Chiral N-heterocyclic Carbene Research Articles

Supported Au Nanoparticles with N-Heterocyclic Carbene Ligands as Active and Stable Heterogeneous Catalysts for Lactonization

Attachment of N-heterocyclic carbenes (NHCs) on the surface of metal nanoparticle (NP) catalysts permits fine-tuning of catalytic activity and product selectivity. Yet, NHC-coated Au NPs have been seldom used in catalysis beyond hydrogenation chemistry. One challenge in this field has been to develop a platform that permits arbitrary ligand modification without having to compromise NP stability toward aggregation or leaching. Herein, we exploit the strategy of supported dendrimer-encapsulated metal clusters (DEMCs) to achieve aggregation-stable yet active heterogeneous Au NP catalysts with NHC ligands. Dendrimers function as aggregation-inhibitors during the NP synthesis, and NHCs, well-known for their strong attachment to the gold surface, provide a handle to modify the stereochemistry, stereoelectronics, and chemical functionality of the NP surface. Indeed, compared to "ligandless" Au NPs which are virtually inactive below 80 °C, the NHC-ligated Au NP catalysts enable a model lactonization reaction to proceed at 20 °C on the same time scale (hours). Based on Eyring analysis, proto-deauration is the turnover-limiting step accelerated by the NHC ligands. Furthermore, the use of chiral NHCs led to asymmetric induction (up to 16% enantiomeric excess) in the lactonization transformations, which demonstrates the potential of supported DEMCs with ancillary ligands in enantioselective catalysis.

Catalytic Enantioselective Aza-Benzoin Reactions of Aldehydes with 2H-Azirines.

The unprecedented enantioselective aza-benzoin reaction of aldehydes with 2H-azirines was developed by utilizing a chiral N-heterocyclic carbene as the catalyst. A wide range of corresponding aziridines can be obtained in good yields with high enantioselectivities. The obtained optically active aziridines should be useful in the synthesis of other valuable molecules.

Highly Enantioselective [5 + 2] Annulations through Cooperative N-Heterocyclic Carbene (NHC) Organocatalysis and Palladium Catalysis.

The highly enantioselective [5 + 2] annulation of enals with vinylethylene carbonates through a cooperative N-heterocyclic carbene (NHC)/Pd catalytic system is reported. The use of a bidentate phosphine ligand was crucial to prevent coordination of the NHC organocatalyst to the active Pd catalyst. The complementary and matched combination of the chiral NHC catalyst and chiral phosphine ligand promotes high levels of both reactivity and enantioselectivity (mostly ≥99% ee).

1,6‐Conjugate Addition of 1,3‐Dicarbonyl Compounds to para‐Quinone Methides Enabled by Noncovalent N‐Heterocyclic Carbene Catalysis

AbstractCatalysis with N‐heterocyclic carbenes (NHCs) via substrate activation through noncovalent interactions offers a great opportunity to perform organic transformations. Herein, we demonstrate an efficient catalytic method for the 1,6‐conjugate addition of 1,3‐dicarbonyl compounds to para‐quinone methides (p‐QMs) using NHCs as Brønsted‐base catalysts. The method is applicable to a wide range of functionalized substrates with respect to both 1,3‐diketones and p‐QMs. An initial study using chiral NHCs provides information on the feasibility of developing a catalytic enantioselective variant of this reaction.

Stable ruthenium olefin metathesis catalysts bearing symmetrical NHC ligands with primary and secondary N-alkyl groups.

Four novel stable Hoveyda-Grubbs-type catalysts containing N,N'-dineopentyl- and N,N'-dicyclohexyl-substituted N-heterocyclic carbene (NHC) ligands with syn and anti phenyl groups on the ring backbone were synthesized and fully characterized. The catalytic potential of these complexes was investigated in metathesis reactions of both standard and renewable substrates. Compared to the Hoveyda-Grubbs second generation catalyst (HGII), all of the new catalysts showed high performances in most of the examined metathesis transformations. In particular, N,N'-dicyclohexyl catalysts gave improved results in the challenging ring-closing metathesis (RCM) reaction to form tetrasubstituted olefins, while catalysts with neopentyl N-groups were found to be more active and Z-selective in cross-metathesis (CM) reactions. Modest enantioselectivities in the asymmetric ring-closing metathesis (ARCM) of achiral trienes with different steric hindrance were observed in the presence of catalysts bearing chiral C2-symmetric NHC ligands.

Importance of the Reducing Agent in Direct Reductive Heck Reactions

AbstractThe role of the reductant in the palladium N‐heterocyclic carbene (NHC) catalyzed reductive Heck reaction and its effect on the mechanism of the reaction is reported. For the first time in this type of transformation, the palladium‐NHC‐catalyzed reductive Heck reaction was shown to proceed in the presence of LiOMe and iPrOH even at 10 °C to give the products very efficiently in excellent yields and with exceptional chemoselectivities. This study shows that the reaction proceeds through two distinct mechanisms that depend on the nature of the reducing agent. In the presence of a protic solvent or acidic medium the reaction undergoes protonation to yield the reduced product, whereas in the absence of proton source, it proceeds through the insertion of the reductant followed by reductive elimination. The kinetic data reveal that the oxidative addition is the rate‐determining step in the reaction. The reaction profiles show first‐order kinetics in aryl iodide and Pd and zero‐order kinetics in LiOMe, benzylideneacetone, and the excess amount of NHC ligand. In addition, the reaction progress kinetic analysis shows that neither catalyst decomposition nor product inhibition occurs during the reaction. DFT calculations of the key steps confirm that the oxidative addition step is the rate‐determining step in the reaction. Deuterium‐labeling experiments indicate that the product is formed by the protonation of the Pd−Calkyl bond of the intermediate formed after enone insertion into the Pd−CAr bond. Application of chiral NHC ligands in the asymmetric reductive Heck reaction only results in poor enantioselectivities (enantiomeric excess up to 20 %) and is also substrate specific. DFT calculations suggest that the migration of the aryl group to the alkene of the substrate is the enantioselectivity‐determining step of the reaction. It is further shown that if the steric bulk at the enone is small (a methyl group), the two transition state barriers from [PdII(L2)(ArI)(enone)] species Cre and Csi, which have the re and si face of the enone substrate coordinated to Pd, are very similar, in line with the experimental results. With a slightly larger group (an isopropyl substituent) a significant difference in energy barriers is calculated (2.6 kcal mol−1), and in the experiment this product is formed with a modest enantiomeric excess (up to 20 %).

A Cooperative Ternary Catalysis System for Asymmetric Lactonizations of α-Ketoesters.

A general and enantioselective N-heterocyclic carbene (NHC)-catalyzed lactonization of simple enals and α-ketoesters has been discovered using a new ternary cooperative catalytic system. The highly selective annulation was achieved by using a combination of a chiral NHC, a hydrogen-bond donor, and a metal salt, facilitating self-assembly of the reactive partners. A proposed model for this new mode of NHC chiral relay catalysis is supported by experimental and computational mechanistic studies.

Potent Anticancer Activity with High Selectivity of a Chiral Palladium N-Heterocyclic Carbene Complex.

Five enantiomeric pairs of palladium complexes of 1,2,4-triazole-derived chiral N-heterocyclic carbene ligands were investigated to probe the influence of chirality on the compound’s anticancer activity. Although no chirality-related influence was observed for any of the enantiomeric pair, strong anticancer activity was seen for a particular pair, (1S,2S,5R)-1c and (1R,2R,5S)-1c, which was significantly more active than the benchmark drug cisplatin for human breast cancer cells, MCF-7 (ca. 24–27-fold), and human cervical cancer cells, HeLa (ca. three- to fourfold). Broadening its scope of application, (1R,2R,5S)-1c also exhibited antiproliferative activity against lung cancer (A549), skin cancer (B16F10), and multidrug-resistant mammary tumor (EMT6/AR1) cell lines. Interestingly, (1R,2R,5S)-1c displayed 8- and 16-fold stronger antiproliferative activity toward B16F10 and MCF-7 relative to their respective noncancerous counterparts, L929 (fibroblast skin cells) and MCF10A (epithelial breast cells), thereby upholding the potential of these complexes for further development as anticancer agents. (1R,2R,5S)-1c inhibited tumor-cell proliferation by blocking the cells at the G2 phase. (1R,2R,5S)-1c caused DNA damage in MCF-7 cells, leading to mitochondrial reactive oxygen species production and subsequently cell death. We also present evidence indicating that (1R,2R,5S)-1c induced p53-dependent programmed cell death in MCF-7 cells.

Enantioselective β-Protonation of Enals via a Shuttling Strategy.

Remote asymmetric protonation is a longstanding challenge due to the small size of protons. Reactions involving electron-deficient olefins pose a further difficulty due to the electrophilic nature of these substrates. We report a shuttling system that delivers a proton in a highly enantioselective manner to the β-carbon of enals using a chiral N-heterocyclic carbene (NHC) catalyst. Choices of a Brønsted base shuttle and a Brønsted acid cocatalyst are critical for highly stereoselective β-protonation of the homoenolate intermediate and regeneration of the NHC catalyst results in functionalization of the carbonyl group. Thioesters with a β-chiral center were prepared in a redox-neutral transformation with an excellent yield and ee.

Copper(I)-Catalyzed Enantioselective Nucleophilic Borylation of Aliphatic Ketones: Synthesis of Enantioenriched Chiral Tertiary α-Hydroxyboronates.

A new method was developed for the first catalytic enantioselective borylation of aliphatic ketones. A variety of substrates reacted efficiently with bis(pinacolato)diboron in the presence of a copper(I)/chiral N-heterocyclic carbene complex catalyst to furnish optically active tertiary α-hydroxyboronates with moderate to high enantioselectivities (up to 94 % ee). Notably, the product could be converted into the chiral tertiary alcohol derivative using a stereospecific boron functionalization process. The theoretical study of the mechanism for the enantioselectivity is also described.

Readily Accessible Unsymmetrical Unsaturated 2,6-Diisopropylphenyl N-Heterocyclic Carbene Ligands. Applications in Enantioselective Catalysis.

A new multicomponent procedure was applied to the synthesis of (a)chiral bulky unsymmetrical unsaturated 2,6-diisopropylphenyl N-heterocyclic carbene (NHC) precursors with excellent selectivity (up to 95%) and good yields. This approach offers access to new chiral NHC ligands, which have found successful applications in both copper-catalyzed asymmetric allylic alkylation and copper-catalyzed asymmetric borylation.

Copper(i)-catalysed asymmetric allylic reductions with hydrosilanes.

A copper(i)-catalysed asymmetric allylic reduction enables a regio- and stereoselective transfer of a hydride nucleophile in an SN2'-fashion onto allylic bromides. This transformation represents a conceptually orthogonal approach to allylic substitution reactions with carbon nucleophiles. A copper(i) complex based upon a chiral N-heterocyclic carbene (NHC) ligand allows for stereoselectivity reaching 99% ee. The catalyst enables a stereoconvergent reaction irrespective of the double bond configuration of the starting materials.

Privileged chiral N-heterocyclic carbene ligands for asymmetric transition-metal catalysis.

Chiral ligands play a central role in enantioselective transition-metal catalysis. The success of achiral N-heterocyclic carbenes (NHCs) as stable electron-rich neutral ligands in homogeneous catalysis led to the development of a manifold of chiral NHCs as stereodirecting ancillary ligands for various enantioselective transformations. Due to the modular design of NHCs and the ease of access to their azolium salt precursors, tailor-made NHCs are readily available. Many chiral NHC scaffolds have been synthesised and tested in catalysis. Herein, we highlight only those NHC structures which have enabled high degrees of enantioselectivity in transition-metal catalysis. Following a brief introduction to the field of chiral NHCs, this tutorial review introduces different categories of chiral NHCs and provides a guide to the structural fine-tuning of ligand requirements and stereochemical models.

Correction: Privileged chiral N-heterocyclic carbene ligands for asymmetric transition-metal catalysis.

Correction for 'Privileged chiral N-heterocyclic carbene ligands for asymmetric transition-metal catalysis' by Daniel Janssen-Müller et al., Chem. Soc. Rev., 2017, DOI: .

Origin of Stereoselectivity in Cooperative Asymmetric Catalysis Involving N-Heterocyclic Carbenes and Lewis Acids toward the Synthesis of Spirooxindole Lactone

An increasing number of examples are now being reported that use chiral N-heterocyclic carbenes (NHCs) in conjunction with Lewis acids to enhance catalytic potential. Herein, we provide molecular insights into an NHC-catalyzed stereoselective annulation reaction between N-methylisatin and an enal leading to spirooxindole lactone in the presence of LiCl as the Lewis acid. Mechanistic features as well as the origin of enantio- and diastereoselectivities of the catalytic reaction have been unraveled using the density functional theory (B3LYP-D3) method. The key mechanistic steps of the reaction are identified to proceed through the formation of a Breslow intermediate between the chiral NHC catalyst and the enal, an enantioselective addition of the re face of this intermediate to the re face of the carbonyl group of N-methylisatin, and an intramolecular proton transfer and lactonization that eventually provide access to (2S,3R)-spirooxindole lactone as the final product. In the most preferred pathway, the Lew...

Enantioselective Cascade Reactions under N-Heterocyclic Carbene Catalysis

The use of chiral N-heterocyclic carbenes (NHCs) as catalysts in asymmetric synthesis has opened a wide range of applications due to their unique ability to generate reaction intermediates with unusual reactivity patterns that very often involve the reversal of the typical polarity associated with the functional groups present in the starting materials. In this sense, the direct activation of aldehydes or surrogates by these reactive species provides different chemical structures (conjugated Breslow intermediates, azolium enolates and dienolates, or unsaturated acyl azolium cations) which constitute excellent platforms for initiating cascade or domino reactions in the presence of a polyfunctional reagent. 1 Introduction 2 Cascade Reactions Initiated by the Participation of Homoenolate Equivalents 3 Cascade Reactions Initiated by the Participation of Azolium Enolates 4 Cascade Reactions Initiated by the Participation of Dienolate Equivalents 5 Cascade Reactions Initiated by the Participation of α,β-Unsaturated Acyl Azolium Intermediates 6 Summary and Outlook

Mechanism and Stereoselectivity in an Asymmetric N-Heterocyclic Carbene-Catalyzed Carbon–Carbon Bond Activation Reaction

The mechanism and origin of stereoinduction in a chiral N-heterocyclic carbene (NHC) catalyzed C-C bond activation of cyclobutenone has been established using B3LYP-D3 density functional theory computations. The activation of cyclobutenone as an NHC-bound vinyl enolate and subsequent reaction with the electrophilic sulfonyl imine leads to the lactam product. The most preferred stereocontrolling transition state exhibits a number of noncovalent interactions rendering additional stabilization. The computed enantio- and diastereoselectivities are in good agreement with the previous experimental observations.

ChemInform Abstract: N‐Heterocyclic Carbenes in Asymmetric Hydrogenation

AbstractReview: 75 refs.

Highly Enantioselective Direct Synthesis of Endocyclic Vicinal Diamines through Chiral Ru(diamine)‐Catalyzed Hydrogenation of 2,2′‐Bisquinoline Derivatives

An asymmetric hydrogenation of 2,2'-bisquinoline and bisquinoxaline derivatives, catalyzed by chiral cationic ruthenium diamine complexes, was developed. A broad range of chiral endocyclic vicinal diamines were obtained in high yields with excellent diastereo- and enantioselectivity (up to 93:7 dl/meso and >99 % ee). These chiral diamines could be easily transformed into a new class of chiral N-heterocyclic carbenes (NHCs), which are important but difficult to access.

Synthesis of New Chiral Benzimidazolylidene–Rh Complexes and Their Application in Asymmetric Addition Reactions of Organoboronic Acids to Aldehydes

A series of novel chiral N-heterocyclic carbene rhodium complexes (NHC–Rh) based on benzimidazole have been prepared, and all of the NHC–Rh complexes were fully characterized by NMR and mass spectrometry. These complexes could be used as catalysts for the asymmetric 1,2-addition of organoboronic acids to aldehydes, affording chiral diarylmethanols with high yields and moderate enantioselectivities.