Search

Under aprotic conditions, the stoichiometric reaction of N-heterocyclic carbenes (NHCs) such as imidazolidin-2-ylidenes with aldehydes affords Breslow Intermediates (BIs), involving a formal 1,2-C-to-O proton shift. We herein report kinetic studies (NMR), complemented by DFT calculations, on the mechanism of this kinetically disfavored H-translocation. Variable time normalization analysis (VTNA) revealed that the kinetic orders of the reactants vary for different NHC-to-aldehyde ratios, indicating different and ratio-dependent mechanistic regimes. We propose that for high NHC-to-aldehyde ratios, the H-shift takes place in the primary, zwitterionic NHC-aldehyde adduct. With excess aldehyde, the zwitterion is in equilibrium with a hemiacetal, in which the H-shift occurs. In both regimes, the critical H-shift is auto-catalyzed by the BI. Kinetic isotope effects observed for R-CDO are in line with our proposal. Furthermore, we detected an H-bonded complex of the BI with excess NHC (NMR).

In the Sharpless asymmetric epoxidation of chiral secondary allylic alcohols, one substrate enantiomer is predominantly converted to the anti-epoxy alcohol. We herein report the first highly syn-selective epoxidation of terminal allylic alcohols using a titanium salalen complex as catalyst, at room temperature, and aqueous hydrogen peroxide as oxidant. With enantiopure terminal allylic alcohols as substrates, the epoxy alcohols were obtained with up to 98 % yield and up to >99 : 1 dr (syn). Catalyst loadings as low as 1 mol % can be applied without eroding the syn-diastereoselectivity. Modification of the allylic alcohol to an ether does not affect the diastereoselectivity either [>99 : 1 dr (syn)]. Inverting the catalyst configuration leads to the anti-product, albeit at lower dr (ca. 20 : 1). The synthetic potential is demonstrated by a short, gram-scale preparation of a tetrahydrofuran building block with three stereocenters, involving two titanium salalen catalyzed epoxidation steps.

We herein report the ammonium salt-catalyzed synthesis of chiral 3,3-disubstituted isoindolinones bearing a heteroatom functionality in the 3-position. A broad variety of differently substituted CF3S- and RS-derivatives were obtained with often high enantioselectivities when using Maruoka's bifunctional chiral ammonium salt catalyst. In addition, a first proof-of-concept for the racemic synthesis of the analogous F-containing products was obtained as well, giving access to one of the rare examples of a fairly stable alpha-F-alpha-amino acid derivative.

Untargeted liquid chromatography-mass spectrometry (LC-MS)-based metabolomics strategies are being increasingly applied in metabolite screening for a wide variety of medical conditions. The long-standing grand challenge in the utilization of this approach is metabolite identification-confidently determining the chemical structures of m/z-detected unknowns. Here, we use a novel workflow based on the detection of molecular features of interest by high-throughput untargeted LC-MS analysis of patient body fluids combined with targeted molecular identification of those features using infrared ion spectroscopy (IRIS), effectively providing diagnostic IR fingerprints for mass-isolated targets. A significant advantage of this approach is that in silico-predicted IR spectra of candidate chemical structures can be used to suggest the molecular structure of unknown features, thus mitigating the need for the synthesis of a broad range of physical reference standards. Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine metabolism, resulting from a mutation in the ALDH7A1 gene that leads to an accumulation of toxic levels of alpha-aminoadipic semialdehyde (alpha-AASA), piperideine-6-carboxylate (P6C), and pipecolic acid in body fluids. While alpha-AASA and P6C are known biomarkers for PDE in urine, their instability makes them poor candidates for diagnostic analysis from blood, which would be required for application in newborn screening protocols. Here, we use combined untargeted metabolomics-IRIS to identify several new biomarkers for PDE-ALDH7A1 that can be used for diagnostic analysis in urine, plasma, and cerebrospinal fluids and that are compatible with analysis in dried blood spots for newborn screening. The identification of these novel metabolites has directly provided novel insights into the pathophysiology of PDE-ALDH7A1.

Titanium-salalen complexes have recently solved a long-standing problem in homogeneous epoxidation catalysis by enabling the selective catalytic epoxidation of terminal, nonconjugated olefins with hydrogen peroxide. In this work, we disclose the mechanism of this intriguing catalyst system, based on XRD analyses, kinetic studies, and NMR elucidation of intermediate structures, complemented by DFT computations. Titanium-salalen catalysts are typically prepared/stored as bis-mu-oxo or mu-oxo-mu-peroxo dimers. Under reaction conditions, while the mu-oxo bridged catalyst dimers remain intact, the epoxidation occurs through an octahedral, yet altered, coordination geometry of the homochiral monomeric subunits. This catalytically active coordination mode is accessed by a slow pre-equilibrium, involving uptake of hydrogen peroxide, and subsequent rearrangement of the coordination sphere of the dinuclear complex. This configuration allows a three-pronged electrophilic activation of hydrogen peroxide, which enables oxygen transfer by the joint action of (i) the Lewis acidic titanium center, (ii) H-bond donation by the ligand's NH, and (iii) mu-chalcogen interaction with the ligand's pentafluorophenyl moieties. This efficient activation of H2O2 by a dinuclear site parallels recent findings on the active sites of the industrial heterogeneous titanium silicalite TS-1 catalyst.

Azolium enolates and acyl azolium cations have been proposed as intermediates in numerous N-heterocyclic carbene (NHC) catalyzed transformations. Acetyl azolium enolates were generated from the reaction of 2-propenyl acetate with both saturated (SIPr) and aromatic (IPr) NHCs, isolated, and characterized (NMR, XRD). Protonation with triflic acid gave the corresponding acetyl azolium triflates which were isolated and characterized (NMR, XRD). Acyl azolium cations have been proposed as immediate precursors of the ester product, for example, in the redox esterification of alpha,beta-enals. Studies with d(3)-acetyl azolium triflate suggest that ester formation originates instead from an azolium enolate intermediate. Furthermore, the acetyl azolium enolate selectively reacted with alcohol nucleophiles in the presence of amines. While the acetyl azolium cation did not react with alcohols, an ester-selective reaction was induced by addition of base, by intermediate formation of the acetyl azolium enolate.

We report the discovery that simple carboxylic acids, such as benzoic acid, boost the activity of N-heterocyclic carbene (NHC) catalysts in the oxidative esterification of aldehydes. A simple and efficient protocol for the transformation of a wide range of sterically hindered alpha- and beta-substituted aliphatic aldehydes/enals, catalyzed by a novel and readily accessible N-Mes-/N-2,4,6-trichlorophenyl 1,2,4-triazolium salt, and benzoic acid as co-catalyst, was developed. A whole series of alpha/beta-substituted aliphatic aldehydes/enals hitherto not amenable to NHC-catalyzed esterification could be reacted at typical catalyst loadings of 0.02-1.0 mol %. For benzaldehyde, even 0.005 mol % of NHC catalyst proved sufficient: the lowest value ever achieved in NHC catalysis. Preliminary studies point to carboxylic acid-induced acceleration of acyl transfer from azolium enolate intermediates as the mechanistic basis of the observed effect.

An efficient oxidative NHC-catalyzed one-step transformation of (S)- or (R)-8-oxocitronellal to nepetalactone (NL) in enantio- and diastereomerically pure form has been developed. Several new and easy to make N-Mes- or N-Dipp-substituted 1,2,4-triazolium salts carrying nitroaromatic groups on N1 were synthesized and evaluated as precatalysts in combination with base and stoichiometric organic oxidant. Under optimized conditions, NLs are accessible in very good yields and diastereomerically pure under mild conditions. The oxidant used could be recovered and recycled under operationally simple conditions.

The rapid development of parasite drug resistance as well as the lack of medications targeting both the asexual and the sexual blood stages of the malaria parasite necessitate the search for novel antimalarial compounds. Eleven organoarsenic compounds were synthesized and tested for their effect on the asexual blood stages and sexual transmission stages of the malaria parasitePlasmodium falciparumusing in vitro assays. The inhibitory potential of the compounds on blood stage viability was tested on the chloroquine (CQ)-sensitive 3D7 and the CQ-resistant Dd2 strain using the Malstat assay. The most effective compounds were subsequently investigated for their effect on impairing gametocyte development and gametogenesis, using the gametocyte-producing NF54 strain in respective cell-based assays. Their potential toxicity was investigated on leukemia cell line Nalm-6 and non-infected erythrocytes. Five out of the 11 compounds showed antiplasmodial activities against 3D7, with half-maximal inhibitory concentration (IC50) values ranging between 1.52 and 8.64 mu M. Three of the compounds also acted against Dd2, with the most active compound As-8 exhibiting an IC(50)of 0.35 mu M. The five compounds also showed significant inhibitory effects on the parasite sexual stages at both IC(50)and IC(90)concentrations with As-8 displaying the best gametocytocidal activity. No hemolytic and cytotoxic effect was observed for any of the compounds. The organoarsenic compound As-8 may represent a good lead for the design of novel organoarsenic drugs with combined antimalarial and transmission blocking activities.

A very small number of cobalt complexes is examined in oncology research. In this work, we investigate the cobalt (III) salen complex MBR-60 that turns out to be a promising anticancer drug. It induces apoptosis in Nalm6 leukemia and BJAB lymphoma cells and overcomes multidrug resistances by blocking the drug efflux pump P-glycoprotein. It further develops the apoptotic effects over the intrinsic pathway. An activation of caspase-3, caspase-8 and caspase-9 can be detected by western blot analysis. The independence of CD95 is shown by similar apoptotic inductions in BJAB and BJAB FADDdn cells. MBR-60 displays synergistic effects with daunorubicin and vincristine and has a selectivity to tumor cells. In comparison to the apoptotic effects of MBR-60 in BJAB lymphoma cells, the cobalt-free ligand 5 does not influence these cells. The research highlights that a cobalt complex has a therapeutic potential for cancer treating with a focus on drug-resistant tumors.