Klaus Bergander

IBiox[(−)-menthyl]: A Sterically Demanding Chiral NHC Ligand

An exceedingly sterically demanding, rigid, and chiral NHC ligand, IBiox[(-)-menthyl] (1), was prepared and structurally characterized. With a buried volume of approximately 50%, this ligand arguably represents one of the most sterically demanding monodentate ligands. The ability to use aryl chloride substrates in intramolecular palladium-catalyzed alpha-arylations reveals its unique reactivity. Moreover, C(2)-symmetric 1 allows the highly enantioselective formation of oxindoles with up to 99% ee.

Functional‐Group Tolerance in Frustrated Lewis Pairs: Hydrogenation of Nitroolefins and Acrylates

Apart from molecular hydrogen (H2), [1] other small molecules, such as CO2, [2] N2O, [3] NO, and SO2, [5] were targeted by frustrated Lewis pairs (FLPs) and resulted in the fixation or activation of these small molecules by Lewis acid interaction. Consequently, functionalized molecules, such as a,b-unsaturated esters, sulfoxides, or nitro compounds, are challenging substrates for FLP-catalyzed hydrogenations, and strategies toward higher functional-group tolerance are topic of current research. So s et al. demonstrated that bulky mesityl-substituted boranes could attain a level of functional-group tolerance according to the size exclusion principle. Other modifications of boranes to achieve stronger and weaker Lewis acidity in conjunction with FLP chemistry were reported. In particular, weaker Lewis acids appear to be favorable for the reduction of electron-deficient double bonds, such as a,b-unsaturated ketones, owing to the pronounced nucleophilicity of the corresponding hydridoborate anion. However, reduced Lewis acidity might also suppress the H2 activation, and a careful balance must be met. To date, there has been no report on the FLP-catalyzed hydrogenation of nitroolefins and acrylates. Only recently, B(C6F5)3 (1) was applied for the reduction of strongly electrophilic malonates at elevated temperatures and pressure (80 8C, 60 bar H2). [10a] Herein we report the reactivity of B(2,6-F2-C6F3)3 (2) as Lewis acid in FLP-catalyzed hydrogenations and its unique structural features in solid state and solution. The unprecedented FLP-mediated hydrogenation of nitroolefins and a,b-unsaturated esters under mild conditions (RT or 40 8C; 4 bar H2) was established. In contrast to the size-exclusion concept, in this case functional-group tolerance was solely achieved by modification of the electronic nature of the Lewis acid and the Lewis base. We initiated our studies with the synthesis of the borane B(2,6-F2-C6H3)3–THF adduct (2·THF) according to Naumann. Surprisingly, 2 has not been studied in FLP chemistry to date, even though it resembles an electronically modified B(C6F5)3 with identical steric shielding. The solidstate structure of 2 was established and displays similar structural features to BPh3 (Figure 1a). [14]

Separation of brompheniramine enantiomers by capillary electrophoresis and study of chiral recognition mechanisms of cyclodextrins using NMR-spectroscopy, UV spectrometry, electrospray ionization mass spectrometry and X-ray crystallography.

Opposite migration order was observed for the enantiomers of brompheniramine [N-[3-(4-bromphenyl)-3-(2-pyridyl)propyl]-N,N-dimethylamine] (BrPh) in capillary electrophoresis (CE) when native beta-cyclodextrin (beta-CD) and heptakis(2,3,6-tri-O-methyl)-beta-CD (TM-beta-CD) were used as chiral selectors. NMR spectrometry was applied in order to obtain information about the stoichiometry, binding constants and structure of the selector-selectand complexes in solution. The data were further confirmed by UV spectrometry and electrospray ionization mass spectrometry. The structure of the complexes in the solid state was determined using X-ray crystallography performed on the co-crystals precipitated from the 1:1 aqueous solution of selector and selectand. This multiple approach allowed an elucidation of the most likely structural reason for a different affinity (binding strength) of BrPh enantiomers towards beta-CD and TM-beta-CD. However, the question about a force responsible for the opposite affinity pattern of BrPh enantiomers towards these CDs could not be answered definitely.

Comparative enantioseparations with native β‐cyclodextrin and heptakis‐(2‐O‐methyl‐ 3,6‐di‐O‐sulfo)‐β‐cyclodextrin in capillary electrophoresis

Twenty‐three cationic chiral analytes were resolved in capillary electrophoresis using native β‐cyclodextrin and single isomer heptakis‐(2‐O‐methyl‐3,6‐di‐O‐sulfo)‐β‐cyclodextrin as chiral selectors. For 12 of 16 chiral analytes resolved with both chiral selectors the enantiomer migration order was opposite. In selected cases the structure of cyclodextrin‐analyte complexes in aqueous solution was investigated using one‐dimensional transverse rotating frame nuclear Overhauser and exchange spectroscopy. It was found that in contrast to mainly inclusion‐type complexes between chiral analytes and β‐cyclodextrin, external complexes are formed between the chiral analytes and structurally crowded, highly charged heptakis‐(2‐O‐methyl‐3,6‐di‐O‐sulfo)‐β‐cyclodextrin.

Mechanistic study of opposite migration order of dimethindene enantiomers in capillary electrophoresis in the presence of native β-cyclodextrin and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin

The possible mechanisms of the opposite affinity pattern of the enantiomers of dimethindene [(R,S)-N,N-dimethyl-3[1(2-pyridyl)ethyl]indene-2-ethylamine] (DIM) towards native beta-cyclodextrin (beta-CD) and heptakis(2,3,6-tri-O-methyl-)-beta-CD (TM-beta-CD) were studied using capillary electrophoresis (CE), NMR spectrometry, electrospray ionization mass spectrometry (ESI-MS) and X-ray crystallography. NMR spectrometry allowed to estimate the stoichiometry of the complex and to determine the binding constants. As found using ESI-MS, together with more abundant 1:1 complex, a complex with 1:2 stoichiometry may also be present in a rather small amount in a solution of DIM and beta-CD. One-dimensional ROESY experiments indicated that the geometry of the complexes of DIM with native beta-CD depends on the ratio of the components in the solution. In the 1:1 solution of DIM and beta-CD the complex may be formed by inclusion of the indene moiety of DIM into the cavity of beta-CD on the primary side and into the cavity of TM-beta-CD into the secondary side. The most likely structural reason for lower affinity of the enantiomers of DIM towards the cavity of TM-beta-CD compared to native beta-CD could be elucidated. The indene moiety does not enter the cavity of TM-beta-CD as deeply as the cavity of beta-CD. This may be the most likely explanation of significantly higher affinity constants of DIM enantiomers towards the latter CD compared to the former one. The marked difference between the structure of the complexes may also be responsible for the opposite affinity pattern of the DIM enantiomers towards beta-CD and TM-beta-CD.

Asymmetric total synthesis and X-ray crystal structure of the cytotoxic marine diterpene (+)-vigulariol.

belongs to the impressively large class of the cladiellin (eunicellin) diterpenes, of which many bear interesting biological activities. (+)-1 has shown to exhibit cyctotoxity against A 549 (human lung adenocarcinoma) cell culture at an IC50 of 18.33 mgmL . Two other soft-coral diterpenes sclerophytin A (2) and polyanthellin A (3) have shown high cytotoxicity and antimalarial activity, respectively. Their attractive molecular architectures and their diverse biological activities previously led to several ingenious total syntheses of some members of this natural product family by the research groups of Paquette, Overman, Crimmins, and Kim. (+)-1 was formed as a by-product during Paquette and coworkers3 synthesis of 2 before it was known to be natural product and was therefore not fully characterized. The total synthesis of rac-1 over 20 linear steps was quite recently published by Clark et al. Herein we present a short and efficient total synthesis and, in addition, the solid-state structure of enantiomerically pure (+)-vigulariol (1), by applying our previous synthetic and mechanistic investigations. As depicted in Scheme 1, (+)-vigulariol (1) could be elaborated by stereoselective epoxidation of the C=C double bond of tricycle 4. Deprotection of the hydroxy group was

Reversible Carbon Dioxide Binding by Simple Lewis Base Adducts with Electron-Rich Phosphines

For the efficient utilization of carbon dioxide as feedstock in chemical synthesis, low-energy-barrier CO2 activation is a valuable tool. We report a metal-free approach to reversible CO2 binding under mild conditions based on simple Lewis base adducts with electron-rich phosphines. Variable-temperature NMR studies and DFT calculations reveal almost thermoneutral CO2 binding with low-energy barriers or stable CO2 adduct formation depending on the phosphines donor ability. The most basic phosphine forms an air-stable CO2 adduct that was used as phosphine transfer agent, providing a convenient access to transition-metal complexes with highly electron-rich phosphine ligands relevant to catalysis.

Enantiomerically Pure 1,3-Dioxanes as Highly Selective NMDA and σ1 Receptor Ligands

We synthesized and investigated the NMDA and σ₁ receptor affinity of enantiomerically pure 2-(2-phenyl-1,3-dioxan-4-yl)ethanamines 17-26. The primary amines (R,R)-18-20 with an axially oriented phenyl moiety in position 2 interacted with high enantioselectivity (eudismic ratios 70-130) and high affinity (K(i)((R,R)-19) = 13 nM) with the PCP binding site of the NMDA receptor. Introduction of an N-benzyl moiety led to potent σ₁ ligands including compound (S,R)-22 (K(i) = 6 nM) with an equatorially oriented phenyl moiety in position 2.

Metabolic Engineering of Saccharomyces cerevisiae for Production of Novel Cyanophycins with an Extended Range of Constituent Amino Acids

ABSTRACT Cyanophycin (multi-l-arginyl-poly-l-aspartic acid; also known as cyanophycin grana peptide [CGP]) is a putative precursor for numerous biodegradable technically used chemicals. Therefore, the biosynthesis and production of the polymer in recombinant organisms is of special interest. The synthesis of cyanophycin derivatives consisting of a wider range of constituents would broaden the applications of this polymer. We applied recombinant Saccharomyces cerevisiae strains defective in arginine metabolism and expressing the cyanophycin synthetase of Synechocystis sp. strain PCC 6308 in order to synthesize CGP with citrulline and ornithine as constituents. Strains defective in arginine degradation (Car1 and Car2) accumulated up to 4% (wt/wt) CGP, whereas strains defective in arginine synthesis (Arg1, Arg3, and Arg4) accumulated up to 15.3% (wt/wt) of CGP, which is more than twofold higher than the previously content reported in yeast and the highest content ever reported in eukaryotes. Characterization of the isolated polymers by different analytical methods indicated that CGP synthesized by strain Arg1 (with argininosuccinate synthetase deleted) consisted of up to 20 mol% of citrulline, whereas CGP from strain Arg3 (with ornithine carbamoyltransferase deleted) consisted of up to 8 mol% of ornithine, and CGP isolated from strain Arg4 (with argininosuccinate lyase deleted) consisted of up to 16 mol% lysine. Cultivation experiments indicated that the incorporation of citrulline or ornithine is enhanced by the addition of low amounts of arginine (2 mM) and also by the addition of ornithine or citrulline (10 to 40 mM), respectively, to the medium.

Mechanistic study on the opposite migration order of clenbuterol enantiomers in capillary electrophoresis with β‐cyclodextrin and single‐isomer heptakis(2,3‐diacetyl‐6‐sulfo)‐β‐cyclodextrin

Opposite migration order was observed for the enantiomers of the chiral β2‐adrenergic drug clenbuterol (CL) in capillary electrophoresis (CE) when resolved with native β‐cyclodextrin (β‐CD) and heptakis (2,3‐diacetyl‐6‐sulfo)‐β‐CD (HDAS‐β‐CD). The possible mechanisms of the affinity reversal of the CL enantiomers depending on the structure of the CD were studied using 1H‐nuclear magnetic resonance (1H‐NMR) spectrometry and one‐dimensional rotating frame nuclear Overhauser and exchange spectrometry (1‐D ROESY). Significant differences were observed between the structure of the (±)‐CL complexes with β‐CD and HDAS‐β‐CD.