Asymmetric hydrogenation of alkenes and imines is of importance for generation of chiral building blocks from prochiral precursors. Enantioselective conversion is achieved by transition metal-based catalysts (typically Ir, Rh, or Ru complexes) modified with chiral organic ligands. 1,2 Whereas the applicability of Rh and Ru catalysts often depends on the presence of a functional group in the substrate, Ir complexes with N,P-ligands can be applied for efficient asymmetric conversion of unfunctionalized substrates. 1,2 Chiral analogues of Crabtree's catalyst 3 such as phosphine-oxazoline (PHOX)-type complexes (Figure 1) are successful examples, providing enantioselective conversion of unfunctionalized alkenes (up to 99% enantiomeric excess, ee) and imines (up to 96% ee). 2,4À7 Rational improvement of chiral hydrogenation catalysts requires detailed knowledge about the reaction pathway. For Ir-(PHOX)-mediated hydrogenations, however, the mechanistic details remain controversial. On the basis of mass spectrometry studies on Ir-(PHOX)-mediated hydrogenation of styrene, Dietiker and Chen suggested an Ir(I)/Ir(III) cycle (mechanism A, Scheme 1-I). 8 The catalytic species is a dihydride-Ir(III) complex formed after oxidative addition of H 2 . Migratory insertion of the substrate into a metalÀhydride bond is followed by reductive elimination of the product and regeneration of Ir(I). 8 DFT studies by Brandt et al., however, indicated that a Ir(I)/Ir(III) cycle is unlikely, 9 and instead, an Ir(III)/Ir(V) cycle (mechanism B, Scheme 1-II) was put forward. Migratory insertion of the substrate occurs simultaneously with oxidative addition of a second H 2 molecule, resulting in an Ir(V) intermediate. Proton transfer to the substrate is accompanied with regeneration of Ir(III). 9 The computational results by Brandt et al. have been questioned by several groups, who pointed out that the heavily truncated achiral model of Ir-(PHOX) employed in calculations (the catalyst was modeled as CH 3 -N-(CH) 3 -P-(CH 3 ) 2 ) 9 is unable to describe the steric and electronic properties of the real system correctly. 5,8,10 DFT calculations by Burgess and co-workers on a full iridiumcarbene oxazoline complex support an Ir(III)/Ir(V) cycle for iridium-mediated alkene hydrogenation, but suggest a slightly different reaction pathway, in which the substrate does not insert into an IrÀhydride bond, but into the Ir-coordinated H 2 molecule (mechanism C, Scheme 1-III). 10 Burgess and co-workers also reported a comparison of mechanism B and C on a full Ir-(PHOX) complex with the simple substrate ethene, indicating an energy difference of only 0.3 kcal mol À1 between these two pathways. 10 Clearly, in order to establish which of the proposed mechanisms is employed by Ir-(PHOX) catalysts, it is necessary to evaluate all proposals with the same model complex of a full Ir-(PHOX) complex and a realistic substrate. Interestingly, concurrently with our study, Andersson and co-workers have performed DFT studies
Sulfur (sulfonium and sulfoxonium) ylides are versatile synthetic precursors for a diverse range of chemical transformations [1] , e. g. they are widely used as methylene synthons in the formation of small rings such as epoxides, aziridines, and cyclopropanes from electrophilic substrates like aldehydes, imines, and enones. Recently, cycloadditions of sulfur ylides to a variety of electrophilic metal (Pd, Fe, Cu, Rh, or Au) associated intermediates have been explored for synthesis of heterocycles (Scheme 1; Type I). [2] Scheme 1. Sulfur ylide-based heterocycle synthesis via a metal-associated intermediate (Type I) or via a metal-carbene complex (Type II).
A new class of chiral N,P-ligands for the Ir-catalyzed asymmetric hydrogenation of aryl alkenes has been developed. These new ligands proved to be highly efficient and tolerates a broad range of substrates. The enantiomeric excesses are in the range of the best ever reported. The results can be rationalized with the proposed selectivity model.
β-Lactam antibiotics are of utmost importance when treating bacterial infections in the medical community. However, currently their utility is threatened by the emergence and spread of β-lactam resistance. The most prevalent resistance mechanism to β-lactam antibiotics is expression of β-lactamase enzymes. One way to overcome resistance caused by β-lactamases, is the development of β-lactamase inhibitors and today several β-lactamase inhibitors e.g. avibactam, are approved in the clinic. Our focus is the oxacillinase-48 (OXA-48), an enzyme reported to spread rapidly across the world and commonly identified in Escherichia coli and Klebsiella pneumoniae. To guide inhibitor design, we used diversely substituted 3-aryl and 3-heteroaryl benzoic acids to probe the active site of OXA-48 for useful enzyme-inhibitor interactions. In the presented study, a focused fragment library containing 49 3-substituted benzoic acid derivatives were synthesised and biochemically characterized. Based on crystallographic data from 33 fragment-enzyme complexes, the fragments could be classified into R or R binders by their overall binding conformation in relation to the binding of the R and R side groups of imipenem. Moreover, binding interactions attractive for future inhibitor design were found and their usefulness explored by the rational design and evaluation of merged inhibitors from orthogonally binding fragments. The best inhibitors among the resulting 3,5-disubstituted benzoic acids showed inhibitory potential in the low micromolar range (IC = 2.9 μM). For these inhibitors, the complex X-ray structures revealed non-covalent binding to Arg250, Arg214 and Tyr211 in the active site and the interactions observed with the mono-substituted fragments were also identified in the merged structures.
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.
We report a series of synthetic cationic amphipathic barbiturates inspired by the pharmacophore model of small antimicrobial peptides (AMPs) and the marine antimicrobials eusynstyelamides. These N,N′-dialkylated-5,5-disubstituted barbiturates consist of an achiral barbiturate scaffold with two cationic groups and two lipophilic side chains. Minimum inhibitory concentrations of 2−8 μg/mL were achieved against 30 multi-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including isolates with extended spectrum β-lactamase−carbapenemase production. The guanidine barbiturate 7e (3,5-di-Br) demonstrated promising in vivo antibiotic efficacy in mice infected with clinical isolates of Escherichia coli and Klebsiella pneumoniae using a neutropenic peritonitis model. Mode of action studies showed a strong membrane disrupting effect and was supported by nuclear magnetic resonance and molecular dynamics simulations. The results express how the pharmacophore model of small AMPs and the structure of the marine eusynstyelamides can be used to design highly potent lead peptidomimetics against multi-resistant bacteria.
CO2 is a promising and sustainable carbon feedstock for organic synthesis. New catalytic protocols for efficient incorporation of CO2 into organic molecules are continuously reported. However, little progress has been made in the enantioselective conversion of CO2 to form enantioenriched molecules. In order to allow CO2 to become a versatile carbon source in academia, and in the fine chemical and pharmaceutical industries, the development of enantioselective approaches is essential. Here we discuss general strategies for CO2 activation and for generation of enantioenriched molecules, alongside selected examples of reactions involving asymmetric incorporation of CO2. Main product classes considered are carboxylic acids and derivatives (C-2 CO2 bonds), and carbonates, carbamates, and polycarbonates (C-OCO bonds). Similarities to asymmetric hydrogenation are discussed, and some strategies for developing novel enantioselective CO2 reactions are outlined.
The mechanism of rhodium-COD-catalyzed hydrocarboxylation of styrene-derivatives and α,β-unsaturated carbonyl compounds with CO2 has been investigated using density functional theory (PBE-D2/IEFPCM). The calculations support a catalytic cycle as originally proposed by Mikami and coworkers including β-hydride elimination, insertion of the unsaturated substrate into a rhodium-hydride bond and subsequent carboxylation with CO2. The CO2 insertion step is found to be rate-limiting. The calculations reveal two interesting aspects: Firstly, during C-CO2 bond formation, the CO2 molecule interacts with neither the rhodium complex nor the organozinc additive. This appears to be in contrast to other CO2 insertion reactions, where CO2-metal interactions have been predicted. Secondly, the substrates show an unusual coordination mode during CO2 insertion, with the nucleophilic carbon positioned up to 3.6 Å away from rhodium. In order to understand the experimentally observed substrate preferences, we have analyzed a set of five alkenes: an α,β-unsaturated ester, an α,β-unsaturated amide, styrene and two styrene-derivatives. The computational results and additional experiments reported here indicate that the lack of activity with amides is caused by a too high barrier for CO2 insertion and is not due to catalyst inactivation. Our experimental studies also reveal two putative side reactions, involving oxidative cleavage or dimerization of the alkene substrate. In the presence of CO2, these alternative reaction pathways are suppressed. The overall insights may be relevant for the design of future hydrocarboxylation catalysts.
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