Vinyloge Acylverbindungen. XVIII [1]. Einfluß sterischer Faktoren auf das Reaktionsverhalten vinyloger Carbonamidiumsalze

Vinylogous Acyl Compounds. XVIII. Influence of Steric Factors on the Reaction Behaviour of Vinylogous Carbonamidium Salts Depending on the size of their N-alkyl groups vinylogous carbonamidium salts show a markedly graduated reactivity under suitable conditions. Thus 2-formyl-vinyl trimethylammonium perchlorate 1a is decomposed by sodium hydroxide yielding only trimethylamine and salts of malondialdehyde 2 , while the analogous triethylammonium salt 1b additionally undergoes a fragmentation to triethylamine, acetylene and formic acid. The reaction of 4-(4-nitrobenzyl)-pyridine with 1 and the analogous 2-benzoylvinylammonium salts 3 to the 1,4-dihydropyridine dye 4 and 5 , respectively, is faster by orders of magnitude in the case R′ = CH₃ than in the case R′ = C₂H₅. Contrary to the 1a -p-nitrophenylhydrazone 6a which can be transformed into the pyrazole 7 the 1b -hydrazone 6b withstands such a ring closure. Depending on the reaction conditions and nature of the substituent R the action of aniline on 1 leads either to the monoanils 8 or to the malondialdehyde dianil salt 9 . While piperidine reacts with 3a as well as with 3b to give N-(2-benzoylvinyl)-piperidine 10 , aniline forms a corresponding vinylogous amide 11 only with 3a. 3b , however, on reaction with aniline · HCl via the intermediate monoanil 12 , yields the vinylogous amidinium salt 13 which is not obtainable from 3a or 11 . Using o-phenylendiamine this reactivity graduation can be utilized for preparing 2-aryl-substituted 1H-1,5-benzodiazepinium salts, e.g. 17 .     

Chiral Quaternary Ammonium Aryloxide/N,O‐Bis(trimethyl‐ silyl)acetamide Combination as Efficient Organocatalytic System for the Direct Vinylogous Aldol Reaction of (5H)‐Furan‐2‐one Derivatives

A chiral quaternary ammonium amide was generated in situ from N,O‐bis(trimethylsilyl)acetamide (BSA) as non‐nucleophilic Brønsted base precursor and the combination of chiral quaternary ammonium halide/sodium aryloxide as chiral Lewis base. This system was applied to an anti‐selective organocatalytic direct vinylogous aldol (ODVA) reaction of (5H)‐furan‐2‐one derivatives with aldehydes. Several 5‐(1′‐hydroxy)‐γ‐butenolides were obtained in good diastereomeric ratios (up to 95/5) and excellent enantioselectivities (up to 94%) with both aliphatic or (hetero)aromatic aldehydes, so providing a rare example of general and efficient conditions for the ODVA reaction.     

Stereoselective Synthesis of Donor-Acceptor Cyclopropapyranone by Intramolecular Cyclopropanation of Vinylogous Carbonates: Application to the Total Synthesis of (±)-Diospongin B

An intramolecular, stereoselective cyclopropanation of vinylogous carbonates with carbenes using copper catalyst is developed for the synthesis of donor-acceptor substituted cyclopropapyranones. Completely regioselective ring cleavage of each of the cyclopropane bonds was achieved under suitable reaction conditions, leading to a diverse array of cyclic ethers. The developed method is utilized in the total synthesis of (±)-diospongin B.     

Synthese von Heterocyclen durch C?C-Knüpfung. I. Edelmetall-katalysierte Cyclisierung von Acrylsäure-diallylamid

Synthesis of Heterocycles by C C-Bond Formation. I. Noble Metal Catalyzed Cyclization of Acrylic Acid Diallyl Amide The action of PdCl₂ on acrylic acid diallyl amide 1 leads, by ring closure between the acryloyl group and one of the allyl groups, to a mixture of the five-membered heterocycles 2, 3, 4, 5 and 6 . Additionally, some 7 and 8 is formed by ring closure involving both allyl groups. The latter reaction is predominant on catalysis by RhCl₃, resulting in the formation of 7 besides some 2, 4 and an isomer 14 . With more RhCl₃, quantitative elimination of allyl groups from N-allyl acid amides is observed.     

The Application of 3-Amino-2H-Azirines as Amino Acid Equivalents

3-amino-2H-azirines undergo a number of ring opening reactions. The cleavage of the azirine-N(1), C(3) double bond leads thereby to synthons which can be considered as amino acid equivalents. The reaction of 3-amino-2H-azirines with carboxylic acids yields N-acyl amino acid amides, which can be converted by a selective amide cleavage to the corresponding N-acyl amino acids. 2-Oxazolin-5-ones are intermediates of this amide cleavage. This reaction sequence has been used for the extension of peptide chains as well as for a number of heterocycle syntheses. Likewise, the described synthesis of cyclic depsipeptides and lactones by direct amide cyclization proceeds via 2-oxazolin-5-one intermediates. The selective amide cleavage was also applied to a novel method for the resolution of enantiomeric amino acid derivatives.     

头孢菌素类药物中间体GCLE的合成研究进展

综述了头孢菌素类药物中间体7-苯乙酰胺-3-氯甲基头孢烷烯酸对甲氧基苄酯的合成工艺。其合成路线主要有闭环前卤化法和闭环后卤化法两种,其中闭环前卤化法是先将青霉素亚砜酯开环后与捕捉剂作用,然后再进行烯丙位的氯化,最后闭环,该法应用广泛,但氯化采用电解饱和食盐水,条件不易控制;闭环后卤化法可分为3-环外亚甲基头孢烷酸直接卤化法、7-ADCA光溴化法、3位的-CH2OH直接卤化,该法研究较早,但成本偏高。     

α-Triazolylboronic Acids: A Promising Scaffold for Effective Inhibitors of KPCs

Boronic acids are known reversible covalent inhibitors of serine β-lactamases. The selectivity and high potency of specific boronates bearing an amide side chain that mimics the β-lactam's amide side chain have been advanced in several studies. Herein, we describe a new class of boronic acids in which the amide group is replaced by a bioisostere triazole. The boronic acids were obtained in a two-step synthesis that relies on the solid and versatile copper-catalyzed azide–alkyne cycloaddition (CuAAC) followed by boronate deprotection. All of the compounds show very good inhibition of the Klebsiella pneumoniae carbapenemase KPC-2, with K_i values ranging from 1 nM to 1 μM, and most of them are able to restore cefepime activity against K. pneumoniae harboring bla_KPC-2. In particular, compound 1 e , bearing a sulfonamide substituted by a thiophene ring, proved to be an excellent KPC-2 inhibitor (K_i=30 nM); it restored cefepime susceptibility in KPC-Kpn cells (MIC=0.5 μg/mL) with values similar to that of vaborbactam (K_i=20 nM, MIC in KPC-Kpn 0.5 μg/mL). Our findings suggest that α-triazolylboronates might represent an effective scaffold for the treatment of KPC-mediated infections.     

Expeditious and Convenient Synthesis of Polycyclic Difluoroboron Complexes of 2‐Oxoindoline‐3‐carboxamides by Tandem Reaction

N‐Aryl‐2‐cyanodiazoacetamides produce polycyclic difluoroboron 2‐oxoindoline‐3‐carboxamide complexes (up to pentacyclic conjugative and fused systems) directly and expeditiously in the presence of boron trifluoride etherate. The boron trifluoride serves as both a catalyst and reactant in the tandem reaction. The tandem reaction includes the carbene aromatic C H insertion, hydrolysis of the cyano group into an amide group, and boronation of the two amide carbonyl groups. The synthetic method features the advantages of wide substrate scope and excellent chemoselectivity.

     

Catalytic,Enantioselective Vinylogous Mukaiyama Aldol Reaction of Furan‐Based Dienoxy Silanes: A Chemodivergent Approach to γ‐Valerolactone Flavan‐3‐ol Metabolites and δ‐Lactone Analogues

The asymmetric synthesis of a set of hydroxyphenyl γ‐valerolactones was achieved starting from 2‐silyloxyfuran and alkoxy‐substituted benzaldehydes as common precursors. Key synthesis steps included an enantioselective vinylogous Mukaiyama aldol reaction and a Barton–McCombie deoxygenation. Five enantioenriched γ‐valerolactone targets were obtained in 5–6 steps, 18–63% overall yields and 82–98 % ee, paving the way for the straightforward entry to this class of biologically effective and poorly available flavan‐3‐ol metabolites. In parallel, an unprecedented one‐pot reductive ring expansion process was fortuitously discovered, yielding racemic δ‐lactone analogues from phenolic butanolide precursors.

     

Acetessigaldehyd-dimethylacetal als Ausgangsstoff für Synthesen

Acetoacetaldehyde Dimethylacetal as a Starting Material for Syntheses The use of acetoacetaldehyde dimethylacetal (1) leads to the introduction of the group \documentclass{article}\pagestyle{empty}\begin{document}$ {\rm =}\mathop {\rm C}\limits^{\mathop |\limits^{{\rm CH}_{\rm 2}}} ---{\rm CH}_{\rm 2} ---{\rm CH(OCH}_{\rm 3} {\rm)}_{\rm 2} $\end{document} by reaction at the carbonyl carbon atom, and of the group CH₃–CO–CH₂–CH?or CH₃–CO–CH?CH– by reaction at the acetalic carbon atom. For synthetic purposes it is important that methanol can be splitten off from 1, and the acetoacetaldehyde enol ether methoxybutenone (2) is generated. With catalytic amounts of acids or bases an equilibrium mixture with 70% 1 and 30% 2 is formed; 2 shows the higher reactivity of a vinylogous acetic ester. 1 as well as 2 can be attacked at each of the four carbon atoms; ring closure reactions were observed with the carbon atom 2 or 4 alone, or with two carbon atoms (6 possibilities, prevalent 2 + 4), and occasionally by participation of two molecules of 1 or 2.     

Thermally reactive phenylethynyl-terminated bis(benzylester) and bis(amide) monomers based on semi-enzymatically produced 6-phenylethynyl picolinic acid

The synthesis and isolation of 6-phenylethynyl picolinic acid (PEPCA; IUPAC name: 6-(2-phenylethynyl)pyridine-2-carboxylic acid) was first demonstrated when Acinetobacter sp. strain F4 was used to biotransform diphenylacetylene to the ring-fission product that underwent facile ring closure to form PEPCA in the presence of ammonium ions. Here, the structure and properties of PEPCA were confirmed by comparison with those of PEPCA that was chemically synthesized. In the chemical route, commercially available 6-bromopicolinic acid was first converted to methyl 6-bromopicolinate using methyl iodide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The resulting methylester was coupled with phenylacetylene by the palladium-catalyzed reaction to yield methyl 6-phenylethynyl picolinate, which was then hydrolyzed by sodium carbonate to afford PEPCA. Both enzymatically and chemically synthesized PEPCA were used to prepare its thermally reactive bis(benzylester) and bis(amide) derivatives. Thus, three phenylethynyl-terminated bis(amide) derivatives were synthesized by treating PEPCA with 1,3-phenylenediamine, 4,4′-oxydianiline or 4,4′-(hexafluoroisopropylidene)dianiline via dicyclohexylcarbodiimide (DCC)-mediated amidation. The bis(benzylester) derivative was prepared from PEPCA and α,α′-dibromo-p-xylene. All the intermediates and final products were characterized by FT-IR, NMR, MS and elemental analysis. The thermal properties of PEPCA and the reactive derivatives were characterized by DSC and TGA. The exothermic peaks of three bis(amide) derivatives were at least 20-40 °C lower than typically reported for the phenylethynyl compounds. Lowered reaction temperatures observed for the thermally-induced free radical polymerization of phenylethynyl groups were attributed to the strong electron-withdrawing capability of the pyridine moiety. Bis(amide) derivatives exhibited excellent thermal stability after previously cured at 300 °C for 30 min and 350 °C for 30 min.     

A New Robust and Efficient Ion‐Tagged Proline Catalyst Carrying an Amide Spacer for the Asymmetric Aldol Reaction

The synthesis of a new, highly efficient cis‐ion‐tagged catalyst ( 8a ), possessing an amide linkage between the imidazolium tag and the proline ring, is described. This new bench‐stable catalyst has been tested in the classic asymmetric aldol condensation between ketones and aldehydes “in the presence” of water, and is proposed as a valuable alternative to the analogous but more sensitive ester cis‐ 2d . Catalyst 8a displayed an excellent efficiency in terms of catalyst loading and stereochemical control.     

Hexafluoroisopropyl Carbamates as Selective MAGL and Dual MAGL/FAAH Inhibitors: Biochemical and Physicochemical Properties

A series of hexafluoroisopropyl carbamates with indolylalkyl- and azaindolylalkyl-substituents at the carbamate nitrogen was synthesized and evaluated for inhibition of the endocannabinoid degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The synthesized derivatives with butyl to heptyl spacers between the heteroaryl and the carbamate moiety were inhibitors of both enzymes. For investigated compounds in which the alkyl chain was partially incorporated into a piperidine ring, different results were obtained. Compounds with a methylene spacer between the piperidine ring and the heteroaromatic system were found to be selective MAGL inhibitors, while an extension of the alkyl spacer to two to four atoms resulted in dual inhibition of FAAH/MAGL. The only small change in enzyme inhibitory activity with variation of the heteroaromatic system indicates that the reactive hexafluoroisopropyl carbamate group is mainly responsible for the strength of the inhibitory effect of the compounds. Selected derivatives were also tested for hydrolytic stability in aqueous solution, liver homogenate and blood plasma as well as for aqueous solubility and for permeability in a Caco-2 cell model. Some compounds showed a slightly higher MAGL inhibitory effect than the known selective MAGL inhibitor ABX-1431 and also partly surpassed this substance with regard to certain physicochemical and biochemical properties such as water solubility and cell permeability.     

Continuous enzymatic synthesis of Z-kyotorphin amide in an enzyme-immobilized fixed-bed reactor

α-Chymotrypsin immobilized on natural and inexpensive supports such as diatomaceous earth was used as catalyst for Z-Tyr-Arg-NH₂ (Z-kyotorphin amide) synthesis. In order to obtain the optimal reaction conditions, a 2² factorial experimental design was used. The factors considered were cosolvent (dimethylformamide) concentration and temperature; optimal product yield was achieved at 40% (v/v) dimethylformamide and 25°C. A sequential kinetic model was considered which generally gave good agreement between experimental and theoretical data for continuous synthesis of Z-kyotorphin amide in a packed-bed immobilized reactor system. The activation energy for the synthesis was determined to be 48.0 ± 2.3 kJ mol^?1.     

Fabrication of photochromic hydrogels using an interpenetrating chitosan network

The synthesis of a novel interpenetrating chitosan network post‐modified with spiropyran (SP) derivatives has been used to develop photochromic hydrogels. We have synthesized succinyl chitosan polymers containing a considerable number of both amines and carboxylic groups. Their intra/inter molecular amide coupling reactions and postmodification with SP derivatives resulted in the photochromic hydrogels functionalized with chitosan‐based interpenetrating polymer network structures. In this hydrogel system, SPs undergo reversible photoresponsive structural switching between a ring‐closed colorless SP form and a ring‐opened purple merocyanine form under specific light‐irradiation conditions. Notably, the photo‐mediated wettabilities and color intensities of the hydrogels increase by the increment in the molecular weight of SP‐functionalized chitosans. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 45120.     

褐煤的生物标志物研究

本工作用氯仿抽提札赉诺尔和寻甸褐煤，抽出物的正己烷可溶部分再用氧化铝－硅胶柱色谱分离。饱和烃和芳烃等生物标志物进一步用ＧＣ，ＧＣ－ＭＳ分析其组成特征。检测出正构烷烃，类异戊二烯烃、萜芳烃和三萜芳烃以及一种未见文献报道的三环二萜烯。札煤的芳烃段分以二萜芳烃为主，而寻甸褐煤则以三萜芳烃为主。文中还讨论了寻甸褐煤中五元和六元Ｅ环三萜芳烃的形成过程。     

An FT-IR study of the conversion of 2-chloropropane, o-dichlorobenzene and dibenzofuran on V2O5-MoO3-TiO2 SCR-DeNOx catalysts

Spectra of the adsorbed species arising from contact of a V₂O₅-MoO₃-TiO₂ model SCR catalyst with ortho-dichlorobenzene (o-DCB) and dibenzofuran (DBF) and their evolution with the temperature are presented and discussed. Dichlorobenzene adsorbs weakly probably on Lewis acid sites through the chlorine atom. A very fast nucleophilic substitution on dichlorobenzene to a chlorophenate species occurs already at RT. On the contrary, adsorption of dibenzofuran is molecular, probably through the oxygen atom on Lewis sites. The aromatic rings of both molecules tend to be later oxidized to give carboxylate species. Parallel experiments with chloropropane show that dehydrochlorination occurs readily, hydrochloric acid is adsorbed quite weakly and that propene can be further oxidized. However, heavier oxidized species like cyclic anhydrides are also formed from chloropropane. The data suggest that the dechloration step of the phenyl ring could be not critical. On the contrary, the building-up of aromatic compounds from smaller molecules is possible and the oxidation of phenyl ring can be slow near reaction conditions. The possibility that the reaction between phenate species and chlorobenzenes give the “de novo” synthesis of dioxins is envisaged.     

一种4-氮甾体激素化合物的合成

以孕甾双烯醇酮醋酸酯为起始原料,经次溴酸钠氧化、甲醇甲酯化得到3-羰基-4-雄甾烯-17-羧酸甲酯,再经Oppenauer氧化、双键的氧化切断、氨解环合、Δ~5双键加氢、酯氨解反应得酰胺类中间产物,然后碘化和脱碘反应进行1,2位脱氢合成非那甾胺.     

Electrochemical synthesis of polypyrrole in ionic liquids

Electrochemical synthesis of inherently conducting polymers such as polypyrrole is traditionally performed in a molecular solvent/electrolyte system such acetonitrile/lithium perchlorate. We report the use of ionic liquids 1-butyl-3-methylimidazolium hexafluorophosphate, 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl) amide and N,N-butylmethylpyrrolidinium bis(trifluoromethanesulfonyl) amide, both as the growth medium and as an electrolyte for the electrochemical cycling of polypyrrole films. Use of the ionic liquid as the growth medium results in significantly altered film morphologies and improved electrochemical activities.     

UV induced reversible chain extension of 1-(2-anthryl)-1-phenylethylene functionalized polyisobutylene

The synthesis of novel 1-(2-anthryl)-1-phenylethylene (APE) di-telechelic polyisobutylenes is described. Utilization of a difunctional cationic initiator and the in situ addition of the non-homopolymerizable APE lead to the formation of di-anthryl telechelic polyisobutylenes. Products were characterized by ¹H NMR spectroscopy and Size Exclusion Chromatography. The polymers were UV irradiated at 365 and 254 nm and the reversible photocycloaddition of anthryl moieties was investigated. The chain extension of di-anthryl telechelic PIBs through photocoupling at 365 nm produced higher molecular weight products from low molecular weight precursors. The effect of precursor polymer concentration on the degree of chain extension was investigated, and intermolecular interactions leading to the formation of tetramers was observed. The photocoupled products were UV irradiated at 254 nm to induce the reversal of photocycloaddition of anthryl groups and to follow the consequent photoscission of polymers.