2-吡咯烷甲醇法合成切叶蚁警戒信息素

甲基庚酮;昆虫信息素;不对称烷基化反应;2-吡咯烷甲醇法合成切叶蚁警戒信息素     

Polymethylated DOTA ligands. 1. Synthesis of rigidified ligands and studies on the effects of alkyl substitution on acid-base properties and conformational mobility

This work describes the synthesis and the conformational properties of new polymethylated macrocyclic ligands of potential interest for magnetic resonance imaging. M4cyclen, (2S,5S,8S,11S)-2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecane, was obtained by cyclotetramerization of (2S)-1-benzyl-2-methylaziridine followed by catalytic hydrogenation. The ligands M4DOTA, [(2S,5S,8S,11S)-4,7,10-tris-carboxymethyl-2,5,8,11-tetramethyl- 1,4,7,10-tetraazacyclododecan-1-yl]acetic acid, and M4DOTMA, (R)-2-[(2S,5S,8S,11S)-4,7,10-tris-((R)-1-carboxyethyl)-2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecan-1-yl]propionic acid, were prepared by carboxyalkylation of M4cyclen in the presence of Na(2)CO(3). The triacetic ligand M4DO3A, [(2S,5S,8S,11S)-4,7-bis-carboxymethyl-2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecan-1-yl]acetic acid, was obtained in good yields without traces of M4DOTA if NaHCO(3) was the acid scavenger when adding the carboxylic arms. In the same conditions, cyclen yielded M4DOTA in 82% yield. The difference between the reactivity of cyclen and M4cyclen is assigned to the high basicity of the substituted tetraamine as estimated by NMR titration. The one- and two-dimensional (1)H and (13)C NMR spectra of M4DOTA and M4DOTMA in the H(4)L or H(6)L(2+) forms are interpreted as arising from a slow exchange between two elongated geometries in which the methyl substituents are in one of the two possible equatorial-like positions, either close to or away from the carboxylic arms. The axial-like positions are sterically too crowded and cannot be occupied by the methyl groups. An elongated conformation is also adopted by DOTMA, (R)-2-[4,7,10-tris-((R)-carboxyethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propionic acid, in the H(6)L(2+) form. The rigidification of the polymethylated ligands allows a detailed NMR analysis that cannot be carried out on the parent unsubstituted ligand DOTA.     

(R)-N-(β-三氯锗取代丙酰基)TTCA酯的合成及其倍半氧化物

β-三氯锗取代丙酰氯1a～1c与(R)TTCA酯反应, 得到光学活性的(R)-N-(β-三氯锗取代丙酰基)TTCA酯3a～3d([α]D^2^0-86.00～-94.35ⅲ)及光学活性的β-三氯锗取代丙酰氯2a～2d。化合物3a～3d经水解得到(R)-N-(β-取代丙酰基)TTCA酯基锗倍半氧化物4a～4d, [α]D^2^0-44.48～-77.00ⅲ。用半经验量子化学MNDO方法研究了反应物和产物最优构型的电子结构及反应的焓变。     

Stereospecific substitution of enantiomerically pure 1-(2-pyridinyl)ethyl methanesulfonate with beta-dicarbony compounds

The alkylation of the sodium salt of the malonic acid diester with (R)-1-(2-pyridinyl)ethyl methanesulfonate (2) gave the dimethyl (R)-[1-(2-pyridinyl)ethyl]malonate (3a), stereospecifically. The alkylation reaction of methyl acetoacetate gave the methyl (2'S,2R/2S)-3-oxo-2-[1-(2-pyridinyl)ethyl]butanoate (3d) along with the methyl (S)-3-[1-(2-pyridinyl)ethoxy]-2-butenoate (4d). The acid hydrolysis and decarboxylation of 3d under acidic conditions gave (R)-4-(2-pyridinyl)pentan-2-one (6), and the alkylation of methyl (R)-[1-(2-pyridinyl)ethyl]acetoacetate with benzyl bromide gave a mixture of C-benzylated and O-benzylated products 7 and 8.     

SuperQuat N-acyl-5,5-dimethyloxazolidin-2-ones for the asymmetric synthesis of alpha-alkyl and beta-alkyl aldehydes

The proclivity of alpha-branched N-2'-benzyl-3'-phenylpropionyl derivatives of (S)-4-benzyl-5,5-dimethyl-, (S)-4-phenyl-5,5-dimethyl-, (S)-4-isopropyl-5,5-dimethyl-, (S)-4-benzyl- and (S)-4-benzyl-5,5-diphenyl-oxazolidin-2-ones to generate directly 2-benzyl-3-phenylpropionaldehyde upon hydride reduction with DIBAL is investigated. The (S)-4-benzyl-5,5-dimethyl-derivative proved optimal for inhibition of endocyclic nucleophilic attack, giving 2-benzyl-3-phenylpropionaldehyde in good yield upon reduction. Application of this methodology for the asymmetric synthesis of chiral aldehydes via diastereoselective enolate alkylation of a range of (S)-N-acyl-4-benzyl-5,5-dimethyloxazolidin-2-ones to afford and array of alpha-substituted-N-acyl-5,5-dimethyloxazolidin- 2-ones (85-94% de) and subsequent reduction with DIBAL afforded directly non-racemic alpha-substituted aldehydes without loss of stereochemical integrity (87-94% ee). The extension of this protocol for the asymmetric synthesis of beta-substituted aldehydes is demonstrated, via the diastereoselective conjugate addition of a range of organocuprates to (S)-N-acyl-4-phenyl-5,5-dimethyloxazolidin-2-ones which proceeds with high diastereoselectivity (generally > 95% de). Reduction of the conjugate addition products with DIBAL gives non-racemic beta-substituted aldehydes in high yields and in high ee (generally > 95% ee). This methodology is exemplified by the asymmetric synthesis of (R)-3-isopropenylhept-6-enal, which has previously been used in the synthesis of (3Z,6R)-3-methyl-6-isopropenyl-3,9-decadien-1-yl acetate, a component of the sex pheromones of the California red scale.     

Regioselective 1,3-Dipolar Cycloaddition Reactions of Unsymmetrical Münchnones (1,3-Oxazolium-5-olates) with 2- and 3-Nitroindoles. A New Synthesis of Pyrrolo[3,4-b]indoles

The unsymmetrical mesoionic münchnones 13 (3-benzyl-2-methyl-4-phenyl-1,3-oxazolium-5-olate) and 14 (3-benzyl-4-methyl-2-phenyl-1,3-oxazolium-5-olate) react with the N-protected 2- and 3-nitroindoles 1 (ethyl 2-nitroindole-1-carboxylate), 6 (3-nitro-1-(phenylsulfonyl)indole), and 17 (ethyl 3-nitroindole-1-carboxylate) in refluxing THF to afford in good to excellent yields the pyrrolo[3,4-b]indoles 15 (2-benzyl-1-methyl-3-phenyl-4-carboethoxy-2,4-dihydropyrrolo[3,4-b]indole), 16 (2-benzyl-3-methyl-1-phenyl-4-carboethoxy-2,4-dihydropyrrolo[3,4-b]indole), 18 (2-benzyl-1-methyl-3-phenyl-4-(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]indole), and 19 (2-benzyl-3-methyl-1-phenyl-4-(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]indole). In several cases the regiochemistry, which is opposite to that predicted by FMO theory, is very high and leads essentially to a single pyrrolo[3,4-b]indole; e.g., 6+13→19 in 74% yield.     

利用Reformatsky反应合成1-β-碳氢霉烯类抗生素中间体

以(2R)-3-[(3S,4R)-1-(叔丁基二甲基硅氧基)乙基]-4-乙酰氧基氮杂环丁-2-酮为母体,2-溴乙(丙)酸酯或2-溴丙酰胺为亲核试剂,通过Reformatsky反应合成了一系列新型的1-β-碳氢霉烯类抗生素中间体——3-{(2R)-2-[(3S,4R)-1-(叔丁基二甲基硅氧基)乙基]氮杂环丁-2-酮-4-基}乙(丙)酸酯(3a～3d)和3-{(2R)-2-[(3S,4R)-1-(叔丁基二甲基硅氧基)乙基]氮杂环丁-2-酮-4-基}-N,N-二取代丙酰胺(3e,3i和3k),其结构经1H NMR和13C NMR表征,其中3a～3e和3i未见文献报道。     

Synthesis and structure of new 3,7-diazabicyclo[3.3.1]nonane derivatives

Aminomethylation of triethylammonium 4-aryl-3,5-dicyano-6-oxo-1,4,5,6-tetrahydropyridin-2-olates and their sulfur and selenium analogs, as well as the structure of formed products, were studied in details. The reaction is of general character and leads to the formation of 7-substituted 9-aryl-2,4-dioxo-, 9-aryl-4-oxo-2-thioxo-, 9-aryl-4-oxo-2-selenoxo-3,7-diazabicyclo[3.3.1]nonane derivatives or their salts. The structures of ethyl 9-(2-chlorophenyl)-5-cyano-7-(4-methylphenyl)-2-oxo-4-thioxo-3,7-diazabicyclo[3.3.1]nonane-1-carboxylate (as a complex with N-methylmorpholine) and triethylammonium salt of 7-benzyl-4-oxo-2-selenoxo-9-(2-thienyl)-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarbonitrile were studied by X-ray crystallography.     

(R)-N-(β-三氯锗丙酰基)四氢噻唑-2-硫酮-4-羧酸甲酯的合成及其晶体结构

三氯锗丙酰氯与(R)-四氢噻唑-2-硫酮-4-羧酸甲酯反应, 得到标题化合物1, [α]~D^2^0-89.40°。经水解得到取代丙酰四氢噻唑-2-硫酮-4-羧酸甲酯基锗倍半氧化物2, X射线衍射法测出标题化合物的晶体结构, 属于正交晶系, 晶胞参数: a=0.6192(1)nm,b=1.1147(4)nm,c=2.1796(8)nm, V=1.5045nm^3, Z=4, 空间群P2~12~12~1。分子中酰胺羰基C=O与C=S基团处于C(4)NC(3)键两侧呈反式。用MNDO分子轨道方法研究了该化合物的电子结构, 电荷和键序分布,前沿轨道性质,讨论了电子光谱性质。     

Asymmetric Synthesis of 2-Arylpropionic Acids

The preparation of (S)-2-(6-methoxy-2-naphtyl)propionic acid (S-Naproxen) 1 and (S)-2-(4-isobutylphenyl)propionic acid (S-Ibuprofen) 2, based on asymmetric alkylation of oxazolidiones 9 and 14, is reported.     

Synthesis of carbon-14 labeled 1-acetoxyethyl 2-(2-fluoro-4-biphenyl)propionate (14C-FP 83)

1-Acetoxyethyl 2-(2-fluoro-4-biphenylyl) [14C-methyl]propionate (14C-Me-FP 83), a novel nonsteroidal antiinflammatory agent for injection, was synthesized in order to investigate the metabolic fate. 14C-Me-FP 83 was obtained by the condensation of 2-(2-fluoro-4-biphenylyl) [14C-methyl]propionic acid with 1-chloroethyl acetate. The chemical yield of 1 was 62% after purification. The specific activity was 258 kBq/mg (6.99 microCi/mg) and its radiochemical purity was 99% in thin layer chromatographic method.     

Assembly of polyamines via amino acids from three components using cobalt(III) template methodology

A versatile and efficient template synthesis has been developed to synthesise novel polyamines [e.g. rac-N3-(3-aminopropyl)butane-1,3-diamine, isospermidine 1] via amino acids [e.g. (2R,4S/2S,4R)-N4-(3-aminopropyl)-2,4-diaminopentanoic acid] using cobalt(III) to assemble the three precursor components in a biomimetic manner.     

3-[N-(4-甲基苯基)氨基羰基]-5-[4-(4-甲酸基苯甲氧基)苯亚甲基]-2,4-噻唑烷二酮的合成

以对甲苯胺和对甲基苯甲酸甲酯为起始原料,经NBS溴化、亲核取代、酸水解和Knoevenagel缩合等6步反应合成了抗细菌生物膜化合物—3-[N-(4-甲基苯基)氨基羰基]-5-[4-(4-甲酸基苯甲氧基)苯亚甲基]-2,4-噻唑烷二酮,总收率57.3％,其结构经1H NMR,ESI-MS和元素分析确证.     

Synthesis of the Chiral Pair of a Novel Thromboxane Antagonist, 3‐[2‐(3‐Benzenesulfonylamino‐7‐oxabicyclo[2.2.1]hept‐2‐yl‐methyl)phenyl] Propionic Acid

Preparation of the enantiomeric pair of 3‐[2‐(3‐benzenesulfonylamino‐7‐oxabicyclo[2.2.1]hept‐2‐yl‐methyl)phenyl] propionic acid, a novel thromboxane antagonist is reported. They are synthesized from either enantiomers of known (1R,2R,3R,4S)‐3‐[2‐(3‐carboxy‐7‐oxabicyclo[2,2,1]hept‐2‐yl‐methyl)phenyl]‐propionic acid methyl ester via epimerization, modified Curtius' rearrangement and sulfonylamino formation. Other derivatives may be prepared similarly.     

Synthesis and characterization of novel 2-(1-benzyl-3-[4-fluorophenyl]-1H-pyrazol-4-yl)-7-fluoro-4H-chromen-4-one derivatives

Novel 1-benzyl-3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehydes 3a to 3e were synthesized via Vilsmeier-Haack reaction of the appropriate 1-benzyl-2-(1-(4-fluorophenyl)ethylidene)hydrazines, derived from 4-fluoroacetophenone 1 with substituted 2-benzylhydrazines 2a to 2e . The base catalyzed condensation of 1-benzyl-3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehydes 3a to 3e with 1-(4-fluoro-2-hydroxyphenyl)ethanone 4 gave (E)-3-(1-benzyl-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-1-(4-fluoro-2-hydroxyphenyl)prop-2-en-1-ones 5a to 5e . On cyclization with dimethyl sulfoxide (DMSO)/I₂, compounds 5a to 5e gave 2-(1-benzyl-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-7-fluoro-4H-chromen-4-ones 6a to 6e . Structures of all novel compounds were confirmed by infrared (IR), proton nuclear magnetic resonance (¹H NMR), carbon nuclear magnetic resonance (¹³C NMR), and mass spectral data. All the synthesized compounds were screened for their antibacterial activities.     

A practical procedure for the synthesis of esonarimod, (R,S)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid,an antirheumatic agent (part 1)

An efficient and practical procedure for the synthesis of esonarimod, (R,S)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (1), a new antirheumatic drug, has been developed. The intermediate, 2-methylene-4-(4-methylphenyl)-4-oxobutanoic acid (2), was prepared by Friedel-Crafts acylation of toluene with itaconic anhydride (3) in the presence of aluminum trichloride and nitrobenzene in 63% yield without silica gel column purification. Compound 1 was prepared by Michael addition of 2 with thioacetic acid (4) in 74% yield. Overall, 1 was obtained in 47% yield from 3. The structures and synthetic mechanisms of by-products (five compounds) of 2 were also clarified.     

The synthesis of azole derivatives from 3-[(4-methylphenyl)amino]propanehydrazide and its N′-phenylcarbamoyl derivatives, and their antibacterial activity

Abstract  

5-[2-[(4-Methylphenyl)amino]ethyl]-1,3,4-oxadiazol-2(3H)-thione, 5-[2-[(4-methylphenyl)amino]ethyl]-1,3,4-oxadiazol-2(3H)-one, N-(2,5-dimethyl-1H-pyrrol-1-yl)-3-[(4-methylphenyl)amino]propanamide, and a series of N-[(phenylcarbamoyl)amino]-3-[(4-methylphenyl)amino]propanamides and 3-[(4-methylphenyl)(phenylcarbamoyl)amino]-N-[(phenylcarbamoyl)amino]propanamides, and their thio analogues were synthesized from 3-[(4-methylphenyl)amino]propanehydrazide. 1,3,4-Oxadiazole-2(3H)-thione was converted to 4-amino-2,4-dihydro-5-[2-[(4-methylphenyl)amino]ethyl]-3H-1,2,4-triazole-3-thione, whereas cyclization of N′-phenylcarbamoyl derivatives provided thiazole, oxadiazoles, and thiadiazole, as well as triazole derivatives. Two of the synthesized compounds exhibited good antibacterial activity against Rhizobium radiobacter.     

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.     

Condensation of 5-(4-methylphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione with haloacetic acids

Reactions of triazolethiones with haloacetic acids were studied with 5-(4-methylphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione as an example. It was proved for the first time by X-ray diffraction that the cyclocondensation of these compounds proceeds regiospecifically to give 2-(4-methylphenyl)[1,3]thiazolo[3,2-b][1,2,4]triazol-6(5H)-one rather than its isomer 3-(4-methylphenyl)[1,3]thiazolo[2,3-c][1,2,4]triazol-5(6H)-one.     

天然海洋环酯肽Stereocalpin A中间体的合成

以D-苯丙氨酸为原料,经过硼氢化钠/碘还原后与三光气在碱性条件下环合得到Evans手性助剂(R)-4-苄基-2-噁唑烷酮(2),然后将其与丙酰氯缩合,经过LDA偶联、反式Aldol等反应,合成了天然环酯肽StereocalpinA中含有的独特结构片段,该片段对3种人实体瘤细胞系(HT-29,B16/F10,HepG2)具有中等细胞毒性,总收率为30.6%。结果表明,合成路线简便可行,反应产率高,立体选择性好。是制备该化合物的有效途径。