Diastereoselective hydroxylation of 6-substituted piperidin-2-ones. An efficient synthesis of (2S,5R)-5-hydroxylysine and related alpha-amino acids

The synthesis of (2S,5R)-5-hydroxy-6-oxo-1,2-piperidinedicarboxylates (5) and related (3S,6R)-3-hydroxy-6-alkyl-2-oxo-1-piperidinecarboxylates has been developed. The approach is based on the asymmetric hydroxylation of enolates generated from the corresponding N-protected-6-substituted piperidin-2-ones. The utility of 5a as a precursor in the synthesis of (2S,5R)-5-hydroxylysine (1), an amino acid unique to collagen and collagen-like proteins, has also been demonstrated. (2S)-6-oxo-1,2-piperidinedicarboxylates (6) required for hydroxylation studies were prepared in 38-74% yield, starting from conveniently protected aspartic acid as inexpensive chiral adduct. Hydroxylation of 6 to 5 proceeds in high yield and excellent diastereoselectivity by treatment of their Li-enolate with (+)-camphorsulfonyloxaziridine at -78 degrees C. Ring opening of di-tert-butyl (2S,5R)-6-oxo-1,2-piperidinedicarboxylate ((5R)-5a) under reductive conditions afforded the corresponding 1,2-diol (17) in 91%, which was further transformed to (2S,5R)-5-hydroxylysine in four steps (84%). 17 is also a versatile intermediate in the preparation of tert-butyl (2S,5R)-2-[(tert-butoxycarbonyl)amino]-5-hydroxy-6-iodohexanoate (3) and tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-[(2R)-oxiranyl]butanoate (4), two amino acid derivatives used in the total synthesis of the bone collagen cross-link (+)-pyridinoline (2a).     

Five new nortropane alkaloids and six new amino acids from the fruit of Morus alba LINNE growing in Turkey

Investigation of the constituents of the fruits of Morus alba LINNE (Moraceae) afforded five new nortropane alkaloids (1-5) along with nor-psi-tropine (6) and six new amino acids, morusimic acids A-F (7-12). The structures of the new compounds were determined to be 2alpha,3beta-dihydroxynortropane (1), 2beta,3beta-dihydroxynortropane (2), 2alpha,3beta,6exo-trihydroxynortropane (3), 2alpha,3beta,4alpha-rihydroxynortropane (4), 3beta,6exo-dihydroxynortropane (5), (3R)-3-hydroxy-12-[(1S,4S)-4-[(1S)-1-hydroxyethyl]-pyrrolidin-1-yll-dodecanoic acid-3-O-beta-D-glucopyranoside (7), (3R)-3-hydroxy-12-[(1S,4S)-4-[(1S)-1-hydroxyethyl]-pyrrolidin-1-yll-dodecanoic acid (8), (3R)-3-hydroxy-12-1(1R,4R,5S)-4-hydroxy-5-methyl-piperidin-1-yll-dodecanoic acid-3-O-beta-D-glucopyranoside (9), (3R)-3-hydroxy-12-[(1R,4R,5S)-4-hydroxy-5-methyl-piperidin-1-yll-dodecanoic acid (10), (3R)-3-hydroxy-12-[(1R,4R,5S)-4-hydroxy-5-hydroxymethyl-piperidin-1-yl]-dodecanoic acid-3-O-beta-D-glucopyranoside (11), and (3R)-3-hydroxy-12-[(1R,4S,5S)-4-hydroxy-5-methyl-piperidin-1-yl]-dodecanoic acid (12) on the basis of spectral and chemical data.     

Synthesis of pyrido[1,2-a]pyrimido[4,5-d]pyrimidin-5-ones. Cyclization reaction of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid with acetic anhydride

Treatment of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid (X) with acetic anhydride under refluxing conditions afforded 10-hydroxy-2-phenyl-5H-pyrido[1,2-a]-pyrimido[4,5-d]pyrimidin-5-one acetate (IX). The intermediate X was prepared from 4-chloro-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (V). The reaction of V with the sodium salt of 2-amino-3-hydroxypyridine at room temperature gave 4-(2-amino-3-pyridyloxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (VI). Treatment of VI with a hot aqueous sodium hydroxide solution and subsequent acidification gave X. Involvement of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecaroboxylic acid ethyl ester (VIII) (Smiles rearrangement product) as an intermediate in the above alkaline hydrolysis reaction of VI to X was demonstrated by the isolation of VIII and its subsequent conversion into X under alkaline hydrolysis conditions. Acetylation of VIII with acetic anhydride in pyridine solution gave 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester acetate (XI), which afforded IX on fusion at 220°. This alternative synthesis of IX from XI supported the structural assignment of IX. Fusion of VI gave 10-hydroxy-2-phenyl-5H-pyrido[1,2-a]pyrimido]4,5-d]pyrimidin-5-one (VII). The latter was also obtained when VIII was fused at 210°. Acetylation of VII with acetic anhydride afforded IX.     

Synthesis and antimicrobial activity of some derivatives of (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide

(7-Hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide (2) was prepared from (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid ethyl ester (1) and 100% hydrazine hydrate. Compound 2, is the key intermediate for the synthesis of several series of new compounds such as Schiff's bases 3a-l, formic acid N'-[2-(7-hydroxy-2-oxo-2H- chromen-4-yl)acetyl] hydrazide (4), acetic acid N'-[2-(7-hydroxy-2-oxo-2H-chromen-4- yl)-acetyl] hydrazide (5), (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid N'-[2-(4- hydroxy-2-oxo-2H-chromen-3-yl)-2-oxoethyl] hydrazide (6), 4-phenyl-1-(7-hydroxy-2- oxo-2H-chromen- 4-acetyl) thiosemicarbazide (7), ethyl 3-{2-[2-(7-hydroxy-2-oxo-2H- chromen-4-yl)-acetyl]hydrazono}butanoate (8), (7-hydroxy-2-oxo-2H-chromen-4-yl)- acetic acid N'-[(4-trifluoromethylphenylimino)methyl] hydrazide (9) and (7-hydroxy-2- oxo-2H-chromen-4-yl)acetic acid N'-[(2,3,4-trifluorophenylimino)-methyl] hydrazide (10). Cyclo- condensation of compound 2 with pentane-2,4-dione gave 4-[2-(3,5- dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-7-hydroxy-2H-chromen-2-one (11), while with carbon disulfide it afforded 7-hydroxy-4-[(5-mercapto-1,3,4-oxadiazol-2-yl)methyl]-2H- chromen-2-one (12) and with potassium isothiocyanate it gave 7-hydroxy-4-[(5- mercapto-4H-1,2,4-triazol-3-yl)methyl]-2H-chromen-2-one (14). Compound 7 was cyclized to afford 2-(7-hydroxy-2-oxo-2H-chromen-4-yl)-N -(4-oxo-2-phenylimino- thiazolidin-3-yl) acetamide (15).     

Phenolic glycosides from Pyrola japonica

Five new phenolic glycosides, 2-beta-D-glucopyranosyloxy-5-hydroxyphenylacetic acid methyl ester (4), 4-hydroxy-2-[3-hydroxy-3-methylbutyl]-5-methylphenyl beta-D-glucopyranoside (5), 4-hydroxy-2-[(E)-4-hydroxy-3-methyl-2-butenyl]-5-methylphenyl beta-D-glucopyranoside (7), 4-hydroxy-2-[(2E,6Z)-8-beta-D-glucopyranosyloxy-3,7-dimethylocta-2,6-dien-1-yl]-5-methylphenyl beta-D-glucopyranoside (8), and 2,7-dimethyl-1,4-dihydronaphthalene-5,8-diol 5-O-beta-D-xylopyranosyl(1-->6)-beta-D-glucopyranoside (10), were isolated from the whole plants of Pyrola japonica (Pyrolaceae), together with androsin, (-)-syringaresinol glucoside, homoarbutin, pirolatin, hyperin, monotropein and chimaphilin.     

Chiral Cyclopentane-Based Mimics of D-myo-Inositol 1,4,5-Trisphosphate from D-Glucose

Two routes from D-glucose to chiral, ring-contracted analogs of the second messenger D-myo-inositol 1,4,5-trisphosphate are described. Methyl alpha-D-glucopyranoside was converted by an improved procedure into methyl 4,6-O-(p-methoxybenzylidene)-alpha-D-glucopyranoside (6) and thence into methyl 2-O-benzyl-3,4-bis-O-(p-methoxybenzyl)-alpha-D-gluco-hexodialdopyranoside (1,5) (14) in four steps. In the first ring-contraction method 14 was converted into methyl 2-O-benzyl-6,7-dideoxy-3,4-bis-O-(p-methoxybenzyl)-alpha-D-gluco-hept-6-enopyranoside (1,5) (15), which on sequential treatment with Cp(2)Zr(n-Bu)(2) followed by BF(3).Et(2)O afforded a mixture of (1R,2S,3S,4R,5S)-3-(benzyloxy)-4-hydroxy-1,2-bis[(p-methoxybenzyl)oxy]-5-vinylcyclopentane (16) and its 4S,5R diastereoisomer 17. Removal of the p-methoxybenzyl groups of 16 and subsequent phosphorylation and deprotection afforded the first target compound, (1R,2R,3S,4R,5S)-3-hydroxy-1,2,4-tris(phosphonooxy)-5-vinylcyclopentane (3). In the second route, intermediate 14 was subjected to SmI(2)-mediated ring contraction to give (1R,2S,3S,4R,5S)-3-(benzyloxy)-4-hydroxy-5-(hydroxymethyl)-1,2-bis[(p-methoxybenzyl)oxy]cyclopentane (20). Benzylation of 20 provided (1R,2S,3S,4R,5S)-3-(benzyloxy)-6-[(benzyloxy)methyl]-4-hydroxy-1,2-bis[(p-methoxybenzyl)oxy]cyclopentane (22) and (1R,2S,3S,4R,5S)-3,4-bis(benzyloxy)-5-(hydroxymethyl)-1,2-bis[(p-methoxybenzyl)oxy]cyclopentane (21), which were elaborated to the target trisphosphates (1R,2R,3S,4R,5S)-3-hydroxy-5-(hydroxymethyl)-1,2,4-tris(phosphonooxy)cyclopentane (4) and (1R,2S,3R,4R,5S)-1,2-dihydroxy-3,4-bis(phosphonooxy)-5-[(phosphonooxy)methyl]cyclopentane (5), respectively. Both 3 and 4 mobilized intracellular Ca(2+), but 4 was only a few fold less potent than D-myo-inositol 1,4,5-trisphosphate, demonstrating that effective mimics can be designed that do not bear a six-membered ring.     

Synthesis and chemistry of some pyridazine nucleosides related to certain 5-substituted pyrimidine nucleosides

Condensation of 3,4-dichloro-6-[(trimethylsilyl)oxy] pyridazine ( 3 ) with 1-O-acetyl-2,3,5-tri-O-benzoyl-β- D -ribofuranose ( 4 ), by the stannic chloride catalyzed procedure, has furnished 3,4-dichloro-1-(2,3,5-tri-O-benzoyl-β- D -ribofuranosyl) pyridazin-6-one ( 5 ). Nucleophilic displacement of the chloro groups and removal of the benzoyl blocking groups from 5 has furnished 3-chloro-4-methoxy-, 3,4-dimethoxy-, 4-amino-3-chloro-, 3-chloro-4-methylamino-, 3-chloro-4-hydroxy-, and 4-hydroxy-3-methoxy-1-β- D -ribofuranosylpyridazin-6-one. An unusual reaction of 5 with dimethylamine is reported. Condensation of 4,5-dichloro-3-nitro-6-[(trimethylsilyl)oxy]pyridazine with 4 yielded 4,5-dichloro-3-nitro-1-(2,3,5-tri-O-benzoyl-β- D -ribofuranosyl)pyridazin-6-one ( 24 ). Nucleophilic displacement of the aromatic nitro groups from 24 is discussed. Condensation of 3 with 3,5-di-O-p-toluoyl 2-deoxy- D -erythro-pentofuranosyl chloride ( 28 ) afforded an α, β mixture of 2-deoxy nucleosides. The synthesis of certain 3-substituted pyridazine 2′-deoxy necleosides are reported.     

Antiangiogenic polyketides from Peperomia dindygulensis Miq

Two new polyketides: 2Z-(heptadec-12-enyl)-4-hydroxy-3,4,7,8-tetrahydro-2H-chromen-5(6H)-one (1) and 2-(heptadec-12-enyl)-5-hydroxy-5,6,7,8-tetrahydrochromen- 4-one (2), together with eleven known compounds: 4-hydroxy-2-[(3,4-methylenedioxy- phenyl)tridecanoyl] cyclohexane-1,3-dione (3), oleiferinone (4), 4-hydroxy-2-[(3,4- methylenedioxyphenyl)undecanoyl]cyclohexane-1,3-dione (5), 4-hydroxy-2-[(11-phenyl- undecanoyl)cyclohexane-1,3-dione (6), proctorione C (7), surinone C (8), 5-hydroxy- 7,8,4'-trimethoxyflavone (9), 5-hydroxy-7,8,3',4'-tetramethoxyflavone (10), 5-hydroxy- 7,3',4'-trimethoxyflavone (11), 5,8-dihydroxy-7,3',4'-trimethoxyflavone (12) and cepharanone B (13) were isolated from the whole plant of Peperomia dindygulensis Miq. Their structures were elucidated by spectroscopic methods, including 2D-NMR techniques. Compounds 2, 3, 5 and 8 inhibited human umbilical vein endothelial cell (HUVEC) proliferation and compounds 5 and 8 sharply suppressed HUVEC tube formation.     

Rhenium tricarbonyl core complexes of thymidine and uridine derivatives

Thymidine and uridine were modified at the C2' and C5' ribose positions to form amine analogues of the nucleosides (1 and 4). Direct amination with NaBH(OAc)3 in DCE with the appropriate aldehydes yielded 1-{5-[(bis(pyridin-2-ylmethyl)amino)methyl]-4-hydroxytetrahydrofuran-2-yl}-5-methyl-1H-pyrimidine-2,4-dione (L1), 1-{5-[(bis(quinolin-2-ylmethyl)amino)methyl]-4-hydroxytetrahydrofuran-2-yl}-5-methyl-1H-pyrimidine-2,4-dione (L2), and 1-[3-(bis(pyridin-2-ylmethyl)amino)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-1H-pyrimidine-2,4-dione (L5), while standard coupling procedures of 1 and 4 with 5-(bis(pyridin-2-ylmethyl)amino)pentanoic acid (2) and 5-(bis(quinolin-2-ylmethyl)amino)pentanoic acid (3) in the presence of HOBT-EDCI in DMF provided a second novel series of bifunctional chelators: 5-(bis(pyridin-2-ylmethyl)amino)pentanoic acid [(3-hydroxy-5-(5-methyl-4-oxo-3,4-dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-yl)methyl] amide (L3), 5-(bis(quinolin-2-ylmethyl)amino)pentanoic acid [(3-hydroxy-5-(5-methyl-4-oxo-3,4-dihydro-2H-pyrimidin-1-yl)tetrahydrofuran-2-yl)methyl] amide (L4), 5-(bis(pyridin-2-ylmethyl)amino)pentanoic acid [2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-3-yl] amide (L6), and 5-(bis(quinolin-2-ylmethyl)amino)pentanoic acid [2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-3-yl] amide (L7). The rhenium tricarbonyl complexes of L1-L4, L6, and L7, [Re(CO)3(LX)]Br (X=1-4, 6, 7: compounds 5-10, respectively), have been prepared by reacting the appropriate ligand with [NEt4][Re(CO)3Br3] in methanol. The ligands and their rhenium complexes were obtained in good yields and characterized by common spectroscopic techniques including 1D and 2D NMR, HRMS, IR, cyclic voltammetry, UV, and luminescence spectroscopy and X-ray crystallography. The crystal structure of complex 6.0.5NaPF6 displays a facial geometry of the carbonyl ligands. The nitrogen donors of the tridentate ligand complete the distorted octahedral spheres of the complex. Crystal data: monoclinic, C2, a = 24.618(3) A, b = 11.4787(11) A, c = 15.5902(15) A, beta = 112.422(4) degrees , Z = 4, D(calc) = 1.562 g/cm3.     

Efficient synthesis of trans- or cis-4(5)-(5-aminomethyltetrahydrofuran-2-yl)imidazoles via diazafulvene intermediates: synthetic approach toward human histamine H4)-ligands

(+)-4(5)-[(2R,5R)-5-aminomethyltetrahydrofuran-2-yl]imidazole [(+)-1, imifuramine] and its 2R,5S-stereoisomer (+)-2 were expected as base compounds to develop selective human histamine H4-receptor ligands. The improved synthesis of (+)-1 was done via cyclization of a diazafulvene intermediate generated by Bu3P/N,N,N',N'-tetramethylazodicarboxamide (TMAD) treatment of a diol 17ab bearing an unsubstituted imidazole moiety in good yields. This methodology also afforded an alternative synthetic route to trans- and cis-ethyl 4(5)-(5-hydroxymethyltetrahydrofuran-2-yl)imidazole carboxylates (5 and 6), reported previously. Also, 4(5)-[(2R,5S)-5-aminomethyltetrahydrofuran-2-yl]imidazole (+)-2 was synthesized from ethyl 4(5)-(2-deoxy-beta-D-ribofuranosyl)imidazole-1-carboxylate (35) via the four steps involving deoxygenation.     

Studies on the constituents of Broussonetia species VIII. Four new pyrrolidine alkaloids, broussonetines R, S, T, and V and a new pyrroline alkaloid, broussonetine U, from Broussonetia kazinoki Sieb

Four new pyrrolidine alkaloids, broussonetines R, S, T, and V and a new pyrroline alkaloid, broussonetine U were isolated from the branches of Broussonetia kazinoki SIEB. (Moraceae) in low yield. Broussonetines R, S and T were formulated as (2R,3R,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(1R)-1-hydroxy-3-[6-(4-hydroxybutyl)-cyclohexy-2-on-1(6)-enyllpropyl] pyrrolidine (1), (2R,3R,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(1R,10S)-1,10,13-trihydroxytridecyl] pyrrolidine (2), (2R,3R,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(1R,5S)-1,5, 13-trihydroxy-10-oxo-tridecyl] pyrrolidine (3). And broussonetines U and V were proposed to be (2S,3S,4S)-2-hydroxymethyl-3, 4-dihydroxy-5-(9-oxo-13-hydroxytridecyl)-5-pyrroline (4), (2R,3S,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(E)-9-oxo-13-hydroxy-3-tridecenyl] pyrrolidine (5), respectively, by spectroscopic and chemical methods.     

Regioselective Synthesis of 5- and 3-Hydroxy-N-Aryl-1H-Pyrazole-4-Carboxylates and Their Evaluation as Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase

In silico evaluation of various regioisomeric 5- and 3-hydroxy-substituted alkyl 1-aryl-1H-pyrazole-4-carboxylates and their acyclic precursors yielded promising results with respect to their binding in the active site of dihydroorotate dehydrogenase of Plasmodium falciparum (PfDHODH). Consequently, four ethyl 1-aryl-5-hydroxy-1H-pyrazole-4-carboxylates and their 3-hydroxy regioisomers were prepared by two-step syntheses via enaminone-type reagents or key intermediates. The synthesis of 5-hydroxy-1H-pyrazoles was carried out using the literature protocol comprising acid-catalyzed transamination of diethyl [(dimethylamino)methylene]malonate with arylhydrazines followed by base-catalyzed cyclization of the intermediate hydrazones. For the synthesis of isomeric methyl 1-aryl-3-hydroxy-1H-pyrazole-4-carboxylates, a novel two-step synthesis was developed. It comprises acylation of hydrazines with methyl malonyl chloride followed by cyclization of the hydrazines with tert-butoxy-bis(dimethylamino)methane. Testing the pyrazole derivatives for the inhibition of PfDHODH showed that 1-(naphthalene-2-yl)-5-hydroxy-1H-pyrazole-4-carboxylate and 1-(naphthalene-2-yl)-, 1-(2,4,6-trichlorophenyl)-, and 1-[4-(trifluoromethyl)phenyl]-3-hydroxy-1H-pyrazole-4-carboxylates (~30% inhibition) were slightly more potent than a known inhibitor, diethyl α-{[(1H-indazol-5-yl)amino]methylidene}malonate (19% inhibition).     

Synthesis and in vitro-Anti-hepatitis B Virus Activities of Several Ethyl 5-Hydroxy-1H-indole-3-carboxylates

IntroductionHepatitis B caused by a virus(HBV)is a commoninfectious disease in the world.According to WHO,700million people have been infected with HBVin theworld[1,2].HBV infection causes severe liver diseasesuch as cirrhosis and may also eventually lead…     

Microbial metabolism. Part 7 : Curcumin

Microbial metabolism of the cancer chemopreventive agent, curcumin [(1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione] (1) with Pichia anomala (ATCC 20170) yielded four major metabolites, 5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)heptan-3-one (2), 5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-(4-hydroxyphenyl)heptan-3-one (3), 1,7-bis(4-hydroxy-3-methoxyphenyl)heptan-3,5-diol (4), 5-hydroxy-1,7-bis(4-hydroxyphenyl)heptane-3-one (5) and two minor products, 1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)heptane-3,5-diol (6) and 1,7-bis(4-hydroxyphenyl)heptane-3,5-diol (7). The structures of compounds 2-5 were established on the basis of spectroscopic data. Compounds 6 and 7 were assigned tentative structures.     

New stilbenoids from Pholidota yunnanensis and their inhibitory effects on nitric oxide production

Six new stilbenoids, a (bibenzyldihydrophenanthrene) ether designated phoyunnanin D (1), a bis(dihydrophenanthrene) ether designated phoyunnanin E (2), and four stilbenes designated phoyunbene A-D (3-6), were isolated from the air-dried whole plant of Pholidota yunnanensis ROLFE. The new compounds were identified as 7-[2-(3-hydroxyphenethyl)-4-hydroxy-6-methoxyphenoxy]-4-hydroxy-2-methoxy-9,10-dihydrophenanthrene (1), 1-[(9,10-dihydro-4-hydroxy-2-methoxy-7-phenanthrenyl)oxy]-4,7-dihydroxy-2-methoxy-9,10-dihydrophenanthrene (2), trans-3,3'-dihydroxy-2',4',5-trimethoxystilbene (3), trans-3,4'-dihydroxy-2',3',5-trimethoxystilbene (4), trans-3,3'-dihydroxy-2',5-dimethoxystilbene (5), and trans-3-hydroxy-2',3',5-trimethoxystilbene (6) based on spectroscopic evidence. Furthermore, the inhibitory effects of compounds 1-6 on nitric oxide production in a murine macrophage-like cell line (RAW 264.7) activated by lipopolysaccharide and interferon-gamma were examined.     

Reaction of 5-hydroxy-L-tryptophan with alkyl isocyanates

5-Hydroxy-L-tryptophan 4 with potassium cyanate gives 5-(5-hydroxy-3-indolylmethyl)hydantoin 5 or N_b-carbamoyl-5-hydroxy-L-tryptophan 6 depending on the reaction conditions. Reaction of 4 with methyl iso-cyanate in acetone provides 5-hydroxy-N_b-methylcarbamoyl-L-tryptophan 7 . Treatment of 4 with ethyl, propyl and isopropyl isocyanates in acetone gives rise to the formation of the corresponding 2-[(3-alkyl-4,4-dimethyl-2-oxo)-1,3-diazetidinyl]-3-(5-hydroxy-3-indolyl)propionic acids 8–10 .     

Design, synthesis, and 1,3-dipolar cycloaddition of (5R)- [and (5S)]-5,6-dihydro-5-phenyl-2H-1,4-oxazin-2-one N-oxides as chiral (E)-geometry-fixed alpha-alkoxycarbonylnitrones

Optically pure (5R)- [and (5S)]-5,6-dihydro-5-phenyl-2H-1, 4-oxazin-2-one N-oxides [(5R)- and (5S)-2] were designed as chiral (E)-geometry-fixed alpha-alkoxycarbonylnitrones 1. The nitrones (5R)- and (5S)-2 were synthesized by three-step oxidation of (R)- and (S)-phenylglycinols [(R)- and (S)-3], condensation of the resulting (R)- and (S)-2-hydroxylamino-2-phenylethanols [(R)- and (S)-5] with glyoxylic acid, and cyclization of the intermediary nitrones (R)- and (S)-6b. The nitrone (5R)-2reacted with olefins 7-14 under mild conditions to afford the corresponding cycloadducts 15-22 as the main products via the least sterically demanding exo modes. Cycloadduct 30 obtained from (5S)-2 and cyclopentadiene was effectively elaborated to (1S,4S, 5R)-4-benzyloxycarbonylamino-2-oxabicyclo[3.3.0]oct-7-en-3-one (28), the key synthetic intermediate of carbocyclic polyoxin C.     

Synthesis and total 1H- and 13C-NMR assignment of cephem derivatives for use in ADEPT approaches

We report the synthesis and total NMR characterization of 5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid-3-[[[(4'-nitrophenoxy)carbonyl]oxy]-methyl]-8-oxo-7-[(2-thienyloxoacetyl)amino]-diphenylmethyl ester-5-dioxide (5), a new cephalosporin derivative. This compound can be used as the carrier of a wide range of drugs containing an amino group. The preparation of the intermediate product, 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-3-[methyl 4-(6-methoxyquinolin-8-ylamino)pentylcarbamate]-8-oxo-7-[(2-thienyloxoacetyl)amino]-diphenylmethyl ester-5-dioxide (6), as well as the synthesis of the antimalarial primaquine prodrug 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-3-[methyl 4-(6-methoxyquinolin-8-ylamino)pentylcarbamate]-8-oxo-7-[(2-thienyloxoacetyl)amino]- 5-dioxide (7) are also described, together with their total (1)H- and (13)C-NMR assignments.     

A new, non-iterative asymmetric synthesis of long-chain 1,3-polyols

A new approach to the asymmetric synthesis of pentadeca-1,3,5,7,9,11,13,15-octols and their derivatives is presented. It is based on the Sharpless asymmetric dihydroxylation (AD) of 4,4'-methylene[(1R,1'S,6R,6'S)-6-acetoxycyclohept-3-en-1-yl]bis(4-methoxybenzoate) (9), derived from a double [3+4] cycloaddition of the 1,1,3-trichloro-2-oxyallyl cation with 2,2'-methylenedifuran (1). The diol (-)-10, obtained in 98.4% ee from 9 with "AD-mix-beta(5x), was oxidised into (2R and 2S,4S,6R)-tetrahydro-2-hydroxy-6-((4S,6S)-(6-hydroxy-4-[(4-methoxybenzoyl)oxy]cyclohept-1-en-1-yl)-2-oxopropyl)-2H-pyran-4-yl 4-methoxybenzoates ((-)-18). By the combinations of Evans' anti and Nasaraka's syn reductions of aldol (-)-18 with the double Mitsunobu reaction, 16 diastereomeric pentadeca-1,3,5,7,9,11,13,15-octols and analogues can be obtained, in principle, with high enantio- and diastereoselectivities.     

Reaction of ethyl γ-bromo-β-methoxycrotonate with carbonyl compounds. Synthesis of 4-methoxy-6-substituted-5,6-dihydro-2H-pyran-2-ones and 3-substituted 3-pyrazolin-5-ones

Ethyl β-methoxycrotonate I reacts with substituted carbonyl compounds II in benzene to give 4-methoxy-6-substituted-5,6-dihydro-2H-pyran-2-ones III. The reaction of IIIa and j with hydrazine hydrate in ethanol leads to 3-[(1′-thienyl-1-hydroxy)methyl]-5-hydroxy-1H-pyrazole (IVa) and 3-[1′-styryl-1′-hydroxy)methyl]-5-hydroxy-1H-pyrazole (IVj) in good yields. The structure of the products were assigned and confirmed on the basis of their elemental analysis and the electronic absorption, infrared and nmr spectra.