Annette Bayer

Synthesis of Indoles and Pyrroles Utilizing Iridium Carbenes Generated from Sulfoxonium Ylides

Metal carbenes can undergo a myriad of synthetic transformations. Sulfur ylides are potential safe precursors of metal carbenes. Herein, we report cascade reactions that involve carbenoids derived from sulfoxonium ylides for the efficient and regioselective synthesis of indoles and pyrroles. The tandem action of iridium and Brønsted acid catalysts enables rapid assembly of the heterocycles from unmodified anilines or readily accessible enamines under microwave irradiation. The key mechanistic steps are the catalytic transformation of the sulfoxonium ylide into an iridium-carbene complex, followed by N-H or C-H functionalization of an aniline or enamine, respectively, and a final acid-catalyzed cyclization. The present method was successfully applied to the synthesis of the densely functionalized pyrrole subunit of atorvastatin.

Antioxidant and Anti-Inflammatory Activities of Barettin

In this paper, we present novel bioactivity for barettin isolated from the marine sponge Geodia barretti. We found that barettin showed strong antioxidant activity in biochemical assays as well as in a lipid peroxidation cell assay. A de-brominated synthetic analogue of barettin did not show the same activity in the antioxidant cell assay, indicating that bromine is important for cellular activity. Barettin was also able to inhibit the secretion of the inflammatory cytokines IL-1β and TNFα from LPS-stimulated THP-1 cells. This combination of anti-inflammatory and antioxidant activities could indicate that barettin has an atheroprotective effect and may therefore be an interesting product to prevent development of atherosclerosis.

Asymmetric N-sulfinyl dienophile Diels–Alder cycloadditions using chiral Ti(IV)-based Lewis acids

Enantioselective Diels–Alder reactions of 1,3-cyclohexadiene with N-sulfinylbenzyl carbamate (1a) or N-sulfinyl-p-toluenesulfonamide (1b) promoted by chiral Ti(IV)-based Lewis acids are reported. The endo-adducts were obtained in 15–76% ee.

Asymmetric Diels–Alder reactions of N-sulfinyl dienophiles using chiral Ti(IV) Lewis acids

Abstract Enantioselective hetero Diels–Alder (HDA) reactions of 1,3-cyclohexadiene with benzyl N-sulfinylcarbamate 1a and with N-sulfinyl-p-toluensulfonamide 1b promoted by chiral Ti(IV)-based Lewis acids are reported. The obtained yields and enantiomeric excesses obtained are heavily dependant on the mode of catalyst preparation. Acceptable reproducibility was obtained with Ti(IV)-catalysts prepared from Me2TiCl2 and chiral diols. Testing of various chiral diols gave the endo adduct in yields of up to 69% with 76% ee. The absolute configuration of the HDA products were established by chemical correlation and verified by X-ray crystallography.

Highly enantioselective hetero Diels–Alder reactions of N-sulfinyl dienophiles promoted by copper(II)- and zinc(II)-chiral bis(oxazoline) complexes

Abstract Hetero Diels–Alder reactions of 1,3-cyclohexadiene with N -sulfinyl dienophiles 1a or 1b , promoted by Cu(II)- or Zn(II)-chiral bis(oxazoline) complexes, afforded endo adducts in high yields (up to 85%) and enantiomeric excess (e.e. of up to >98%) under stoichiometric conditions. With 10 mol% loading of the Zn(II) catalyst up to 75% e.e. was obtained for the endo adduct ( endo : exo =10:1, total yield 68%).

Substrate Binding in the Asymmetric Dihydroxylation Reaction − Investigation of the Stereoselectivity in the Dihydroxylation ofCs-Symmetric Divinylcarbinol Derivatives

The mechanism of the asymmetric dihydroxylation (AD) reaction has been hotly disputed. We have studied the stereochemical outcome of the AD reaction on a series of Cs-symmetric divinylcarbinol derivatives in order to shed light on the binding mode of the substrate to the osmium tetroxide−ligand complex. The product distribution is dependent on the size of the allylic substituent, and on the type and class of ligand. It is postulated that the diastereospecificity of the reactions originates from attractive forces between the substrate and the ligand. These interactions are independent of the interactions responsible for the enantioselectivity in the AD reaction.

Metallo-β-lactamase inhibitors by bioisosteric replacement: preparation, activity and binding

Bacterial resistance is compromising the use of β-lactam antibiotics including carbapenems. The main resistance mechanism against β-lactams is hydrolysis of the β-lactam ring mediated by serine- or metallo-β-lactamases (MBLs). Although several inhibitors of MBLs have been reported, none has been developed into a clinically useful inhibitor. Mercaptocarboxylic acids are among the most prominent scaffolds reported as MBL inhibitors. In this study, the carboxylate group of mercaptocarboxylic acids was replaced with bioisosteric groups like phosphonate esters, phosphonic acids and NH-tetrazoles. The influence of the replacement on the bioactivity and inhibitor binding was evaluated. A series of bioisosteres of previously reported inhibitors was synthesized and evaluated against the MBLs VIM-2, NDM-1 and GIM-1. The most active inhibitors combined a mercapto group and a phosphonate ester or acid, with two/three carbon chains connecting a phenyl group. Surprisingly, also compounds containing thioacetate groups instead of thiols showed low IC50 values. High-resolution crystal structures of three inhibitors in complex with VIM-2 revealed hydrophobic interactions for the diethyl groups in the phosphonate ester (inhibitor 2b), the mercapto bridging the two active site zinc ions, and tight stacking of the benzene ring to the inhibitor between Phe62, Tyr67, Arg228 and His263. The inhibitors show reduced enzyme activity in Escherichia coli cells harboring MBL. The obtained results will be useful for further structural guided design of MBL inhibitors.

A Concise Total Synthesis of Breitfussin A and B

The first total synthesis of breitfussin A and B is described. The approach features two palladium-catalyzed cross-couplings installing the indole and pyrrole onto the oxazole core and selective lithiation/iodination of a common indole-oxazole fragment providing 2,4-diiodinated or 2-iodinated oxazoles as potential precursors for breitfussin A and B, respectively. An unexpected acid promoted deiodination was utilized in the synthesis of breitfussin B. Comparison of the synthetic material with previously reported spectral data of isolated breitfussin A and B verified the structure of the breitfussin framework.

Screening and Design of Inhibitor Scaffolds for the Antibiotic Resistance Oxacillinase-48 (OXA-48) through Surface Plasmon Resonance Screening.

The spread of antibiotic resistant bacteria is a global threat that shakes the foundations of modern healthcare. β-Lactamases are enzymes that confer resistance to β-lactam antibiotics in bacteria, and there is a critical need for new inhibitors of these enzymes for combination therapy together with an antibiotic. With this in mind, we have screened a library of 490 fragments to identify starting points for the development of new inhibitors of the class D β-lactamase oxacillinase-48 (OXA-48) through surface plasmon resonance (SPR), dose-rate inhibition assays, and X-ray crystallography. Furthermore, we have uncovered structure-activity relationships and used alternate conformations from a crystallographic structure to grow a fragment into a more potent compound with a KD of 50 μM and an IC50 of 18 μM.

Effects of docosahexaenoic (22:6n-3), tetracosapentaenoic (24:5n-3) and tetracosahexaenoic (24:6n-3) acids on the desaturation and elongation of n-3 polyunsaturated fatty acids in trout liver microsomes

The effects of long chain n-3 polyunsaturated fatty acids (PUFA) on the desaturation and elongation systems involved in the conversion of 18:3n-3 to 24:6n-3 were investigated. Microsomes were prepared from the livers of rainbow trout and incubated with 14C-labelled 18:3n-3 and cofactors required for elongation and/or desaturation in the presence of 22:6n-3, 24:5n-3 or 24:6n-3. The formation of 24:6n-3 was significantly inhibited in the presence of 50 microM 22:6n-3, 24:5n-3 or 24:6n-3, whereas the amount of radiolabelled 20:5n-3 formed was inhibited by only 24:5n-3 or 24:6n-3 at the same concentration. When malonyl-CoA was omitted from the incubation system to allow the measurement of desaturation in the absence of elongation, the Delta6 desaturation of 14C-18:3n-3 to 14C-18:4n-3 was inhibited by approximately 25% in the presence of 24:5n-3 or 24:6n-3 but was not affected by 22:6n-3. The Delta5 desaturation of 14C-20:4n-3 was not affected by the presence of any of the long chain PUFA and no significant effect of 18:3n-3, 22:6n-3 or 24:6n-3 on the Delta6 desaturation of 24:5n-3 to 24:6n-3 was observed. To permit the measurement of individual elongation reactions, KCN was included in the incubation medium to inhibit desaturation and 14C-labelled 18:3n-3, 18:4n-3, 20:4n-3, 20:5n-3 and 22:5n-3 were examined as substrates. 18:4n-3 and 22:5n-3 were more extensively used for elongation than 18:3n-3, 20:4n-3 and 20:5n-3. The presence of 22:6n-3, 24:5n-3 or 24:6n-3 in the incubation system had no effect on any of the specific elongations of any of the substrates examined. It is concluded that, in the conversion of 18:3n-3 to 24:6n-3 by trout liver microsomes, the Delta6 desaturation of 18:3n-3 may be subjected to direct feedback inhibition and that 24:5n-3 may be preferred over 18:3n-3 as a substrate for Delta6 desaturation.