Chiral Catalysts Research Articles

H8‐BINOL‐Derived Chiral η6‐Benzene Ligands: New Opportunities for the Ruthenium‐Catalyzed Asymmetric C−H Activation

Given the tremendous success of (p‐cymene)RuII‐catalyzed C−H activation over the past 20 years, the community has long been aware that the development of chiral η6‐benzene (Ben) ligands should be a potent strategy for achieving the attractive but incredibly underdeveloped ruthenium(II)‐catalyzed asymmetric C−H activation. However, it has rarely been achieved due to the severe difficulty in developing proper chiral Ben ligands. In particular, designing chiral Ben ligands by connecting a benzene fragment to a chiral framework including benzene rings remained an unsolved challenge until this effort. Here we present a novel class of axially chiral Ben ligands derived from readily available (S)‐5,5',6,6',7,7',8,8'‐octahydro‐1,1'‐bi‐2‐naphthol ((S)‐H8‐BINOL) in 4‐8 steps. Notably, when coordinated with ruthenium, such chiral Ben ligand containing three benzene rings only forms one of the three possible isomeric BenRuII complexes. The related chiral BenRuII catalysts could effectively catalyze the asymmetric C−H activation of N‐sulfonyl ketimines with alkynes, affording a range of chiral spirocyclic sultams in up to 99% yield with up to >99% ee. These catalysts are expected to find broad applications in future.

Crystalline Olefin-Linked Chiral Covalent Organic Frameworks as a Platform for Asymmetric Catalysis.

The construction of olefin-linked chiral covalent organic frameworks (COFs) with high crystallinity is highly desirable while remains great challenge due to the poor reversibility of the formation reaction for the olefin linkages during the in situ structural self-healing process. Herein, we successfully synthesized two sets of enantiomeric olefin-linked COFs. The chiral catalytic groups are uniformly distributed on the pore walls of COFs, resulting in the full exposure of catalytic sites to the reactants in asymmetric catalysis. The as-prepared (R)/(S)-CCOF8 exhibits excellent catalytic performance with exceeding 99% enantiomeric excess in the enantioselective electrophilic amination reaction. Moreover, the heterogeneous chiral catalysts are conveniently recycled and could maintain the performance after ten catalytic cycles. Our findings expand the scope to construct stable and crystalline chiral COFs for the asymmetric catalysis.

Crystalline Olefin‐Linked Chiral Covalent Organic Frameworks as a Platform for Asymmetric Catalysis

The construction of olefin‐linked chiral covalent organic frameworks (COFs) with high crystallinity is highly desirable while remains great challenge due to the poor reversibility of the formation reaction for the olefin linkages during the in situ structural self‐healing process. Herein, we successfully synthesized two sets of enantiomeric olefin‐linked COFs. The chiral catalytic groups are uniformly distributed on the pore walls of COFs, resulting in the full exposure of catalytic sites to the reactants in asymmetric catalysis. The as‐prepared (R)/(S)‐CCOF8 exhibits excellent catalytic performance with exceeding 99% enantiomeric excess in the enantioselective electrophilic amination reaction. Moreover, the heterogeneous chiral catalysts are conveniently recycled and could maintain the performance after ten catalytic cycles. Our findings expand the scope to construct stable and crystalline chiral COFs for the asymmetric catalysis.

Chiral Bisphosphine-Catalyzed Asymmetric Staudinger/aza-Wittig Reaction: An Enantioselective Desymmetrizing Approach to Crinine-Type Amaryllidaceae Alkaloids.

An unprecedented chiral bisphosphine-catalyzed asymmetric Staudinger/aza-Wittig reaction of 2,2-disubstituted cyclohexane-1,3-diones is reported, enabling the facile access of a broad range of cis-3a-arylhydroindoles in high yields with excellent enantioselectivities. The key to the success of this work relies on the first application of chiral bisphosphine DuanPhos to the asymmetric Staudinger/aza-Wittig reaction. An effective reductive system has been established to address the challenging PV═O/PIII redox cycle associated with the chiral bisphosphine catalyst. In addition, comprehensive experimental and computational investigations were carried out to elucidate the mechanism of the asymmetric reaction. Leveraging the newly developed chemistry, the enantioselective total syntheses of several crinine-type Amaryllidaceae alkaloids, including (+)-powelline, (+)-buphanamine, (+)-vittatine, and (+)-crinane, have been accomplished with remarkable conciseness and efficiency.

Effect of the U-Shaped Cavity of Conformationally Flexible Chiral Lewis-Acidic Boron-Based Catalysts in Multiselective Diels-Alder Reactions.

The effect of the U-shaped cavity of conformationally flexible chiral Lewis acidic boron-based catalysts in multiselective Diels-Alder reactions was investigated. The U-shaped catalysts can recognize substituents at the terminal acetylene moiety of propynal based on steric factors and can also recognize alkyne and alkene substrates based on the match/mismatch between the catalysts and substrates. Moreover, even in a mixture of different catalysts and substrates, the desired competitive reactions can proceed multiselectively. This proof-of-concept study should contribute to the development of artificial enzyme-like catalysis in vitro.

Synergistic Palladium/Copper‐Catalyzed 1,4‐Difunctionalization of 1,3‐Dienes for Stereodivergent Construction of 1,5‐Nonadjacent Stereocenters

AbstractThe construction of two distal stereocenters through a single catalytic process is of great interest in organic synthesis. While there are some successful reports regarding stereodivergent preparation of 1,3‐ or 1,4‐stereocenters, the more challenged 1,5‐nonadjacent stereocenters have never been achieved in a stereodivergent fashion. Herein we describe a synergistic palladium/copper catalysis for 1,4‐difunctionalization reactions of 1,3‐dienes, providing access to 1,5‐nonadjacent quaternary stereocenters. Because each of the two catalysts separately controlled one of the newly formed stereocenters, stereodivergent synthesis of all four diastereomers of the products could readily be achieved simply by choosing an appropriate combination of chiral catalysts. Experimental and computational studies supported a mechanism involving a Heck/Tsuji–Trost cascade reaction, and the origins of the stereoselectivity were elucidated.

Synergistic Palladium/Copper-Catalyzed 1,4-Difunctionalization of 1,3-Dienes for Stereodivergent Construction of 1,5-Nonadjacent Stereocenters.

The construction of two distal stereocenters through a single catalytic process is of great interest in organic synthesis. While there are some successful reports regarding stereodivergent preparation of 1,3- or 1,4-stereocenters, the more challenged 1,5-nonadjacent stereocenters have never been achieved in a stereodivergent fashion. Herein we describe a synergistic palladium/copper catalysis for 1,4-difunctionalization reactions of 1,3-dienes, providing access to 1,5-nonadjacent quaternary stereocenters. Because each of the two catalysts separately controlled one of the newly formed stereocenters, stereodivergent synthesis of all four diastereomers of the products could readily be achieved simply by choosing an appropriate combination of chiral catalysts. Experimental and computational studies supported a mechanism involving a Heck/Tsuji-Trost cascade reaction, and the origins of the stereoselectivity were elucidated.

Photoinduced Pd-Catalyzed Enantioselective Carboamination of Dienes via Aliphatic C-H Bond Elaboration.

Three-component diene carboaminations offer a potent means to access synthetically valuable allylic amines with rapid molecular complexity escalation. The existing literature primarily discloses racemic examples, necessitating the use of halides/pseudohalides as substrates. This paper introduces a photoinduced Pd-catalyzed enantioselective three-component carboamination of aryl-substituted 1,3-dienes, leveraging aliphatic C-H bonds for rapid synthesis. The reaction employs 10 mol % of chiral palladium catalyst and an excess aryl bromide as the HAT reagent. This approach yields diverse chiral allylamines with moderate to excellent enantioselectivities. Notably, it stands as the first instance of an asymmetric three-component diene carboamination reaction, directly utilizing abundant C(sp3)-H bearing partners, such as toluene-type substrates, ethers, amines, esters, and ketones. The protocol exhibits versatility across amines, encompassing aliphatic, aromatic, primary, and secondary derivatives. This method could serve as a versatile platform for stereoselective incorporation of various nucleophiles, dienes, and C(sp3)-H bearing partners.

Mechanisms, regio- and stereoselectivities involved in NHC[sbnd]catalyzed dearomatizing annulation of ester with ylide: A computational study

The catalytic mechanism for dearomatizing annulation of ester with ylide by a chiral NHC catalyst is investigated by density functional theory (M06–2X) computations. After precatalyst activation giving active NHC, the transformation proceeds via five steps: (1) nucleophilic addition of the NHC to ester, (2) α−CH deprotonation to generate acylazolium intermediate, (3) coupling acylazolium intermediate with ylide to form a new C − C bond, (4) ring closure and (5) elimination of the NHC with formation of the annulation product tricyclic dihydroisoquinoline. The regio- and stereoselectivity controlling step is C − C bond formation. For regioselectivity, local reactivity index analysis indicates that the C1-addition is more favorable than either C3 or C4 addition. The stereoselectivity for the formation of SS-configurational product is ascribed to a number of noncovalent interactions (C–H·O, C–H·N and C–H·π). Electron localization function (ELF) analyses reveal the important role of the NHC in Ccarbonyl−Ocarbonyl bond breaking. These results enable both in-depth understanding of NHC catalysis and rational design of catalytic reactions.

Stereoselective Synthesis and Catalytical Application of Perillaldehyde-Based 3-Amino-1,2-diol Regioisomers.

A library of regioisomeric monoterpene-based aminodiols was synthesised and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The synthesis of the first type of aminodiols was achieved starting from (-)-8,9-dihydroperillaldehyde via reductive amination, followed by Boc protection and dihydroxylation with the OsO4/NMO system. Separation of formed stereoisomers resulted in a library of aminodiol diastereoisomers. The library of regioisomeric analogues was obtained starting from (-)-8,9-dihydroperillic alcohol, which was transformed into a mixture of allylic trichloroacetamides via Overman rearrangement. Changing the protecting group to a Boc function, the protected enamines were subjected to dihydroxylation with the OsO4/NMO system, leading to a 71:16:13 mixture of diastereoisomers, which were separated, affording the three isomers in isolated form. The obtained primary aminodiols were transformed into secondary derivatives. The regioselectivity of the ring closure of the N-benzyl-substituted aminodiols with formaldehyde was also investigated, resulting in 1,3-oxazines in an exclusive manner. To explain the stability difference between diastereoisomeric 1,3-oxazines, a series of comparative theoretical modelling studies was carried out. The obtained potential catalysts were applied in the reaction of aromatic aldehydes and diethylzinc with moderate to good enantioselectivities (up to 94% ee), whereas the opposite chiral selectivity was observed between secondary aminodiols and their ring-closed 1,3-oxazine analogues.

Rhodium(II)-Catalyzed Asymmetric Cyclopropanation and Desymmetrization of [2.2]Paracyclophanes.

Chiral [2.2]paracyclophane derivatives are of considerable interest because of their potential in asymmetric catalysis and the development of chiral materials. This study describes the scope of rhodium-catalyzed reactions of aryldiazoacetates with [2.2]paracyclophanes. The reaction with the parent [2.2]paracyclophane resulted in cyclopropanation at two positions, the ratio of which is catalyst-controlled. Because of the strain in the system, one of the cyclopropanes exists primarily as the norcaradiene structure, whereas the other preferentially exists as the cycloheptatriene conformer. In contrast, the reaction with [3.3]paracyclophane results in benzylic C-H functionalization. The reactions with substituted [2.2]paracyclophanes using chiral catalysts can result in either kinetic resolution or desymmetrization. The Rh2(S-p-PhTPCP)]4-catalyzed reaction of monosubstituted paracyclophanes results in kinetic resolution with a selectivity (s) factor of up to 20, whereas reactions on C2v-symmetric disubstituted [2.2]paracyclophanes with Rh2(S-TPPTTL)4 [TPPTTL = 2-(1,3-dioxo-4,5,6,7-tetraphenylisoindolin-2-yl)-3,3-dimethylbutanoate] results in effective desymmetrization to form cycloheptatriene-incorporated paracyclophanes in 78-98% ee.

Chiral Biocatalytic Oxidations at 90 °C in Microemulsions Driven by Electrocatalytic Oxygen Reduction to Hydrogen Peroxide

AbstractChirality plays a significant role in the manufacture of pharmaceuticals and fine chemicals. The use of chemical catalysts to control stereoselectivity relies on the use of chiral catalysts with labor–intensive synthesis and purification. Natural enzymes offer inherent stereoselectivity, making them attractive catalysts for this purpose. We report here chiral biocatalytic oxidations in microemulsions driven by horseradish peroxidase coupled with a synthetic Cu2+‐polymer catalyst. This hybrid system features crosslinked layer–by–layer (LBL) films composed of polyions with Cu2+‐containing pyrene–labelled poly(2‐hydroxy‐3‐dipicolylamino) propyl methacrylate (Py−PGMADPA) to drive oxygen reduction to form hydrogen peroxide. Peroxide in turn activates horseradish peroxidase (HRP) crosslinked in LbL films on magnetic particle beads to biocatalytically oxidize styrene, ethylbenzene, and methyl phenylacetate to chiral products. R‐stereoisomers of these reactants were selectively formed with a high enantiomeric excess of ≥80 % at 90 °C. The enzyme films show high thermal stability at 90 °C in cetyltrimethylammonium bromide microemulsion. Reactions at 90 °C were essentially complete in 2 hr. This hybrid approach opens a door to new designs of biocatalytic syntheses using a separate electrocatalyst for enzyme activation.

A directed enolization strategy enables by-product-free construction of contiguous stereocentres en route to complex amino acids.

Homochiral α-amino acids are widely used in pharmaceutical design as key subunits in chiral catalyst synthesis or as building blocks in synthetic biology. Many synthetic methods have been developed to access rare or unnatural variants by controlling the installation of the α-stereocentre. By contrast, and despite their importance, α-amino acids possessing β-stereocentres are much harder to synthesize. Here we demonstrate an iridium-catalysed protocol that allows the direct upconversion of simple alkenes and glycine derivatives to give β-substituted α-amino acids with exceptional levels of regio- and stereocontrol. Our method exploits the native directing ability of a glycine-derived N-H unit to facilitate Ir-catalysed enolization of the adjacent carbonyl. The resulting stereodefined enolate cross-couples with a styrene or α-olefin to install two contiguous stereocentres. The process offers very high levels of regio- and stereocontrol and occurs with complete atom economy. In broader terms, our reaction design offers a unique directing-group-controlled strategy for the direct stereocontrolled α-alkylation of carbonyl compounds, and provides a powerful approach for the synthesis of challenging contiguous stereocentres.

Carbene‐Catalyzed Asymmetric Ring‐Opening Reaction of Biaryl Lactams to Access Axially Chiral Biaryls†

Comprehensive SummaryAxially chiral biaryls represent the most important class of atropisomers, and they widely exist in natural products and biologically active molecules. They also constitute a unique scaffold for chiral ligands and catalysts in organic synthesis. The development of synthetic methods to obtain such chiral compounds has received widespread attention, among which catalytically atroposelective ring‐opening of configurationally labile compounds represents one of the most attractive strategies. Various substrates with strained cyclic structures, such as the renowned Bringmann's lactones, can undergo asymmetric transformation into stable atropisomers. Known advancement primarily relies on metal catalyst combined with well‐designed chiral ligands, the approaches utilizing organocatalysis as a critical resolution strategy are notably scarce. In this study, we disclosed a N‐heterocyclic carbene (NHC)‐catalyzed asymmetric ring‐opening reaction of biaryl lactams via direct atroposelective nucleophilic activation. The optimized bulky carbene catalyst ensures that the reaction can proceed under mild conditions, affording the desired product with good to excellent yields and atroposelectivity.

Axially Chiral Copper Catalyst for Asymmetric Synthesis of Valuable Diversely Substituted BINOLs

Axially Chiral Copper Catalyst for Asymmetric Synthesis of Valuable Diversely Substituted BINOLs

General, Modular Access toward Immobilized Chiral Phosphoric Acid Catalysts and Their Application in Flow Chemistry.

Chiral phosphoric acids (CPAs) are among the most frequently used organocatalysts, with an ever-increasing number of applications. However, these catalysts are only obtained in a multistep synthesis and are poorly recyclable, which significantly deteriorates their environmental and economic performance. We herein report a conceptually different, general strategy for the direct immobilization of CPAs on a broad scope of solid supports including silica, polystyrene, and aluminum oxide. Solid-state catalysts were obtained in high yields and thoroughly characterized with elemental analysis by inductively coupled plasma-optical emission spectrometry (ICP-OES), nitrogen sorption measurements, thermogravimetric analysis, scanning transmission electron microscopy/energy-dispersive X-ray spectroscopy (STEM/EDX) images, and solid-state NMR spectroscopy. Further, the immobilized catalysts were applied to a variety of synthetically valuable, highly stereoselective transformations under batch and flow conditions including transfer hydrogenations, a Friedländer condensation/transfer hydrogenation sequence, and Mannich reactions under cryogenic flow conditions. Generally, high yields and stereoselectivities were observed along with robust catalyst stability and reusability. After being used for 10 runs under batch conditions, no loss of selectivity or catalytic activity was observed. Under continuous-flow conditions, the heterogeneous system was in operation for 19 h and the high enantioselectivity remained unchanged throughout the entire process. We expect our approach to extend the applicability of CPAs to a higher level, with a focus on flow chemistry and a more environmentally friendly and resource-efficient use of these powerful catalysts.

A Simple Tool to Benchmark Reactivity in Asymmetric Catalysis

AbstractHerein, we report a simple and noninvasive experimental protocol in which a series of relative reaction rates may be obtained by way of single competition experiments. This approach permits a quantitative comparison of any given number of chiral catalysts relative to a ‘benchmarking’ chiral catalyst – a particularly useful tool since catalyst design and selection have remained largely dependent on chemical intuition. We apply this benchmarking approach towards an asymmetric N-heterocyclic carbene (NHC) catalyzed intramolecular Stetter reaction as a proof-of-concept study. In doing so, we demonstrate a rapid method to assess the complex interplay between catalyst reactivity and stereoelectronic effects – an analytical approach that has heretofore not been attempted for NHCs. To showcase the generality of this method, we apply it to an enantioselective Rh(I)-catalyzed [2+2+2] cycloaddition of alkenyl isocyanates and aryl alkynes for a series of chiral phosphoramidite ligands. The results described herein demonstrate that this inexpensive and easily adoptable protocol can reveal complex yet subtle steric and stereoelectronic effects of vastly different chiral catalyst structures, which can further aid with catalyst development and selection for a clearly defined application.

Bimetallic Ru/Ru-Catalyzed Asymmetric One-Pot Sequential Hydrogenations for the Stereodivergent Synthesis of Chiral Lactones.

Asymmetric sequential hydrogenations of α-methylene γ- or δ-keto carboxylic acids are established in one-pot using a bimetallic Ru/Ru catalyst system, achieving the stereodivergent synthesis of all four stereoisomers of both chiral γ- and δ-lactones with two non-vicinal carbon stereocenters in high yields (up to 99%) and with excellent stereoselectivities (up to >99% ee and >20:1 dr). The compatibility of the two chiral Ru catalyst systems is investigated in detail, and it is found that the basicity of the reaction system plays a key role in the sequential hydrogenation processes. The protocol can be performed on a gram-scale with a low catalyst loading (up to 11000 S/C) and the resulting products allow for many transformations, particularly for the synthesis of several key intermediates useful for the preparation of chiral drugs and natural products.

Organocatalytic Atroposelective Construction of Pentatomic Heterobiaryl Diamines through Arylation of 5-Aminoisoxazoles with Azonaphthalenes.

An efficient catalytic asymmetric Michael-type reaction of azonaphthalenes with 5-aminoisoxazoles has been developed. The reaction was based on the utilization of a chiral phosphoric acid as the catalyst, delivering a large panel of axially chiral heterobiaryl diamines in generally good yields with excellent enantioselectivities. The gram-scale reaction and postmodification of the chiral product demonstrated their potentials in the synthesis of chiral catalysts and ligands. This approach not only provides a useful method for the construction of pentatomic heterobiaryl scaffolds but also offers new members to the axially chiral diamine family with promising applications in synthetic and medicinal chemistry.

Asymmetric Mannich Reaction of Isatin-Derived Ketimines with α-Fluoroindanones Catalyzed by a Chiral Phase-Transfer Catalyst.

A highly enantioselective Mannich reaction of α-fluoroindanones with isatin-derived N-Boc-ketimines catalyzed by a quinine-derived phase-transfer catalyst was developed. A variety of 3-substituted 3-amino-2-oxindoles bearing fluorine-containing, vicinal, tetrasubstituted stereocenters were constructed using this protocol in high yields (83-95%), with moderate to excellent enantioselectivities (66-91%) and high diastereoselectivities (up to >99:1).