Stereochemistry of the Reaction Intermediates of Prolinol Ether Catalyzed Reactions Characterized by Vibrational Circular Dichroism Spectroscopy

Spectroscopic characterizations of key reaction intermediates are often considered the final confirmation of a reaction mechanism. This proof-of-principle study showcases the application of vibrational circular dichroism (VCD) spectroscopy for the characterization of in situ generated reaction intermediates using the key intermediates of enamine catalysis of Jørgensen–Hayashi-type prolinol ether catalysts as model system. By comparison of experimental and computed spectra, the enamines are shown to preferentially adopt an anti-conformation with E-configured C=C bond. For the parent prolinol catalyst, the structure and stereochemistry of the oxazolidine side product is determined as well. This study thus demonstrates that VCD spectra can provide insights into structural preferences of organocatalysts that utilize a covalent activation mechanism. Thereby it outlines new fields of applications for VCD spectroscopy and finally adds the technique to the toolbox of physical organic chemistry for in-depth mechanistic studies.     

Stereochemical Communication within a Chiral Ion Pair Catalyst

Ionic interactions are increasingly appreciated as a key, asymmetry‐inducing factor in enantioselective catalytic transformations, including those involving Brønsted acid or base catalysis, phase‐transfer catalysis, and related processes. However, a detailed understanding of these interactions is often lacking. Herein, we show how an enantiopure anion enforces a chiral conformation onto a catalytically relevant achiral cation. Specifically, we use vibrational circular dichroism (VCD) spectroscopy to monitor the transmission of stereochemical information from a chiral phosphate anion to a flexible manganese(III)–salen cation. We show that VCD can be used to study solvent effects and that the obtained chiroptical data directly and quantitatively correlate with the experimentally observed enantioselectivity in an asymmetric olefin epoxidation reaction.     

轴不稳定手性配体的开发及其在不对称催化反应中的应用

轴不稳定配体应用于不对称催化有其独到的特点, 不同于传统的轴稳定手性配体. 综述了轴不稳定的噁唑啉、双膦、单膦、双羟基及N—O等配体的开发及其在不对称催化中的应用.     

Dynamic Kinetic Resolution of Heterobiaryl Ketones by Zinc‐Catalyzed Asymmetric Hydrosilylation

A diastereo‐ and highly enantioselective dynamic kinetic resolution (DKR) of configurationally labile heterobiaryl ketones is described. The DKR proceeds by zinc‐catalyzed hydrosilylation of the carbonyl group, thus leading to secondary alcohols bearing axial and central chirality. The strategy relies on the labilization of the stereogenic axis that takes place thanks to a Lewis acid–base interaction between a nitrogen atom in the heterocycle and the ketone carbonyl group. The synthetic utility of the methodology is demonstrated through stereospecific transformations into either N,N‐ligands or appealing axially chiral, bifunctional thiourea organocatalysts.     

Importance of Intermolecular Hydrogen Bonding for the Stereochemical Control of Allene–Enone (3+2) Annulations Catalyzed by a Bifunctional,Amino Acid Derived Phosphine Catalyst

The origin of stereoselectivity in the (3+2) annulation of allenes and enones catalyzed by an amino acid derived phosphine catalyst has been investigated by the use of dispersion‐corrected density functional theory. An intermolecular hydrogen bond between the intermediate zwitterion and the enone was found to be the key interaction in the two enantiomeric transition states. Additional stabilization is provided by intermolecular hydrogen‐bonding interactions between acidic positions on the catalyst backbone and the substrate. Enantioselectivity occurs because the intermolecular hydrogen bond in the transition state leading to the minor enantiomer is only possible at the expense of reactant distortion.     

过渡金属催化不对称C-H键官能团化反应构建轴手性联芳基化合物研究进展

在手性分子中,轴手性化合物占据着非常重要的地位.从原子和步骤经济性方面考虑,利用不对称碳-氢官能团化反应构建轴手性化合物是最简洁高效的方法.随着过渡金属催化的不对称碳-氢键官能团化领域的逐步发展,利用该策略来构建轴手性联芳基化合物的研究成果也不断涌现.本文综述了通过过渡金属钯、铑和铱催化的不对称碳-氢键官能团化反应合成轴手性联芳基化合物的最新进展.此外,还介绍了利用这些方法合成多种轴手性配体及其催化的不对称反应,以及这些方法在天然产物合成中的应用.     

Merger of Visible Light Induced Oxidation and Enantioselective Alkylation with a Chiral Iridium Catalyst

A single chiral octahedral iridium(III) complex is used for visible light activated asymmetric photoredox catalysis. In the presence of a conventional household lamp and under an atmosphere of air, the oxidative coupling of 2‐acyl‐1‐phenylimidazoles with N,N‐diaryl‐N‐(trimethylsilyl)methylamines provides aminoalkylated products in 61–93 % yields with high enantiomeric excess (90–98 % ee). Notably, the iridium center simultaneously serves three distinct functions: as the exclusive source of chirality, as the catalytically active Lewis acid, and as a central part of the photoredox sensitizer. This conceptionally simple reaction Scheme may provide new avenues for the green synthesis of non‐racemic chiral molecules.     

Asymmetric Hydroformylation Using a Rhodium Catalyst Encapsulated in a Chiral Capsule

Supramolecular capsules can be used to change the activity and selectivity of a catalyst through the influence of the second coordination sphere, reminiscent of how enzymes control the selectivity of their processes. In enzymes, this approach is used to also control the enantioselectivity of reactions in which the active catalytic site is often not chiral but the second coordination sphere is. We are interested in the possibility to generate a chiral second coordination sphere around an otherwise achiral transition metal complex for asymmetric catalysis. In this paper we show that the ligand template approach can be used to generate a chiral second coordination sphere around a rhodium complex, which is used in asymmetric hydroformylation.     

Pristine Graphene as a Racemization Catalyst for Axially Chiral BINOL

Despite versatile applications of functionalized graphene in catalysis, applications of pure, unfunctionalized graphene in catalysis are in their infancy. This work uses both computational and experimental approaches to show that single-layer graphene can efficiently catalyze the racemization of axially chiral BINOL in solution. Using double-hybrid density functional theory (DHDFT) we calculate the uncatalyzed and catalyzed Gibbs free reaction barrier heights in a number of representative solvents of varying polarity: benzene, diphenyl ether, dimethylformamide (DMF), and water. These calculations show that (i) graphene can achieve significant catalytic efficiencies (▵▵G^≠_cat) varying between 47.2 (in diphenyl ether) and 60.7 (in DMF) kJ mol⁻¹. An energy decomposition analysis reveals that this catalytic activity is driven by electrostatic and dispersion interactions. Based on these computational results, we explore the graphene-catalyzed racemization of axially chiral BINOL experimentally and show that single-layer graphene can efficiently catalyze this process. Whilst the uncatalyzed racemization requires high temperatures of over 200 °C, a pristine single-layer graphene catalyst makes it accessible at 60 °C.     

Asymmetric Hydrogenation of Cationic Intermediates for the Synthesis of Chiral N,O-Acetals

For over half a century, transition-metal-catalyzed homogeneous hydrogenation has been mainly focused on neutral and readily prepared unsaturated substrates. Although the addition of molecular hydrogen to C=C, C=N, and C=O bonds represents a well-studied paradigm, the asymmetric hydrogenation of cationic species remains an underdeveloped area. In this study, we were seeking a breakthrough in asymmetric hydrogenation, with cationic intermediates as targets, and thereby anticipating applying this powerful tool to the construction of challenging chiral molecules. Under acidic conditions, both N- or O-acetylsalicylamides underwent cyclization to generate cationic intermediates, which were subsequently reduced by an iridium or rhodium hydride complex. The resulting N,O-acetals were synthesized with remarkably high enantioselectivity. This catalytic strategy exhibited high efficiency (turnover number of up to 4400) and high chemoselectivity. Mechanistic studies supported the hypothesis that a cationic intermediate was formed in situ and hydrogenated afterwards. A catalytic cycle has been proposed with hydride transfer from the iridium complex to the cationic sp² carbon atom being the rate-determining step. A steric map of the catalyst has been created to illustrate the chiral environment, and a quantitative structure–selectivity relationship analysis showed how enantiomeric induction was achieved in this chemical transformation.     

Towards an Observation of Active Conformations in Asymmetric Catalysis: Interaction‐Induced Conformational Preferences of a Chiral Thiourea Model Compound

The observation of the active species is the goal of most spectroscopic investigations on enantioselective organocatalysts in solution. Although NMR spectroscopy is widely applied, it has low sensitivity for conformational changes or the chiral nature of the interactions. In the present work, we exemplify the use of vibrational circular dichroism (VCD) spectroscopy for the characterization of a chiral thiourea model compound in nonpolar and polar solvents, as well as for a detailed analysis of its interaction with a model reactant. We discuss solvent‐induced conformational changes of the thiourea, and provide evidence for an unexpected binding topology between the thiourea and an acetate anion. The results clearly showcase the possibilities offered by using VCD spectroscopy in the characterization of chiral organocatalysts.     

Catalytic Asymmetric Construction of Axially Chiral Indole-Based Frameworks: An Emerging Area

Axially chiral indole-based frameworks have been recognized as a class of important five-membered heterobiaryls and developing catalytic asymmetric approaches for constructing these frameworks in an enantioselective manner is highly desirable. In recent years, synthetic chemists have paid much attention to this research field, and rapid developments have occurred. At this point, a range of axially chiral indole-based scaffolds have been constructed via various catalytic asymmetric reactions based on different strategies. Thus, the catalytic asymmetric construction of axially chiral indole-based frameworks has become an emerging area. This minireview summarizes the rapid advances in this field and gives some insights into future developments, which will help this research field to thrive.     

Using a tripod as a chiral chelating ligand: chemical exchange between equivalent molecular structures in palladium catalysis with 1,1,1-tris(oxazolinyl)ethane ("trisox")

Threefold symmetrical chiral podands may simplify the stereochemistry of key catalytic intermediates for cases in which they only act as bidentate ligands. This applies to systems in which chemical exchange between the different kappa2-coordinated forms takes place and in which the non-coordinated sidearm may play a direct or indirect role at some earlier or later stage in the catalytic cycle. Palladium(II)-catalysed allylic substitutions provide appropriate test reactions along these lines. A series of neutral dichloropalladium(II) complexes, [PdCl2(iPr-trisox)] (1a), [PdCl2(Ph-trisox)] (1b), [PdCl2(Bn-trisox)] (1c) and [PdCl2(Ind-trisox)] (1d) (trisox=1,1,1-tris(oxazolinyl)ethane) were synthesised by reaction of the respective trisox derivative with [PdCl2(PhCN)2] and characterised inter alia by 15N NMR spectroscopy. Direct detection of the heteronuclei without isotope enrichment and with "normal" sample concentrations was achieved with the aid of a cryogenically cooled NMR probe on a 600 MHz NMR spectrometer. Whereas the 15N nuclei of the coordinated oxazoline rings resonate at delta=160-167 ppm and appear as two singlets due to their diastereotopicity, the signal assigned to the dangling oxazoline "arm" is observed at delta=238-240 ppm. Variable-temperature NMR studies along with a systematic series of magnetisation transfer experiments established exchange between ligating and non-ligating oxazoline rings. Reaction of [Pd(allyl)(cod)]BF4 (cod=cyclooctadiene) with Ph-trisox in CH(2)Cl(2) gave the corresponding allyl complex 2, for which fast exchange between the three oxazoline heterocycles as well as between the exo and endo diastereomers was observed along with a very slow eta3-eta1-eta3 process of the allyl fragment (magnetisation transfer). Palladium(0) complexes were prepared by reaction of trisox derivatives or sidearm-functionalised BOX (BOX=bis(oxazolinyl)dimethylmethane) ligands with [Pd(nbd)(alkene)] (nbd=norbornadiene, alkene=maleic anhydride or tetracyanoethylene). X-ray diffraction studies of the iPr-trisox and Ph-trisox complexes (3a and 3b) established Y-shaped trigonal planar coordination geometries with the trisox ligand coordinated in a bidentate fashion, whilst the pi-coordinated maleic anhydride ligand adopts one of the two possible diastereotopic orientations. As the catalytic test reaction, the allylic alkylation of 1,3-diphenylprop-2-enyl acetate substrate with dimethyl malonate as nucleophile (in the presence of N,O-bis(trimethylsilyl)acetamide) was investigated for the trisox derivatives, their BOX analogues, and a series of less symmetric "sidearm" functionalised bisoxazolines. The trisoxazoline-based catalysts generally induce a better enantioselectivity compared to their bisoxazoline analogues and display significant reduction of the induction period as well as rate enhancement.     

Dynamic Covalent Chemistry within Biphenyl Scaffolds: Reversible Covalent Bonding,Control of Selectivity,and Chirality Sensing with a Single System

Axial chirality is a prevalent and important phenomenon in chemistry. Herein we report a combination of dynamic covalent chemistry and axial chirality for the development of a versatile platform for the binding and chirality sensing of multiple classes of mononucleophiles. An equilibrium between an open aldehyde and its cyclic hemiaminal within biphenyl derivatives enabled the dynamic incorporation of a broad range of alcohols, thiols, primary amines, and secondary amines with high efficiency. Selectivity toward different classes of nucleophiles was also achieved by regulating the distinct reactivity of the system with external stimuli. Through induced helicity as a result of central‐to‐axial chirality transfer, the handedness and ee values of chiral monoalcohol and monoamine analytes were reported by circular dichroism. The strategies introduced herein should find application in many contexts, including assembly, sensing, and labeling.     

Silver-Catalysed Enantioselective Addition of O?H and N?H Bonds to Allenes: A New Model for Stereoselectivity Based on Noncovalent Interactions

The ability of silver complexes to catalyse the enantioselective addition of O H and N H bonds to allenes is demonstrated for the first time by using optically active anionic ligands that were derived from oxophosphorus(V) acids as the sources of chirality. The intramolecular addition of acids, alcohols, and amines to allenes can be achieved with up to 73 % ee. The exploitation of a C H anomeric effect allowed the absolute configuration of a sample of 2-substituted tetrahydrofuran of low ee to be unambiguously assigned by comparison of the chiroptical ORD and VCD measurements with calculated spectra. In the second part of the work, the origin of the stereoselectivity was probed by DFT free-energy calculations of the transition states. A new model of enantiomeric differentiation was developed that was based on noncovalent interactions. This model allowed us to identify the source of stereoselectivity as weak attractive interactions; such dispersive forces are often overlooked in asymmetric catalysis. A new computational approach was developed that represents these interactions as colour-coded isosurfaces that are characterised by the reduced density-gradient profile.