Alcohol Side Chain Research Articles

Functionalized Alkylidenecyclobutanes from a Cyclopent‐2‐enone Substrate via a Tandem Photochemical Transformation and an Allylic Substitution Protocol

AbstractA four‐step metal‐free procedure is described for the transformation of 4‐hydroxy‐2‐methylcyclopent‐2‐enone derivatives into highly functionalized E‐alkylidenecyclobutanes featuring oxygenated tetrasubstituted centers. The key intermediate is a (cyclobutenyl)propane‐1,3‐diol diester, easily accessed via a tandem photochemical reaction, which undergoes an original Brønsted acid‐catalyzed allylic substitution reaction with alcohols to give the title products with ester‐protected primary alcohol side chains.

Organocatalyzed enantio- and diastereoselective isomerization of prochiral 1,3-cyclohexanediones into nonalactones bearing distant stereocenters.

The lactonization of 2-(2-nitrophenyl)-1,3-cyclohexanediones containing an alcohol side chain and up to three distant prochiral elements is reported by isomerization under the mediation of simple organocatalysts such as quinidine. Through a process of ring expansion, strained nonalactones and decalactone are produced with up to three stereocenters in high er and dr (up to 99 : 1). Distant groups, including alkyl, aryl, carboxylate and carboxamide moieties, were examined.

Tricky Isomers-The Evolution of Analytical Strategies to Characterize Plasmalogens and Plasmanyl Ether Lipids.

Typically, glycerophospholipids are represented with two esterified fatty acids. However, by up to 20%, a significant proportion of this lipid class carries an ether-linked fatty alcohol side chain at the sn-1 position, generally referred to as ether lipids, which shape their specific physicochemical properties. Among those, plasmalogens represent a distinct subgroup characterized by an sn-1 vinyl-ether double bond. The total loss of ether lipids in severe peroxisomal defects such as rhizomelic chondrodysplasia punctata indicates their crucial contribution to diverse cellular functions. An aberrant ether lipid metabolism has also been reported in multifactorial conditions including Alzheimer’s disease. Understanding the underlying pathological implications is hampered by the still unclear exact functional spectrum of ether lipids, especially in regard to the differentiation between the individual contributions of plasmalogens (plasmenyl lipids) and their non-vinyl-ether lipid (plasmanyl) counterparts. A primary reason for this is that exact identification and quantification of plasmalogens and other ether lipids poses a challenging and usually labor-intensive task. Diverse analytical methods for the detection of plasmalogens have been developed. Liquid chromatography–tandem mass spectrometry is increasingly used to resolve complex lipid mixtures, and with optimized parameters and specialized fragmentation strategies, discrimination between ethers and plasmalogens is feasible. In this review, we recapitulate historic and current methodologies for the recognition and quantification of these important lipids and will discuss developments in this field that can contribute to the characterization of plasmalogens in high structural detail.

Thermodynamic destabilization of azurin by four different tetramethylguanidinium amino acid ionic liquids

The thermal unfolding of the copper redox protein azurin was studied in the presence of four different amino acid-based ionic liquids (ILs), all of which have tetramethylguanidium as cation. The anionic amino acid includes two with alcohol side chains, serine and threonine, and two with carboxylic acids, aspartate and glutamate. Control experiments showed that amino acids alone do not significantly change protein stability and pH changes anticipated by the amino acid nature have only minor effects on the protein. With the ILs, the protein is destabilized and the melting temperature is decreased. The two ILs with alcohol side chains strongly destabilize the protein while the two ILs with acid side chains have weaker effects. Unfolding enthalpy (ΔHunf°) and entropy (ΔSunf°) values, derived from fits of the unfolding data, show that some ILs increase ΔHunf°while others do not significantly change this value. All ILs, however, increase ΔSunf°. MD simulations of both the folded and unfolded protein conformations in the presence of the ILs provide insight into the different IL-protein interactions and how they affect the ΔHunf° values. The simulations also confirm that the ILs increase the unfolded state entropies which can explain the increased ΔSunf° values.

A Stereodivergent Strategy for Total Syntheses of Antirhine Alkaloids.

Total syntheses of the antirhine alkaloids are described. The cyanide-catalyzed imino-Stetter reaction of the aldimine derived from ethyl 2-aminocinnamate and 4-bromopyridine-2-carboxaldehyde provided a 2-pyridinyl substituted indole-3-acetate, which was further converted into the corresponding indoloquinolizidinium intermediate through C-ring formation. Subsequent trans-selective installation of the homoallylic alcohol side-chain at C-15 in the resulting indoloquinolizidinium allowed the total syntheses of antirhine and its known epimer.

A Novel Reverse Phase HPLC Method for the Quantification of Potential Genotoxic Impurities in Doripenem Monohydrate: A Broad-Spectrum Carbapenem Antibiotic Drug

A novel sensitive gradient reverse phase high performance liquid chromatographic (RP-HPLC) method has been developed and validated for the quantification of potential genotoxic impurities in doripenem monohydrate (DORIBAX) drug substance, namely mono-p-nitrobenzyl malonate, 1β-methyl bicyclic ketoester, desilylated β-keto ester, 1β-methyldiazoazetidinone, deprotected doripenem side chain, N-protected mercapto alcohol, protected doripenem and doripenem side chain. The analysis performed on Alliance Waters e2695 separation module on C18 (250 × 4.6) mm, 5 μm (make: Inertsil) column, oven temperature maintained at 40 ºC and UV detection at 270 nm. The separation was accomplished using buffer (pH 6.0 ± 0.05) and acetonitrile in the ratio of 98:2 v/v as mobile phase-A and acetonitrile as mobile phase-B, flow rate: 1.0 mL/min and injection volume: 50 μL. The proposed method was validated as per ICH guidelines in terms of limit of detection (LOD), limit of quantification (LOQ), linearity, precision, accuracy and specificity.

Revealing Structural Modifications of Lignin in Acidic γ-Valerolactone-H2O Pretreatment.

γ-valerolactone (GVL)/H2O/acid solvent mixtures has been used in chemical pretreatment of lignocellulosic biomass, it was claimed that GVL lignins were structurally close to proto (native) lignins, or having low molecular weight with narrow polydispersity, however, the structural changes of GVL lignins have not been investigated. In this study, β-O-4 (β-aryl ether, GG), β-5 (phenylcoumaran), and β-β (resinol) lignin model compounds were treated by an acidic GVL-H2O solvent system, a promising pretreatment of lignocellulose for biomass utilization, to investigate the structural changes possibly related to the lignin involved. NMR characterization of the products isolated from the treated GG indicated that a phenyl dihydrobenzofuran, having typical C-H correlations at δC/δH 50.74/4.50 and 93.49/4.60 ppm in its HSQC spectrum, was produced from GG. In the pretreatment, the released formaldehyde from GG reacted fast with GG to form a novel 1,3-dioxane intermediate whose characteristic HSQC signals were: δC/δH 94.15–94.48/4.81–5.18 ppm and 80.82–83.34/4.50–4.94 ppm. The β-5 model, dihydrodehydrodiconiferyl alcohol, was converted into phenylcoumarone and stilbene having benzaldehyde that resulted from the allyl alcohol side chain. The β-β model, syringaresinol, was isomerized to form a mixture of syringaresinol, epi-, and dia-syringaresinol although being degraded slightly.

Highly diastereoselective synthesis of 3-methylenetetrahydropyrans by palladium-catalyzed oxa-[4 + 2] cycloaddition of 2-alkenylbenzothiazoles.

A highly diastereoselective synthesis of 3-methylenetetrahydropyrans via palladium-catalyzed oxa-[4 + 2] cycloaddition of 2-alkenylbenzothiazoles with allyl carbonates bearing a nucleophilic alcohol side chain is presented. This synthetic methodology tolerates a wide variety of 2-alkenylbenzothiazoles and afforded the desired 3-methylenetetrahydropyrans in good yields and excellent dr. In addition, further derivatizations resulted in new scaffolds, making them useful synthetic precursors.

Protecting Groups in Peptide Synthesis.

The protection of amino acid reactive functionalities including the α-amino group, the side chain (amines, carboxylic acids, alcohols, and thiols), or the carboxylic acid terminus is an essential strategy in peptide chemistry. This is mandatory to prevent polymerization of the amino acids and to minimize undesirable side reactions during the synthetic process. Proper protecting group manipulation strategies can maximize the yield of the desired product or allow the construction of complex peptide-based structures. Thus, the compatibility and orthogonality of each protecting group are key to achieve the proper control of molecular structure. Herein, we describe some common protecting groups and their general unmasking methods, in order to mask and expose amine, carboxylic acid, alcohol, and thiol functionalities to achieve the synthesis of peptides and related molecules.

Strong Microheterogeneity in Novel Deep Eutectic Solvents.

With the increasing application of template assisted syntheses in deep eutectic solvents and successful application of hydrophobic deep eutectic solvents in extraction processes, where microheterogeneity plays a major role, suggestions for novel deep eutectic solvents which exhibit strong microheterogeneity are desirable. Therefore, classical molecular dynamics simulations were carried out on deep eutectic solvent systems constructed of choline chloride and some of its derivatives mixed with ethylene glycol in a molar composition of 1 : 2 since this is the optimal parent composition. The derivatives consisted of a series of elongated alkyl side chains and elongated alcohol side chains. Of these series only choline chloride ethylene glycol has been investigated experimentally, the other systems are suggested and theoretically investigated as possible target for synthesis. Our domain analysis supported by the clear distinction of polar and nonpolar parts from the electrostatic potentials reveals that strong microheterogeneity within these novel hypothetical deep eutectic solvents exists. Rather stretched than crumbled side chains maximize possible interaction sites for both polar and nonpolar parts which make the suggested compounds valuable objectives for experiments in order to exploit the microheterogeneity in deep eutectic solvents.

Characterization of a novel aryloxyphenoxypropionate herbicide-hydrolyzing carboxylesterase with R-enantiomer preference from Brevundimonas sp. QPT-2

Abstract Aryloxyphenoxypropionate (AOPP) herbicides with a chiral center are widely used to selectively remove annual and perennial grasses. However, the study of the enzymes involved in enantioselective degradation of AOPP herbicides is limited. A novel family VIII carboxylesterase gene, estwx, hydrolyzed the ester bond cleavage of AOPP herbicides to form the corresponding acid and alkyl side chain alcohol, was cloned from Brevundimonas sp. strain QPT-2 and overexpressed in E. coli BL21. The purified recombinant EstWX was shown to hydrolyze a wide range of AOPP herbicides with various catalytic efficiencies. The enantioselectivity assay indicated that EstWX preferentially catalyzed the hydrolysis of the R-enantiomer of AOPP herbicides. The S73, K76, Y196 together with W368 residues, especially S73 and Y196, were essential for the catalytic function of the carboxylesterase. EstWX is a promising candidate for the bioremediation of multiple AOPP herbicide-contaminated environments and for future mechanism studies on the enantioselective degradation of chiral AOPP herbicides.

Time-Resolved Spectroscopic Observation and Characterization of Water-Assisted Photoredox Reactions of Selected Aromatic Carbonyl Compounds.

In recent years, unusual and efficient self-photoredox reactions were detected for selected benzophenone derivatives (BPs) and anthraquinone derivatives (AQs) in aqueous environments by Wan and co-workers, where the carbonyl undergoes reduction to the corresponding alcohol and a side-chain alcohol group undergoes oxidation to the corresponding carbonyl. To unravel the photoredox reaction mechanisms of these types of BPs and AQs in aqueous environments, we have utilized a combination of time-resolved spectroscopy techniques such as femtosecond transient absorption, nanosecond transient absorption, and nanosecond time-resolved resonance Raman spectroscopy to detect and characterize the electronic absorption and vibrational spectra of the intermediates and transient species from the femtosecond to microsecond time region after they are generated in the photoredox reactions. With the assistance of density functional theory calculations to simulate the electronic absorption and Raman spectra, the structural and kinetic information on the key reactive intermediates is described. Furthermore, the reaction pathways were calculated by finding the transition states connecting with the reactant and product complexes to better understand the photoredox reaction mechanism. In this Account, we summarize some of our time-resolved spectroscopic observations and characterization of water-assisted photoredox reactions of selected BPs and AQs. In the strong hydrogen-donor solvent isopropanol, the commonly studied photoreduction reaction for aromatic carbonyls via an intermolecular hydrogen atom tranfer process was observed for BPs and AQs. The photoredox reactions for the investigated BPs and AQs in aqueous environments occur on the triplet excited-state surface. Under moderately acidic aqueous conditions, the photoredox reactions for BPs and AQs are triggered by a proton transfer (PT) pathway. In neutral aqueous solutions, AQs may also undergo proton-coupled electron transfer (PCET) leading to the photoredox reaction, while BPs generate the ketyl radical species. Both BPs and AQs prefer the photohydration reaction in high-proton-concentration aqueous solutions (pH 0). The PT and PCET processes were found to offer more possibilities for the aromatic carbonyl compounds to lead to new photochemical reactions like the unusual photoredox reactions associated with BPs and AQs described here. Clear characterization of the photophysical pathways and the photochemical reactions of representative aromatic carbonyl compounds in aqueous environments not only provides fundamental information to better understand the photochemistry of carbonyl-containing compounds but also will facilitate the development of applications of these systems, like photochemical synthesis, drugs, and photolabile protecting groups. In addition, the importance of water molecules in the photochemical reactions of interest here may also lead to further understanding of how water influences the photochemistry of related carbonyl-containing compounds in aqueous environments.

1,4-Benzodioxane Lignans: An Efficient, Asymmetric Synthesis of Flavonolignans and Study of Neolignan Cytotoxicity and Antiviral Profiles.

1,4-Benzodioxane lignans are a class of bioactive compounds that have received much attention through the years. Herein research pertaining to both 1,4-benzodioxane flavonolignans and 1,4-benzodioxane neolignans is presented. A novel synthesis of both traditional 1,4-benzodioxane flavonolignans and 3-deoxyflavonolignans is described. The antiviral and cytotoxic activities of 1,4-benzodioxane neolignans were then investigated; eusiderins A, B, G, and M, deallyl eusiderin A, and nitidanin, which contain the 1,4-benzodioxane motif but lack the chromanone motif found in the known antiviral flavonolignans, were tested. Notably, it was found that all eusiderin 1,4-benzodioxane neolignans exhibited greater antiviral activity than the potent and well-known silybin flavonolignans. While most modifications of the C-1' side chain did not significantly alter the cytotoxicity or antiviral activity, eusiderin M and nitidanin, which contain an allylic alcohol side chain, had lower cytotoxicity. All the eusiderins had similar antiviral activities, with eusiderin B having the best selectivity index. These results show that the chromanone moiety of the flavonolignans is not essential for bioactivity.

Synthesis and Biological Evaluation of Derivatives of Indoline as Highly Potent Antioxidant and Anti-inflammatory Agents.

We describe the preparation and evaluation of novel indoline derivatives with potent antioxidant and anti-inflammatory activities for the treatment of pathological conditions associated with chronic inflammation. The indolines are substituted at position 1 with chains carrying amino, ester, amide, or alcohol groups, and some have additional substituents, Cl, MeO, Me, F, HO, or BnO, on the benzo ring. Concentrations of 1 pM to 1 nM of several compounds protected RAW264.7 macrophages against H2O2 induced cytotoxicity and LPS induced elevation of NO, TNF-α, and IL-6. Several derivatives had anti-inflammatory activity at 1/100th of the concentration of unsubstituted indoline. Four compounds with ester, amine, amide, or alcohol side chains injected subcutaneously in mice at a dose of 1 μmol/kg or less, like dexamethasone (5.6 μmol/kg) prevented LPS-induced cytokine elevation in the brain and peripheral tissues. Subcutaneous injection of 100 μmol/kg of these compounds caused no noticeable adverse effects in mice during 3 days of observation.

New tetramic acid derivatives from the deep-sea-derived fungus Cladosporium sp. SCSIO z0025

Eight new tetramic acid derivatives, cladosporiumins A–H (1–8) were isolated from a culture broth of Cladosporium sp. SCSIO z0025 derived from the deep-sea sediment collected from Okinawa Trough. Their structures were elucidated by extensive spectroscopic data analysis. Compounds 1–3 were unique 3-acyltetramic acids with a hexyl enic alcohol side chain and a six-membered lactone ring substituted at C-3 of the 2, 4-pyrrolidinedione skeleton. The absolute configurations of chiral carbons of the 2, 4-pyrrolidinedione unit in 1–4 and 7 were established by quantum chemical calculations of the electronic circular dichroism (ECD) spectra. And the absolute configurations of chiral carbons of the six-membered lactone ring in 1–3 were established by density functional theory calculation of their 13C NMR chemical shifts. In addition, all the compounds were tested for cytotoxic, antibacterial, anti-biofilm, and AchE inhibitory activities.

A triad of residues is functionally transferrable between 5-HT3 serotonin receptors and nicotinic acetylcholine receptors

Cys-loop receptors are pentameric ligand-gated ion channels that facilitate communication within the nervous system. Upon neurotransmitter binding, these receptors undergo an allosteric activation mechanism connecting the binding event to the membrane-spanning channel pore, which expands to conduct ions. Some of the earliest steps in this activation mechanism are carried out by residues proximal to the binding site, the relative positioning of which may reflect functional differences among members of the Cys-loop family of receptors. Herein, we investigated key side-chain interactions near the binding site via mutagenesis and two-electrode voltage-clamp electrophysiology in serotonin-gated 5-HT3A receptors (5-HT3ARs) and nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes. We found that a triad of residues aligning to Thr-152, Glu-209, and Lys-211 in the 5-HT3AR can be exchanged between the homomeric 5-HT3AR and the muscle-type nAChR α-subunit with small functional consequences. Via triple mutant cycle analysis, we demonstrated that this triad forms an interdependent network in the muscle-type nAChR. Furthermore, nAChR-type mutations of the 5-HT3AR affect the affinity of nicotine, a competitive antagonist of 5-HT3ARs, in a cooperative manner. Using mutant cycle analyses between the 5-HT3A triad, loop A residues Asn-101 and Glu-102, β9 residue Lys-197, and the channel gate at Thr-257, we observed that residues in this region are energetically linked to the channel gate and are particularly sensitive to mutations that introduce a net positive charge. This study expands our understanding of the differences and similarities in the activation mechanisms of Cys-loop receptors.

The Synthesis of Fragrant Natural Products from Santalum album L.: (+)-(Z)-α-Santalol and (-)-(Z)-β-Santalol.

The synthetic challenges associated with the selective synthesis of α-Santalene (1), (Z)-α-Santalol (2), β-Santalene (3), and most importantly (Z)-β-Santalol (4) have interested the world's synthetic chemists for decades. These molecules, lovely examples of nature's exquisite creations, have been isolated from East Indian Sandalwood Oil (Santalum album L.) and have stimulated chemists to develop new and efficient methodologies to synthesize them. The synthesis and evolution of various approaches to the [2.2.1]bicycloheptane ring system present in β-Santalene (3) and the even more challenging selective synthesis of the (Z)-allylic alcohol sidechain present in both (Z)-α-Santalol (2) and ((Z)-β-Santalol (4) will be covered in this review.

Palladium‐catalyzed Oxa‐[4+2] Annulation of para‐Quinone Methides

AbstractA palladium‐catalyzed oxa‐[4+2] annulation of para‐quinone methides with allyl carbonates bearing a nucleophilic alcohol side chain has been developed. This method provided an efficient strategy to the construction of 2‐oxaspiro‐cyclohexadienones via 1,6‐conjugated addition‐mediated allylation in moderate to good yields. Preliminary results on asymmetric derivatives promised potential in the synthesis of enantioenriched frameworks.magnified image

Peptide—protein interactions within human hair keratins

We selected 1235 decapeptides from human hair proteins encoded by human genes of keratins and keratin associated proteins. The peptides were linked to glass arrays and screened for their affinity towards a solution of human hair extracted keratin fraction. Based on the physicochemical properties of the peptides, ten variables were studied: content of different types of amino acid side chains (cysteine, hydrophobic, polar, basic, acidic, aromatic rings, amide, alcohol side chains), isoelectric point, and net charge. We found differences statistically significant on the binding affinity of peptides based on their content of cysteine, hydrophobic and polar amino acids, mainly containing alcohols. These results point to the formation of hydrophobic interactions and disulfide bonds between small peptides and human hair keratins as the main driving forces for the interaction of possible cosmetic peptides, namely designed to strength human hair. As so, our results enlighten the nature of the interaction of keratin based materials with human hair, which are claimed to enhance hair fiber strength, and enable a more directed and sustained hair care peptide design.

PH Dependence of Interfacial Water in the Presence of Amino Acid Side Chains Revealed by Heterodyne-Detected Sum-Frequency Generation Spectroscopy

Proteins are built of amino acid residues that differ from each other only by their side chain. The pH-dependent response of these side chains on protein surface is vital for various biological processes. Here we have investigated the aqueous interface in the presence of different amino acid side chains at varying pH (bulk) using heterodyne-detected vibrational sum-frequency generation (HD-VSFG) spectroscopy. It is observed that amine/imidazolic (e.g., lysine/histidine) and alcoholic (e.g., serine and threonine) side chains preferentially orient the interfacial water as “H-down” (i.e., the water hydrogens are pointed toward the aqueous bulk) in acidic solution (pH ∼2). At physiological pH (7.4), the interfacial water takes “H-up” orientation (i.e., the water hydrogens are pointed away from the aqueous bulk) for the alcoholic/imidazolic side chains but remains “H-down” for the amine containing side chain. On further increasing the pH (up to 12.0), the interfacial water becomes increasingly H-up oriented, r...