Synthesis of (-)-7-epiaustraline and (-)-1-epicastanospermine

Highly efficient and selective syntheses of the title compounds are described. The cornerstone of the synthetic plan is the tandem inter [4 + 2]/inter [3 + 2] cycloaddition process. These syntheses differ from previous applications of this strategy in that they incorporate an alkylation in the hydrogenolysis step to close the second ring of the azabicyclic systems. Notable features of the sequence are (1) the highly regio- and stereoselective [3 + 2] cycloaddition of nitronate 15 with siloxymethyl (Z)-beta-silylvinyl ketone (Z)-22b and (2) the highly selective reduction of the resulting ketone 24a with L-Selectride. A single-crystal X-ray structure analysis of synthetic (-)-7-epiaustraline confirmed that the targeted structure was successfully synthesized. This stimulated a reexamination of the structural assignment of the natural product. (-)-1-Epicastanospermine was synthesized in four steps from the common intermediate 27a. The absolute configuration of (-)-1-epicastanospermine was assured by single-crystal X-ray structure analysis of intermediate (-)-27a. Thus, the sign of the optical rotation had to be revised. The overall efficiency of these syntheses were 9 steps and 23% yield for (-)-7-epiaustraline and 10 steps and 20% yield for (-)-1-epicastanospermine     

2-[2-(4,6-二甲基)-嘧啶基]-4-苯基-1,2,4-噁二唑烷-3,5-二酮的合成

异氰酸苯醇和N-[2-(4,6-二甲基)-嘧啶基]-羟胺(5)反应生成1-[2-(4,6-二甲基)-嘧啶基]-1-羟基-3-苯基脲(6)。化合物(6)在三乙胺存在下和氯甲酸乙醇反应生成2-[2-(4,6-二甲基)-嘧啶基]-4-苯基-1,2,4-噁二唑烷-3,5-二酮(1)。     

3-(2-二唑啉基)-色酮类化合物的合成研究

报道了取代的邻羟基苯乙酮(1a～1e)经Vilsmeier-Haack反应一步制得3-醛基色酮(2a～2e),2a～2e与取代的芳酰肼(3a～3c)缩合制得15个酰腙类化合物(4a～4o),4a～4o在醋酸酐作用下关环得15个3-(2-苝二唑啉基)-色酮(5a～5o),并通过元素分析,IR,~1H NMR和MS诺数据确证了上述化合物的结构。     

5-[5-(3-吡啶)-2H-四唑亚甲基]-2-芳酰氨基-1,3,4-噻二唑的合成

本文首先用5-(3-吡啶)-2H-四唑乙酰基酰肼与芳酰基异硫氰酸盐反应制备成化合物1-[5-(3-吡啶)-2H-四唑乙酰基]-4-芳酰氨基硫脲化合物1a～j, 然后用冰醋酸回流处理1a～j得到一系列化合物5-[5-(3-吡啶)-2H-四唑亚甲基]-2-芳酰氨基-1,3,4-噻二唑2a～j . 化合物1a～b在强碱介质中首先发生降解, 然后进行环化反应 .     

无外加催化剂条件下邻取代芳香醛与5,5-二甲基-1,3-环己二酮的反应研究

在DMF溶剂中,不外加催化剂使邻取代芳香醛(1)与5,5-二甲基-1,3-环己三酮(2)发生缩合和加成反应生成3,3,6,6-四甲基-4a-羟基-9-芳基-1,8二氧化-2,3,4,4a,5,6,7,8,9a-十氢化-1H氧杂蒽(3a～3d)。在同样条件下,邻羟基芳香醛与5,5-二甲基-1,3-环己三酮则发生缩合,加成和脱水反应生成3,3-二甲基-9-(5,5-二甲基-3-羟基-2-环己烯-1-酮-2-基)-1-氧代-2,3,4,9-四氢化-1 氧杂蒽(4a～4b)。用单晶X-射线分析法确定了产物3a和4a的晶体结构。     

Tele-substitution reactions in the naphthalene series : The behaviour of 1,4 - dimethyl - 2 - nitro - 3 - phenylsulphonyl - and 2,3 - bisphenylsulphonyl - 1,4 - dimethyl - naphthalene towards sodium arenethiolates and secondary aliphatic amines

1,4 - Dimethyl - 2 - nitro - 3 - phenylsulphonylnaphthalene (2) reacts with sodium benzenethiolate in DMSO at 120° to give 1 - methyl - 2 - nitro - 4 - phenylthiomethylnaphthalene (4) [tele-substitution product (TSP) of the phenylsulphonyl group] and 1,4 - dimethyl - 3 - phenylsulphonyl - 2 - phenylthionaphthalene (5) [normal substitution product (NSP) of the nitro group]. The analogous reactions of 2 with sodium 2,4,6- trimethylbenzenethiolate and of 2,3 - bisphenylsulphonyl -1,4 - dimethylnaphthalene (3) with sodium benzenethiolate or aliphatic amines give only TSPs of the phenylsulphonyl group. In the case of the reaction of 2 with aliphatic amines both the possible TSPs (tele-substitution of the phenylsulphonyl or of the nitro group) were isolated in 9:1 relative yield. All the data show that the phenylsulphonyl is a leaving group far better than the nitro in such tele-substitution processes. The mechanism previously proposed to account for the formation of TSPs from 1,4-dimethyl - 2,3 - dinitronaphthalene is strongly supported by the obtained results.     

Enzymatic synthesis of (-)- and (+)-acetoxyhexamides and (-)- and (+)-hydroxyhexamides.

The enantioselective hydrolysis of (+/-)-4-(1-acetoxyethyl)-N-(cyclohexylcarbamoyl)-benzenesulfona mides 3 with lipase Amano P from Pseudomonas sp. in a water-saturated solvent gave (R)-4-(1-hydroxyethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide 2 (39%, > 99% ee) and unchanged (S)-3 (50%, 62% ee). On the other hand, enantioselective esterification of (+/-)-2 with lipase Amano P in the presence of vinyl acetate provided (R)-3 (41%, > 99% ee) and unchanged (S)-2 (46%, 78% ee).     

[Z]-2-(芳基锡基)-1-(9-芴醇)乙烯的合成、结构与性质

用三苯基氢化锡,三对甲苯基氢化锡作为锡氢化试剂与9-乙炔基-9-芴醇进行反应,合成了2个有机锡化合物:[Z]-2-(三苯基锡基)-1-(9-芴醇)乙烯(1)和[Z]-2-(三对甲苯基锡基)-1-(9-芴醇)乙烯(2)。化合物1和2分别与ICl,Br~2,I~2反应,得到6个有机锡一卤化物,6个有机锡二卤化物和2个有机锡混合卤化物(3-16)。有机锡一碘化物7,13和有机锡二碘化物8,14与KOH乙醇溶液反应,分别得到相应的有机锡氢氧化物17,18和有机锡氧化物19,20。有机锡二碘化物8,14分别与含氮双齿配体1,10-邻菲罗啉(Phen),2,2'-联吡啶(Bipy),8-羟基喹啉(Oxin)反应,得到6个相应的配合物21-26。26个新化合物通过元素分析,锡含量测定,IR,^1HNMR测定对其结构进行了表征。同时测定了化合物2的晶体结构,晶体属单斜晶系,空间群P2~1/c。化合物2是以Sn原子为中心扭曲的四面体构型。     

Planarization of B7- and B12- clusters by isoelectronic substitution: AlB6- and AlB11-

Small boron clusters have been shown to be planar from a series of combined photoelectron spectroscopy and theoretical studies. However, a number of boron clusters are quasiplanar, such as B(7)(-) and B(12)(-). To elucidate the nature of the nonplanarity in these clusters, we have investigated the electronic structure and chemical bonding of two isoelectronic Al-doped boron clusters, AlB(6)(-) and AlB(11)(-). Vibrationally resolved photoelectron spectra were obtained for AlB(6)(-), resulting in an accurate electron affinity (EA) for AlB(6) of 2.49 ± 0.03 eV. The photoelectron spectra of AlB(11)(-) revealed the presence of two isomers with EAs of 2.16 ± 0.03 and 2.33 ± 0.03 eV, respectively. Global minimum structures of both AlB(6)(-) and AlB(11)(-) were established from unbiased searches and comparison with the experimental data. The global minimum of AlB(6)(-) is nearly planar with a central B atom and an AlB(5) six membered ring, in contrast to that of B(7)(-), which possesses a C(2v) structure with a large distortion from planarity. Two nearly degenerate structures were found for AlB(11)(-) competing for the global minimum, in agreement with the experimental observation. One of these isomers with the lower EA can be viewed as substituting a peripheral B atom by Al in B(12)(-), which has a bowl shape with a B(9) outer ring and an out-of-plane inner B(3) triangle. The second isomer of AlB(11)(-) can be viewed as an Al atom interacting with a B(11)(-) cluster. Both isomers of AlB(11)(-) are perfectly planar. It is shown that Al substitution of a peripheral B atom in B(7)(-) and B(12)(-) induces planarization by slightly expanding the outer ring due to the larger size of Al.     

Enantiocontrolled synthesis of (-)-9-epi-pentazocine and (-)-aphanorphine

We have developed novel asymmetric routes to (-)-9- epi-pentazocine and (-)-aphanorphine from a d-tyrosine derivative. The tricyclic frameworks of (-)-9- epi-pentazocine and (-)-aphanorphine were assembled stereoselectively via intramolecular Friedel-Crafts reaction of the corresponding bicyclic precursors, generated with titanium-promoted enyne cyclization and indium-initiated atom-transfer radical cyclization, respectively.     

Synthetic cephalosporins. VII. Synthesis and antibacterial activity of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(3-(3-hydroxy-4-pyridon-1-yl)-3- carboxypropoxyimino)acetamido]-3-(1,2,3-thiadiazol-5-yl)-thiomethyl-3- cephem-4-carboxylic acid and its related compounds

Synthesis and antibacterial activity of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(3-(3-hydroxy-4-pyridon-1-y l)-3- carboxypropoxyimino)acetamido]-3-(1,2,3-thiadiazol-5-yl)thio methyl-3-cephem-4-carboxylic acid (12a) and its related compounds are described. Compound 12a exhibited excellent antibacterial activity against gram-negative bacteria, including Pseudomonas aeruginosa.     

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.     

A formal total synthesis of the sesterterpenoid (+/-)-dysidiolide and approaches to the syntheses of (+/-)-6-epi-, (+/-)-15-epi-, and (+/-)-6,15-bisepidysidiolide

A formal total synthesis of the sesterterpenoid (+/-)-dysidiolide (1), a structurally novel sponge metabolite that inhibits the cdc25A protein phosphatase, and approaches to the syntheses of (+/-)-15-epi- (34), (+/-)-6-epi- (36), and (+/-)-6, 15-bisepidysidiolide (39) are described.     

The autoxidation of 2-(2-aminophenyl)-3- methylindole

Fischer indolisation of 2-aminophenyl ethyl ketone phenylhydrazone using glacial acetic acid saturated with hydrogen chloride as catalyst affords 3-methylindolo(l′:2′-3:4)2-methylquinazoline and 2-(2-aminophenyl)-3-methylindole. The latter compound is autoxidised to 2-(2-amino-phenyl)-3-hydroxy-3-methyl-3H-indole, a reaction which is shown to be dependent upon the presence of the primary amino group at the 2-position of the 2-phenyl substituent and which is much slower than the corresponding autoxidation of 2-(2-hydroxyphenyl)-3-methylindole to 3-hydroxy-2-(2-hydroxyphenyl)-3-methyl-3H-indole previously reported.Nitration of isopropyl phenyl ketone occurs preferentially at the ortho- rather than the meta- positions of the benzene nucleus.     

Bromo derivatives of 1-(4-hydroxyphenyl)dihydrouracil and 1-(4-hydroxyphenyl)-5- or -6-metehyldihydrouracils

Bromination of 1-(4-hydroxyphenyl)dihydrouracil and its 6-methyl derivative with bromine in refluxing acetic acid gave 1-(3,5-dibromo-4-hydroxyphenyl)-5-bromo-, 1-(3,5-dibromo-4-hydroxyphenyl)-5-bromo-, and 1-(3,5-dibromo-4-hydroxyphenyl)-5-bromo-6-methyldihydrouracils and 1-(3,5-dibromo-4-hydroxyphenyl)-5-methyluracil. 5-Bromo- and 5,5-dibromodihydrouracils were dehydrobrominated, and the same compounds undergo decomposition to 3,5-dibromo-4-hydroxyphenylurea upon alkaline hydrolysis.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1251–1254, September, 1982.     

Synthesis of (Z)-4-hydroxytamoxifen and (Z)-2-[4-[1-(p-hydroxyphenyl)-2-phenyl]-1butenyl]phenoxyacetic acid

The synthesis of (Z)-4-hydroxytamoxifen and (Z)-2-[4-[1-(p-hydroxyphenyl)-2-phenyl]-1-butenyl]phenoxyacetic acid was accomplished using a McMurry reaction as the key step. The perfluorotolyl derivatives of the McMurry products enabled the separation of the minor undesirable geometrical isomer. The methodology proceeds without E,Z isomerization, employs a very mild final debenzylation step compatible with a large array of functional groups, and can be applied to the generation of a variety of 4-hydroxytamoxifen analogues.     

Synthesis of 1-(dimethylsulfamoyl)-2- and 5-imidazolecarboxaldehydes. Rearrangement of 1-(dimethylsulfamoyl)-5-imidazole-carboxaldehyde to the 4-carboxaldehyde

Lithiation of 1-(dimethylsulfamoyl)imidazole by n-butyllithium, followed by substitution with dimethylformamide provided 1-(dimethylsulfamoyl)-2-imidazolecarboxaldehyde in 19% yield. When 1-(dimethylsulfamoyl)-2-(tert-butyldimethylsilyl)imidazole was lithiated by sec-butyllithium, followed by methyl formate, there was obtained 1-(dimethylsulfamoyl)-2-(tert-butyldimethylsilyl)-5-imidazolecarbox-aldehyde (57%). Removal of the silyl group by acetic acid yielded 1-(dimethylsulfamoyl)-5-imidazolecarbxaldehyde ( 11 , 96%) as a gum. Isomerization of 11 took place slowly at room temperature (10 days), or faster in tetrahydrofuran solution containing triethylamine (2 hours) to form crystalline 1-(dimethylsul-famoyl)-4-imidazolecarboxaldehyde (12) in 68% yield. Proton and carbon-13 nmr spectra were analyzed to determine the structure of the isomers. However, only X-ray crystallography established the structure of 1-(dimethylsulfamoyl)-4-imidazolecarboxaldehyde, unequivocally. A mechanism for the isomerization of 11 to 12 is proposed.     

Practical synthesis of methyl(E)-2-(3-(3-(2-(7-chloro-2- quinolinyl)ethenyl)phenyl)-3-oxopropyl)benzoate,a key intermediate of Montelukast

A novel and practical synthetic route is presented for the preparation of methyl-(E)-2-(3-(3-(2-(7-chloro-2-quinolinyl)ethenyl) phenyl)-3-oxopropyl)benzoate,the key intermediate of Montelukast,a leukotriene antagonist.The main diarylpropane framework was prepared via a polarity conversation reaction resulting in an acyl anion equivalent followed by a nucleophilic substitution reaction.The overall yield of this approach was 61%.This method is simple for operation and suitable for industrial production.     

2-(5-取代苯氧甲基-1,3,4-噻二唑-2-亚胺基)-5-(取代苯基亚甲基)-4- 噻唑啉酮的合成

以2-氨基-5-取代苯氧甲基-1,3,4-噻二唑(1)为起始原料, 合成了中间体2-氯乙酰氨基-5-取代苯氧甲基-1,3,4-噻二唑)-2-乙酰亚胺(2)和2-(5-取代苯氧甲基-1,3,4-噻二唑-2-亚胺基)-4-噻唑啉酮(3), 化合物3进一步与取代苯甲醛发生类Knoevenagle缩合反应, 得到了一系列2-(5-取代苯氧甲基-1,3,4-噻二唑-2-亚胺基)-5-(取代苯基亚甲基)-4-噻唑啉酮类化合物4a～4p. 目标化合物4a～4p的结构经IR, ¹H NMR和元素分析确证.     

(E)-1-alkyl-4-

(E)-1-Alkyl-4-[2-(alkylsulfonyl)-1-ethenyl]pyridinium salts were synthesized in two steps. These sulfones were stable at pH 7.3 and underwent a nucleophilic vinylic substitution (S(N)V) with mercaptans, including thiouracile, to give the corresponding 4-(thiovinyl)-pyridinium salts. The X-ray diffraction structure of (E)-1-methyl-4-[2-(ethylsulfanyl)-1-ethenyl]pyridinium iodide indicated conjugation of the sulfur with the pyridinium ring. (Z)-1-Methyl-4-[2-(methylsulfanyl)-1-ethenyl]pyridinium iodide, prepared from the corresponding thioether by reaction with methyl iodide in diethyl ether, underwent isomerization to the E isomer in a first-order reaction in deuterated [D6]DMSO with an activation energy of 14 kcalmol(-1). At pH 7, the (E)-1-methyl-4-[2-(methylsulfonyl)-1-ethenyl]pyridinium iodide (19) reacted specifically with thiols. The reaction of this sulfone with glutathione in a TES buffer at pH 7 was a second-order reaction (k = 4,100 M(-1)s(-1) at 30 degrees C) and gave the corresponding substitution product with an intense long wavelength absorption band (lambdamax=360 nm, epsilon = 27,500 M(-1)cm(-1)). The modification of different enzymes of known structure with 19 showed the high selectivity of this reagent towards thiol groups and its usefulness in the quantitative determination of free thiol groups in proteins.