Photomediated Hydro- and Deuterodecarboxylation of Pharmaceutically Relevant and Natural Aliphatic Carboxylic Acids.

Herein, we report a photomediated hydro- and deuterodecarboxylation of different primary, secondary, and tertiary carboxylic acids catalyzed by an organic pyrimidopteridine photoredox catalyst. The reaction was optimized by a statistical design of experiment (DoE). Under optimized reaction conditions, the conversion of commercially available nonsteroidal anti-inflammatory drugs (NSAIDs) in tablet form and on gram scale was realized. The scope of the application comprises primary, secondary, and tertiary aliphatic biologically active carboxylic acids. A deuterium incorporation of up to 95% by using D2O as inexpensive deuterium source was achieved. A sensitivity assessment as well as experiments aiding the elucidation of the reaction mechanism are discussed.

Pyrimidopteridine-catalyzed Photo-mediated Hydroacetoxylation.

Herein we report a photo-mediated formal addition of carboxylic acids to activated alkenes catalyzed by a pyrimidopteridine photoredox catalyst. The decarboxylation of aliphatic carboxylic acids upon single-electron oxidation is countered in the presence of electron-rich alkenes and a hydroacetoxylation is observed. Mechanistic proposals have been made based on CV measurements, competitive Stern-Volmer quenching and EPR experiments. Evidence that tetra-N-substituted pyrimidopteridines function as dual photoredox and hydrogen atom transfer catalyst was supported by spectroscopic means.

Synthesis, Coordination Chemistry, and Mechanistic Studies of P,N-Type Phosphaalkene-Based Rh(I) Complexes.

The synthesis of P,N-phosphaalkene ligands, py-CH═PMes* (1, py = 2-pyridyl, Mes* = 2,4,6-tBu-C6H2) and the novel quin-CH═PMes* (2, quin = 2-quinolinyl) is described. The reaction with [Rh(µ-Cl)cod]2 produces Rh(I) bis(phosphaalkene) chlorido complexes 3 and 4 with distorted trigonal bipyramidal coordination environments. Complexes 3 and 4 show a pronounced metal-to-ligand charge transfer (MLCT) from Rh into the ligand P═C π* orbitals. Upon heating, quinoline-based complex 4 undergoes twofold C-H bond activation at the o-tBu groups of the Mes* substituents to yield the cationic bis(phosphaindane) Rh(I) complex 5, which could not be observed for the pyridine-based analogue 3. Using sub- or superstoichiometric amounts of AgOTf the C-H bond activation at an o-tBu group of one or at both Mes* was detected, respectively. Density functional theory (DFT) studies suggest an oxidative proton shift pathway as an alternative to a previously reported high-barrier oxidative addition at Rh(I). The Rh(I) mono- and bis(phosphaindane) triflate complexes 6 and 7, respectively, undergo deprotonation at the benzylic CH2 group of the phosphaindane unit in the presence of KOtBu to furnish neutral, distorted square-planar Rh(I) complexes 8 and 9, respectively, with one of the P,N ligands being dearomatized. All complexes were fully characterized, including multinuclear NMR, vibrational, and ultraviolet-visible (UV-vis) spectroscopy, as well as single-crystal X-ray and elemental analysis.

Mechanistic Insight into the Mode of Action of Acid ß-Glucosidase Enhancer Ambroxol.

Ambroxol (ABX) is a mucolytic agent used for the treatment of respiratory diseases. Bioactivity has been demonstrated as an enhancement effect on lysosomal acid ß-glucosidase (ß-Glu) activity in Gaucher disease (GD). The positive effects observed have been attributed to a mechanism of action similar to pharmacological chaperones (PCs), but an exact mechanistic description is still pending. The current study uses cell culture and in vitro assays to study the effects of ABX on ß-Glu activity, processing, and stability upon ligand binding. Structural analogues bromohexine, 4-hydroxybromohexine, and norbromohexine were screened for chaperone efficacy, and in silico docking was performed. The sugar mimetic isofagomine (IFG) strongly inhibits ß-Glu, while ABX exerts its inhibitory effect in the micromolar range. In GD patient fibroblasts, IFG and ABX increase mutant ß-Glu activity to identical levels. However, the characteristics of the banding patterns of Endoglycosidase-H (Endo-H)-digested enzyme and a substantially lower half-life of ABX-treated ß-Glu suggest different intracellular processing. In line with this observation, IFG efficiently stabilizes recombinant ß-Glu against thermal denaturation in vitro, whereas ABX exerts no significant effect. Additional ß-Glu enzyme activity testing using Bromohexine (BHX) and two related structures unexpectedly revealed that ABX alone can refunctionalize ß-Glu in cellula. Taken together, our data indicate that ABX has little in vitro ability to act as PC, so the mode of action requires further clarification.

Palladium-Catalyzed Synthesis of N,N-Dimethylanilines via Buchwald-Hartwig Amination of (Hetero)aryl Triflates.

This work delineates the synthesis of N,N-dimethylaniline derivatives from dimethylamines and aryl triflates. The palladium-catalyzed C-N bond formation proceeds in excellent yields, using an unsophisticated catalytic system, a mild base, and triflates as electrophiles, which are readily available from inexpensive phenols. N,N-Dimethylanilines are multifunctional reaction partners and represent useful but underutilized building blocks in organic synthesis.

Photo-Mediated Decarboxylative Giese-Type Reaction Using Organic Pyrimidopteridine Photoredox Catalysts.

The decarboxylative Giese-type reaction offers a versatile methodology for the radical alkylation of electron-deficient alkenes. Photo-mediated variants often require a pre-activation of carboxylic acids and/or employment of costly transition-metal photocatalysts. Herein, we present a metal-free photocatalyzed decarboxylative Giese-type addition to electron-deficient alkenes using pyrimidopteridine N-oxides as organic photoredox-active catalysts. This protocol comprises mono-, di-, and trisubstituted aliphatic, α-amino, and α-oxy acids as well as a variety of electron-deficient alkenes. Moreover, post-synthetic derivatization and applications are presented.

Pyrimidopteridine N-Oxide Organic Photoredox Catalysts: Characterization, Application and Non-Covalent Interaction in Solid State.

Herein we report the photo- and electrochemical characterization of pyrimidopteridine N-oxide-based heterocycles. The potential of their application as organic photoredox catalysts is showcased in the photomediated contra-thermodynamic E→Z isomerization of cinnamic acid derivatives and oxidative cyclization of 2-phenyl benzoic acid to benzocoumarin using molecular oxygen as a mild oxidant. Furthermore, unprecedented intermolecular non-covalent n-π-hole interactions in solid state are discussed based on crystallographic and theoretical data.

Nickel-Catalyzed Dearomative trans-1,2-Carboamination.

We describe the development of an arenophile-mediated, nickel-catalyzed dearomative trans-1,2-carboamination protocol. A range of readily available aromatic compounds was converted to the corresponding dienes using Grignard reagents as nucleophiles. This strategy provided products with exclusive trans-selectivity and high enantioselectivity was observed in case of benzene and naphthalene. The utility of this methodology was showcased by controlled and stereoselective preparation of small, functionalized molecules.

Synthesis of (+)-Pancratistatins via Catalytic Desymmetrization of Benzene.

A concise synthesis of (+)-pancratistatin and (+)-7-deoxypancratistatin from benzene using an enantioselective, dearomative carboamination strategy has been achieved. This approach, in combination with the judicious choice of subsequent olefin-type difunctionalization reactions, permits rapid and controlled access to a hexasubstituted core. Finally, minimal use of intermediary steps as well as direct, late stage C-7 hydroxylation provides both natural products in six and seven operations.

Arenophile-Mediated Dearomative Reduction.

A dearomative reduction of simple arenes has been developed which employs a visible-light-mediated cycloaddition of arenes with an N-N-arenophile and in situ diimide reduction. Subsequent cycloreversion or fragmentation of the arenophile moiety affords 1,3-cyclohexadienes or 1,4-diaminocyclohex-2-enes, compounds that are not synthetically accessible using existing dearomatization reactions. Importantly, this strategy also provides numerous opportunities for further derivatization as well as site-selective functionalization of polynuclear arenes.

Regioselective ruthenium-catalyzed carbonylative direct arylation of five-membered and condensed heterocycles.

A ruthenium-catalyzed carbonylative CH bond arylation process for the three-component synthesis of complex aryl-(hetero)aryl ketones in an aqueous solution has been developed. By exploiting the ortho-activating effect of nitrogen-containing directing groups, a regioselective, successive twofold C(sp(2))-C(sp(2)) bond formation has been achieved. This straightforward catalytic process provides access to versatile products prevalent in multiple bioactive compounds and supplies a valuable functional group for subsequent transformations.

Alternative metals for homogeneous catalyzed hydroformylation reactions.

Transition-metal-catalyzed hydroformylation reactions constitute one of the most powerful tools for C-C bond formation in organic synthesis and represent an outstanding example of the application of homogeneous catalysis on an industrial scale. This process allows for the straightforward conversion of inexpensive chemical feedstock into broadly applicable aldehydes, which serve as major building blocks for numerous chemical products. These products are highly valuable for the chemical industry and used as plasticizers, detergents, and surfactants on a million ton scale. Moreover, aldehydes serve as versatile chemical intermediates for the production of fine chemicals and pharmaceuticals. Currently, most of the bulk hydroformylation processes rely on rhodium-based catalysts. The increasing demand and resulting high cost of this precious metal has resulted in alternative transition-metal catalysts becoming highly desirable. The following Review summarizes the progress achieved utilizing Ru, Ir, Pd, Pt, and Fe catalysts in hydroformylation reactions.

1-[(Methyl-sulfon-yl)-oxy]pyridin-1-ium methane-sulfonate.

The title mol-ecular salt, C6H8NO3S+·CH3O3S-, consists of a cationic sulfonated pyridine N-oxide moiety and a methane-sulfonate anion. An N-O bond length of 1.4004 (15) Šis observed in the cation. In the crystal, weak C-H⋯O inter-actions link the components into a three-dimensional network.

Role of endoplasmic reticulum stress and protein misfolding in disorders of the liver and pancreas.

The endoplasmic reticulum (ER) is the site of synthesis and folding of membrane and secretory proteins. The fraction of protein passing through the ER represents a large proportion of the total protein in the cell. Protein folding, glycosylation, sorting and transport are essential tasks of the ER and a compromised ER folding network has been recognized to be a key component in the disease pathogenicity of common neurodegenerative, metabolic and malignant diseases. On the other hand, the ER protein folding machinery also holds significant potential for therapeutic interventions. Many causes can lead to ER stress. A disturbed calcium homeostasis, the generation of reactive oxygen species (ROS) and a persistent overload of misfolded proteins within the ER can drive the course of adisease. In this review the role of ER-stress in diseases of the liver and pancreas will be examined using pancreatitis and Wilson´s disease as examples. Potential therapeutic targets in ER-stress pathways will also be discussed.

Dearomative dihydroxylation with arenophiles.

Aromatic hydrocarbons are some of the most elementary feedstock chemicals, produced annually on a million metric ton scale, and are used in the production of polymers, paints, agrochemicals and pharmaceuticals. Dearomatization reactions convert simple, readily available arenes into more complex molecules with broader potential utility, however, despite substantial progress and achievements in this field, there are relatively few methods for the dearomatization of simple arenes that also selectively introduce functionality. Here we describe a new dearomatization process that involves visible-light activation of small heteroatom-containing organic molecules-arenophiles-that results in their para-cycloaddition with a variety of aromatic compounds. The approach uses N-N-arenophiles to enable dearomative dihydroxylation and diaminodihydroxylation of simple arenes. This strategy provides direct and selective access to highly functionalized cyclohexenes and cyclohexadienes and is orthogonal to existing chemical and biological dearomatization processes. Finally, we demonstrate the synthetic utility of this strategy with the concise synthesis of several biologically active compounds and natural products.

Rhodium-catalysed alkoxylation/acetalization of diazo compounds: one-step synthesis of highly functionalised quaternary carbon centres.

An intermolecular tandem reaction for the rapid build-up of densely functionalised α-alkoxy-ß-oxo-esters has been developed. This novel process applies the easy to handle trimethyl orthoformate as a C1-building block in the rhodium(II)-catalysed alkoxylation/acetalization of donor-acceptor substituted diazo compounds. The concomitant C-O/C-C bond formation reaction gives products with unique quaternary carbon centers, substituted by groups of different oxidation level (ester, protected aldehyde and alkoxide).

Rhodium(II)-Catalyzed Annulation of Azavinyl Carbenes Through Ring-Expansion of 1,3,5-Trioxane: Rapid Access to Nine-Membered 1,3,5,7-Trioxazonines.

The rhodium(II)-catalyzed denitrogenative coupling of N-alkylsulfonyl 1,2,3-triazoles with 1,3,5-trioxane led to nine-membered-ringed trioxazonines in moderate-to-good yields. 1,3,5-Trioxane, acting as an oxygen nucleophile, reacted with the α-aza-vinylcarbene intermediate, giving rise to ylide formation, which was probably the key step in the reaction. Triazoles that contained aryl substituents with various electronic and steric features on the C4 carbon atom were well-tolerated. The synthesis of trioxazonine derivatives was achieved through a one-pot, two-step procedure from 1-mesylazide and a terminal alkyne by combining Cu(I)-catalyzed 1,3-dipolar cycloaddition and rhodium-catalyzed transformations.

Well-defined ruthenium(II) carboxylate as catalyst for direct C-H/C-O bond arylations with phenols in water.

The ruthenium(II) carboxylate complex [Ru(O(2)CMes)(2)(p-cymene)] enabled efficient direct arylations of unactivated C-H bonds with easily available, inexpensive phenols. Extraordinary chemoselectivity of the well-defined ruthenium catalyst set the stage for challenging C-H/C-O bond functionalizations to occur under solvent-free conditions as well as in water, and allowed first direct C-H bond arylations with user-friendly diaryl sulfates as electrophiles.

Versatile synthesis of isocoumarins and α-pyrones by ruthenium-catalyzed oxidative C-H/O-H bond cleavages.

An inexpensive cationic ruthenium(II) catalyst enabled the expedient synthesis of isocoumarins through oxidative annulations of alkynes by benzoic acids. This C-H/O-H bond functionalization process also proved applicable to the preparation of α-pyrones and was shown to proceed by rate-limiting C-H bond ruthenation.