A convenient synthesis of C-22 and C-25 stereoisomers of cephalostatin north 1 side chain from spirostan sapogenins

A simple transformation of the eight-carbon side chain of a natural spirostan sapogenin into the cephalostatin north 1 spiroketal moiety is described. This methodology, based on an intramolecular hydrogen abstraction reaction promoted by alkoxy radicals, permits the synthesis of C-22 and C-25 stereoisomers of the dioxaspiro[4.4]nonane cephalostatin ring system. The acid-catalyzed isomerization of the spirocenter in the different isomers is studied. [reaction: see text]     

Outer-ring stereochemical modulation of cytotoxicity in cephalostatins

[structure: see text] 20- and 25'-epimers of cephalostatin 7, prepared by directed unsymmetrical pyrazine synthesis, address outer-ring topographical and stability questions and intimate an oxacarbenium ion rationale for the role in bioactivity of the spiroketal (E/F, E'/F') rings of this class of antitumor agents.     

Unified Asymmetric Total Syntheses of (−)‐Alotaketals A–D and (−)‐Phorbaketal A

The novel tricyclic spiroketal alotane‐type sesterterpenoids showed strikingly different biological activities and potency with subtle structural alterations. Asymmetric total syntheses of the tricyclic sesterterpenoids (−)‐alotaketals A–D and (−)‐phorbaketal A were accomplished [29–31 steps from (−)‐malic acid] in a collective way for the first time. The key features of the strategy included 1) a new cascade cyclization of vinyl epoxy δ‐keto‐alcohols to forge the common tricyclic spiroketal intermediate, 2) a late‐stage allylic C−H oxidation, and 3) olefin cross‐metathesis to install the different side chains.     

Synthesis of chiral building blocks for cephalostatin analogues

The present paper describes the synthesis of 5‐azido‐6‐ketones (14) and 6‐hydroxy‐5‐ketone (20) from Hajos Wiechert ketone as chiral building blocks for cephalostatin analogues. The synthesis of symmetric cephalostatin analogue from 6‐hydroxy‐5‐ketone has also been reported. The characterization of the each synthesized compounds was carried out by IR, ¹H‐NMR, ¹³C‐NMR and High resolution Mass Spectrometry.     

Palladium‐Catalyzed Asymmetric Construction of Vicinal Tertiary and All‐Carbon Quaternary Stereocenters by Allylation of β‐Ketocarbonyls with Morita–Baylis–Hillman Adducts

Palladium‐catalyzed regio‐, diastereo‐, and enantioselective allylic alkylation of β‐ketocarbonyls with Morita–Baylis–Hillman adducts has been developed using a spiroketal‐based diphosphine (SKP) as the ligand, thus affording a range of densely functionalized products bearing vicinal tertiary and all‐carbon quaternary stereodyad in high selectivities. The utility of the protocol was demonstrated by the facile synthesis of some complex molecules by simple product transformations.     

Alternative spiroketalization methods toward purpuromycin: a diketone approach to prevent benzofuran formation

The central portion of purpuromycin has been assembled via a classical spiroketalization reaction. Key to promoting this reaction mode versus benzofuran formation was the oxidation state of the spiroketal core. With a higher oxidation state, even the electron-deficient isocoumarin found in purpuromycin could be employed directly in the spiroketalization. The two halves of the spiroketalization precursor were joined via a nitrile oxide/styrene 1,3-dipolar cycloaddition. A very mild selenium dioxide oxidation was used to introduce the required oxidation state of the spiroketal core.     

Application of a nanostructured sensor based on graphene‐ and ethyl 2‐(4‐ferrocenyl[1,2,3]triazol‐1‐yl)acetate‐modified carbon paste electrode for determination of methyldopa in the presence of phenylephrine and guaifenesin

We introduce a new method to determine methyldopa without the interference of phenylephrine and guaifenesin. For this purpose, a carbon paste electrode was modified with graphene and ethyl 2‐(4‐ferrocenyl[1,2,3]triazol‐1‐yl)acetate. According to electrochemical studies, oxidation current of methyldopa on the surface of the modified electrode increased and shifted towards negative potentials. This modified electrode demonstrated two linear ranges of 0.4–30.0 μM and 30.0–500.0 μM with a detection limit of 0.08 μM. No change was observed in the sensitivity of the modified electrode towards methyldopa in the presence of phenylephrine and guaifenesin, which enables the simultaneous or independent measurement of the three moieties. The efficiency of the proposed modified electrode was evaluated through the determination of these substances in real samples.     

Analytical applications of gold electrodes modified with monolayers of thiolated cyclodextrins

The sequential method for the preparation of cyclodextrin monolayers is used to prepare modified electrodes responsive towards selected guest molecules: ferrocene, ibuprofen, methylene blue, dopamine and menadione. The inclusion into cyclodextrin cavities is monitored using cyclic voltammetry and the mediating role of the immobilized molecules towards solution species is shown on the example of dopamine oxidation.     

A practical approach to the synthesis of insect antifeedant tonghaosu analogs

Tonghaosu and its analogs are a class of structurally interesting spiroketal enol‐ether compounds. A practical route to furandiol, a key intermediate for their syntheses, was developed. Using Friedel‐Crafts benzoylation of 3‐(2‐fury I) propyl acetate, a diarylketone was obtained in high yield, which was further transformed into corresponding furandiol by reduction with NaBH₄ in basic medium with simultaneous ester hydrolysis. The furandiol was then cyclized into the desired spiroketal enol‐ether compound in the presence of CuSO₄ 5H₂O.     

NADH Oxidation Catalyzed by Electropolymerized Azines on Carbon Nanotube Modified Electrodes

Electropolymerizing azines on a carbon nanotube (CNT) modified electrode yields a high‐surface area interface with excellent electrocatalytic activity towards NADH oxidation. Electrodeposition of poly(methylene green) (PMG) and poly(toluidine blue) (PTBO) on the carboxylated CNT‐modified electrodes was achieved by cyclic voltammetry. The PMG‐CNT interface demonstrates 5.0 mA cm^?2 current density for NADH oxidation at 50 mV vs. Ag|AgCl in 20 mM NADH solution. The kinetics of NADH electrocatalysis were analyzed using a quantitative mass‐transport‐corrected model with NADH bulk concentration and applied potential as independent variables. This high‐rate poly(azine)‐CNT interface is potentially applicable to high‐performance bioconversion, bioenergy and biosensors involving NADH‐dependent dehydrogenases.     

Influence of Metal Nanoparticles on the Electrocatalytic Oxidation of Glucose by Poly(NiIIteta) Modified Electrodes

Conductive polymeric [Ni^II(teta)]²⁺ (teta=C‐meso‐5,5,7,12,12,14‐hexamethyl‐1,4,8,11‐tetra‐azacyclotetradecane) films (poly(Ni)) have been deposited on the surface of glassy carbon (GC), Nafion (Nf) modified GC (GC/Nf) and Nf stabilized Ag and Au nanoparticles (NPs) modified GC (GC/Ag‐Nf and GC/Au‐Nf) electrodes. The cyclic voltammogram of the resulting electrodes, show a well defined redox peak due to oxidation and reduction of poly(Ni) system in 0.1 M NaOH. They show electrocatalytic activity towards the oxidation of glucose. AFM studies reveal the formation of poly(Ni) film on the modified electrodes. Presence of metal NPs increases electron transfer rate and electrocatalytic oxidation current by improving the communication within the Nf and poly(Ni) films. In the presence of metal NPs, 4 fold increase in current for glucose oxidation was observed.     

Stereoselective total synthesis of (-)-spirofungin A by utilising hydrogen-bond controlled spiroketalisation

The stereoselective total synthesis of the spiroketal containing Streptomyces metabolite (?)‐spirofungin A ( 1 ) is described. A key step involved a spiroketalisation controlled by an intramolecular H‐bond which favoured the desired spiroketal 4 (13:1 ratio). The presence of the intramolecular H‐bond in 4 is possibly due to a 1,5‐alkyne–oxygen interaction. Other key steps include an efficient cross‐metathesis to form the spiroketal precursor, a tin mediated syn‐aldol reaction and a Stille cross‐coupling reaction to create the C22? C23 bond. A final Wittig extension followed by deprotection gave (?)‐spirofungin A ( 1 ).     

Asymmetric Synthesis of Spiroketals with Aminothiourea Catalysts

Chiral spiroketal skeletons are found as core structures in a range of bioactive compounds. These natural compounds and their analogues have attracted much attention in the field of drug discovery. However, methods for their enantioselective construction are limited, and easily available optically active spiroketals are rare. We demonstrate a novel catalytic asymmetric synthesis of spiroketal compounds that proceeds through an intramolecular hemiacetalization/oxy‐Michael addition cascade mediated by a bifunctional aminothiourea catalyst. This results in spiroketal structures through the relay formation of contiguous oxacycles, in which multipoint recognition by the catalyst through hydrogen bonding imparts high enantioselectivity. This method offers facile access to spiroketal frameworks bearing an alkyl group at the 2‐position, which are prevalent in insect pheromones. Optically active (2S,5S)‐chalcogran, a pheromone of the six‐spined spruce bark beetle, and an azide derivative could be readily synthesized from the bicyclic reaction product.     

Designed Spiroketal Protein Modulation

Spiroketals are structural motifs found in many biologically active natural products, which has stimulated considerable efforts toward their synthesis and interest in their use as drug lead compounds. Despite this, the use of spiroketals, and especially bisbenzanulated spiroketals, in a structure‐based drug discovery setting has not been convincingly demonstrated. Herein, we report the rational design of a bisbenzannulated spiroketal that potently binds to the retinoid X receptor (RXR) thereby inducing partial co‐activator recruitment. We solved the crystal structure of the spiroketal–hRXRα–TIF2 ternary complex, and identified a canonical allosteric mechanism as a possible explanation for the partial agonist behavior of our spiroketal. Our co‐crystal structure, the first of a designed spiroketal–protein complex, suggests that spiroketals can be designed to selectively target other nuclear receptor subtypes.     

A diastereoselective formal synthesis of berkelic acid

A formal synthesis of berkelic acid is reported. The strategy employs the combination of a chiral exocyclic enol ether and an achiral isochromanone to afford the chroman spiroketal core via a base-triggered generation and cycloaddition of an o-quinone methide intermediate. Other key steps include equilibration of the spiroketal, intramolecular benzylic oxidation, and lactone addition/hemiketal reduction; all occur with good diastereoselectivity.     

Electrochemical Preparation of Brilliant‐Blue‐Modified Poly(diallyldimethylammonium Chloride) and Nafion‐Coated Glassy Carbon Electrodes and Their Electrocatalytic Behavior Towards Oxygen and L‐Cysteine

Brilliant blue FCF‐modified glassy carbon electrodes have been prepared by cycling the Nafion (or poly(diallyldimethylammonium chloride) (PDDAC)) coated electrodes repeatedly 15 cycles in brilliant blue FCF (BB FCF) dye solution. The BB FCF molecules are incorporated into Nafion coating by cycling the film‐covered electrode between +0.3 to 1.2 V (vs. Ag/AgCl) in pH 1.5 BB FCF solution while PDDAC‐coated electrode cycled between 0 to ?1.0 V (vs. Ag/AgCl) in pH 6.5 BB FCF solution to immobilize the dye. Electrostatic interaction between dye molecule and PDDAC was predominant in PDDAC coating whereas immobilization of dye in Nafion film attributed to the combined effect of electrostatic and hydrophobic interactions. The voltammetric features of BB FCF‐modified electrodes resemble that of surface‐confined redox couples. The peak potentials of BB FCF‐incorporated PDDAC‐coated electrode were shifted to more positive potential region with decreasing pH of contacting solution. BB FCF‐modified electrodes showed electrocatalytic activity towards reduction of oxygen and oxidation of L ‐cysteine with significant decease of overvoltage compared to unmodified electrode. The BB FCF‐modified Nafion‐coated electrode was tested for its analytical applications toward determination of L ‐cysteine. The linear range of calibration plot at BB FCF‐modified Nafion‐coated electrode is 10 to 100 μM, which coincides with L ‐cysteine levels in biological fluids. Sensitivity and detection limit of the electrode are 111 nA μM^?1 and 0.5 μM, respectively.     

Chemical variation of natural product-like scaffolds: design and synthesis of spiroketal derivatives

The design and synthesis of spiroketal structures and their chemical modification, leading to a collection of new small molecules for biological evaluation as orally-bioavailable lead compounds is described. Both [6,5]- and [6,6]-membered ring spiroketal units have been prepared in a stereochemically-varying fashion starting from commercially available (R)- or (S)-glycidol, in ten, eleven and twelve linear steps, in overall yields of 45, 40 and 20%, respectively. Further elaboration according to Lipinski's guidelines has given a collection of structurally-diverse, new spiroketal derivatives in high yields and with high purity.     

Electropreparation of Poly(benzophenone‐4) Film Modified Electrode and Its Electrocatalytic Behavior Towards Dopamine,Ascorbic Acid and Nitrite

The oxidation of benzophenone‐4 (2‐hydroxy‐4‐methoxybenzophenone‐5‐sulfonic acid) at glassy carbon electrode gives rise to stable redox active electropolymerized film during repetitive potential cycling between 0 to 1.3 V (Ag/AgCl). Cyclic voltammogram of poly(benzophenone‐4) film shows a redox couple with well‐defined peaks. The redox response of the modified electrode was found to be depending on the pH of the contacting solution. The peak potentials were shifted to a less positive region with increasing pH and the dependence of the peak potential was found to be 51 mV/pH. The electrocatalytic behavior of poly(benzophenone‐4) film modified electrode towards oxidation of dopamine, ascorbic acid and reduction of nitrite was investigated. The oxidation of dopamine and ascorbic acid occurred at less positive potential on poly(benzophenone‐4) film compared to bare glassy carbon electrode. For dopamine, the overpotential was reduced about 180 mV. Feasibility of utilizing poly(benzophenone‐4) film coated electrode in analytical estimation of dopamine, ascorbic acid and nitrite was also demonstrated.     

Fabrication and Application of a Sensitive and Highly Stable Copper Hexacyanoferrate Modified Carbon Ionic Liquid Paste Electrode for Hydrogen Peroxide and Glucose Detection

A three‐factor mixture design and response surface methodology were employed to find the optimal weight ratio of graphite powder, n‐dodecylpyridinium hexafluorophosphate and paraffin for the fabrication of a copper hexacyanoferrate modified carbon ionic liquid paste electrode (CuHCFe‐CILPE). The fabricated sensor showed electrocatalytic activity towards oxidation and reduction of hydrogen peroxide. It also was observed that the electrocatalytic activity for hydrogen peroxide oxidation was much higher than the electrocatalytic activity for hydrogen peroxide reduction. Glucose oxidase was then successfully immobilized on the surface of the proposed sensor to examine the possibility of using CuHCFe‐CILPE for the biosensor fabrication.     

Electrochemical Detection of 2‐Naphthol at a Glassy Carbon Electrode Modified with Tosflex Film

In this study, a Tosflex (a perfluoro‐anion‐exchange membrane) modified glassy carbon electrode has been used to detect 2‐naphthalenol (2‐naphthol) in aqueous solutions in order to demonstrate the electroanalytical application of Tosflex. 2‐naphthol polymerizes upon electrochemical oxidation at a glassy carbon electrode; however, the current related to this oxidation is too small for analytical purpose at low concentration level. A Tosflex polymer modified glassy carbon electrode (TFGCE) was found of having capability to improve the detection limit because 2‐naphthol molecules deprotonated in basic solutions to form 2‐naphtholate anions that were accumulated to TFGCE by the anion‐exchange characteristic of Tosflex. The accumulated 2‐naphtholate anions were determined with the following differential pulse voltammetry. With 3 minutes accumulation at +0.05 V, the dependence of oxidation current versus concentration was linear from 8×10^?7 M to 1×10^?5 M with a regression coefficient of 0.999 and a detection limit of 2×10^?7 M. Unlike many other anion‐exchange polymer modified electrodes, the TFGCE is stable at highly basic condition.