Nucleoside von Fluorzuckern. XVI. Halogensubstitutionen und Konfigurationsumkehr am Lactolring vom 6′-Fluor-D-glucopyranosyl-thymin

Nucleosides of Fluorine Carbohydrates. XVI. Halogene Substitutions and Inversion of Configuration at the Lactol Ring of 6′-Fluoro-D-glucopyranosyl Thymine 1-(6′-Deoxy-6′-fluoro-β-D-glucopyranosyl)-thymine 1 reacts with equimolar amounts' of tosyl chloride to give the 2′-O-tosyl derivative 2 . Treatment of 1 with mesyl chloride gives predominantly a derivative with three sulfonyl groups in the molecule. 2 reacts both with bromides and iodides but not with fluorides to give the corresponding 2′-deoxy-2′-halogeno derivatives. 2 can be transformed into an 2,2′-anhydronucleoside 10 that reacts with HCl, HBr and HF/AlF₃ to give the 2′-chloro-, 2′-bromo-, and 2′-fluoro derivatives of 1-(2′,6′-dideoxy-6′-fluoro-β-D-glucopyranosyl)-thymine 7 , 12 , and 13 respectively. Hydrogenation of 7 affords the 6′-fluoro analog of the nucleoside phosphorylase inhibitor “deoxyglucosyl thymine” possessing a defined β-configuration. The alkaline hydrolysis of the anhydronucleoside 10 yields the 1-(6′-deoxy-6′-fluoro-β-D-mannopyranosyl)-thymine 15 , the epimer of 1 .     

Synthese und biochemische Aktivität perfluoralkylierter Derivate des 5′-Desoxy-5′-fluor und 2′,5′-Didesoxy-5′-fluor-uridins

Synthesis and Biochemical Activity of Perfluoroalkylated Derivatives of 5′-Deoxy-5′-fluoro-, and 2′, 5′-Dideoxy-5′-fluorouridine 5-Perfluoroalkylated 5′-deoxy-5′-fluoro-, and 2′,5′-dideoxy-5′-fluorouridine are obtained by the reaction of 5′-fluorouridine or 2′,5′-dideoxy-5′-fluorouridine, respectively, with a perfluoroalkyl-coppercomplex in DMSO under inert conditions, and at temperatures of about 100 °C. Analogously 5-perfluoroethyl, 5-perfluorobutyl, and 5-perfluorohexyl derivatives of uridine, and 5-perfluoroethyl, and 5-perfluorobutyl derivatives of 2′-deoxyuridine could be isolated. It is shown either by mass spectroscopy or by ¹H-n.m.r. spectroscopy that the substitution always takes place at the 5-position of the pyrimidine. The 5-perfluoroethyl derivatives are particularly effective as cytostatics.     

α-氟代半乳糖的合成

α-氟代半乳糖是一类重要的1-氟代糖,可在化学-酶法催化过程中作为糖基供体合成各类重要的半乳糖苷化合物,但这类氟代糖的大量获得至今没有完整实用的合成方法。作者以D-半乳糖为原料,将其全乙酰化获得五乙酰基-β-半乳糖,用吡啶-氟化氢络合物在-20℃进行氟化反应,得到四乙酰基-α-氟代半乳糖,然后用甲醇钠/甲醇溶液进行脱乙酰反应,TLC及核磁共振氢谱验证所得产物,成功获得α-氟代半乳糖(δ=5.57,J1,2=2.7,J1,F=53.9 Hz)。     

Transformation von Uridin- zu Cytidinderivaten durch selektive Aminierung

Transformation of Uridine Derivatives into Cytidines via Selective Amination The synthesis of some 5-fluorosubstituted cytidine 2 derivatives via amination of corresponding uridine derivatives 1 is described. 5-Substituted 4-tetrazolo pyrimidinone derivatives 5 are key intermediates in the procedure. The method used is extended to other fluorinated starting materials, e.g. fluorinated uridinedinueleotides 7 or 2′-deoxy-2′-fluorouridine 9 . The fluoro containing products are easily available by fluorination with elemental fluorine or hydrogene fluoride.     

The STOBBE Condensation,Part IX. The cyclisation of (E)-3-Methoxycarbonyl-4-(5′-methyl-2′-thienyl)-but-3-enoic acid,and α,β-bis-(5-methyl thenylidene)-succinic anhydride,to benzothiophen derivatives

The condensation of 5-methyl-thiophen-2-aldehyde with dimethyl succinate in the presence of potassium t-butoxide or sodium hydride gave predominantly (E)-3-methoxy-carbonyl-4-(5′-methyl-2′-thienyl)-but-3-enoic acid 1a , whose configuration is proved by cyclisation with sodium acetate in acetic anhydride to the corresponding benzothiophen derivatives 2 . Alcoholysis of the derived (E)-carboxy-4-(5′-methyl-2′-thienyl)-but-3-enoic anhydride 3 gives the half-ester 1c which is isomeric with the half-ester 1a . Condensation also gave the α,β-bis-(5-methyl thenylidene)-succinic acid 4a in small amounts. The derived anhydride 5 yields on pyrolysis 4-(5′methyl-2′-thienyl)-2-methyl-benzothiophen-5,6-dicarboxylic anhydride 6 .     

Synthese und Strukturaufklärung von 19-Nor-pregnanderivaten mit stickstoffhaltigen Vierringen in 14,15-Stellung

Synthesis and Structural Elucidation of 19-Nor-pregnane Derivatives with Nitrogen-Containing Four-Membered Rings in 14,15-Position The introduction of a C₂ side chain in the 17-position of 3-methoxy-14β, 15β-(3′,4′-azetidine)-estra-1,3,5(10)-trien-17β-ol ( 1 ) is described. Hydroboration of the 17-ethylidene compound 4 gives a mixture of the 17αH and 17α-pregnane derivatives 6 and 6a in 70% and 10% yields, respectively. Birch reaction of 6 , followed by oxidation yields the 14β,15β-(3′,4′-azetidine)-19-nor-pregn-4-ene-3,20-dione ( 12 ). The new compounds were characterized by ¹H-n.m.r. The structure of product 13 was determined by X-ray crystallography.     

β-环糊精-Cu(Ⅱ)配合物催化氧化邻苯二酚及其反应动力学

以β-环糊精(β-CD)作为骨架,经磺酰化反应、卤代反应和与L-组氨酸的亲核取代反应,得到了两种β-环糊精-组氨酸衍生物配体,再将配体与Cu(Ⅱ)配位,合成了具有多酚氧化酶催化活性的β-环糊精-Cu(Ⅱ)配合物。采用元素分析、傅里叶变换红外光谱、核磁共振波谱和原子吸收光谱等方法对配体和配合物的结构进行了表征。以O₂为氧化剂,用分光光度法测定了它们催化邻苯二酚氧化反应的性能,并考察了反应温度、pH值等因素对催化反应速率的影响。结果表明：β-环糊精-Cu(Ⅱ)配合物具有良好的催化性能;C-2位修饰得到的环糊精类金属衍生物因为活性基团与反应中心之间相对位置适宜,表现出较大的加速效果;反应动力学表明组胺基配位Cu(Ⅱ) 、β- CD疏水空腔和碱催化作用是反应加速的3个因素。     

Efficient blockwise synthesis of pyruvated di- and trisaccharide fragments related to Klebsiella K26 capsular polysaccharides

Pyruvated di- and trisaccharide fragments representing the immunodominant side chains of Klebsiella K26 capsular polysaccharides are prepared. Phenyl 4′,6′-O-benzylidene-1-thio-β-D-lactoside ( 1 ) is converted in 4 steps into the corresponding pyruvated 1-thio-lactoside ( 2 ) and transformed into the imidate ( 4 ). Coupling of the latter with Z-protected 5-aminopentanol gives the pyruvated disaccharide fragment ( 6 ) upon deblocking. Similarly, imidate ( 4 ) is coupled to allyl 2,3-di-O-benzoyl-3-O-(1-fluoro-1,1,3,3-tetraisopropyl-1,3-disiloxane-3-yl)-α-D-glucopyranoside ( 8 ) to give the corresponding trisaccharide fragment upon deblocking.     

Silylation-Mediated Oxidation of 2,2′-Anhydro-5,6-dihydro-5-azacytidine

Reaction of 5,6-dihydro-5-azacytidine hydrochloride 1 with 2-acetoxy-isobutyryl chloride produced 5′-O-(2,5,5-trimethyl-1,3-dioxolan-4-on-2-yl)-3′-O-acetyl-5,6-dihydro-2,2′-anhydro-1-β-D-arabinofuranosyl-5-azacytosine hydrochloride 2 , which upon partial hydrolysis with EtOH/HCl at 4°C gave 3′-O-acetyl-5,6-dihydro-2,2′-anhydro-1-β-D-arabinofuranosyl-5-azacytosine hydrochloride 3 . The hydrolysis of 3 with EtOH/HCl at 25°C gave 2,2′-anhydro-5,6-dihydro-1-β-D-arabinofuranosyl-5-azacytosine hydrochloride 4 . Silylation oxidation of 3 and 4 with BSTFA or BSA in acetonitrile produced the N-substituted derivatives of 1-β-D-arabinofuranosyl-5-azacytosine 8 and 7 , respectively.     

Organofluorine compounds and fluorinating agents. 14. Thermotropic Liquid-Crystalline Glycosyl Fluorides

The liquid crystalline 6-O-alkyl-α-D-galactopyranosyl fluorides ( 3a–f ) and the mesogenic 6-O-dodecyl-α-D-glucopyranosyl fluoride ( 7 ) were prepared from the homologous 6-O-alkyl-1,2:3,4-di-O-isopropylidene-α-D-galactopyranosides ( 1a–f ) and from the methyl 2,3,4-tri-O-benzyl-glucopyranoside ( 4 ), respectively, in two and three steps. The fluorinations of 1a–f to the α-fluorides 2a–f and of 5 to the α-fluoride 6 were carried out with the reagent system HF/nitromethane/acetic anhydride, which simultaneously effects the complete exchange of the isopropylidene groups ( 1a-f ) and of the benzyl groups ( 5 ) for acetyl functions in the non-glycosidic positions. Moreover, the 6-O-dodecyl-2,3,4-tri-O-acetyl-α-D-galactopyranosyl fluoride ( 11 ) was prepared in three steps from the 6-O-dodecylgalactopyranose ( 8 ). The stereoselective introduction of the fluoride into the β-anomeric position ( 10 → 11 ) was achieved by bromide-fluoride exchange with the two-phase system triethylamine-trishydrofluoride/petroleum ether. Dodecyl 6-deoxy-6-fluoro-α-D-glucopyranoside ( 13 ), prepared from the glucoside 12 with the fluorinating agent DAST, shows a narrow monotropic S_A-phase and lyotropic liquid crystalline behaviour in contact with water. Dodecyl 6-deoxy-6-fluoro-β-D-galactopyranoside ( 17 ), prepared in three steps from the acetal 14 , does not form mesophases. The liquid crystalline behaviour of the amphiphilic glycosyl fluorides 3a–f , 7 , and of the 6-deoxy-6-fluoro derivative 13 is described.     

Oxidation of catechol catalyzed by β-cyclodextrin-Cu(Ⅱ) complexes and its reaction kinetics

以β-环糊精(β-CD)作为骨架,经磺酰化反应、卤代反应和与L-组氨酸的亲核取代反应,得到了两种β-环糊精-组氨酸衍生物配体,再将配体与Cu(Ⅱ)配位,合成了具有多酚氧化酶催化活性的β-环糊精-Cu(Ⅱ)配合物。采用元素分析、傅里叶变换红外光谱、核磁共振波谱和原子吸收光谱等方法对配体和配合物的结构进行了表征。以O₂为氧化剂,用分光光度法测定了它们催化邻苯二酚氧化反应的性能,并考察了反应温度、pH值等因素对催化反应速率的影响。结果表明：β-环糊精-Cu(Ⅱ)配合物具有良好的催化性能;C-2位修饰得到的环糊精类金属衍生物因为活性基团与反应中心之间相对位置适宜,表现出较大的加速效果;反应动力学表明组胺基配位Cu(Ⅱ) 、β- CD疏水空腔和碱催化作用是反应加速的3个因素。     

氮苷1-(2,′3,′4,′6′-O-四乙酰基-β-D-吡喃葡萄糖基)-咪唑的制备

以D-葡萄糖(Ⅰ)、醋酸酐为原料,在无水吡啶中制得中间体1,2,3,4,6-O-五乙酰基-D-葡萄糖(Ⅱ),收率为87.5%。在HB r/CH3COOH条件下对Ⅱ异头碳上的乙酰基进行溴代,制得1-溴-2,3,4,6-O-四乙酰基-D-葡萄糖(Ⅲ),不经分离,在相转移催化剂TEBA催化下,Ⅲ直接与2,4-二硝基苯酚反应得到酚苷1-O-(2,′4′-二硝基苯)-2,3,4,6-O-四乙酰基-β-D-葡萄糖苷(Ⅳ),最后Ⅳ与1-三甲基硅基-咪唑在无水四氯化锡的催化下,室温反应52 h制得氮苷1-(2,′3,′4,′6′-O-四乙酰基-β-D-吡喃葡萄糖基)-咪唑(Ⅴ),此步反应收率为90%。     

6-氯和6-甲氧基嘌呤核苷的合成

以四乙酰呋喃核糖(Ⅰ)和6 氯嘌呤(Ⅱ)为原料,在对甲苯磺酸(TsOH)存在下,运用微波固态反应得到中间体2′,3′,5′ 三乙酰基 6 氯嘌呤核苷(Ⅲ),收率为80 1%。该中间体再用NH3/CH3OH和Na2CO3/CH3OH处理,分别合成了6 氯 9 β D 嘌呤核苷(Ⅳ)和6 甲氧基 9 β D 嘌呤核苷(Ⅴ),收率分别为78 8%和76 9%。Ⅳ和Ⅴ的总收率分别为63 1%和61 6%,结构经1HNMR和元素分析证实。最佳的缩合条件是n(Ⅰ)∶n(Ⅱ)=1∶1,m(TsOH)/m(6 氯嘌呤)=0 03,595W微波辐射4 5min,462W微波辐射1min和119W微波辐射0 5min;生成Ⅳ的氨解条件为室温反应2h,生成Ⅴ的碱解条件为回流5h。     

NMR-spektroskopische Untersuchungen zum Konformations-verhalten von 2′- und 3′-halogensubstituierten Pyrimidinnucleosiden

N.M.R. Spectroscopical Investigations on the Conformational Behaviour of Some 2′ - and 3′-Halogen-substituted Pyrimidine Nucleosides A series of 2′- and 3′-halogenated pyrimidine nucleosides has been synthesized and investigated by ¹H, ¹³C and ¹⁹F n.m.r. spectroscopy. The ¹H and ¹³C chemical shifts for the positions 2′ and 3′ depend linearly but oppositely on the substituent electronegativities X_R. The conformational equilibrium N ⇌ S of the nucleosides in solution is determined. An approximately linear correlation between the prefered gauche-gauche interaction of the exocyclic CH₂OH groups and the ribose N conformation has been found.     

Darstellung und Reaktionen von 2-Mercapto-6-thioxo-thiopyran-3-carbonsäure-Derivaten

Synthesis and Reactions of 2-Mercapto-6-thioxo-thiopyran-3-carboxylate derivatives 6-Amino-thiopyran-2-thiones ( 1 ) react with dihydrogen sulfide in the presence of pyridine and triethyl amine to yield 6-thioxo-thiopyran-2-thiolates ( 2 ). Methylation of 2 gives the methylthio compounds 3 and 4 . Further methylation of 3a and 4a yields the thiapyrylium salt ( 7 ). The reaction of 2-imino-thiopyran ( 6 ) with carbon disulfide represents another route to the 6-methylthio-thiopyran-2-thione ( 4a ). The 2-methylthio-thiopyran-6-thione ( 3a ) undergoes substitution of the methylthio group with amines to 8 or reacts with phenylhydrazine to phenylhydrazono-thiopyrane ( 9c ). 6-Thioxo-thiophen-2-thiolates ( 2a , b ) react with hydrazine hydrate to give hydrazono-thiopyranes ( 10a , b ) which can be S-methylated. On the contrary 2c gives with hydrazine hydrate under ring transformation the pyridine-2-thiolate ( 11 ). N,S-Acetals ( 12 ) and 1,3,4-thiadiazoles ( 15 ), which give rise to new pyridine derivatives ( 14 ) and ( 17 ), can be obtained from 1-Amino-pyridin-2-thiolate ( 11 ).     

Umsetzung von Bromderivaten des 6β-Bromcholest-4-en-3-ons mit NaBH4 und 13C-NMR-spektroskopische Charakterisierung der Reduktionsprodukte

Reaction of Bromo Derivatives of 6β-Bromocholest-4-en-3-one with NaBH₄ and ¹³C-NMR Spectroscopic Characterization of the Reduction Products Bromo derivatives of 6β-bromcholest-4-en-3-one ( 1a–f ) were reduced with sodium borohydride. The main product of the reduction of 2α,6β-dibromcholest-4-en-3-one ( 1b ) was 2α-bromocholesterol ( 2b ). In other cases the corresponding derivatives of 6β-bromocholest-4-en-3β-ol ( 3a ) were formed. The chemical shifts of all new products were determined. They confirmed the structure of these new compounds.     

苯噻菌胺的合成研究

对氟苯胺在盐酸的作用下与硫氰酸铵反应得到对氟苯基硫脲,然后在溴的作用下环化得到2-氨基-6-氟苯并噻唑;2-氨基-6-氟苯并噻唑水解并与氯化锌反应得2-氨基-5-氟苯硫酚锌盐;2-氨基-5-氟苯硫酚锌盐与D-丙氨酸-N-羰酐反应得到(R)-1-(6-氟-2-苯噻唑)乙胺。最后,(R)-1-(6-氟-2-苯噻唑)乙胺与L-缬氨酸和氯甲酸异丙酯反应得到目的产物苯噻菌胺,总收率51.2%(以对氟苯胺计)。     

Synthese von 1-(β-D-Arabinofuranosyl)-pyrimidinen

Syntheses of 1-(β-D-Arbinofuranosyl)-pyrimidines New synthetic methods of 1-(β-D-arabinofuranosyl)-pyrimidines are described. 1-(β-D-arabinofuranosyl)-uracil, 1-(β-D-arabinofuranosyl)-5-fluorouracil, 1-(β-D-arabinofuranosyl)-thymine, and 1-(β-D-arabinofuranosyl)-cytosine can be obtained in a high yield by the splitting of the anhydrobond in 2,2′-anhydropyrimidines in dipolar aprotic solvents, such as HMPT, DMF, and DMSO, respectively, in the presence of activated elemental copper. Unlike the formation of cyclopyrimidiens ribonucleosides are directly transformed to the corresponding arabinofuranosyl derivatives by the reaction with diphenylcarbonate and NaHCO₃ in the presence of copper. The reaction proceeds probably via an intermediate formation of the cycloproduct. Further aspects on the mechanism are described.     

Synthese,Reaktivität und 1H-NMR-Daten von 14,15-Methylenderivaten der Androstan- und Östratrienreihe

Synthesis, Reactivity and ¹H-NMR-Spectroscopy of 14,15-Methylene Derivatives of the Androstane and Estratriene Series Under the activating and syn-directing effect of the 17-hydroxy group the Simmons Smith cyclopropanation of 14,15-unsaturated 17-hydroxy steroids of the androstane and estratriene series 1a, 5 and 9 affords the 14,15-methylene steroids 2a, 6 and 10 with cis position of the 14,15-methylene and 17-hydroxy groups in a stereospecific reaction. Oxidation of these compounds yields the 17-keto derivatives 3, 7 and 11 , which were reduced to the compounds 4a, 8 and 12 with trans position of the 14,15-methylene and 17-hydroxy groups by complex hydrides or diborane. In a phase transfer catalyzed reaction dichloro- or dibromocarbene was added to 3β, 17β-diacetoxy-5α-androst-14-ene 1b forming the 14β, 15β-dihalogenmethylene steroids 13 and 14 . The 17-keto steroids 7 and 11 were transformed into 17-methyl and 17-ethynyl derivatives 15–20 . Cleavage of the cyclopropane ring of 2a, 2b and 3 by catalytic hydrogenation affords the 14β-methyl derivatives 21–23 , the acid catalyzed ring opening with hydrogen chloride yields the 14β-chloro, 15β-methyl derivatives 24–29 . Structure elucidation has been established by ¹H n.m.r. and mass spectroscopy. The configuration at C17, C14 and C15 was also determined by means of ¹H n.m.r. spectroscopy, using the chemical shifts of the 18-protons, the coupling constants and the chemical shifts of the 17-protons. The configuration of the 17-disubstituted steroids was established with the aid of an europium shift reagent.     

Photochemie von Aminoketonen. XV. Photochemische Acylgruppenwanderung in N-Tosyl-β-aminovinyl-phenyl-ketonen

Photochemistry of Aminoketones. XV. Photochemical Acyl Migration in N-Tosyl-β-aminovinyl-phenyl-ketones N-Tosyl-β-aminovinyl-phenyl-ketones 1a – i are prepared in good yields from β-chlorovinyl- phenyl-ketones by reaction with the sodium salts of tosyl amides in dry DMF at room temperature. In contrast to the relatively photostable N, N-dialkyl-β-aminovinyl-aryl-ketones the electronically excited 1 give irreversible chemical reactions within a few minutes. Among other not identified photoproducts the α-tosyl-β-aminovinyl-phenyl-ketones 2 were found. From the experimental results it is evident that the migration of the tosyl group prefers a radical-type two step reaction through an intermediate X / Y of a (1,5)-N→O-tosylrearrangement.