Steroid Total Synthesis,Part II; (−)-17β-Hydroxy-des-A-androst-9-en-5-one

Based on the results obtained in the racemic series (part I), (—)-17β-hydroxy-des-A-androst-9-en-5-one has been synthesized, starting with (S)-(—)-5-heptanolide. The key step, viz. the condensation of (S)-(—)-7-hydroxy-1-nonen-3-one (or its amine adduct) with 2-methyl-cyclopentane-1, 3-dione involves an asymmetric induction. Model experiments with (R)-(+)-5-decanolide leading to the enantiomeric homolog of the BCD-tricyclic compound are also described.     

(2S,4S,SFc)-2-[2-(Diphenyl­thio­phosphinoyl)­ferrocenyl]-4-methoxy­methyl-1,3-dioxane

The title compound, [Fe(C₅H₅)(C₂₃H₂₄O₃PS)], is a very useful inter­mediate for the synthesis of enanti­omerically pure (S)-2-[(diphenyl­thio­phosphinoyl)ferrocenyl]methanol or (S)-2-(diphenyl­thio­phosphinoyl)ferrocene­carboxaldehyde. The dioxane ring has a chair conformation and is twisted with respect to the cyclo­penta­dienyl ring to which it is attached. There is an inter­molecular C—H⋯O hydrogen-bonding inter­action which links the mol­ecules into C(8) chains developing parallel to the a axis. Owing to this weak inter­action, the two cyclo­penta­dienyl rings are twisted with respect to each other by 16.0 (3)°, and so have a conformation which might be regarded as inter­mediate between eclipsed and staggered. The absolute configuration deduced from the X-ray analysis fully confirms the sterochemistry expected from the chemical pathway.     

Absolute Conformation and Configuration of (2S, 3S)-3-Acetoxy-5-(dimethylaminoethyl)-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one Chloride (Dilthiazem Hydrochloride)

Resolution of racemic cis-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl) propionic acid ( 2 ) via the cinchonidine salt 3 , and brucine salt 4 , isolation of the calcium salts (+)- and (?)- 5 , as well as their cyclization to enantiomeric 1,5-benzothiazepines (+)- and (?)- 1 , are described. X-Ray single-crystal analysis reveals (2S, 3S) absolute configuration of (+)- 1 on the basis of tentative comparison of CD data with those for the 1,4-benzodiazepine derivative (+)- 8 of known absolute configuration.     

Chiroptical Assignment of the Anomeric Configuration of 4-(α,β-D-lyxopyranosyl)- and 4-(α,β-D-lyxofuranosyl)-2-phenyl-2H-1,2,3-Triazole C-Nucleoside Anomeric Pairs: Extension of the CD Triazole Rule

The circular dichroism of the anomeric 4-(α,β-D-lyxopyranosyl)- and 4-(α,β-D-lyxofuranosyl)-2-phenyl-2H-1,2,3-triazole C-nucleoside analogs obtained by acid-catalyzed dehydrative cyclization of 4-(D-galacto-pentitol-1-yl)-2-phenyl-2H-1,2,3-triazole analog was studied. A correlation between the sign of the Cotton effect at the maximal UV absorption and the absolute configuration of the anomeric carbon atom was obtained and used for their anomeric configuration assignment. This correlation supports the CD triazole rule for anomeric assignment and is in accord with the assignment obtained by NMR spectral studies.     

Nucleosides and nucleotides. 2. Synthesis of both anomers of 1-(5'-O-phosphoryl-2'-deoxy-D-ribofuranosyl)-2(1H)-pyridone

The two anomeric 1-(2′-deoxy-D -ribofuranosyl)-2(1H)-pyridones 6 and 7 were synthesized from 2-pyridone and 3,5-di-(O-p-toluoyl)-2-deoxy-D -ribofuranosyl chloride ( 2 ) via the di-O-p-toluoyl derivatives 3 and 4 using the mercuric halide procedure. Phosphorylation of the nucleosides 6 and 7 by bis-(2,2,2-trichloroethyl)-chlorophosphate gave the phosphate esters 8 and 9 together with some 2-(bis-[2,2,2-trichloroethyl]-phosphoryloxy)-pyridine 10 , which proved to be very labile. Structure and configuration of compounds 6 to 9 were established by spectral methods, the configurations being derived from the chemical shifts of the sugar protons and the splitting patterns of the anomeric protons (‘triplet-quartet rule’). The specific rotations of 3 , 4 , 6 , 7 , 8 and 9 show that the three pairs of anomers represent exceptions to Hudson's rule of isorotation. Reductive removal of the trichloroethyl groups in 8 and 9 with zinc proceeds stepwise, yielding the phosphoro-diesters 13 and 14 and the two desired anomeric 5′-nucleotides 15 and 16 . These latter were purified and characterised as the ammonium salts. Enzymatic cleavage by the 5′-nucleotidase of Crotalus adamanteus venom took place only in the ‘natural’ β-series. The ‘unnatural’ α-anomers were resistent to the enzyme. The structure of 10 was established by spectral methods and confirmed by synthesis.     

The synthesis of 2-substituted azino-3-(β-D-ribofuranosyl)-5-carboxymethylenethiazolidin-4- ones

2-(1-Isopropylidene)azino-3-β-D-ribofuranosyl-5- methoxycarbonylmethylenethiazolidin-4-one (IV) and 2-(1-methylbenzilidene)azino-3-β-D-ribofuranosyl-5-carboxymethylenethiazolidin-4-one were prepared by independent synthesis utilizing either acid catalyzed fusion of 2-(1-isopropylidene)azino-5-methoxycarbonylmethylenethiazolidin-3(H)-4-one (II) with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose, silylation procedure with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide or by cyclization of new isopropylidene and/or methylbenzilidene derivatives (VII) of 4-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)thiosemicarbazide (VI) with maleic anhydride and subsequent methylation. The synthetic approach has unambigously established the glycosilation site as well as anomeric configuration, which was additionally derived from pmr spectral data.     

The synthesis and PMR study of certain 3-substituted 2-(β-D-Ribofuranosyl)indazoles

The synthesis of 3-cyano-2-(β-D-ribofuranosyl)indazole (4) has been accomplished by a condensation of N-trimethylsilyl-3-cyanoindazole (1) with 2,3,5-tri-O-aeetyl-D-ribofuranosyl bromide (2) followed by subsequent deacetylation. The reactivity of the 3-cyano group was demonstrated by the conversion of 4 to 2-(β-D-ribofuranosyl)indazole-3-carboxamide (5) and 2-(β-D-ribofuranosyl)indazole-3-thiocarboxamide (6). The site of ribosylation and the assignment of anomeric configuration for 4 is discussed. The magnetic anisotropy effect of the exocyclic group at C3 on the anomeric proton as determined by pmr spectroscopy is discussed.     

三[2-(2'-肟亚甲基苯氧基)乙基]胺的合成、表征及量化研究

合成了三[2-(2'-肟亚甲基苯氧基)乙基]胺, 测定了其IR, NMR和单晶结构, 晶体C₂₇H₃₀N₄O₆属三斜晶系, 空间群R-3r, 晶胞参数为: a＝1.9100(2) nm, b＝1.9100(2) nm, c＝1.9100(2) nm, ＝109.500(2), ＝109.500(2). ＝109.500(2), Z＝6. 结构解析最终一致性因子R₁＝0.0568, wR₂＝0.1766. 分子间通过氢键和范德华力形成3D网状超分子结构. 使用HyperChem6.0程序中半经验ZINDO/1方法和G98量子化学程序包, 在B3LYP/6-311G**基组水平上对化合物电荷分布进行了量子化学计算.     

Nucleosides. Part L.. Structure of lumazine N1-(2′-deoxy-D-ribonucleosides) ( = 1-(2′-deoxy-D-ribofuranosyl)pteridine-2,4(1H,3H)-diones): A revision of the anomeric configuration

The anomeric configuration of the glycosidic bond in lumazine N¹-(2′-deoxy-D -ribonucleosides) 1–6 was investigated by NOE difference spectroscopy. The former configurational assignment of the α - and β -D -anomers 1 and 2, 3 and 4 , and 5 and 6 , respectively, has to be reversed to be in agreement with the physical data. Additional proof is presented by X-ray analysis of 3 and 6 . Chemical interconversions of 1-(2′-deoxy-β-D -ribofuranosyl)-6,7-diphenyllumazine ( 6 ) into 2,3′ -anhydrolumazine 2′-deoxyribonucleosides 16 and 17 are also in agreement with the revised anomeric configuration.     

Zur Konfiguration des Vitamin-D3-Metaboliten 25, 26-Dihydroxycholecalciferol: Synthese von (25S,26)- und (25R,26)-Dihydroxycholecalciferol

Configuration of the Vitamin-D₃-Metabolite 25,26-Dihydroxycholecalciferol: Synthesis of (25S,26)- and (25R,26)-Dihydroxycholecalciferol For selective synthesis of the title compounds, (25S)- 1b and (25R)- 1b (Scheme 1), the protected cholesterol precursors (25S)- 6 and (25R)- 6 were prepared from stigmasterol-derived steroid-units 4a-d and C₅-side chain building blocks 5a–d by Grignard- or Wittig-coupling (Scheme 2), the configuration at C(25) of the target compounds being already present in the C₅-units. Conversion of the cholesterol intermediates to the corresponding vitamin-D₃ derivatives was carried out via the 7,8-didehydrocholesterol compounds (25S)- 2b and (25R)- 2b (Scheme 1), using the established photochemical-thermal transformation of the 5,7-diene system to the seco-triene system of cholecalciferol. The configuration at C(25) of the cholesterol precursors as assigned on basis of the known configuration of the C₅-units used, was found to be in agreement with the result of a single crystal X-ray analysis on compound 11 . The configuration at C(25) remained untouched on conversion of the cholesterol ring system to the seco-triene system of vitamin D₃ as evident from comparison of the lanthanide-induced CD. Cotton effects observed for (25S)- 3b and (25S) 1b . 25,26-Dihydroxycholecalciferol observed as a natural vitamin-D₃ metabolite has (25S)-configuration.     

Synthesis and mass spectral fragmentation of 2-methylthio-7-(p-R-phenyl)-8-phenoxy-4,5-benzo-3-aza-2-nonem. III

A series of new 2-methylthio-7-(p-R-phenyl)-8-phenoxy-4,5-benzo-3-aza-2-nonem, IIIa, have been synthesized by regiospecific cycloaddition of phenoxyacetyl on to 2-methylthio-4-(p- R -phenyl)-3H-1,5-benzodiazepines IV. The structure was established by ir, ¹H-nmr and ms spectral data together with ¹³C-nmr spectral data of desulfurization products, VIa. Likewise, a study has been made of the fragmentation upon electron impact of IIIa and IV. All the spectra analyzed contain molecular ions and the principal fragmentation routes takes place either from the molecular ion or from m/e (M⁺ — 134) ion. This ion is the base peak for all the compounds analyzed.     

Reaktion von 3-(Dimethylamino)-2H-azirinen mit 1,3-Thiazolidin-2-thion

Reaction of 3-(Dimethylamino)-2H-azirines with 1,3-Thiazolidine-2-thione Reaction of 3-(dimethylamino)-2H-azirines 1 and 1,3-thiazolidine-2-thione ( 6 ) in MeCN at room temperature leads to a mixture of perhydroimidazo[4,3-b]thiazole-5-thiones 7 and N-[1-(4,5-dihydro-1,3-thiazol-2-yl)alkyl]-N′,N′-dimethylthioureas 8 (Scheme 2), whereas, in i-PrOH at ca. 60°, 8 is the only product (Scheme 4). It has been shown that, in polar solvents or under Me₂NH catalysis, the primarily formed 7 isomerizes to 8 (Scheme 4). The hydrolysis of 7 and 8 leads to the same 2-thiohydantoine 9 (Scheme 3 and 5). The structure of 7a, 8c , and 9b has been established by X-ray crystallography (Chapt. 4). Reaction mechanisms for the formation and the hydrolysis of 7 and 8 are suggested.     

Synthese und Bestimmung des Chiralitätssinns von (+)-(R)-1-Azabicylo[3.3.1]nonan-2-on

Synthesis and Determination of the Chirality Sense of (+)-(R)-1-Azabicyclo[3.3.1]nonan-2-one Optically active (+)-(R)-1-azabicyclo[3.3.1]nonan-2-one ((+)- 1 ) of known absolute configuration is synthesized in the following way: Resolution of (±)-piperidin-3-ethanol ((±)- 2 ) by fractional recrystallization of its diastereoisomeric salts with (+)-3-bromocamphor-8-sulfonic acid from EtOH gave a less soluble salt that yielded(+)- 2 . The chirality sense of (+)- 2 was shown to be (R) by chemical correlation with the enantiomers of 3-oxocyclopentaneacetic acid ((±)- 8 ) of known absolute configuration. This correlation was effected by a Beckmann rearrangement of the oxime (R)-9 to the pyridone (S)- 10 followed by a direct reduction with LiAlH₄ to give the enantiomer (?)-(S)- 2 that was characterized as its benzyloxycarbonyl derivative (?)-(S)- 3 . The alcohol (+)-3 was converted via (+)- 4 into the nitrile (+)-5 which gave by hydrogenolysis and hydrolysis the (R)-configurated hydrochloride (+)- 6 which was cyclized to the bicyclic (5R)-lactam (+)- 1 in 67% yield by heating with 2 equiv. of dibutyltin(IV) oxide in toluene. The nonplanar amide function in (+)- 1 with the substituents at the N-atomarranged in a trigonal pyramid causes two rather intense Cotton effects at 242 (Δ?_max = +19.5) and 211 nm(Δ?_max = ?17.9) in the CD spectrum. If the molecules of (+)- 1 do exist mainly in the chair-twistboat conformation, the amide chromophore is pyramidally deformed in a sense defined by the absolute configuration at C(5). Therefore, the CD spectrum of the (5R)-lactam (+)- 1 can be used to test theories describing the chiroptical properties of distorted amides.     

Synthese von (Methylthio)penam-Derivaten durch Keten-Addition an 4,5-Dihydro-5-(methylthio)-1,3-thiazole

Synthesis of (Methylthio)penam Derivatives via Keten Addition onto 4,5-Dihydro-5-(methylthio)-1,3-thiazoles The 4,5-dihydro-5-(methylthio)-2-phenyl-1,3-thiazoles 3a and 3b , easily prepared from the corresponding 1,3-thiazol-5(4H)-thiones and MeLi, react with dichloroacetyl chloride ( 5a ) and acidoacetyl chloride ( 5b ) in the presence of Et₃N to give (methylthio)penam derivatives 6 (Table 1). The reaction mechanism is either a [2 + 2] cycloaddition of in situ generated ketene or a two-step reaction (Scheme 2). The structure of 6f has been confirmed by X-ray crystallography (Fig. 2). The relative configuration of 6a-e follow from comparison of their ¹H-NMR spectra with those of 6f (Fig. 1). The 6-azidopenams 6d and 6f have been reduced to aminopenams 8a and 8b , respectively. Acylation of 8a with phenacetyl chloride yields 9 (Scheme 4).     

Crystal and molecular structure of methyl(±)-2-((1R,3R)-3-{ 2-[(3S)-1-ethyl-3-hydroxy-2-oxo-2,3-dihydro-1H-3-indolyl]acetyl}-2,2-dimethylcyclobutyl) acetate

The structure of methyl (±)-2-((1R,3R)-3-{ 2-[(3S)-1-ethyl-3-hydroxy-2-oxo-2,3-dihydro-1H-3-indolyl]acetyl}-2,2-dimethylcyclobutyl) acetate has been determined by single crystal X-ray diffraction. The crystal belongs to triclinic system; parameters of the unit cell are: a = 6.551(1) Å, b = 11.506(1) Å, c = 14.334(1) Å, α = 101.41(1)°, β = 97.57(1)°, γ = 104.72(1)°; space group P-1, Z = 2, composition C₂₁H₂₇NO₅. The structure of N-ethyloxindole fragment is usual for the present class of compounds. The configuration of the formed asymmetric carbon atom C(3) of the pyrrole ring along with the configuration of C(12) and C(14) atoms of 2,2-dimethylcyclobutane ring form the side chain of the molecule were determined. There is observed the generation of centrosymmetrical dimers in the crystal structure due to realized intermolecular hydrogen bond of O-H...O type, 2.808(2) Å.     

Synthesen des Analgetikums 2-[1-(m-Methoxyphenyl)-2-cyclohexen-1-yl]-N,N -dimethyl-äthylamin

Syntheses of the Analgesic 2-[1-(m-Methoxyphenyl)-2-cyclohexen-1-yl] -N,N-dimethyl-ethylamine Three principal routes to 2-[1-(m-methoxyphenyl)-2-cyclohexen-1-yl]- N,N-dimethyl-ethylamine (13) , a compound with interesting analgesic properties, are described. In the first, derivatives of [1-(m-methoxyphenyl)-2-cyclohexen-1-yl]acetic acid (10) (alternatively the ethyl ester 29 , the dimethylamide 32 or the nitrile 34 ) serve as crucial intermediates. All three can be synthesized from 2-(m-methoxyphenyl)cyclohexanone (1) by sequences comprising successively C-alkylation ( 1→2,4,5; Scheme 1), reduction of the ketone carbonyl group ( 2→6;4→18;5→19; Scheme 1 and 2) and elimination ( 16→29; 18→32; 19→34; Scheme 2). The relative configuration of the cyclohexanols 16, 18, 19 and of a series of related compounds is established by chemical correlation with the lactone 30 the structure of which follows from ¹H-NMR. data (Scheme 2). The second route creates the intermediates 29 and 32 by ester- or amide-enolate-Claisen-type-rearrangement reactions starting from 3-(m-methoxyphenyl)-2-cyclohexen-1-ol ( 39; Scheme 3). Compounds 29, 32 and 34 are transformed into the target molecule 13 by standard reactions. A Hofmann elimination of the quaternary ammonium fluoride 50 (X=F), derived from the known cis-perhydroindoline 48 , is the essential step in the third approach to 13 (Scheme 4).     

1,3-Dipolare Cycloadditionen von 2-(Benzonitrilio)-2-propanid mit 4,4-Dimethyl-2-phenyl-2-thiazolin-5-thion und Schwefelkohlenstoff

1,3-Dipolar Cycloadditions of 2-(Benzonitrilio)-2-propanide with 4,4-Dimethyl-2-phenyl-2-thiazolin-5-thione and Carbon Disulfide Irradiation of 2,2-dimethyl-3-phenyl-2H-azirine ( 11 ) in the presence of 4,4-dimethyl-2-phenyl-2-thiazolin-5-thione ( 7 ) yields a mixture of the three (1:1)-ad-ducts 8 , 12 and 13 (Schemes 3 and 6). The formation of 8 and 12 can be explained by 1,3-dipolar cycloaddition of 2-(benzonitrilio)-2-propanide ( 1b ) to the C, S-double bond of 7. Photochemical isomerization of 12 leads to the third isomer 13 (Schemes 3 and 7). Photolysis of the azirine 11 in the presence of carbon disulfide gives a mixture of two (2:l)-adducts, namely 12 and 13 (Scheme 4). A reaction mechanism via the intermediate formation of the 3-thiazolin-5-thione b is postulated. The structure of the heterocyclic spiro compound 13 has been established by single-crystal X-ray structure determination (cf. Fig. 1 and 2).     

Configurational assignment by 13C NMR of stereoisomeric 3-bromo-3-acyl derivatives of 5α- and 5β- androstane

The configurational assignment of stereoisomeric 3-bromo-3-acyl derivatives of steroids in both the 5α and 5β series has been carried out by comparing the ¹³C chemical shifts of C-3. A downfield shift is observed for C-3, bearing a bromine and an acyl group, on going from the isomer with an equatorial bromine to that with an axial bromine. This rule has been established by comparison of the ¹³C chemical shifts of model compounds in 4-tert-butylcyclohexanes of known configuration.     

Synthesis of 2-(β-D-ribofuranosyl)pyrimidines,A new class of C-nucleosides

A new C-glycosyl precursor for C-nucleoside synthesis, 2,5-anhydroallonamidine hydrochloride ( 4 ) was prepared and utilized in a Traube type synthesis to prepare 2-(β-D-ribofuranosyl)pyrimidines, a new class of C-nucleosides. The anomeric configuration of 4 was confirmed by single-crystal X-ray analysis. Reaction of 4 with ethyl acetoacetate gave 6-methyl-2-(β-D-ribofuranosyl)pyrimidin-4-(1H)-one ( 5 ). Reaction of 4 with diethyl sodio oxaloacetate gave 2-(β-D-ribofuranosyl)pyrimidin-6(1H)-oxo-4-carboxylic acid ( 6 ). Esterification of 6 with ethanolic hydrogen-chloride gave the corresponding ester 7 which when treated with ethanolic ammonia gave 2-(β-D-ribofuranosyl)pyrimidin-6(1H)-oxo-4-carboxamide ( 8 ). Condensation of 2,5-anhydroallonamidine hydrochloride ( 4 ) with ethyl 4-(dimethylamino)-2-oxo-3-butenoate ( 9 ), gave ethyl 2-(β-D-ribofuranosyl)pyrimidine-4-carboxylate ( 10 ). Treatment of 10 with ethanolic ammonia gave 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamide ( 11 ). Single-crystal X-ray analysis confirmed the β-anomeric configuration of 11. Acetylation of 11 followed by treatment with phosphorus pentasulfide and subsequent deprotection with sodium methoxide gave 2-(β-D-ribofuranosyl)pyrimidine-4-thiocarboxamide ( 14 ). Dehydration of the acetylated amide 12 with phosphorous oxychloride provided 2-(β-D-ribofuranosyl)pyrimidine-4-carbonitrile ( 15 ). Treatment of 15 with sodium ethoxide gave ethyl 2-(β-D-ribofuranosyl)pyrimidine-4-carboximidate ( 16 ), which was converted to 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamidine hydrochloride ( 17 ) by treatment with ethanolic ammonia and ammonium chloride. Treatment of 16 with hydroxylamine yielded 2-(β-D-ribofuranosyl)pyrimidine-4-N-hydroxycarboxamidine ( 18 ). Treatment of 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamide ( 11 ) with phosphorus oxychloride gave the corresponding 5′-phosphate, 19 , Coupling of 19 with AMP using the carbonyldiimidazole activation procedure gave the corresponding NAD analog, 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamide-(5′ ? 5′)-adenosine pyrophosphate ( 20 ).     

Stereochemistry of diastereoisomeric propionyl esters of 4-(2-furyl)-3-methyl-1-phenethyl-piperidin-4-ols and the analgesic ether derived from their acid-catalysed ethanolysis

The stereochemistry of diastereoisomeric propionyl esters of 4-(2-furyl)-3-methyl-1-phenethylpiperidin-4-ols has been established by ¹³C NMR analysis. Both isomers, after acid-catalysed ethanolysis, are converted to the corresponding 4-ethoxy derivative of configuration (t-3-Me, r-4-OEt) that correlates with its analgesic properties.