Formation of Dehydrohexahydroxydiphenoyl Esters by Oxidative Coupling of Galloyl Esters in an Aqueous Medium Involved in Ellagitannin Biosynthesis

Hexahydroxydiphenoyl (HHDP) and dehydrohexahydroxydiphenoyl (DHHDP) groups are the major acyl components of ellagitannins, which are polyphenols whose biosynthesis have attracted considerable attention; however, the mechanisms of the production of HHDP and DHHDP in the ellagitannin biosynthesis have not been clarified. With the aim of elucidating such a mechanism, this study investigates the CuCl₂-mediated oxidation of simple galloyl derivatives in an aqueous medium. It is shown that the oxidation of methyl gallate affords a DHHDP-type dimer, whose reduction with Na₂S₂O₄ yields an HHDP-type dimer. However, the oxidation of the HHDP-type product over CuCl₂ does not afford the parent DHHDP ester. The oxidation of 1,4-butanediol digallate under the same conditions produces a DHHDP-type product via the intramolecular coupling of galloyl groups. These results strongly suggest that the DHHDP group is the initial product of the oxidative coupling of two galloyl groups in the ellagitannin biosynthesis, and subsequent reductive metabolism affords HHDP esters.     

Total Synthesis of Mallotusinin

The total synthesis of mallotusinin, which bears a tetrahydroxydibenzofuranoyl (THDBF) bridge between the 2-oxygen and 4-oxygen of glucose on corilagin with a 3,6-O-(R)-hexahydroxydiphenoyl (HHDP) bridge, is described. The key features of the total synthesis are: 1) improvements of our previously reported method to synthesize corilagin; 2) establishment of the THDBF skeleton via an unusual intramolecular S_NAr reaction of an HHDP analogue, and 3) the application of a two-step bislactonization strategy for a HHDP bridge construction into the 2,4-O-THDBF bridge. Oxidative phenol coupling of 1,2,4-orthoacetyl-3,6-di-(4-O-benzylgalloyl)-α-d -glucopyranose and the orthoester cleavage of the coupling product without the pyranose-furanose ring transformation are key reactions for the improved synthesis of corilagin, which enabled the adequate supply of a corilagin precursor that was required to develop the mallotusinin synthesis. These established methods are expected to help develop the synthesis of other ellagitannins with a bridge between the two oxygens of corilagin.     

Synthetic studies toward C-glucosidic ellagitannins: a biomimetic total synthesis of 5-O-desgalloylepipunicacortein A

C-glucosidic ellagitannins constitute a subclass of bioactive polyphenolic natural products with strong antioxidant properties, as well as promising antitumoral and antiviral activities that are related to their capacity to interact with both functional and structural proteins. To date, most synthetic efforts toward ellagitannins have concerned glucopyranosic species. The development of a synthetic strategy to access C-glucosidic ellagitannins, whose characteristic structural feature includes an atropoisomeric hexahydroxydiphenoyl (HHDP) or a nonahydroxyterphenoyl (NHTP) unit that is linked to an open-chain glucose core by a C-aryl glucosidic bond, is described herein. The total synthesis of the biarylic HHDP-containing 5-O-desgalloylepipunicacortein?A (1?β) was achieved by either using the natural ellagic acid bis-lactone as a precursor of the requested HHDP unit or by implementing an atroposelective intramolecular oxidative biarylic coupling to forge this HHDP unit. Both routes converged in the penultimate step of this synthesis to enable a biomimetic formation of the key C-aryl glucosidic bond in the title compound.     

Synthetic Studies toward C‐Glucosidic Ellagitannins: A Biomimetic Total Synthesis of 5‐O‐Desgalloylepipunicacortein A

C‐glucosidic ellagitannins constitute a subclass of bioactive polyphenolic natural products with strong antioxidant properties, as well as promising antitumoral and antiviral activities that are related to their capacity to interact with both functional and structural proteins. To date, most synthetic efforts toward ellagitannins have concerned glucopyranosic species. The development of a synthetic strategy to access C‐glucosidic ellagitannins, whose characteristic structural feature includes an atropoisomeric hexahydroxydiphenoyl (HHDP) or a nonahydroxyterphenoyl (NHTP) unit that is linked to an open‐chain glucose core by a C‐aryl glucosidic bond, is described herein. The total synthesis of the biarylic HHDP‐containing 5‐O‐desgalloylepipunicacortein A ( 1 β ) was achieved by either using the natural ellagic acid bis‐lactone as a precursor of the requested HHDP unit or by implementing an atroposelective intramolecular oxidative biarylic coupling to forge this HHDP unit. Both routes converged in the penultimate step of this synthesis to enable a biomimetic formation of the key C‐aryl glucosidic bond in the title compound.     

Asymmetric Suzuki–Miyaura Cross‐Coupling for the Synthesis of Chiral Biaryl Compounds as Potential Monophosphine Ligands

Efficient asymmetric Suzuki–Miyaura coupling reactions have been employed for the first time to synthesize chiral biaryl compounds with phosphinate groups as chiral auxiliaries. A series of functionalized chiral biaryls are thereby synthesized in excellent yields and good diastereoselectivities (up to >95:5 d.r.) and axially chiral monophosphorus ligands are obtained through further functionalizations.     

核桃仁中多酚类物质的液相/电喷雾质谱分析

利用HPLC-ESI-MSn方法对核桃(Juglans regia L.)仁中多酚类物质组成进行了分析,发现的多酚类物质有鞣花酰基葡萄糖4种异构体、橡椀酰基葡萄糖2种异构体、二鞣花酰基葡萄糖2种异构体、二没食子酰基葡萄糖2种异构体、鞣花酰基和橡椀酰基葡萄糖3种异构体.结果表明,采用HPLC-ESI-MSn方法可以对核桃仁中多酚类物质进行有效的分析.     

Oxazolidinones as chiral auxiliaries in asymmetric aldol reactions applied to total synthesis

Asymmetric aldol reactions of oxazolidinones as chiral auxiliaries have been achieved and attracted significant consideration as one of the most powerful synthetic tools for the carbon–carbon bond-forming reactions. The methodology has been highly successful in the stereoselective construction of a number of natural products, antibiotics, and other medicinally important compounds. The present review is focused on the utility and versatility of oxazolidinones (Evans chiral auxiliaries) in the asymmetric aldol condensations for the total synthesis of natural products and complex targets.     

Total synthesis of (-)-corilagin

The synthesis of corilagin was achieved by the integration of the development of the oxidative coupling of the symmetrically protected gallates and the temporarily ring-opened synthetic route for the 3,6-hexahydroxydiphenoyl (HHDP) bridge. This is the first total synthesis of the 1C4/B-ellagitannins, which contain ring-flipped glucose.     

Ferroptosis-Inhibitory Effect and Possible Mechanisms of Ellagitannin Geraniin

The search for safe and effective ferroptosis-inhibitors has become an important topic. Geraniin, an ellagitannin bearing hexahydroxydiphenoyl (HHDP) and dehydrohexahydroxydiphenoyl (DHHDP) groups, was observed to inhibit erastin-induced ferroptosis in bone marrow-derived mesenchymal stem cells (bmMSCs). To determine the mechanism, geraniin was further analyzed using UV-vis spectra and several colorimetric assays, where its IC₅₀ values were always much lower than that of the Trolox positive control. When interacted with several free radicals, geraniin gave no radical adduct formation (RAF) peak in the ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry. In conclusion, geraniin exhibits ferroptosis-inhibitory potential towards erastin-treated bmMSCs; such potential may mainly stem from its strong lipid peroxidation (LPO)-inhibition, Fe²⁺-chelating, and antioxidant actions. Geraniin gives neither dimer nor radical adduct, owing to the bulky HHDP (or DHHDP) group; thus, it is considered as a safe and effective ferroptosis-inhibitor.     

Control of axial chirality in absence of transition metals based on arynes

The modular construction of enantioenriched biaryl derivatives is presented. This approach is based on (1) an almost quantitative access to polybrominated precursors via a transition metal-free aryl–aryl coupling, the ARYNE coupling, (2) the regioselective introduction of a traceless chiral auxiliary (an enantiopure para-tolylsulfinyl group), (3) the chemoselective functionalization of this auxiliary, and (4) subsequent regioselective functionalization of the remaining bromine atoms without any racemization during these steps. Next, the atroposelective coupling of in situ generated arynes and aryllithiums bearing various chiral auxiliaries (tert-butyl sulfoxide, para-tolyl sulfoxide, and tartrate-derived chiral diethers and oxazolines) is described and applied to the formal synthesis of (−)-steganacin.     

New auxiliaries for copper-catalyzed asymmetric Michael reactions: generation of quaternary stereocenters at room temperature

Dialkyl amides of L-valine, L-isoleucine, and L-tert-leucine (2) are excellent chiral auxiliaries for the construction of quaternary stereocenters at ambient temperature. Enaminoesters 3, prepared from these auxiliaries 2 and Michael donors 1, undergo a copper-catalyzed asymmetric Michael reaction with methyl vinyl ketone (MVK, 4) to afford products 5 in 70-90% yield and 90-99% ee (enantiomeric excess). The exclusion of moisture or oxygen is not necessary. The auxiliaries 2 are readily available by standard procedures. After workup they can be recovered almost quantitatively.     

Menthone and p-menthyl-3-carboxaldehyde as chiral auxiliaries

Two chiral auxiliaries and the role they play in the preparation of chiral carbonyl compounds and heterocyclic compounds are presented. Key reactions include S(N)2' displacements, Mitsunobu with hydrazoic acid, and 3,3-sigmatropic rearrangements. One of the auxiliaries serves many functions and is removed either by oxidative cleavage or RCM reaction.     

A New Method of Resolution of Racemic 6,6''''-Dihydroxy-5,5''''- biquinoline Using (S)-( + )-Camphorsulfonyl Chloride

The chiral ligand bearing C2-symmetric binaphthyl backbonce (e. g. BINOL, BINAP) is one of the widely used chiral auxiliaries in catalytic asymmetric synthesis. [1] Numerous synthetic approaches to these two compounds have been developed. In contrast, the C2-symmetric ligands containing heterocyclic moiety has been relatively less explored.     

Enantioselective Staudinger synthesis of beta-lactams catalyzed by a planar-chiral nucleophile

The development of efficient methods for the stereoselective generation of beta-lactams is an important goal, due to their biological activity and their utility as synthetic intermediates. The Staudinger reaction, an overall [2 + 2] cycloaddition of a ketene with an imine, provides a nicely convergent route to this family of compounds. Nearly all studies to date of asymmetric variants of the Staudinger reaction have focused on the use of chiral auxiliaries to control the stereochemistry of the beta-lactam. In this report, we establish that a planar-chiral derivative of 4-(pyrrolidino)pyridine serves as a very effective enantioselective catalyst for the Staudinger beta-lactam synthesis, coupling a range of symmetrical and unsymmetrical ketenes with an array of imines with very good stereoselection and yield.     

A synthetic strategy leading to monodisperse PPV oligomers by coupling reactions of vinyltrimethylsilanes

A novel strategy for the synthesis of well-defined oligo(phenylenevinylene)s was developed. The procedure is entirely based upon two coupling processes, both involving vinyltrimethylsilanes. Bis(styryl)benzenes 2a-g bearing two octyloxy groups in the central aromatic ring and various substituents on the external aromatic rings were prepared in good yield by a regio- and stereoselective coupling reaction of 1 with different arenediazonium tetrafluoroborates. Oligomers with a more extended conjugated system, 4a-c, and with m-phenylene subunits 13a,b, were also readily obtained by conversion of the unsaturated trimethylsilyl derivatives 3a,c,d to the corresponding boron derivatives and a subsequent coupling reaction with compounds 2a and 2c.     

Synthesis and evaluation of a new biselector s-triazine based chiral stationary phase for enantioselective HPLC: potentiality of the approach and perspectives

A s-triazine scaffold bearing a free and a protected amino group was used for connecting two different chiral auxiliaries, whose enantiodiscriminating capabilities in enantioselective chromatography are well documented. A biselector system was synthesized and, after linkage to silica gel, used for the chromatographic resolution of different racemic analytes, chosen among the compounds resolved by the two different isolated chiral auxiliaries. The obtained chromatographic results were compared with literature data related to the use of the two chiral stationary phases (CSPs) whose chiral moieties constitute the biselector CSP, allowing us to gain useful information about potentialities and limitations of this approach for obtaining independent CSPs having broader applicability with respect to the classical independent monoselector CSPs.     

HPLC enantioresolution of (R,S)-baclofen using three newly synthesized dichloro-s-triazine reagents having amines and five others having amino acids as chiral auxiliaries

Enantioresolution of (R,S)-baclofen was accomplished using a newly synthesized set of three chiral derivatizing reagents (CDRs) having amines [(S)-(-)-α,4-dimethylbenzylamine, (-)-cis-myrtanylamine and (R)-(-)-1-cyclohexylethylamine] as chiral auxiliaries in cyanuric chloride and another set of five CDRs having amino acids (L-Leu, D-Phg, L-Val, L-Met and L-Ala) as chiral auxiliaries. These eight CDRs were used for synthesis of diastereomers of (R,S)-baclofen under microwave irradiation. The diastereomers were separated on a reversed-phase C(18) column using mixtures of methanol with aqueous trifluoroacetic acid with UV detection at 230 nm. Chromatographic data obtained for the two sets of diastereomers were compared among themselves and among the two groups. The method was validated for limit of detection, linearity, accuracy and precision.     

Diastereoselective synthesis of quaternary substituted thioindolines from sulfur ylide intermediates

We have examined the coupling reactions of 2-thioindoles with vinyl diazoacetates in the presence of Rh(II) catalysts. While attempted enantio- and/or diastereoselective couplings using chiral catalysts and/or chiral auxiliaries on the vinyl diazoacetate have been largely unsuccessful, substrates having resident chirality on fused thiopyrans gave thioindolines with moderate to high diastereoselectivities.     

三组分串联反应一锅合成多环稠合的1,5-苯并二氮杂䓬化合物

以取代的邻苯二胺、1,3-环戊二酮或1,3-环己二酮(5,5-二甲基-1,3-环己二酮)、2,3-二羰基化合物为原料,无水乙醇为溶剂,对甲苯磺酸为催化剂,经2~5 h串联反应一锅合成43种新颖的1,5-苯并二氮杂?化合物,产率最高可达95%.该反应序列首先通过两次的亲核加成-脱水反应过程,形成分子内亚胺和烯胺结构的活性中间体,然后再经分子内的碳碳偶联环合-质子转移等过程,生成多环稠合的1,5-苯并二氮杂?目标化合物,实现了在一个反应体系中形成一个二氮杂七元环和四个新化学键(两个C—N,一个C=C,一个C—C).该方法操作简单,反应便捷,对环境友好,产率高,为1,5-苯并二氮杂?化合物的合成提供绿色环保,高效简便的合成思路.     

Cholic acid derivatives containing both 2-naphthylcarbamate and 3,5-dinitrophenylcarbamate groups: a combined circular dichroism-molecular mechanics approach to the definition of their molecular conformation

CD spectra of the chiral auxiliaries for enantioselective HPLC N-allyl-N'-methyl-3,12-bis(2-naphthyl)carbamoyloxy-7-(3,5-dinitrophenyl)carbamoyloxycholan-24-amide (1), N-allyl-N'-methyl-3-(3,5-dinitrophenyl)carbamoyloxy-7,12-bis(2-naphthyl)carbamoyloxycholan-24-amide (2), N-allyl-N'-methyl-3,7-bis(2-naphthyl)carbamoyloxy-12-(3,5-dinitrophenyl)carbamoyloxycholan-24-amide (3), and N-allyl-N'-methyl-3,7,12-tris(2-naphthyl)carbamoyloxycholan-24-amide (4) are presented. To determine the preferred conformations of those chiral auxiliaries, a random search based on the aromatic side-chain conformational degrees of freedom was performed and the energy was minimized using two different molecular mechanics force fields. The low energy structures presenting common features were arranged in groups and selected exploiting appropriate filters. The calculation of theoretical CD spectra according to the De Voe model has allowed a further discrimination among the conformations, specifying which of them gave calculated CD spectra in acceptable agreement with the experimental ones. Finally, taking into account the additivity of the contributions of each 2-naphthylcarbamate chromophore to the CD spectrum of the cholic acid derivatives, and, hence, choosing, for derivatives 1-3, those conformations in which the 2-naphthylcarbamate groups take a similar disposition as in 4, the preferentially assumed conformation of each compound was obtained. A molecular dynamics simulation in the presence of acetonitrile allowed the fluctuations of one of the structures, used as a test case, depending on environmental effects, to be examined.