The practical synthesis of a uterine relaxant, bis(2-[[(2S)-2-([(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)-phenyl]ethyl]amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy]-N,N-dimethylacetamide) sulfate (KUR-1246)

The synthetic route for a uterine relaxant, bis(2-[[(2S)-2-([(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)-phenyl]ethyl]amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy]-N,N-dimethylacetamide) sulfate (KUR-1246), was established by the coupling of optically active components, the bromohydrin 14 and the amine 24. We now describe the practical synthesis of these two optically active components. Bromohydrin 14 was obtained by the asymmetric borane reduction of the prochiral phenacyl bromide 13 using a catalyst prepared from aluminum triethoxide and a chiral amino alcohol. The other optically active component 24 was prepared from (S)-AMT.     

Synthesis and dehydration reaction of 1-(4-benzyloxyphenyl)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphth-2-ol: possible intermediate of Lasofoxifene

The paper deals with a simple and sufficient synthesis of key precursor of Lasofoxifene. The 1-(4-benzyloxyphenyl)-6-methoxy-2-phenyl-3,4-dihydronaphthalene was prepared by a sequence of five reactions steps: first 1-(4-benzyloxyphenyl)-6-methoxy-3,4-dihydronaphthalene was prepared (70%), and this was quantitatively epoxidized to 7b-[4-(benzyloxy)phenyl]-5-methoxy-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene. Catalytic (ZnI₂) isomerization of the epoxide gave 1-(4-benzyloxyphenyl)-6-methoxy-1,2,3,4-tetrahydronaphthalen-2-one (75%). Its subsequent reaction with phenylmagnesium bromide gave 1-(4-benzyloxyphenyl)-6-methoxy-2-phenyl-1,2,3,4-tetrahydro-2-naphthol (87%). Acid-catalysed dehydration of this alcohol by polyphosphoric acid (25°C) provides 1-(4-benzyloxyphenyl)-6-methoxy-2-phenyl-1,4-dihydronaphthalene (80%). Dehydration in the system of acetic anhydride/polyphosphoric acid gives 1-(4-benzyloxyphenyl)-6-methoxy-2-phenyl-3,4-dihydronaphthalene (66%).     

The Synthesis of (±)-11-Deoxydaunomycinone via Regioselective Tandem Diels-Alder Reactions

The 2,5-dimethylidene-3,6-bis[(Z)-(2-nitrophenyl)sulfenylmethylidene]-7-oxabicyclo[2.2.1]heptane ( 13 ) can be used to generate polyfunctional and multicyclic molecules with high regio- and stereoselectivity via two successive Diels-Alder additions using two different dienophiles. This principle has been applied to the synthesis of (±)-11-deoxydaunomycinone ( 7 ), the aglycone of an important antitumor drug. The 2,3-didehydroanisole adds to 13 and gives the monoadduct 14 with high regioselectivity. No trace of bis-adduct is observed. The 1,4-epoxy-1,2,3,4-tetrahydro-5-methoxy-3-methylidene-2-[(Z)-(2-nitrophenyl)sulfenylmethylidene]anthracene ( 15 ) obtained on treating 14 with K₂CO₃ adds to methyl vinyl ketone to give [(1RS, 2SR, 5RS,12RS)-5,12-epoxy-1,2,3,4,5,12-hexahydro-7-methoxy-1-(2-nitrophenyl)sulfenyl-2-naphthacenyl]methyl ketone ( 16 ) with high regio- and stereoselectivity. The acid-catalyzed 7-oxanorbornadiene→phenol rearrangement of 16 is regioselective and gives (5-acetoxy-3,4-dihydro-7-methoxy-2-naphthacenyl) methyl ketone ( 20 ) which was transformed into (±)-7,11-dideoxydaunomycinone ((±)- 24 ), a known precursor of 7 .     

Investigations toward the total syntheses of proapoiphine and homoproaporphine alkaloids

The reaction of 1,2,3,5-telrahydro-6-methoxy-1 -[2-(4-methoxy-1,4-eyelohexadien-1 -yl)eth-yl]-l-methyl-7-isoquinolinol ( 12 ) with hot phosphoric acid afforded (±)-tetrahydro-homoglazio-vine ( 14 ) in good yield. Similar treatment of 1,2,3,4-tetrahydro-6-methoxy-l -[2-(4-methoxy-1,4-cyelohexadien-l-yl)methyl]-2-methyl-7-isoquinolinol ( 13 ) did not produce the desired (±)-tetra-hydroglaziovine ( 18 ) but rather a mixture of diastereomeric 4,5,6,6a?,7,7a?,8,9,11, 11a?-deca-hydro-l-hydroxy-2-metlu>xy-6-methyl-10H-dibenzo[(de,g]quinolin-l-ones (16 and 17) was obtained.     

Optical resolution by preferential crystallization of (1RS,3RS)-1,2,3,4-tetrahydro-6,7-dihydroxy-1-methyl-3-isoquinolinecarboxylic acid

The racemic structure of (1RS,3RS)-1,2,3,4-tetrahydro-6,7-dihydroxy-1-methyl-3-isoquinolinecarboxylic acid [(1RS,3RS)-1] was examined based on the melting point, solubility, and IR spectrum, with the aim of optical resolution by preferential crystallization. (1RS,3RS)-1 was indicated from these results to exist as a conglomerate. The successive optical resolution by preferential crystallization of (1RS,3RS)-1 yielded (1S,3S)- and (1R,3R)-1 with optical purities of 85--95% at 66--81% degrees of resolution, which were fully purified by recrystallization.     

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.     

Asymmetric synthesis of [2,3-(13)C(2),(15)N]-4-benzyloxy-5,6-diphenyl-2,3,5,6-tetrahydro-4H-oxazine-2-one via lipase TL-mediated kinetic resolution of benzoin: general procedure for the synthesis of [2,3-(13)C(2),(15)N]-L-alanine.

Lipase TL-mediated kinetic resolution of benzoin proceeded to give the corresponding optically pure (R)-benzoin (R)-1. On the other hand, (S)-benzoin O-acetate (S)-7 could be hydrolyzed without epimerization to give (S)-benzoin (S)-1 under alkaline conditions. Furthermore, both enantiomers of benzoin (1) were converted to [(15)N]-(1R,2S)- and (1S,2R)- 2-amino-1,2-diphenylethanol (3a and 3b), respectively, according to the procedure reported previously. [2,3-(13)C(2),(15)N]-(5S,6R)-4-benzyloxy-5,6-diphenyl-2,3,5,6-tetrahydro-4H-oxazine-2-one (10) was synthesized from ethyl [1,2-(13)C(2)]bromoacetate and (1R,2S)-2-amino-1,2-diphenylethanol (3b) in three steps. Finally, [2,3-(13)C(2),(15)N]-L-alanine (12) was prepared via alkylation of the lactone 10 and hydrogenation of the alkylated product 11.     

R 和 s-1-(3'-溴-4'-甲氧基)苄基-2-甲基-6-甲氧基-7-羟基-1, 2,3,4-四氢异喹啉的合成

本文报道了R和S-1-(3'-溴-4'-甲氧基)苄基-2-甲基-6-甲氧基-7-羟基-1,2,3,4-四氢异喹啉的合成。     

Synthesis and antiulcer activity of 4-substituted 8-[(2-benzimidazolyl)sulfinylmethyl]-1,2,3,4-tetrahydroquinoli nes and related compounds

A series of 4-substituted 8-[(2-benzimidazolyl)sulfinylmethyl]-1,2,3,4-tetrahydroquinolin es was synthesized and examined for their (H+ + K+)adenosine triphosphatase (ATPase)-inhibitory and antisecretory activities against histamine-induced gastric acid secretion in rats. Many compounds tested were potent inhibitors of (H+ + K+)ATPase. Most compounds showed antisecretory activity. The antiulcer activity against water-immersion stress-induced gastric ulcer, aspirin-induced gastric ulcer and gastric necrosis induced by hydrochloric acid also were tested in the rat. Some of these compounds, in particular, 4-(N-allyl-N-methylamino)-1-ethyl-8-[(5-fluoro-6-methoxy-2-benzimidazoly l) sulfinylmethyl]-1-ethyl-1,2,3,4-tetrahydroquinoline (XVIIx) were found to have potent activity. The structure-activity relationships are discussed.     

Optically active antifungal azoles. IX. An alternative synthetic route for 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4- triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]- 3(2H,4H)-1,2,4-triazolone and its analogs

A new route for the synthesis of the optically active antifungal azole TAK-187, 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-tria zol-1- yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4 - triazolone, was established. The key synthetic intermediate, 2-[(1R)-2-(2,4-difluorophenyl)-2-oxo-1-methylethyl]-4-[4-(2,2,3,3- tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (8), was prepared starting from the esters (11a, b) of (S)-lactic acid in a stereocontrolled manner. This optically active propiophenone derivative 8 was converted to the one carbon-elongated (1R,2S)-diol 7, which was then reacted with 1H-1,2,4-triazole to yield TAK-187. This newly developed route was applied to the synthesis of the analogs (25a, b--28a, b) containing an imidazolone or imidazolidinone nucleus.     

A novel synthetic approach to very late antigen-4 antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid via tert-butyl trans-[(4S)-Methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate as a key intermediate

This contribution describes a novel synthetic approach to very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (1) via tert-butyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) as a key intermediate. The synthesis, which includes n-Bu?NSO?H that catalyzed basic etherification of 12 and iodine-mediated cyclization to provide the 2,4-disubstituted pyrrolidine frame of 2b, is designed to utilize trans-4-hydroxycyclohexanecarboxylic acid (9) as a commercially available starting material.     

A concise synthesis of a very late antigen-4 antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid via reductive etherification

This contribution describes a concise synthesis to ethyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) as a key intermediate of very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (1). The synthesis employs a reductive etherification as a key reaction using (2S,4S)-1-benzyloxycarbonyl-4-methoxypyrrolidine-2-carboxyaldehyde (12) and trans-4-triethylsilyloxycyclohexanecarboxilic acid ethyl ester (13b). This synthesis provides 2b in 6 steps with 38% overall yield from commercially available starting material.     

(1R,3S,4S)-2-苄氧羰基-2-氮杂双环[2.2.1]庚烷-3-羧酸的合成

以(R)-(+)-α-甲基苄胺为原料,依次经缩合,Diels-Alder反应,还原,Cbz-保护和水解反应,合成了抗丙肝新药HCV NS3/4A蛋白酶拟肽类抑制剂的重要中间体——(1R,3S,4S)-2-苄氧羰基-2-氮杂双环[2.2.1]庚烷-3-羧酸,总收率66%,其结构经1H NMR和ESI-MS确证。     

Chemistry of acyl(imidoyl)ketenes. 8*. Thermolysis of 3-alkoxycarbonyl- 5-phenyl-1,2,4,5-tetrahydropyrrolo[1,2-a]- quinoxaline-1,2,4-triones. Structure of 2-(3-oxo-4-phenyl-3,4-dihydro-2-quinoxalinyl)- 2,4-di(ethoxycarbonyl)-6-phenyl-2,3,5,6-tetrahydro- 1h-pyrido[1,2-a]quinoxaline-1,3,5-trione

3-Alkoxycarbonylmethylene-1-phenyl-1,2,3,4-tetrahydro-2-quinoxalones, obtained by the interaction of dialkyl esters of oxaloacetic acid and N-phenyl-o-phenylenediamine, react with oxalyl chloride with the formation of 3-alkoxycarbonyl-5-phenyl-1,2,4,5-tetrahydropyrrolo[1,2-a]quinoxaline-1,2,4-triones. Alkoxycarbonyl(2-oxo-1-phenyl-1,2-dihydro-3-quinoxalinyl)ketenes, generated on thermal decarbonylation of the latter, are stabilized by participation in a [4+2] cyclodimerization reaction with the formation of 2,4-di(alkoxycarbonyl)-2-(3-oxo-4-phenyl-3,4-dihydro-2-quinoxalinyl)-6-phenyl-2,3,5,6-tetrahydro-1H-pyrido[1,2-a]quinoxaline-1,3,5-triones. The crystal and molecular structure of the di(ethoxycarbonyl) derivative have been investigated by X-ray structural analysis.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1501–1506, October, 2004.     

The synthesis of 2-benzazocines using ring-closing metathesis as a key step

A number of protected 7-isopropoxy-8-methoxy-1,2,3,6-tetrahydro-2-benzazocines were synthesized from 2-allyl-3-isopropoxy-4-methoxybenzaldehyde using ring-closing metathesis as the key step. In addition, two 9-isopropoxy-8-methoxy-3,6-dihydro-2-benzazocines were synthesized from 5-isopropoxy-4-methoxy-2-[(1E)-3-phenyl-2-propenyl]benzaldehyde, which in turn was obtained from the thermal Claisen-Cope rearrangement of 4-methoxy-3-{[(2E)-3-phenyl-2-propenyl]oxy}benzaldehyde. Finally, five of the 2-benzazocine compounds were tested for anti-cancer activity.     

Optically active cyclohexene derivative as a new antisepsis agent: an efficient synthesis of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242)

Two new synthetic methods were established for the efficient synthesis of optically active cyclohexene antisepsis agent, ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate [(R)-1: TAK-242)]. The first method involved recrystallization from methanol of the diastereomeric mixture (6RS,1'R)-7, obtained by esterification of carboxylic acid 3 with (S)-1-(4-nitrophenyl)ethanol [(S)-5)] to give the desired isomer (6R,1'R)-7 with 99% de in 32% yield. Subsequent catalytic hydrogenolysis and esterification gave (R)-1 with >99% ee. The second method employed enantioselective hydrolysis of acetoxymethyl ester 9a (prepared by alkylation of 3 with bromomethyl acetate) with Lipase PS-D to give the eutomeric enantiomer (R)-9a with excellent enantioselectivity (>99% ee) and high yield (48%). The desired (R)-1 was then obtained by transesterification with ethanol in the presence of concentrated sulfuric acid without loss of ee. Of these, the procedure employing enzymatic kinetic resolution using Lipase PS-D is the more efficient and practical preparation of (R)-1.     

Synthesis of a C(29)-C(51) subunit of spongistatin 1 (Altohyrtin A) starting from (R)-3-benzyloxy-2-methylpropan-1-ol

A protected C(29)-C(51) subunit ((+)-38) of spongistatin 1 has been obtained. Key steps involve the aldol condensation of (3S, 4R)-3-methyl-7-[(p-methoxybenzyl)oxy]-4-[(triethylsilyl)oxy]octan- 2-o ne ((-)-6) with (tert-butyl)dimethylsilyl 4-deoxy-2, 3-di-O-(methoxymethyl)-4-methyl-6-O-(tert-butyl)dimethylsilyl)-bet a-D -glycero-L-gluco-heptodialdo-1,5-pyranoside ((+)-7) and a C-glycosidation of (4R,7R&S,E)-7, 8-dichloro-2-methylidene-1-(trimethylsilyl)oct-5-en-4-yl p-methoxybenzoate (16). Aldehyde (+)-7 was derived from (R)-3-benzyloxy-2-methylpropan-1-ol ((+)-10) in 13 formal steps but requiring the isolation of five intermediate products only. The longest linear synthetic scheme converts (+)-10 into (+)-38 in 2% overall yield (isolation of 11 intermediate products).     

Asymmetric Synthesis and DNA Intercalation of (-)-6-[[(Aminoalkyl)oxy]methyl]-4-demethoxy-6,7- dideoxydaunomycinones(1)(,)

The BF(3).Et(2)O-promoted Diels-Alder addition of 1-acetylvinyl RADO(Et)-ate (RADO(Et)-ate = 3-ethyl-2-oxo-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-exo-carboxylate) to 1-(dimethoxymethyl)-2,3,5,6-tetramethylidene-7-oxabicyclo[2.2.1]heptane led to one major monoadduct that added to 1,2-didehydrobenzene and was converted into (-)-4-demethoxy-7-deoxydaunomycinone and (2R)-12-acetoxy-2-acetyl-5-(bromomethyl)-1,2,3,4-tetrahydronaphthacen-2-yl RADO(Et)-ate. The latter compound was used to construct (8R)-8-acetyl-6,8-dihydroxy-11-[[(3'-[(aminopropyl)oxy]-, -4'-[(aminobutyl)oxy], and -5'-[(aminopentyl)oxy]methyl]-7,8,9,10-tetrahydronaphthacene-5,12-dione hydrochloride (-)-8, (-)-9, (-)-10, respectively, as well as (8R)-8-acetyl-6,8-dihydroxy-11- [[[2'-[(3"-aminopropyl)amino]ethyl]oxy]- ((-)-11) and -[[3'-[(3"-aminopropyl)amino]propyl]oxy]methyl]-7,8,9, 10-tetrahydronaphthacene-5,12-dione hydrochloride ((-)-12). (8R)-8-Acetyl-6,8-dihydroxy-11-[[(alpha-L-daunosaminyl)oxy]methyl]-7,8,9,10-tetrahydronaphthacene-5,12-dione hydrochloride ((-)-13), a mimic of idarubicin, was also prepared. Absorbance and fluorescence titration experiments showed (-)-8, (-)-9, and (-)-10 to intercalate calf thymus DNA whereas (-)-11, (-)-12, and (-)-13 did not. The best intercalator was (-)-9 (K(b) = (1.1 +/- 0.1) x 10(5) M(-)(1)) with the [(4'-aminobutyl)oxy]methyl chain. Inhibition of topoisomerase II-induced DNA strand religation was observed for (-)-8 at a concentration of 50 &mgr;M.     

Molecular and crystal structures of (6R, 7R, 14S)-6,14-etheno-7-[(1R)-1-hydroxyethyl]- and (6R, 7R, 14S)-6,14-etheno-7-[(1S)-1-hydroxyethyl]-6,7,8,14-tetrahydro-17-nor-17-phenylthebaine

The crystal structures and absolute configurations of (6R,7R,14S)-6,14-etheno-7-[(1R)-1-hydroxyethyl]-6,7,8,14-tetrahydro-17-nor-17-phenylthebaine and (6R,7R,14S)-6,14-etheno-7-[(1S)-1-hydroxyethyl]-6,7,8,14-tetrahydro-17-nor-17-phenylthebaine were established by X-ray diffraction analysis. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2245–2250, November, 1998.     

Optically active antifungal azoles. XIII. Synthesis of stereoisomers and metabolites of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (TAK-456)

1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone [(1R,2R)-1: TAK-456] is a new antifungal agent selected as a candidate for clinical trials. The three stereoisomers [(1S,2R)-, (1S,2S)- and (1R,2S)-1] of this compound were prepared as authentic samples to determine the enantiomeric and diastereomeric purity of TAK-456 as well as to compare their in vitro antifungal activity. Pharmacokinetic studies of TAK-456 using rats identified the existence of metabolites in the liver homogenate. The structures of the major metabolites were assigned as 4-hydroxy-2-imidazolidinone (3) and/or 5-hydroxy-2-imidazolidinone (4), based on HPLC and LC/MS/MS analyses. These hydroxylated compounds, 3 and 4, were prepared by reduction of the corresponding imidazolidinediones, 11 and 12, and confirmed to be identical to the metabolites by HPLC. In vitro antifungal activities of the three stereoisomers and the synthesized metabolites were considerably weaker than TAK-456.