Selective Hydrogen Atom Abstraction through Induced Bond Polarization: Direct α‐Arylation of Alcohols through Photoredox,HAT, and Nickel Catalysis

The combination of nickel metallaphotoredox catalysis, hydrogen atom transfer catalysis, and a Lewis acid activation mode, has led to the development of an arylation method for the selective functionalization of alcohol α‐hydroxy C?H bonds. This approach employs zinc‐mediated alcohol deprotonation to activate α‐hydroxy C?H bonds while simultaneously suppressing C?O bond formation by inhibiting the formation of nickel alkoxide species. The use of Zn‐based Lewis acids also deactivates other hydridic bonds such as α‐amino and α‐oxy C?H bonds. This approach facilitates rapid access to benzylic alcohols, an important motif in drug discovery. A 3‐step synthesis of the drug Prozac exemplifies the utility of this new method.     

Investigations of Scope and Mechanism of Nickel‐Catalyzed Transformations of Glycosyl Trichloroacetimidates to Glycosyl Trichloroacetamides and Subsequent,Atom‐Economical,One‐Step Conversion to α‐Urea‐Glycosides

The development and mechanistic investigation of a highly stereoselective methodology for preparing α‐linked‐urea neo‐glycoconjugates and pseudo‐oligosaccharides is described. This two‐step procedure begins with the selective nickel‐catalyzed conversion of glycosyl trichloroacetimidates to the corresponding α‐trichloroacetamides. The α‐selective nature of the conversion is controlled with a cationic nickel(II) catalyst, [Ni(dppe)(OTf)₂] (dppe=1,2‐bis(diphenylphosphino)ethane, OTf=triflate). Mechanistic studies have identified the coordination of the nickel catalyst with the equatorial C₂‐ether functionality of the α‐glycosyl trichloroacetimidate to be paramount for achieving an α‐stereoselective transformation. A cross‐over experiment has indicated that the reaction does not proceed in an exclusively intramolecular fashion. The second step in this sequence is the direct conversion of α‐glycosyl trichloroacetamide products into the corresponding α‐urea glycosides by reacting them with a wide variety of amine nucleophiles in presence of cesium carbonate. Only α‐urea‐product formation is observed, as the reaction proceeds with complete retention of stereochemical integrity at the anomeric C?N bond.     

Selective Hydrogen Atom Abstraction through Induced Bond Polarization: Direct α‐Arylation of Alcohols through Photoredox,HAT, and Nickel Catalysis

The combination of nickel metallaphotoredox catalysis, hydrogen atom transfer catalysis, and a Lewis acid activation mode, has led to the development of an arylation method for the selective functionalization of alcohol α‐hydroxy C−H bonds. This approach employs zinc‐mediated alcohol deprotonation to activate α‐hydroxy C−H bonds while simultaneously suppressing C−O bond formation by inhibiting the formation of nickel alkoxide species. The use of Zn‐based Lewis acids also deactivates other hydridic bonds such as α‐amino and α‐oxy C−H bonds. This approach facilitates rapid access to benzylic alcohols, an important motif in drug discovery. A 3‐step synthesis of the drug Prozac exemplifies the utility of this new method.     

Copper Photoredox Catalyzed A3’ Coupling of Arylamines,Terminal Alkynes,and Alcohols through a Hydrogen Atom Transfer Process

The first successful example of the three‐component coupling of N‐alkylanilines, terminal alkynes, and alcohols was achieved at room temperature by a visible‐light‐mediated copper‐catalyzed photoredox hydrogen‐atom transfer process. This method allows preparation of propargylamines through uniquely selective α‐C?H bond activation of unactivated alkylalcohols. Preliminary studies indicate that formation of α‐oxy radical is operative. This approach facilitates rapid access to biologically important propargylamines from methanol as an abundant feedstock.     

α‐Aminoxy Oligopeptides: Synthesis,Secondary Structure,and Cytotoxicity of a New Class of Anticancer Foldamers

α‐Aminoxy peptides are peptidomimetic foldamers with high proteolytic and conformational stability. To gain an improved synthetic access to α‐aminoxy oligopeptides we used a straightforward combination of solution‐ and solid‐phase‐supported methods and obtained oligomers that showed a remarkable anticancer activity against a panel of cancer cell lines. We solved the first X‐ray crystal structure of an α‐aminoxy peptide with multiple turns around the helical axis. The crystal structure revealed a right‐handed 2₈‐helical conformation with precisely two residues per turn and a helical pitch of 5.8 Å. By 2D ROESY experiments, molecular dynamics simulations, and CD spectroscopy we were able to identify the 2₈‐helix as the predominant conformation in organic solvents. In aqueous solution, the α‐aminoxy peptides exist in the 2₈‐helical conformation at acidic pH, but exhibit remarkable changes in the secondary structure with increasing pH. The most cytotoxic α‐aminoxy peptides have an increased propensity to take up a 2₈‐helical conformation in the presence of a model membrane. This indicates a correlation between the 2₈‐helical conformation and the membranolytic activity observed in mode of action studies, thereby providing novel insights in the folding properties and the biological activity of α‐aminoxy peptides.     

The Reaction Studies of α‐Chloroformylarylhydrazines with Thiols,Thioureas and α‐Cyclodiketones

The reactions of α‐chloroformylarylhydrazines 1 with various types of mercaptan, thiourea and α‐cyclodiketone have been studied intensively. 1‐Arylhydrazinecarbothioates 2 were obtained via thioesterization when α‐chloroformylarylhydrazines reacted with thiols. On the other hand, compounds 3 were obtained when α‐chloroformylarylhydrazines reacted with thio‐containing heterocyclic compounds, which suggested a totally different mechanism in these types of reactions. Further studies on the reaction of α‐chloroformylarylhydrazines 1 with thiourea compounds confirmed a novel cyclization and de‐cyclization mechanism, which led to give 2‐arylhydrazinecarboximidamides 5 and 1,3,4‐thiadiazolin‐5‐ones 6 . In addition, various 1,3,4‐oxadiazines 9 were obtained by reacting α‐chloroformylarylhydrazines with α‐cyclodiketones, showing ring cyclization was involved in this type of reaction.     

Ferrocenylalkyl azoles: bioactivity,synthesis, structure

The toxicity of ferrocenylethyl benzotriazole ( 1 ) and other ferrocene compounds including ferrocenylmethyl benzimidazoles ( 4,5,6,11 ), ferricenium salts ( 3,9,10 ) and ferrocenylmethyl adenine ( 7 ), was studied. All ferrocene complexes under investigation showed low or medium toxicities. On the basis of an earlier model of chemical carcinogenesis, the antitumor activity of ferrocenylalkyl azoles 1, 8 and ferricenium salts 9, 10 was studied in vivo in the so‐called sub‐capsular test on human tumors. This effectiveness was compared with that of cisplatin. A series of ferrocenylalkyl azoles were synthesized by interacting azoles either with α‐hydroxyalkyl ferrocenes FcC(OH)R₁R₂ in organic solvent in the presence of aqueous HBF₄ in quantitative yields or with trimethyl(aminomethyl)ferrocene iodide in an aqueous‐basic medium in good yields. The X‐ray determinations of molecular and crystal structures of α‐(1‐benzotriazolyl)ethylferrocene ( 1 ) and α‐(1‐naphthatriazolyl)ethylferrocene ( 12 ) were performed. Copyright © 2008 John Wiley & Sons, Ltd.     

Potassium N‐Iodo p‐Toluenesulfonamide (TsNIK,Iodamine‐T): A New Reagent for the Oxidation of Hydrazones to Diazo Compounds

A new reagent for the oxidation of hydrazones to diazo compounds is described. N‐Iodo p‐toluenesulfonamide (TsNIK, iodamine‐T) allows the preparation of α‐diazoesters, α‐diazoamides, α‐diazoketones and α‐diazophosphonates in good yield and in high purity after a simple extractive work‐up. α‐Diazoesters were also obtained in high yield from the corresponding ketones through a one‐pot process of hydrazone formation/oxidation.     

Selective α‐Oxyamination and Hydroxylation of Aliphatic Amides

Compared to the α‐functionalization of aldehydes, ketones, even esters, the direct α‐modification of amides is still a challenge because of the low acidity of α‐CH groups. The α‐functionalization of N−H (primary and secondary) amides, containing both an unactived α‐C−H bond and a competitively active N−H bond, remains elusive. Shown herein is the general and efficient oxidative α‐oxyamination and hydroxylation of aliphatic amides including secondary N−H amides. This transition‐metal‐free chemistry with high chemoselectivity provides an efficient approach to α‐hydroxy amides. This oxidative protocol significantly enables the selective functionalization of inert α‐C−H bonds with the complete preservation of active N−H bond.     

Effects of solvent,casting temperature,and guest/host stoichiometries on the properties of shape memory material based on partial α‐CD‐PEG inclusion complex

A series of supramolecular inclusion complex (IC) films were formed by threading α‐cyclodextrin (α‐CD) molecules over poly(ethylene glycol) (PEG), according to the designed ratio of α‐CD/PEG. Because of containing α‐CD‐PEG inclusion crystallites as physical crosslinks and uncovered PEG crystallites as “switch phase”, the resulting supramolecular α‐CD‐PEG partial ICs displayed a shape memory effect. The properties of the materials were investigated by ¹H‐NMR, X‐ray diffraction (XRD), differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), and swelling measurement. It was found that the casting temperature, solvent, and the ratio of α‐CD‐PEG inclusion/PEG had great influence on the formation and properties of α‐CD‐PEG partial ICs. The modes of complexes on different conditions were proposed. © 2010 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 48: 951–957, 2010     

Umpolung Reactions of α‐Imino Esters: Useful Methods for the Preparation of α‐Amino Acid Frameworks

This paper summarizes our recent efforts toward the development of tandem reactions utilizing umpolung reactions of α‐imino esters. A highly diastereoselective tandem N‐alkylation–Mannich reaction of α‐imino esters was developed. A tandem N‐alkylation–addition reaction of α‐imino esters derived from ethyl glyoxylate with various aldehydes proceeded to give 1,2‐amino alcohols. The same reaction also proceeded efficiently using a novel flow system comprising two connected microreactors. Novel syntheses of α‐quaternary alkynyl amino esters and allenoates were developed through the use of umpolung N‐addition to β,γ‐alkynyl α‐imino esters, followed by regioselective acylation. In addition, a highly regioselective tandem N‐alkylation–vinylogous aldol reaction of β,γ‐alkenyl α‐imino esters was discovered. N‐Alkylation of α‐iminophosphonates followed by a Horner–Wadsworth–Emmons reaction with aldehydes occurred to afford enamines, which can be used in a four‐component coupling reaction with methyl vinyl ketone. α‐N‐Acyloxyimino esters served as highly efficient substrates for the N,N,C‐trialkylation reaction to introduce various nucleophiles at the imino nitrogen and carbon atoms.     

The Kabachnik–Fields and Pudovik Reactions on the Basis of E,Z‐Citral and Its Imines and (R,S)‐Citronellal

The Kabachnik–Fields reaction of E,Z‐citral with diethyl phosphite in the presence of isobutylamine has been found to form α‐aminophosphonates. The Pudovik reactions of diethyl phosphite with prenyl imines prepared on the basis of E,Z‐citral with isobutylamine also allowed us to obtain the same α‐aminophosphonates. We have managed to synthesize α‐aminophosphonates by the reaction of O,O‐dialkyl trimethylsilyl phosphites with prenyl imines in the presence of water or diethylamine. α‐Aminophosphonates were also synthesized by the reaction of diethyl phosphite with (R,S)‐citronellal in the presence of alkylamines. α‐Aminophosphonates obtained showed bacteriostatic activity against Staphylococcus aureus and Bacillus cereus. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 24:36–42, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21060     

A simple,convenient and expeditious approach to cineol

A convenient two‐step protocol preparation of cineol (1‐isopropyl‐4‐methyl‐7‐oxabicyclo[2,2,1]heptane) from α‐terpineol (p‐menth‐1‐en‐8‐ol) is reported. The phenylselenoetherification of α‐terpineol with PhSeX (X = Cl, Br, I) as a key step is described. α‐Terpineol reacts with PhSeX to form the corresponding phenylselenoether in short reaction time and in quantitative yield. A subsequent reduction with Bu₃SnH to cineol proceeds in high yield (98%) © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:468–470, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20044     

Enzymatic Synthesis of α‐d‐Xylosylated Malto‐oligosaccharides by Phosphorylase‐catalyzed Xylosylation

This paper describes the enzymatic synthesis of α‐d‐xylosylated malto‐oligosaccharides by phosphorylase‐catalyzed xylosylation of maltotetraose. When the xylosylation was carried out using α‐d‐xylose‐1‐phosphate as a glycosyl donor in the presence of phosphorylase, xylosylated oligosaccharides were produced with high conversion. α‐d‐Xylosyl‐(1→4)‐maltotetraose was isolated as the main product. Glucoamylase‐catalyzed reaction of the isolated material revealed that one α‐xyloside unit is positioned at the nonreducing end.     

Light‐Driven Organocatalysis Using Inexpensive,Nontoxic Bi2O3 as the Photocatalyst

The development of enantioselective catalytic processes that make use of sunlight as the energy source and nontoxic, affordable materials as catalysts represents one of the new and rapidly evolving areas in chemical research. The direct asymmetric α‐alkylation of aldehydes with α‐bromocarbonyl compounds can be successfully achieved by combining bismuth‐based materials as low‐band‐gap photocatalysts with the second‐generation MacMillan imidazolidinone as the chiral catalyst and simulated sunlight as a low‐cost and clean energy source. This reaction also proceeded with high efficiency when the reaction vial was exposed to the morning sunlight on a clear September day in Tarragona, Spain.     

A Metallaphotoredox Strategy for the Cross‐Electrophile Coupling of α‐Chloro Carbonyls with Aryl Halides

Here, we demonstrate that a metallaphotoredox‐catalyzed cross‐electrophile coupling mechanism provides a unified method for the α‐arylation of diverse activated alkyl chlorides, including α‐chloroketones, α‐chloroesters, α‐chloroamides, α‐chlorocarboxylic acids, and benzylic chlorides. This strategy, which is effective for a wide variety of aryl bromide coupling partners, is predicated upon a halogen atom abstraction/nickel radical‐capture mechanism that is generically successful across an extensive range of carbonyl substrates. The construction and use of arylacetic acid products have further enabled two‐step protocols for the delivery of valuable building blocks for medicinal chemistry, such as aryldifluoromethyl and diarylmethane motifs.     

Light‐Driven Organocatalysis Using Inexpensive,Nontoxic Bi2O3 as the Photocatalyst

The development of enantioselective catalytic processes that make use of sunlight as the energy source and nontoxic, affordable materials as catalysts represents one of the new and rapidly evolving areas in chemical research. The direct asymmetric α‐alkylation of aldehydes with α‐bromocarbonyl compounds can be successfully achieved by combining bismuth‐based materials as low‐band‐gap photocatalysts with the second‐generation MacMillan imidazolidinone as the chiral catalyst and simulated sunlight as a low‐cost and clean energy source. This reaction also proceeded with high efficiency when the reaction vial was exposed to the morning sunlight on a clear September day in Tarragona, Spain.     

Self‐Assembled Cyclic d,l‐α‐Peptides as Generic Conformational Inhibitors of the α‐Synuclein Aggregation and Toxicity: In Vitro and Mechanistic Studies

Many peptides and proteins with large sequences and structural differences self‐assemble into disease‐causing amyloids that share very similar biochemical and biophysical characteristics, which may contribute to their cross‐interaction. Here, we demonstrate how the self‐assembled, cyclic d,l ‐α‐peptide CP‐2 , which has similar structural and functional properties to those of amyloids, acts as a generic inhibitor of the Parkinson′s disease associated α‐synuclein (α‐syn) aggregation to toxic oligomers by an ?off‐pathway“ mechanism. We show that CP‐2 interacts with the N‐terminal and the non‐amyloid‐β component region of α‐syn, which are responsible for α‐syn′s membrane intercalation and self‐assembly, thus changing the overall conformation of α‐syn. CP‐2 also remodels α‐syn fibrils to nontoxic amorphous species and permeates cells through endosomes/lysosomes to reduce the accumulation and toxicity of intracellular α‐syn in neuronal cells overexpressing α‐syn. Our studies suggest that targeting the common structural conformation of amyloids may be a promising approach for developing new therapeutics for amyloidogenic diseases.     

Exploration and Optimization of an Efficient One‐pot Sequential Synthesis of Di/tri‐substituted Thiazoles from α‐Bromoketones,Thioacids Salt,and Ammonium Acetate

Exploration of scope of an optimized one‐pot sequential procedure for preparing of 2,4‐di‐ and 2,4,5‐tri‐substituted thiazoles has been accomplished. The synthesis was performed by the initial formation of a β‐keto‐thioester intermediate from nucleophilic substitution of α‐bromoketones with thioacid potassium salts, followed by treatment with ammonium acetate and one equivalent of acetic acid in toluene to form imine intermediate eventually leading to cyclization yielding thiazoles. This procedure should be highlighted with a flexible way to control the substitution pattern around thiazole ring by choosing appropriately substituted α‐bromoketones even containing acid labile functionality and thioacid potassium salts, and thus its applicability is very wide.     

Direct Umpolung Morita–Baylis–Hillman like α‐Functionalization of Enones via Enolonium Species

Herein we report on the umpolung of Morita–Baylis–Hillman type intermediates and application to the α‐functionalization of enone C?H bonds. This reaction gives direct access to α‐chloro‐enones, 1,2‐diketones and α‐tosyloxy‐enones. The latter are important intermediates for cross‐coupling reaction and, to the best of our knowledge, cannot be made in a single step from enones in any other way. The proposed mechanism is supported by spectroscopic studies. The key initial step involves conjugate attack of an amine (DABCO or pyridine), likely assisted by hypervalent iodine acting as a Lewis acid leading to formation of an electrophilic β‐ammonium‐enolonium species. Nucleophilic attack by acetate, tosylate, or chloride anion is followed by base induced elimination of the ammonium species to give the noted products. Hydrolysis of α‐acetoxy‐enones lead to formation of 1,2‐diketones. The α‐tosyl‐enones participate in Negishi coupling reactions under standard conditions.