Chiral Ion Pair Research Articles

Asymmetric Bromination/Semipinacol Rearrangement Enabled by Brønsted Acids of Stereogenic-at-Cobalt(III) Complexes.

On the basis of the chiral ion pair between catalytic anionic stereogenic-at-cobalt(III) complexes and halonium ion intermediates, an asymmetric halogenation/semipinacol rearrangement reaction has been established using N-bromosuccinimide as the halogen source. This protocol provides an alternative approach for accessing a diverse set of chiral β-bromocycloketones in good yields with high enantioselectivities (≤96% yield, 95.5:4.5 er).

Chirality in Singlet Fission: Controlling Singlet Fission in Aqueous Nanoparticles of Tetracenedicarboxylic Acid Ion Pairs.

The singlet fission characteristics of aqueous nanoparticles, self-assembled from ion pairs of tetracene dicarboxylic acid and various amines with or without chirality, are thoroughly investigated. The structure of the ammonium molecule, the counterion, is found to play a decisive role in determining the molecular orientation of the ion pairs and its regularity, spectroscopic properties, the strength of the intermolecular coupling between the tetracene chromophores, and the consequent singlet fission process. Using chiral amines has led to the formation of crystalline nanosheets and efficient singlet fission with a triplet quantum yield as high as 133% ±20% and a rate constant of 6.99×109s-1. The chiral ion pairs also provide a separation channel to free triplets with yields as high as 33% ±10%. In contrast, nanoparticles with achiral counterions do not show singlet fission, which gave low or high fluorescence quantum yields depending on the size of the counterions. The racemic ion pair produces a correlated triplet pair intermediate by singlet fission, but no decorrelation into two free triplets is observed, as triplet-triplet annihilation dominates. The introduction of chirality enables higher control over orientation and singlet fission in self-assembled chromophores. It provides new design guidelines for singlet fission materials.

Enantioselective Sulfonation of Enones with Sulfinates by Thiourea/Tertiary-Amine Catalysis

AbstractChiral γ-keto sulfones are significant structures in both organic synthesis and pharmaceutical chemistry. Although there are many choices for obtaining racemic forms, only a few enantioselective methods have been reported. We have developed a simple way for obtaining chiral γ-keto sulfones in moderate yields and moderate enantiomeric ratios. Readily available sulfinates were directly used as substrates that could be converted into sulfinic acids by treatment with boric acid. The bifunctional catalyst forms a chiral ion pair with the sulfinic acid and controls the enantioselectivity of the sulfonation through hydrogen bonding.

Stereodivergent Construction of Csp3 -Csp3 Bonds Bearing Vicinal Stereocenters by Synergistic Palladium and Phase-Transfer Catalysis.

Synergistic catalysis has emerged as one of the most powerful tools for stereodivergent formation of Csp3 -Csp3 bonds bearing vicinal stereocenters. Despite the many successes that have been achieved in this field, stereodivergent Csp3 -Csp3 coupling reactions involving stabilized nucleophiles remain challenging because of the competing single-catalysis pathway. Herein, we report a synergistic palladium/phase-transfer catalyst system that enables diastereodivergent Csp3 -Csp3 coupling reactions of 1,3-dienes with stabilized nucleophile oxindoles. Both the syn and anti coupling products, bearing quaternary and tertiary vicinal stereocenters, could be selectively produced in good yields with high enantio- and diastereoselectivities. Non-covalent activation of the stabilized nucleophile via chiral ion pair in a biphasic system is a crucial success factor in achieving diastereodivergence.

Stereodivergent Construction of Csp3−Csp3Bonds Bearing Vicinal Stereocenters by Synergistic Palladium and Phase‐Transfer Catalysis

AbstractSynergistic catalysis has emerged as one of the most powerful tools for stereodivergent formation of Csp3−Csp3bonds bearing vicinal stereocenters. Despite the many successes that have been achieved in this field, stereodivergent Csp3−Csp3coupling reactions involving stabilized nucleophiles remain challenging because of the competing single‐catalysis pathway. Herein, we report a synergistic palladium/phase‐transfer catalyst system that enables diastereodivergent Csp3−Csp3coupling reactions of 1,3‐dienes with stabilized nucleophile oxindoles. Both thesynandanticoupling products, bearing quaternary and tertiary vicinal stereocenters, could be selectively produced in good yields with high enantio‐ and diastereoselectivities. Non‐covalent activation of the stabilized nucleophile via chiral ion pair in a biphasic system is a crucial success factor in achieving diastereodivergence.

Enantioselective Ugi and Ugi-azide reactions catalyzed by anionic stereogenic-at-cobalt(III) complexes

Ugi reactions and related variations are proven to be atom and step-economic strategies for construction of highly valuable peptide-like skeletons and nitrogenous heterocycles. The development of structurally diverse range of novel catalytic systems and the discovery of new approaches to accommodate a broader scope of terminating reagents for asymmetric Ugi four-component reaction is still in high demand. Here, we report a strategy that enables enantioselective Ugi four-component and Ugi-azide reactions employing anionic stereogenic-at-cobalt(III) complexes as catalysts. The key nitrilium intermediates, generated through the nucleophilic addition of isocyanides to the chiral ion-pair which consists of stereogenic-at-cobalt(III) complexes counteranion and a protonated iminium, are trapped by either carboxylic acids or in situ-generated hydrazoic acid, delivering α-acylamino amides and α-aminotetrazoles in good to excellent enantioselectivities (up to 99:1 e.r.).

Stereoselective Synthesis of Sulfinate Esters via a Chiral Ion Pair

Key words cation catalysis - sulfinate esters - asymmetric catalysis - stereoselectivity - ion pair

Asymmetric Azidation under Hydrogen Bonding Phase-Transfer Catalysis: A Combined Experimental and Computational Study.

Asymmetric catalytic azidation has increased in importance to access enantioenriched nitrogen containing molecules, but methods that employ inexpensive sodium azide remain scarce. This encouraged us to undertake a detailed study on the application of hydrogen bonding phase-transfer catalysis (HB-PTC) to enantioselective azidation with sodium azide. So far, this phase-transfer manifold has been applied exclusively to insoluble metal alkali fluorides for carbon–fluorine bond formation. Herein, we disclose the asymmetric ring opening of meso aziridinium electrophiles derived from β-chloroamines with sodium azide in the presence of a chiral bisurea catalyst. The structure of novel hydrogen bonded azide complexes was analyzed computationally, in the solid state by X-ray diffraction, and in solution phase by 1H and 14N/15N NMR spectroscopy. With N-isopropylated BINAM-derived bisurea, end-on binding of azide in a tripodal fashion to all three NH bonds is energetically favorable, an arrangement reminiscent of the corresponding dynamically more rigid trifurcated hydrogen-bonded fluoride complex. Computational analysis informs that the most stable transition state leading to the major enantiomer displays attack from the hydrogen-bonded end of the azide anion. All three H-bonds are retained in the transition state; however, as seen in asymmetric HB-PTC fluorination, the H-bond between the nucleophile and the monodentate urea lengthens most noticeably along the reaction coordinate. Kinetic studies corroborate with the turnover rate limiting event resulting in a chiral ion pair containing an aziridinium cation and a catalyst-bound azide anion, along with catalyst inhibition incurred by accumulation of NaCl. This study demonstrates that HB-PTC can serve as an activation mode for inorganic salts other than metal alkali fluorides for applications in asymmetric synthesis.

Tethered Counterion-Directed Catalysis: Merging the Chiral Ion-Pairing and Bifunctional Ligand Strategies in Enantioselective Gold(I) Catalysis.

Tethering a metal complex to its phosphate counterion via a phosphine ligand enables a new strategy in asymmetric counteranion-directed catalysis (ACDC). A straightforward, scalable synthetic route gives access to the gold(I) complex of aphosphine displaying a chiralphosphoric acid function. The complex generates a catalytically active species with an unprecedented intramolecular relationship between the cationic Au(I) center and the phosphate counterion. The benefits of tethering the two functions of the catalyst are demonstrated here in a tandem cycloisomerization/nucleophilic addition reaction, by attaining high enantioselectivity levels (up to 97% ee) at an unusually low 0.2 mol % catalyst loading. Remarkably, the method is also compatible with a silver-free protocol.

Enantioselective α-Amination of Acyclic 1,3-Dicarbonyls Catalyzed by N-Heterocyclic Carbene.

Herein, we describe a method for the catalytic enantioselective α-amination of α-substituted acyclic 1,3-ketoamides and 1,3-amidoesters that affords the products possessing N-substituted quaternary stereocenters with a chiral N-heterocyclic carbene (NHC). The reaction is based on the utilization of an intrinsic Brønsted base characteristic of NHC that enables the catalytic formation of a chiral ion pair comprising the enolate and the azolium ion. A series of challenging open-chain α-substituted 1,3-dicarbonyls are aminated via this method with ee's of ≤99%.

Asymmetric Synthesis of Griffipavixanthone Employing a Chiral Phosphoric Acid-Catalyzed Cycloaddition.

Asymmetric synthesis of the biologically active xanthone dimer griffipavixanthone is reported along with its absolute stereochemistry determination. Synthesis of the natural product is accomplished via dimerization of a p-quinone methide using a chiral phosphoric acid catalyst to afford a protected precursor in excellent diastereo- and enantioselectivity. Mechanistic studies, including an unbiased computational investigation of chiral ion-pairs using parallel tempering, were performed in order to probe the mode of asymmetric induction.

Counterion-Induced Asymmetric Control in Ring-Opening of Azetidiniums: Facile Access to Chiral Amines.

Counterion-induced stereocontrol is a powerful tool in organic synthesis. However, such enantiocontrol on tetrahedral ammonium cations remains challenging. Described here is the first example of using chiral anion phase-transfer catalysis to achieve intermolecular ring-opening of azetidiniums with excellent enantioselectivity (up to 97 % ee). Precise control over the formation and reaction of the chiral ion pair as well as inhibition of the background reaction by the biphasic system is key to the success of the reaction.

Counterion‐Induced Asymmetric Control in Ring‐Opening of Azetidiniums: Facile Access to Chiral Amines

AbstractCounterion‐induced stereocontrol is a powerful tool in organic synthesis. However, such enantiocontrol on tetrahedral ammonium cations remains challenging. Described here is the first example of using chiral anion phase‐transfer catalysis to achieve intermolecular ring‐opening of azetidiniums with excellent enantioselectivity (up to 97 % ee). Precise control over the formation and reaction of the chiral ion pair as well as inhibition of the background reaction by the biphasic system is key to the success of the reaction.

Enamine/Dienamine and Brønsted Acid Catalysis: Elusive Intermediates, Reaction Mechanisms, and Stereoinduction Modes Based on in Situ NMR Spectroscopy and Computational Studies.

ConspectusOver the years, the field of enantioselective organocatalysis has seen unparalleled growth in the development of novel synthetic applications with respect to mechanistic investigations. Reaction optimization appeared to be rather empirical than rational. This offset between synthetic development and mechanistic understanding was and is generally due to the difficulties in detecting reactive intermediates and the inability to experimentally evaluate transition states. Thus, the first key point for mechanistic studies is detecting elusive intermediates and characterizing them in terms of their structure, stability, formation pathways, and kinetic properties. The second key point is evaluating the importance of these intermediates and their properties in the transition state.In the past 7 years, our group has addressed the problems with detecting elusive intermediates in organocatalysis by means of NMR spectroscopy and eventually theoretical calculations. Two main activation modes were extensively investigated: secondary amine catalysis and, very recently, Brønsted acid catalysis. Using these examples, we discuss potential methods to stabilize intermediates via intermolecular interactions; to elucidate their structures, formation pathways and kinetics; to change the kinetics of the reactions; and to address their relevance in transition states. The elusive enamine in proline-catalyzed aldol reactions is used as an example of the stabilization of intermediates via inter- and intramolecular interactions; the determination of kinetics on its formation pathway is discussed. Classical structural characterization of intermediates is described using prolinol and prolinol ether enamines and dienamines. The Z/E dilemma for the second double bond of the dienamines shows how the kinetics of a reaction can be changed to allow for the detection of reaction intermediates. We recently started to investigate substrate–catalyst complexes in the field of Brønsted acid catalysis. These studies on imine/chiral phosphoric acid complexes show that an appropriate combination of highly developed NMR and theoretical methods can provide detailed insights into the complicated structures, exchange kinetics, and H-bonding properties of chiral ion pairs. Furthermore, the merging of these structural investigations and photoisomerization even allowed the active transition state combinations to be determined for the first time on the basis of experimental data only, which is the gold standard in mechanistic investigations and was previously thought to be exclusively the domain of theoretical calculations.Thus, this Account summarizes our recent mechanistic work in the field of organocatalysis and explains the potential methods for addressing the central questions in mechanistic studies: stabilization of intermediates, elucidation of structures and formation pathways, and addressing transition state combinations experimentally.

Collaborative effect of Mn-porphyrin and mesoporous SBA-15 in the enantioselective epoxidation of olefins with oxygen

The rational design of heterogeneous, low cost transition metal complexes that can catalyze olefin with high enantioselectivity and activity has been a challenging goal for the synthetic chemist. In this study a chiral ion pair strategy was used for the synthesis of a biomimetic efficient manganese-tetrapyridylporphyrin (H2TPyP) catalyst for the asymmetric epoxidation of olefins with O2. Complex Mn-TPyP was covalently linked to mesoporous SBA-15 in heme-type environments and its counter ion was replaced by l-tartrate anion (SBA15-[Mn(TPyP)TA]). Chiral and achiral homogeneous analogous of Mn-TPyP were also prepared. The Mn-porphyrin confined in nanoreactors of SBA-15 exhibited enhanced activity (TOF = 652 h−1) and enantiomeric excess (ee 93%) compared with the value obtained when the same chiral catalyst functioned in homogeneous solution (TOF 97 h−1 and ee 83%) in the oxidation of 1-decene with O2/isobutyraldehyde. The high specific surface area, uniformly sized pore channels and site isolated active centers of the catalyst may contribute to the high activity and enantioselectivity. SBA15-[Mn(TPyP)TA] was structurally stable and could be recycled for repeated use. Total turnover number in the oxidation of styrene after five cycles was 47,400 with 86% epoxide selectivity and ee 86%.

Molecular Recognition in Asymmetric Counteranion Catalysis: Understanding Chiral Phosphate-Mediated Desymmetrization.

We describe the first theoretical study of a landmark example of chiral anion phase-transfer catalysis: the enantioselective ring-opening of meso-aziridinium and episulfonium cations promoted by asymmetric counteranion-directed catalysis (ACDC). The mechanism of ion-pairing, ring-opening, and catalyst deactivation have been studied in the condensed phase with both classical and quantum methods using explicitly and implicitly solvated models. We find that the stability of chiral ion-pairs, a prerequisite for asymmetric catalysis, is dominated by electrostatic interactions at long range and by CH···O interactions at short range. The decisive role of solvent upon ion-pair formation and of nonbonding interactions upon enantioselectivity are quantified by complementary computational approaches. The major enantiomer is favored by a smaller distortion of the substrate, demonstrated by a distortion/interaction analysis. Our computational results rationalize the stereoselectivity for several experimental results and demonstrate a combined classical/quantum approach to perform realistic modeling of chiral counterion catalysis in solution.

Recent Advances in Enantioselective Brønsted Base Organocatalytic Reactions

Enantioselective Brønsted base catalyzed reactions have established themselves as powerful tools for the construction of optically pure compounds. Most strategies aim at improving these reactions involve the modification of substrates to decrease the pK a of the acidic proton. Typically, an electron-withdrawing group such as an ester or a fluorine is placed at the α-carbon, where the proton is also residing. The activation of less active proton, thus, becomes a major challenge in this field of research. In order to overcome this pK a barrier, some new innovative approaches have been demonstrated in recent years. The implementation of dual activation modes and the development of organocatalytic Brønsted superbases are selected to be discussed in this minireview.1 Introduction2 Dual Activation Using Lewis Acid and Brønsted Base3 Dual Activation Using Iminium Catalyst and Brønsted Base4 Chiral Brønsted Superbase5 Chiral Ion-Pair Brønsted Base6 Summary and Outlook

Catalytic Enantioselective Synthesis of Lactams through Formal [4+2] Cycloaddition of Imines with Homophthalic Anhydride

AbstractAn amide‐thiourea compound, operating through a novel ion pairing mechanism, is an efficient organocatalyst for the asymmetric reaction of homophthalic anhydride with imines. N‐aryl and N‐alkyl imines readily undergo formal [4+2] cycloaddition to provide lactams with high levels of enantio‐ and diastereoselectivity. The nature of the key chiral ion pair intermediate was elucidated by DFT calculations.

Catalytic Enantioselective Synthesis of Lactams through Formal [4+2] Cycloaddition of Imines with Homophthalic Anhydride.

An amide-thiourea compound, operating through a novel ion pairing mechanism, is an efficient organocatalyst for the asymmetric reaction of homophthalic anhydride with imines. N-aryl and N-alkyl imines readily undergo formal [4+2] cycloaddition to provide lactams with high levels of enantio- and diastereoselectivity. The nature of the key chiral ion pair intermediate was elucidated by DFT calculations.

Catalytic enantioselective aza-Diels-Alder reactions of unactivated acyclic 1,3-dienes with aryl-, alkenyl-, and alkyl-substituted imines.

A catalytic enantioselective aza-Diels-Alder reaction of unactivated acyclic dienes with aryl-, alkenyl-, and alkyl-substituted imines is described. With 5-10 mol% loadings of a new Brønsted acid catalyst, the aza-Diels-Alder reaction of unactivated acyclic dienes proceeded to give the corresponding aza-Diels-Alder adducts in high yields (up to 98%) with excellent enantioselectivity (up to 98% ee). Preliminary DFT calculations suggest that the reaction proceeds through a chiral ion pair intermediate.