Hemiacetal Research Articles

Simple structural elucidation of ostreocin-B, a new palytoxin congener isolated from the marine dinoflagellate Ostreopsis siamensis, using complementary positive and negative ion liquid chromatography/quadrupole time-of-flight mass spectrometry.

Ostreocin-B is a new palytoxin congener of comparable complexity. Elucidation of the chemical structure by nuclear magnetic resonance has been hampered due to limited sample availability. More importantly, the dihedral angles of protons at the base of the hydroxyl groups on the ring structures are predicted to produce little couplings and thus disrupt connectivity. The present investigation solved the problem through mass spectrometry. Structural elucidation was performed by high-performance liquid chromatograph coupled to a quadrupole time-of-flight mass spectrometer equipped with an electrospray ionization source operated in positive and negative ion mode. Measurement parameters were optimized to achieve high sensitivity and a high ratio of singly charged ions. Ostreocin-D (C127 H219 N3 O53 ), another palytoxin congener possessing an unambiguously determined structure, was used as a template. The molecular formula of ostreocin-B, C127 H219 N3 O54 , indicates that it has one more oxygen atom than ostreocin-D. Comparison of the product ion spectra in negative ion mode indicates the occurrence of hydroxyl substitution at C44 in ostreocin-B, unlike in ostreocin-D. Positive ion spectra also support the 44-OH substructure by producing conjugated polyenes ascribable to the sequential loss of hydroxyls on the cyclic hemiacetal. The planar structure of ostreocin-B is assigned to 42-hydroxy-3,26-didemethyl-19-deoxypalytoxin (=44-hydroxyostreocin-D). The method used in this study is an excellent tool to obtain structural information on interspecies and intrastrain variation of palytoxin congeners in marine organisms.

Alashinol H, an epoxylignan with an unusual six-membered cyclic hemiacetal from Syringa pinnatifolia

A new 7, 9′-epoxylignan, alashinol H (1), which features a rare six-membered cyclic hemiacetal, was isolated from the stem barks of Syringa pinnatifolia. The structure was elucidated based on spectroscopic data including HRESIMS and NMR. Its absolute configuration was resolved by GIAO NMR shifts and ECD calculations. A putative biosynthetic pathway of this compound is proposed. Alashinol H showed a moderate inhibitory effect against NO production in BV-2 murine microglia cells.

Synthesis and application of N-hydroxy(tetrahydrofuran-2-yl)amines

Data on synthesis, reactivity and bioactivity of N-hydroxy(tetrahydrofuran-2-yl)amines were discussed in the present review. General approaches to chiral N-glycosylhydroxylamines based on reactions of hydroxylamine with cyclic five-membered hemiacetals or dihydrofurans as well as reactions of tetrahydrofuran-containing nitrones with nucleophiles were systematized. The application of N-hydroxy(tetrahydrofuran-2-yl)amines in the synthesis of chiral heterocycles, aminophosphonic acids, N-hydroxypropargylamines, as well as natural compounds (for example, sieboldin A), pharmaceuticals (Zileuton) and their analogs was demonstrated. It was found that depending on substituents, N-hydroxy(tetrahydrofuran-2-yl)-amines can act as lipoxygenase inhibitors, and show antioxidant, antitumor, antibacterial, and other types of activities.

Asymmetric Organocatalytic One-Pot, Two-Step Sequential Process to Synthesize Chiral Acetal-Containing Polycyclic Derivatives from Cyclic Hemiacetals and Enones.

We have developed an efficient one-pot, two-step sequential process to synthesize biologically and synthetically important chiral acetal-containing polycyclic derivatives. This novel protocol had been proved to proceed via Michael-lactolization-oxocarbenium ion ring-closing sequence, which was initiated by a key reactive enamine intermediate and interrupted the previously established reaction pathway of two different enones used in this work, and generated the corresponding cycloadducts with excellent stereoselectivity bearing up to seven continuous stereocenters. Both chiral and racemic starting cyclic hemiacetals worked well in this strategy. The synthetic applications of the obtained polycyclic products have also been demonstrated.

Quercetin inhibits advanced glycation end product formation via chelating metal ions, trapping methylglyoxal, and trapping reactive oxygen species

Physiological concentration of Mg2+, Cu2+, and Zn2+ accelerated AGE formation only in glucose-mediated conditions, which was effectively inhibited by chelating ligands. Only quercetin (10) inhibited MGO-mediated AGE formation as well as glucose- and ribose-mediated AGE formation among 10 polyphenols (1-10) tested. We performed an additional structure-activity relationship (SAR) study on flavanols (10, 11, 12, 13, and 14). Morin (12) and kaempherol (14) showed inhibitory activity against MGO-mediated AGE formation, whereas rutin (11) and fisetin (13) did not. These observations indicate that 3,5,7,4'-tetrahydroxy and 4-keto groups of 10 are important to yield newly revised mono-MGO adducts (16 and 17) and di-MGO adduct (18) having cyclic hemiacetals, while 3'-hydroxy group is not essential. We propose here a comprehensive inhibitory mechanism of 10 against AGE formation including chelation effect, trapping of MGO, and trapping of reactive oxygen species (ROS), which leads to oxidative degradation of 18 to 3,4-dihydroxybenzoic acid (15) and other fragments.

Asymmetric Organocatalytic Synthesis of Benzopyran‐ and Benzofuran‐Fused Polycyclic Acetals

AbstractAn efficient organocatalytic method for the asymmetric preparation of benzopyran‐ and benzofuran‐fused polycyclic acetals is described for the first time. This useful approach includes an interesting tunable Michael–acetalization of nitrostyrenes or α‐aromatization–acetalization of quinones. Under mild conditions, simple cyclic hemiacetals could be stereoselectively converted into four different types of polyheterocycles that serve as scaffolds for a number of bioactive natural products.magnified image

Enantioresolution and quantification of monosaccharides by comprehensive two‐dimensional gas chromatography

This work presents the development of a simple and efficient analytical protocol for the direct enantioselective resolution of sugars. A racemic mixture of the C3 sugar d,l-glyceraldehyde and the C5 monosaccharides d,l-arabinose, d,l-ribose, d,l-xylose, and d,l-lyxose was subjected to derivatization with trifluoroacetic anhydride, and corresponding derivatives were separated on a β‐cyclodextrin column with excellent resolution factors. Even though each aldopentose shows beside the linear form four predominant cyclic hemiacetals being the α- and β-furanose along with the α- and β‐pyranose, we show that the overall enantiomeric excess of each compound can be precisely determined. Moreover, the measured detection limit for derivatized aldopentoses ranges from 0.015 to 0.019pmol on the column, while the quantification limit varies from 0.5 to 0.64pmol on the column.

Roles of 5-lipoxygenase and cyclooxygenase-2 in the biosynthesis of hemiketals E2 and D2 by activated human leukocytes.

The 2 hemiketal (HK) eicosanoids HKD2 and HKE2 are the major products of the biosynthetic crossover of the 5-lipoxygenase (5-LOX) and cyclooxygenase-2 (COX-2) pathways. HKs result from the rearrangement of a di-endoperoxide intermediate formed in the COX-2-dependent oxygenation of 5S-hydroxyeicosatetraenoic acid (5S-HETE). We analyzed HK biosynthesis in human leukocytes stimulated ex vivo and defined the biosynthetic roles of 5-LOX and COX-2, using inhibitors and incubations with exogenous substrates. Activation of leukocytes with LPS followed by treatment with the calcium ionophore A23187 resulted in the formation of PGE2, 5-HETE, and LTB4 as the principal metabolites of COX-2 and 5-LOX, respectively. The formation of HKD2 and HKE2 was highest after 15 min LPS treatment, and at that time, levels were similar to PGE2, but less than 5-HETE and LTB4 The time course of HK formation paralleled that of 5-HETE and LTB4, implying the availability of the 5S-HETE substrate as a limiting factor in biosynthesis rather than expression levels of COX-2. Specific inhibitors of COX-2 and 5-LOX decreased formation of HKD2 and HKE2 Platelets did not form HKs from exogenous 5S-HETE, implying that COX-1 is not involved. HKs are early products during an inflammatory event and require cells that express 5-LOX and COX-2 for their biosynthesis.-Giménez-Bastida, J. A., Shibata, T., Uchida, K., Schneider, C. Roles of 5-lipoxygenase and cyclooxygenase-2 in the biosynthesis of hemiketals E2 and D2 by activated human leukocytes.

Solid-state 17O NMR study of 2-acylbenzoic acids and warfarin

We report synthesis and solid-state 17O NMR characterization of four site-specifically 17O-labeled 2-acylbenzoic acids (2-RC(O)C6H4COOH) where R=H and CH3): 2-[3-17O]formylbenzoic acid, 2-[1,2-17O2]formylbenzoic acid, 2-[3-17O]acetylbenzoic acid, and 2-[1,2,3-17O3]acetylbenzoic acid. In the solid state, both 2-formyl- and 2-acetyl-benzoic acids exist as the cyclic phthalide form each containing a five-membered lactone ring and a cyclic hemiacetal/hemiketal group. Static and magic-angle-spinning 17O NMR spectra were recorded at 14.1 and 21.1T for these compounds, from which the 17O chemical shift and nuclear quadrupolar coupling tensors were determined for each oxygen site. These results represent the first time that 17O NMR tensors are fully characterized for lactone, cyclic hemiacetal, and cyclic hemiketal functional groups. We also report solid-state 17O NMR data for the cyclic hemiketal group an anticoagulant drug, warfarin. Experimental 17O NMR tensors in these compounds were compared with computational results obtained with a periodic DFT code BAND.

Organocatalytic Cationic Ring-Opening Polymerization of a Cyclic Hemiacetal Ester

We report the bulk cationic ring-opening polymerization of renewably sourced 2-methyl-1,3-dioxan-4-one (MDO) to yield a polyester with hydrolytically and thermally sensitive linkages that facilitate degradation. Neat monomer was successfully polymerized using a variety of protic acids as catalysts. We discovered that, with these catalysts, the cationic polymerization of MDO proceeds via two distinct mechanistic routes, namely, the activated monomer (AM) and active chain-end (ACE) mechanisms. The kinetics of these competing mechanistic avenues were investigated by employing diphenylphosphoric acid (DPP) with or without an alcohol initiator. Without an exogenous initiator, the polymerization propagates via a dioxacarbenium ion that rapidly adds more MDO to produce high-molar-mass poly(2-methyl-1,3-dioxan-4-one) (PMDO). However, we found no clear relationship between [MDO]0/[protic acid]0 and resultant molar mass, suggesting that the ACE mechanism is not well-controlled. This conclusion was further supported...

ChemInform Abstract: Multicomponent Synthesis of Cyclic Depsipeptide Mimics by Ugi Reaction Including Cyclic Hemiacetals Derived from Asymmetric Organocatalysis.

AbstractPolysubstituted nine‐membered‐ring lactones are prepared by Ugi reaction of enantiomerically enriched cyclic hemiacetals with a wide range of α‐amino acids and isocyanides of aliphatic, peptidic, glycosidic, and lipidic nature.

Selective transformation of tricyclic peroxides with pronounced antischistosomal activity into 2-hydroxy-1,5-diketones using iron (II) salts

The present work deals with selective transformations of peroxides into organic compounds via the cleavage of the O–O bond using variable valence metals. A selective transformation of tricyclic peroxides promoted by Fe2+ salts was discovered. This selective transformation is unexpected for compounds with structural features which allow diverse decomposition pathways. 2-Hydroxy-1,5-diketones are prepared in yields up to 92% in the reactions of tricyclic peroxides with FeSO4, Fe(ClO4)2, or FeCl2. This is a new preparative method for the synthesis of 1,5-diketones. 2-Hydroxy-1,5-diketones in CDCl3 at 25 °C exist mainly in the open-chain form of the hydroxyketone over the cyclic hemiacetal. The results of this work can be of interest to understand the mechanism of the antiparasitic action of peroxides.

Kinetics of Acid-Catalyzed Dehydration of Cyclic Hemiacetals in Organic Aerosol Particles in Equilibrium with Nitric Acid Vapor.

Previous studies have shown that 1,4-hydroxycarbonyls, which are often major products of the atmospheric oxidation of hydrocarbons, can undergo acid-catalyzed cyclization and dehydration in aerosol particles to form highly reactive unsaturated dihydrofurans. In this study the kinetics of dehydration of cyclic hemiacetals, the rate-limiting step in this process, was investigated in a series of environmental chamber experiments in which secondary organic aerosol (SOA) containing cyclic hemiacetals was formed from the reaction of n-pentadecane with OH radicals in dry air in the presence of HNO3. A particle beam mass spectrometer was used to monitor the formation and dehydration of cyclic hemiacetals in real time, and SOA and HNO3 were quantified in filter samples by gravimetric analysis and ion chromatography. Measured dehydration rate constants increased linearly with increasing concentration of HNO3 in the gas phase and in SOA, corresponding to catalytic rate constants of 0.27 h(-1) ppmv(-1) and 7.0 h(-1) M(-1), respectively. The measured Henry's law constant for partitioning of HNO3 into SOA was 3.7 × 10(4) M atm(-1), ∼25% of the value for dissolution into water, and the acid dissociation constant was estimated to be <8 × 10(-4), at least a factor of 10(4) less than that for HNO3 in water. The results indicate that HNO3 was only weakly dissociated in the SOA and that dehydration of cyclic hemiacetals was catalyzed by molecular HNO3 rather than by H(+). The Henry's law constant and kinetics relationships measured here can be used to improve mechanisms and models of SOA formation from the oxidation of hydrocarbons in dry air in the presence of NOx, which are conditions commonly used in laboratory studies. The fate of cyclic hemiacetals in the atmosphere, where the effects of higher relative humidity, organic/aqueous phase separation, and acid catalysis by molecular H2SO4 and/or H(+) are likely to be important, is discussed.

Multicomponent Synthesis of Cyclic Depsipeptide Mimics by Ugi Reaction Including Cyclic Hemiacetals Derived from Asymmetric Organocatalysis.

The synthesis of novel cyclic depsipeptide mimics by means of an organocatalytic conjugate addition, leading to chiral cyclic hemiacetals, followed by a multicomponent reaction with α-amino acids and isocyanides, is described. The initial organocatalytic step is employed for the asymmetric derivatization of α,β-unsaturated aldehydes to 4,5-disubstituted 2-hydroxytetrahydropyrans, which are next used as chiral bifunctional substrates on the Ugi five-center three-component reaction, giving rise to nine-membered-ring lactones. This sequential approach proved to be suitable for the rapid generation of molecular complexity through the combination of aliphatic, dipeptidic, glucosidic, and lipidic isocyanides with several amino acids, thus giving access to amido-, glyco-, and lipo-depsipeptide scaffolds featuring natural product-like structures.

Determination of the isomeric forms proportion of fluorogenic naphthalene-2,3-dicarboxaldehyde in a binary mixture of water:methanol using electrochemical methods

The electrochemical response of the fluorogenic label naphthalene-2,3-dicarboxyaldehyde (NDA) in a binary mixture of water/methanol was characterized with cyclic voltammetry (CV) and differential pulse voltammetry (DPV) electrochemical techniques. Naphthalene-2,3-dicarboxyaldehyde does exist in three isomeric forms in aqueous solution: the unhydrated dialdehyde (DA), the acyclic monohydrated (MA) and the cyclic hemiacetal (HAC). The study underlines that the proportion of each of them varies according to the working pH. At low and high pH, the dialdehyde form is in larger proportion than the acyclic monohydrated form. Conversely at intermediate pH, the concentration of the acyclic form is in greater proportion than the dialdehyde form. These results allowed us to determine the optimal pH of 9 for which the labeling of biomolecules could be more efficient due to the base catalyzed regeneration of the unhydrated form. At this pH, the data processing from the analysis of measured currents and estimation of diffusion coefficients of each form according to the semi-empirical models of Wilke–Chang, Scheibel, Reddy–Doraiswamy and Lusis–Ratcliff allowed us to obtain the concentration of dialdehyde (0.28mM), acyclic monohydrated (0.57mM) and cyclic hemiacetal monohydrated (0.15mM) forms starting from 1mM naphthalene-2,3-dicarboxyaldehyde.

ChemInform Abstract: Organocatalytic Aldol Addition Reaction of Cyclic Hemiacetals to Aldehydes.

AbstractThe L‐proline catalyzed aldol reaction of cyclic hemiacetals to aromatic aldehydes followed by reduction with Et3SiH provides secondary alcohols with high enantioselectivities and good to moderate diastereoselectivities.

ChemInform Abstract: Organocatalytic Enantioselective Michael Addition of Cyclic Hemiacetals to Nitroolefins: A Facile Access to Chiral Substituted 5‐ and 6‐Membered Cyclic Ethers.

AbstractFew synthetic elaborations of the Michael adducts obtained are also reported, including syntheses of 2,3‐disubstituted cyclic ethers, α‐substituted lactones and analogues of the antidepressant drug venlafaxine.

First example of 2,3-dihydropyridines aromatization through hemiacetal elimination

First example of 2,3-dihydropyridines aromatization through hemiacetal elimination

Organocatalytic aldol addition reaction of cyclic hemiacetals to aldehydes

An organocatalytic aldol reaction of cyclic hemiacetals to aldehydes was developed. As a seldom reported nucleophile in organocatalysis, cyclic hemiacetals herein provided a smooth method to approach a series of cyclic ether substrates with excellent ee value, good yields, and good to moderate diastereoselectivity. The absolute configuration and relative configuration were determined by a Mosher method and 2D NMR spectral analysis of the derivative, respectively.

Study of the Chemical Structure of Dialdehyde Carboxymethyl Cellulose Produced by Periodate Oxidation under Different Conditions

13C nuclear magnetic resonance, paramagnetic resonance, and ultraviolet spectroscopy and high-resolution gel permeation chromatography were used to investigate the process of periodate oxidation of carboxymethyl cellulose and the structure and molecular weight characteristics of its oxidised forms produced under different conditions. It was shown that, in solution and in the solid state, aldehyde groups in the oxidised units exist in the form of cyclic hemiacetals. An examination was made of the existence of all the main cyclic intramolecular hemiacetal structures, and the most probable were proposed. The influence of the degree of periodate oxidation on the molecular weight characteristics and hydrolytic stability of dialdehyde carboxymethyl cellulose was studied.