-α-l-threo-hex-4-enopyranoside (1), into gabosines and deoxy-carbahexoses is described. The treatment of 2 with mercuric trifluoroacetate in dry methanol gives the organomercuric chloride 3, which by demercuration with lithium aluminum hydride affords the 4-C-deoxy-4-methyl-1,5-bis-glycoside 4. The acid hydrolysis of 4 produces a mixture of the two diastereoisomeric 2-methyl-cyclohex-2-enones 6 and 7, catalytically reduced to carba-sugars 10 and 11. Structures and stereochemistry of all isolated compounds were determined by 1D and 2D NMR experiments.     

Polyhydroxylated pyrrolidines, III. Synthesis of new protected 2,5-dideoxy-2,5-iminohexitols from d-fructose

The readily available 3-O-benzoyl-4-O-benzyl-1,2-O-isopropylidene-β-d-fructopyranose (6) was straightforwardly transformed into 5-azido-3-O-benzoyl-4-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-d-fructopyranose (8), after treatment under modified Garegg's conditions followed by reaction of the resulting 3-O-benzoyl-4-O-benzyl-5-deoxy-5-iodo-1,2-O-isopropylidene-α-l-sorbopyranose (7) with lithium azide in DMF. O-debenzoylation at C(3) in 8, followed by oxidation and reduction caused the inversion of the configuration to afford the corresponding β-d-psicopyranose derivative 11 that was transformed into the related 3,4-di-O-benzyl derivative 12. Cleavage of the acetonide of 12 to give 13 followed by O-tert-butyldiphenylsilylation afforded a resolvable mixture of 14 and 15. Compound 14 was transformed into (2R,3R,4S,5R)- (17) and (2R,3R,4S,5S)-3,4-dibenzyloxy-2′,5′-di-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (18) either by a tandem Staudinger/intramolecular aza-Wittig process and reduction of the resulting intermediate Δ²-pyrroline (16), or only into 18 by a high stereoselective catalytic hydrogenation. When 15 was subjected to the same protocol, (2S,3S,4R,5R)- (21) and (2R,3S,4R,5R)-3,4-dibenzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (22) were obtained, respectively.     

New phenanthrenes from Trigonostemon lii Y.T. Chang

Three new phenanthrenes, thrigonosomone A (1), 6,9-O-dedimethyltrigonostemone (2), and thrigonosomone B (3) were isolated from Trigonostemon lii. Their structures were elucidated by spectroscopic methods. Thrigonosomone A (1) possessed a novel seven-membered cyclic anhydride moiety, and its relative configuration was determined by chemical computation and ROESY experiment. The cytotoxicity of compounds 1-3 was also evaluated.     

Two efficient ways to 2-O- and 5-O-feruloylated 4-nitrophenyl α-l-arabinofuranosides as substrates for differentiation of feruloyl esterases

4-Nitrophenyl 2-O-(E)-feruloyl-α-l-arabinofuranoside 1 and 4-nitrophenyl 5-O-(E)-feruloyl-α-l-arabinofuranoside 2 have been synthesized by two different routes. Monoferuloylation was accomplished by a chemoenzymatic sequence employing a regioselective transesterification catalyzed by lipases. The feruloyl group was introduced to enzymatically prepared 2,3- and 3,5-diacetates of 4-nitrophenyl α-l-arabinofuranoside by reaction with 4-O-acetylferuloyl chloride. Removal of the protecting acetyl groups yielded 1 and 2. An alternative chemical synthesis suitable for preparation of larger quantities of 1 and 2 also is presented. The new substrates represent convenient tools to differentiate feruloyl esterases on the basis of their substrate specificity.