Stereoselective synthesis of azasugars by electrochemical oxidation

A new method using electrochemical oxidation has been exploited for the stereoselective synthesis of 2,3,6-trihydroxylated 5S-piperidine derivatives. The electrochemical method was successively used for the conversion of N-protected piperidines to N-protected 1-methoxypiperidines and for the conversion of 1-methoxy-2,3-didehydropiperidine derivatives to 1,2,3-triacetoxypiperidine derivatives. The method provided a new synthetic route to 2S,3S,6-triacetoxy-5S-methylpiperidine and 2R,3R,6-triacetoxy-5S-methylpiperidine.     

Synthesis of chiral,non-racemic ferrocene derivatives by ortho-metallation and partial reductive removal of ortho-directing amino groups

Chiral, non-racemic 1,2-disubstituted ferrocenes have been prepared from monosubstituted ferrocene derivatives by amine-mediated ortho-directed reactions and subsequent partial reductive removal of the stereogenic ortho-directing group. It was found that the ortho-directing amino group of 2-substituted derivatives of N,N-dimethylaminoethyl-ferrocene and similar compounds can, after quaternisation with methyl iodide, be reductively removed with sodium borohydride to give 2-substituted methyl- or ethylferrocenes. In most cases the substituents I, Br, COOEt, P(O)Ph₂ and CN tolerate the reaction conditions used. In addition, a few examples are reported that show how the use of LiTMP allows 2-bromo- and especially 2-cyano-substituted derivatives to be further ortho-lithiated and reacted to give 1,2,3-trisubstituted ferrocenes.     

Selective synthesis of (E)-triethyl(2-arylethenyl)silane derivatives by reaction of aryl bromides with triethyl vinylsilane catalysed by a palladium-tetraphosphine complex

Cis, cis, cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane / 0.5 [PdCl(C₃H₅)]₂ system catalyses the Heck reaction of vinylsilane derivatives with a range of aryl bromides with high ratio substrate/catalyst in good yields. The formation of mixtures of styrene, (E)-triethyl(2-arylethenyl)silane and triethyl(1-arylethenyl)silane derivatives was observed in some cases. Very high selectivities (up to 100%) in favour of the formation of (E)-triethyl(2-arylethenyl)silane derivatives were obtained in the presence of sodium acetate as base. With other bases such as potassium carbonate, the formation of large amounts of styrene derivatives was observed. The reaction tolerates several functions such as fluoro, trifluoromethyl, methoxy, dimethylamino, acetyl, formyl, benzoyl, carboxylate, nitro or nitrile. Moreover, turnover numbers up to 10,000 can be obtained for this reaction.     

Enantiomeric purity enrichment of (R)-tetrahydrothiophene-3-ol sulfonyl derivatives by crystallization

(R)-Tetrahydrothiophene-3-ol sulfonyl derivatives 3–19 were prepared by introduction of various sulfonyl groups at the hydroxyl group of (R)-tetrahydrothiophene-3-ol 1 with low enantiomeric purity (68–74% ee). Crystallization was applied to improve their enantiomeric purity. Improvement in enantiomeric purity depended on the introduced sulfonyl group. The enantiomeric purity of enantiomeric sulfonyl derivatives was improved to more than 90% ee by simple crystallization without using seed crystals. These products from crystallization provided not only higher %ee crystals but also a higher %ee mother liquor. The enantiomeric purity of diastereomeric sulfonyl derivatives was improved remarkably, and the product of the derivative 18 provided the mother liquor with 100% de. Crystallization of these sulfonyl derivatives showed a novel and interesting feature that mother liquors with high enantiomeric purity were obtained in many cases.     

An efficient one-pot synthesis of spiro dihydrofuran fluorene and spiro 2-hydroxytetrahydrofuran fluorene derivatives via [3+2] oxidative cycloaddition mediated by CAN

Spiro dihydrofuran fluorene derivatives were prepared via [3+2] oxidative cycloaddition of 1,3-dicarbonyl compounds to 9-benzylidene-9H-fluorene and 2-(9H-fluorene-9-ylidene)-1-phenylethanone derivatives mediated by ceric ammonium nitrate. In the case of the reaction of 9-benzylidene-9H-fluorene with acyclic 1,3-dicarbonyl compounds, spiro 2-hydroxytetrahydrofuran fluorene derivatives were obtained.     

Removal of boron(III) by N-methylglucamine-type cellulose derivatives with higher adsorption rate

To obtain adsorbents for boron(III) derived from a natural polymer, two forms (powder and fiber) of N-methylglucamine-type cellulose derivatives were newly synthesized. After the graft polymerization of two forms of cellulose with vinyl monomer having epoxy groups, the N-methylglucamine-type cellulose derivatives were obtained by the reaction of the grafted cellulose with N-methylglucamine. The adsorption capacities of the cellulose derivatives for boron(III) were the same levels as that of a commercially available N-methylglucamine-type polystyrene resin. However, the cellulose derivatives adsorbed boron(III) more quickly than the polystyrene resin. The adsorption and desorption of boron(III) with a column method using the cellulose fiber were achieved at a higher flow rate than that using the polystyrene resin. In addition, the boron(III), adsorbed on the cellulose fiber column, was quantitatively recovered with dilute hydrochloric acid in 20- and 200-fold increased concentrations. Consequently, it was found that the cellulose derivatives were superior to the polystyrene resin as adsorbents for boron(III) for treatment of a large quantity of wastewater.     

Aza-Michael reactions catalyzed by samarium diiodide

Samarium diiodide catalyzes the Michael addition of aromatic amines onto α,β-unsaturated N-acyloxazolidinones to form β-aminoacid derivatives. Aza-Michael reactions can be followed by an amidation reaction with the aromatic amine, leading to β-aminoamides. β-Amino-N-acyloxazolidinones are selectively obtained with o-anisidine, while amidation reaction is observed with p-anisidine.     

Prenylation of tyrosine and derivatives by a tryptophan C7-prenyltransferase

7-DMATS from Aspergillus fumigatus and SirD from Leptosphaeria maculans catalyse a C7-prenylation of l-tryptophan and an O-prenylation of l-tyrosine in nature, respectively. SirD was reported to catalyse the C7-prenylation of l-tryptophan and some derivatives thereof in vitro. We report here the O-prenylation of tyrosine and O- or N-prenylation of its derivatives by 7-DMATS. These results provide experimental evidence for the close relationship of tyrosine O- and tryptophan C7-prenyltransferases regarding their substrate and catalytic promiscuity.     

Electronic effects of icosahedral carboranes: mechanistic alteration in solvolysis of α-(o-carboranyl)benzyl tosylates by electronic effect of substituents

Solvolysis of α-(o- and m-carboranyl)benzyl toluene-p-sulfonates bearing a range of substituents at the 3- or 4-position of the benzyl group has been investigated. The rates of hydrolysis of m-carboranyl derivatives increased linearly with increasing electron-releasing character of the substituent group (ρ=−5.37 correlated to σ⁺), which indicates that the hydrolysis proceeds through a typical S_N1 process. In contrast, the hydrolysis rates of the o-carboranyl derivatives with a wide range of electron-withdrawing substituents did not show significant change, but suddenly began to show a linear increase with increasing electron-releasing character of the substituents (ρ=−5.91 correlated to σ⁺). Moreover, the optical purity of the retentive hydrolysis of the o-carboranyl derivatives rapidly declined with increasing electron-donating effects of the substituents. This indicates that the mechanism of the hydrolysis changes from the retentive mechanism to an S_N1 mechanism.     

A new synthesis of ring-fused alkylidenecyclobutanes by ring-enlargement reaction of bicyclo[n.1.0]alkylidene derivatives

Bicyclo[n.1.0]alkylidene derivatives (ring-fused alkylidenecyclopropanes) reacted with diazomethane to give spiro-pyrazolines regioselectively. Thermal decomposition of spiro-pyrazolines resulted in ring-enlargement and afforded ring-fused alkylidenecyclobutanes (bicyclo[n.2.0]alkylidene derivatives) in high yields.     

Reduction of various ketones by red algae

The reduction of acetophenone derivatives, (+)- and (−)-camphorquinones and steroidal ketones using red algae (Cyanidioschyzon merolae 10D and Cyanidium caldarium) was investigated. It was found that fluoro, chloro and bromo acetophenone derivatives 1a–i were reduced with good enantioselectivity. On the contrary, reduction of methyl and methoxy acetophenone 1j–o showed low enantioselectivity. The reduction followed Prelog’s rule, giving the (S)-alcohols in all cases. Moreover, (+)- camphorquinone 5a was reduced to give (−)-3S- exo-hydroxycamphor 5d as the major product with high stereoselectivity in high yield. In addition, it was found that reduction of 5α-androstane-3,17-dione 8a gave the 3α-OH isomer (3α-OH/3β-OH = 76/24) with high stereoselectivity. Overall it was found that C. merolae and C. caldarium were able to reduce various substrates.     

Stereodivergent synthesis of both (2S)- and (2R)-1-monoricinolein derivatives by lipase-catalyzed hydrolysis or transesterification directed to new ferroelectric liquid crystals

The preparation of both (2S)- and (2R)-1-monoricinolein derivatives has been developed to synthesize ferroelectric liquid crystals. Lipase-catalyzed hydrolysis of 2-protected-1,3-diricinoleins provided (2S)-1-monoricinolein derivatives with high diastereoselectivities, while transesterification of 2-protected glycerols with vinyl recinoleate gave (2R)-1-monoricinolein counterparts in good yields with high diastereoselectivities.     

Synthesis of 1-thio-phytosphingolipid analogs by microwave promoted reactions of thiols and aziridine derivatives

A practical and versatile method for the synthesis of 1-thio-phytosphingolipid analogs through regioselective nucleophilic ring-opening reactions of phytosphingosine aziridine derivatives with thiols is described. The reactions were carried out with N-acylaziridines and a variety of thiol compounds. Microwave irradiation highly improved the yield of the ring-opening reaction and the intermediate N-acyl adducts were converted into 1-S-phytosphingolipid analogs, such as phytoceramide and phytosphingosine derivatives.     

Aerobic oxidation of cumene catalysed by 4-alkyloxycarbonyl-N-hydroxyphthalimide

4-Hexyloxycarbonyl-, 4-dodecyloxycarbonyl- and 4-hexadecyloxycarbonyl-N-hydroxyphthalimides were synthesised using trimellitic anhydride chloride as the starting material. The obtained lipophilic derivatives of N-hydroxyphthalimide were applied as catalysts of the cumene oxidation reaction with oxygen performed in polar acetonitrile, in non-polar tert-butylbenzene and in the absence of a solvent. The courses of reactions catalysed by N-hydroxyphthalimide and its derivatives were compared.      

Acylative kinetic resolution of racemic aromatic β-hydroxy esters catalyzed by chiral nucleophilic N-(1-arylethyl)benzoguanidines

An efficient acylative kinetic resolution of racemic aromatic β-hydroxy esters with cyclohexanecarboxylic anhydride was achieved using newly designed (R)-N-methylbenzoguanidine ((R)-NMBG) derivatives. A series of (R)-NMBG derivatives was synthesized by modifying the original (R)-NMBG catalyst with the introduction of branched N-substituents containing a stereogenic center, and their catalytic performance was evaluated. (R,R)-N-(1-(β-1-Naphthyl)ethyl)benzoguanidine [(R,R)-NβNpEtBG] was found to function as an efficient acyl transfer catalyst for the reaction of a broad variety of substrates, regardless of the substituent type and substitution pattern.     

Kinetic resolution of vic-amino alcohols catalyzed by a chiral Cu(II) complex

Kinetic resolution of N-benzoylated vic-amino alcohols was achieved by benzoylation in the presence of copper triflate and (R,R)-Ph-BOX as catalysts. The observed enantioselectivity was moderate to high. The method was applied to a kinetic resolution of racemic prolinol and piperidinemethanol derivatives as well as an asymmetric desymmetrization of 2-amino-1,3-diol derivatives.     

Synthesis of Ferulenol by Engineered Escherichia coli: Structural Elucidation by Using the In Silico Tools

4-Hydroxycoumarin (4HC) has been used as a lead compound for the chemical synthesis of various bioactive substances and drugs. Its prenylated derivatives exhibit potent antibacterial, antitubercular, anticoagulant, and anti-cancer activities. In doing this, E. coli BL21(DE3)pLysS strain was engineered as the in vivo prenylation system to produce the farnesyl derivatives of 4HC by coexpressing the genes encoding Aspergillus terreus aromatic prenyltransferase (AtaPT) and truncated 1-deoxy-D-xylose 5-phosphate synthase of Croton stellatopilosus (CstDXS), where 4HC was the fed precursor. Based on the high-resolution LC-ESI(±)-QTOF-MS/MS with the use of in silico tools (e.g., MetFrag, SIRIUS (version 4.8.2), CSI:FingerID, and CANOPUS), the first major prenylated product (named compound-1) was detected and ultimately elucidated as ferulenol, in which information concerning the correct molecular formula, chemical structure, substructures, and classifications were obtained. The prenylated product (named compound-2) was also detected as the minor product, where this structure proposed to be the isomeric structure of ferulenol formed via the tautomerization. Note that both products were secreted into the culture medium of the recombinant E. coli and could be produced without the external supply of prenyl precursors. The results suggested the potential use of this engineered pathway for synthesizing the farnesylated-4HC derivatives, especially ferulenol.     

Accumulation Pattern of Flavonoids during Fruit Development of Lonicera maackii Determined by Metabolomics

Lonicera maackii (Caprifoliaceae) is a large, upright shrub with fruits that contain many bioactive compounds. Flavonoids are common active substances in L. maackii. However, there is a dearth of information about the accumulation of these flavonoids and their possible medicinal value. We used targeted metabolomics analysis based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to analyze five developmental stages of L. maackii fruit. A total of 438 metabolites were identified in the five developmental stages, including 81 flavonoids and derivatives. The 81 flavonoids included 25 flavones and derivatives, 35 flavonols and derivatives, two isoflavones, three cyanidins and derivatives, eight procyanidins, and eight flavanones. In addition, we outlined the putative flavonoid biosynthesis pathway and screened their upstream metabolites. More importantly, we analyzed the accumulation patterns of several typical flavones and flavonols. The results reported here improved our understanding of the dynamic changes in flavonoids during fruit development and contributed to making full use of the medicinal value of L. maackii fruit.     

Simple construction of fused and spiro nitrogen/sulfur containing heterocycles by addition of thioamides or thioureas on cycloalkenyl-diazenes: examples of click chemistry

New 1-cycloalkenyl-1-diazenes have been obtained in good yields from cyclic β-ketoesters and hydrazine derivatives. They furnished new cycloalkyl[d][1,3]thiazolines with thioamides or new spirocycloalkyl-thiazolinones with thioureas. Moreover they gave, with imidazolidine-2-thione and tetrahydropyrimidine-2-thione, new and interesting spiro[cycloalkyl-1,2′-imidazo[2,1-b][1,3]thiazole] or spiro[cycloalkyl-1,2′-[1,3]thiazolo[3,2-a]pyrimidine] derivatives, respectively. Cycloalkyl[d][1,3]thiazolines were useful for the further preparation of unknown thia-triaza-tricyclo derivatives. Novel hexahydro-1,3-benzothiazoles have been achieved by reaction of N,N′-dialkylthioureas on N-1-phenyl-2-(1-cyclohexenyl)-1-diazene-1-carboxyamide. The acidic hydrolysis of spirocycloalkyl-thiazolinones produced 2-imino-5-(ω-carboxyalkyl)-4-thiazolidinones.     

Synthesis of highly substituted dihydropyrrolophenanthridine derivatives by tandem reaction

The efficient cross-coupling of bromo(iso)quinoline to 1,6-diynes with the Pd-catalyzed system was established. Using unactivated simple diynes with bromo(iso)quinoline in the presence of palladium catalytic system afforded different kinds of rare 7,11-diphenyl-9,10-dihydro-8H-pyrrolo[3,4-j]phenanthridine derivatives through regioselective C–H functionalization in one step. Different diynes (a–p) and different bromo(iso)quinolines were shown to be very active in the reaction. Thus, the generality of this process makes the reaction highly valuable in view of the synthetic and medicinal importance of these pyrrolo[3,4-j]phenanthridine derivatives.