Catalytic Asymmetric Reaction Research Articles

Axis-Unfixed Biphenylphosphine-Oxazoline Ligands: Design and Applications in Asymmetric Catalytic Reactions.

The design and synthesis of chiral ligands plays an important role in asymmetric catalytic reactions. Over the past decades, various types of chiral phosphine-oxazolines (PHOX ligands) have been developed and have greatly advanced the field of asymmetric catalysis. Novel chiral PHOX ligand with an axis-unfixed biphenyl backbone, developed by our group, have shown interesting coordination behavior and excellent chiral inducing ability in various transition-metal-catalyzed asymmetric reactions. This personal account focuses on our developed axis-unfixed biphenylphosphine-oxazoline ligand (BiphPHOX), including an overview of its design and applications, which will provide inspiration for the exploration of novel ligands and related reactions.

Catalytic asymmetric silicon-carbon bond-forming transformations based on Si-H functionalization

In view of the exciting advancement on silicon-carbon bond-forming transformations achieved in the past decade, this review intends to show a unified illustration of the recent findings on enantioselective Si-H bond functionalization aided by asymmetric catalysis. Accordingly, this review describes the enantioselective silicon-carbon bond-forming Si-H bond functionalization, focusing on the reactivity and stereoselectivity in catalytic asymmetric hydrosilylation, carbene Si-H insertion, Si-H silylation, and Si-C bond-forming cross-coupling reactions that were achieved with high enantioselectivity in the presence of transition-metal catalyst systems. This review highlights recent and representative examples of the enantioselective Si-H bond functionalization, discusses the origins of silicon-involving stereoselectivities, and evaluates the substrate scopes and limitations in these catalytic asymmetric Si-H bond functionalization reactions due to the special reactivity of different hydrosilanes.

Catalytic Enantioselective Amination of Enol Silyl Ethers Using a Chiral Paddle-Wheel Diruthenium Complex

A chiral paddle-wheel dinuclear ruthenium catalyst was applied to a catalytic asymmetric nitrene-transfer reaction with enol silyl ethers. The ruthenium catalyst was applicable to aliphatic enol silyl ethers as well as aryl-containing enol silyl ethers. The substrate scope of the ruthenium catalyst was superior to that of analogous chiral paddle-wheel rhodium catalysts. α-Amino ketones derived from aliphatic substrates were obtained in up to 97% ee with the ruthenium catalyst, while analogous rhodium catalysts resulted in only moderate enantioselectivity.

Chiral Aldehyde-Palladium Catalysis Enables Asymmetric Synthesis of α-Alkyl Tryptophans via Cascade Heck-Alkylation Reaction.

The first catalytic asymmetric cascade Heck-alkylation reaction of NH2-unprotected amino acid esters with N-(2-iodophenyl)allenamides is reported in this work. Under the promotion of a combining catalytic system comprising a chiral aldehyde, a chiral palladium complex, and the Lewis acid ZnCl2, the title reaction takes place smoothly, giving optically active α-alkyl tryptophan derivatives in moderate to good yields and excellent enantioselectivities. The target products can be converted into other structurally complex chiral indoles without the loss of enantioselectivities.

Organocatalytic Asymmetric Dearomatization Reaction for the Construction of Axially Chiral Urazole Embedded Naphthalenones

AbstractHerein we disclose a catalytic asymmetric dearomatization reaction of β‐naphthols with 4‐aryl‐1,2,4‐triazole‐3,5‐diones. A chiral phosphoric acid with spiro motif was found to be effective for this reaction. The chiral urazole embedded naphthalenones having both axial and central chirality were obtained in good to high yields (70–85%) with high diastereo‐ and enantioselectivities (>20:1, 8–96% ees), having C−N rotational energy barrier 31.54 K.Cal.mol−1 and t1/225 °C=589.8 years. The scope of the reaction was broad and few applications including a bromo‐amination reaction have been demonstrated.magnified image

Copper-Catalyzed Enantioselective Borylative Allyl-Allyl Coupling of Allenes and Allylic gem-Dichlorides.

A catalytic asymmetric reaction between allenes, bis(pinacolato)diboron, and allylic gem-dichlorides is reported. The method involves the coupling of a catalytically generated allyl copper species with the allylic gem-dichloride and provides chiral internal 1,5-dienes featuring (Z)-configured alkenyl boronate and alkenyl chloride units with high levels of chemo-, regio-, enantio-, and diastereoselectivity. The synthetic utility of the products is demonstrated with the synthesis of a range of optically active compounds. DFT calculations reveal key noncovalent substrate-ligand interactions that account for the enantioselectivity outcome and the diastereoselective formation of the (Z)-alkenyl chloride.

Visible-light-mediated catalytic asymmetric synthesis of α-amino esters via free carbene insertion into N[sbnd]H bond

A method that facilitates the construction of valuable chiral products exploiting simple high energy intermediates in an atom- and sustainable fashion could prove highly enabling for asymmetric synthesis. Free carbenes are one kind of such high energy intermediates and their utilization in catalytic asymmetric reactions is still elusive, due to the existence of severe racemic background reaction. In our pursuit to develop catalytic asymmetric NH insertion reaction of free carbene, a general chiral Brønsted acid-catalyzed enantioselective protonation of the in situ generated ammonium ylide was discovered under visible-light irradiation of diazo compound in the presence of arylamine, furnishing the desired α -amino esters with moderate to high enantioselectivity and yield. More importantly, it was found there is a remarkable correlation between the enantioselectivity of product and substituent electronic parameter (σpara) of substrates. This work not only demonstrates chiral phosphoric acid catalysis is compatible with free carbene insertion reactions without disturbing deactivation OH insertion side reactions, but also indicates the pKa of arylamine is also a significant parameter for turning the enantioselectivity of the reaction. The method disclosed herein is expected to bring new insights into the use of free carbene in the catalytic asymmetric reactions under metal free conditions.

Asymmetric reactions involving aryne intermediates.

Although arynes are usually considered fleeting intermediates, they are highly valuable synthons because they enable the introduction of aromatic rings and the simultaneous formation of new bonds at two sites. Although catalytic reactions using transition metals are excellent method for constructing complex polycyclic aromatic molecules in a single step, the use of asymmetric catalysis for the capture of arynes remains a crucial goal for the progress of aryne chemistry. Catalytic asymmetric reactions of arenes are challenging, requiring sufficient interactions between the neutral and highly reactive short-lived aryne intermediates in a stereo-controlled fashion. In addition, spontaneous decomposition, as well as side reactions, has hindered their development and, until recently, highly enantioselective reactions using arynes had remained elusive. This Review highlights asymmetric reactions using arynes, featuring diastereoselective, enantioselective and catalytic enantioselective reactions.

Sigma-Bond Metathesis as an Unusual Asymmetric Induction Step in Rhodium-Catalyzed Enantiodivergent Synthesis of C-N Axially Chiral Biaryls.

Mechanistic understanding of asymmetric induction plays a crucial role in designing new catalytic asymmetric reactions. Reported herein is atroposelective access to C-N axially chiral isoquinolones via rhodium-catalyzed C-H activation of N-alkoxy benzamides and annulation with imidoyl sulfoxonium ylides. The coupling system proceeded with excellent functional group tolerance, and different conditions were identified to afford one or the other enantiomeric product each in excellent enantioselectivity for a representative class of the sulfoxonium ylide reagent, thus making both enantiomers readily available using the same catalyst. Experimental and computational studies revealed a pathway of C-H alkylation and enantio-determining formal nucleophilic substitution-C-N cyclization that is mediated by the rhodium catalyst via σ-bond metathesis as the asymmetric induction mechanism. Computational studies indicated that the solvent-dependent enatiodivergence originated from different levels of σ-bond metathesis mediated by neutral versus cationic rhodium species.

Enantioselective Synthesis of Dispirooxindole Derivatives via Asymmetric Catalytic Cascade Reactions

AbstractA series of optically active 3,3′-pyrrolidinyl-dispirooxindole derivatives containing a CF3 moiety have been efficiently constructed through asymmetric catalytic cascade reactions catalyzed by cinchona-derived bifunctional squaramide catalyst, bearing four contiguous stereogenic centers, two of which are vicinal spiro-stereocenters. Additionally, a wide range of substituted products were achieved with moderate to high yields (up to 99% yield) and excellent stereoselectivities (up to >20:1 dr for all cases and up to 99% ee).

Organocatalytic DYKAT of Si-Stereogenic Silanes.

Chiral organosilanes do not exist in nature and are therefore absent from the "chiral pool". As a consequence, synthetic approaches toward enantiopure silanes, stereogenic at silicon, are rather limited. While catalytic asymmetric desymmetrization reactions of symmetric organosilicon compounds have been developed, the utilization of racemic silanes in a dynamic kinetic asymmetric transformation (DYKAT) or dynamic kinetic resolution (DKR) would significantly expand the breadth of accessible Si-stereogenic compounds. We now report a DYKAT of racemic allyl silanes enabled by strong and confined imidodiphosphorimidate (IDPi) catalysts, providing access to Si-stereogenic silyl ethers. The products of this reaction are easily converted into useful enantiopure monohydrosilanes. We propose a spectroscopically and experimentally supported mechanism involving the epimerization of a catalyst-bound intermediate.

Catalytic Asymmetric Imine Cross-Coupling Reaction

Catalytic asymmetric cross-coupling of imines constitutes a particularly desirable method for the synthesis of chiral vicinal diamines directly from readily available achiral precursors. The potential of this method lies in the possibility of utilizing a variety of imines as reacting partners. However, the realization of highly stereoselective cross-coupling of two different imines proved to be a formidable challenge. Herein we report an unprecedented catalytic asymmetric cross-coupling reaction that tolerates a variety of ketimines and aldimines as nucleophiles and electrophiles, respectively. The realization of this reaction resulted from the development of a new chiral ammonium catalyst, which was guided by insights from studies of catalyst-substrate interactions. With a 0.5 mol % loading of an organocatalyst, this reaction proceeded in a highly diastereo- and enantioselective manner to afford a diverse range of chiral vicinal diamines as nearly single stereoisomers. This catalytic reaction establishes a new approach for the asymmetric synthesis of chiral vicinal diamines.

Directed evolution of artificial enzymes with new-to-nature functions.

Directed evolution mimics the Darwinian evolution in the test tube, consisting of iterative rounds of diversity generation followed by screening/selection. This simple yet powerful algorithm has been widely used for enzyme engineering since the early 1990s. In this lecture, I will highlight a few of our recent accomplishments in the development and application of directed evolution tools for engineering artificial enzymes with new-to-nature functions. Specifically, I will discuss three examples related to the design and creation of artificial photoenzymes catalyzing abiological reactions, including repurposing of a naturally occurring ene-reductase for photoenzymatic enantioselective intermolecular radical hydroalkylation, engineering of a ketoreductase for enantioselective intermolecular radical conjugated addition, and engineering of an ene-reductase for enantioselective intermolecular radical hydroamination. These abiological asymmetric catalytic reactions are extremely difficult or impossible to achieve by non-enzymatic catalysis such as chemical catalysis, photocatalysis, eletrocatalysis, or organocatalysis. Further detailed mechanistic studies using computational and experimental approaches shed light on the origin of enantioselectivity.

Copper-Catalyzed Enantioselective Doyle-Kirmse Reaction of Azide-Ynamides via α-Imino Copper Carbenes.

[2,3]-Sigmatropic rearrangement reaction involving sulfonium ylide (Doyle-Kirmse reaction) generated from metal carbenes represents one of the powerful methods for the construction of C(sp3 )-S and C-C bonds. Although significant advances have been achieved, the asymmetric versions via the generation of sulfonium ylides from metal carbenes have been rarely reported to date, and they have so far been limited to diazo compounds as metal carbene precursors. Here, we describe a copper-catalyzed enantioselective Doyle-Kirmse reaction via azide-ynamide cyclization, leading to the practical and divergent assembly of an array of chiral [1,4]thiazino[3,2-b]indoles bearing a quaternary carbon stereocenter in generally moderate to excellent yields and excellent enantioselectivities. Importantly, this protocol represents a unique catalytic asymmetric Doyle-Kirmse reaction via a non-diazo approach and an unprecedented asymmetric [2,3]-sigmatropic rearrangement via α-imino metal carbenes.

Catalytic Asymmetric Deoxygenative Cyclopropanation Reactions by a Chiral Salen-Mo Catalyst.

The catalytic asymmetric cyclopropanation reaction of alkenes with diazo compounds is a direct and powerful method to construct chiral cyclopropanes that are essential to drug discovery. However, diazo compounds are potentially explosive and often require hazardous reagents for their preparation. Here, we report on the use of 1,2-dicarbonyl compounds as safe and readily available surrogates for diazo compounds in the direct catalytic asymmetric deoxygenative cyclopropanation reaction. Enabled by a class of simple and readily accessible chiral salen-Mo catalysts, the reaction proceeded with generally good enantioselectivities and yields toward a wide range of substrates (80 examples). Preliminary mechanistic studies suggested that the proposed μ-oxo bridged dinuclear Mo(III)-species was the catalytically active species. This strategy not only provides a promising route for the synthesis of chiral cyclopropanes but also opens a new window for the potential applications of chiral salen-Mo complexes in asymmetric catalysis.

Asymmetric transfer hydrogenation of ketones catalyzed by chiral macrocyclic cobalt(II) complexes

Using easily available CoBr2 and chiral cyclic PxNy-type ligands as starting materials, novel chiral cyclic cobalt(II) complexes could be conveniently prepared. Furthermore, we obtained the single crystals suitable for X-ray diffraction to confirm the structures of these cobalt(II) complexes. The asymmetric transfer hydrogenation (ATH) of ketones catalyzed by these well-designed cobalt(II) complexes was investigated. Among them, cobalt(II) complex containing chiral macrocyclic iminophosphine ligand CyP2N4 exhibited high catalytic activity and enantioselectivity (up to 99% ee). Density functional theory (DFT) calculations suggested that cobalt(II) complex (R,R,R',R')-CyP2N4-Co(II) (C1) is easier to form metal hydride, which is the key intermediate during the enantioselective transfer hydrogenation reaction. Study results also revealed that the unique macrocyclic structure of complex C1 could form a special microenvironment around cobalt ion. Therefrom the substrate coordinated with the central metal along this specific reaction channel during the asymmetric catalytic reaction, resulting high enantioselectivity.

Catalytic asymmetric interrupted Attanasi reaction: access to fused 2,3-dihydropyrroles with vicinal quaternary carbons.

The first catalytic asymmetric interrupted Attanasi reaction has been established. Under the catalysis of a bifunctional organocatalyst, the condensation of cyclic β-keto esters with azoalkenes readily occurred, delivering a variety of bicyclic fused 2,3-dihydropyrroles with vicinal quaternary stereogenic centers in good yields and with good to excellent enantioselectivities (27 examples, up to 96% yield and 95% ee).

Simple purification of small-molecule-labelled peptides via palladium enolate formation from β-ketoamide tags.

Palladium enolates derived from β-ketocarbonyl compounds serve as key intermediates in various catalytic asymmetric reactions. We found that the palladium enolate formed from β-ketoamide is stable in air and moisture and we applied this property to develop a peptide purification system using β-ketoamide as a small affinity tag in aqueous media. A solid-supported palladium complex successfully captured β-ketoamide-tagged molecules as palladium enolates and released them in high yield upon acid treatment. Optimum conditions for the catch and release of tagged peptides from a mixture of untagged peptides were established. To demonstrate the value of this methodology in identifying the binding site of a ligand to its target protein, we purified and identified a peptide containing the ligand-binding site from the tryptic digest of cathepsin B labelled with a covalent cathepsin B inhibitor containing a β-ketoamide tag.

Mechanochemical asymmetric three-component Mannich reaction involving unreactive arylamines.

We report here a mechanochemical protocol for an asymmetric three-component Mannich reaction involving unreactive arylamines with simple cyclic ketones and arylaldehydes catalyzed by (S)-proline with a chiral diol. In this mechanochemical protocol, ball milling enables reaction acceleration and enantioselectivity control. The reported asymmetric three-component Mannich reactions usually involve reactive arylamines such as p-anisidine and phenylamine, while the catalytic asymmetric Mannich reactions involving unreactive arylamines in solution did not proceed smoothly or gave low yields and enantioselectivities. However, the use of ball-milling techniques overcomes the deficiency of the batch systems in solution and avoids the use of toxic organic solvents. The desired products were obtained in moderate-to-good yields (49%-80%) with good-to-high enantioselectivities (up to 99% ee). This is the first example of a mechanochemically activated catalytic asymmetric three-component Mannich reaction involving unreactive arylamines.

Aggregation-Induced Catalysis: Asymmetric Catalysis with Chiral Aggregates.

So far, there have been 4 methods to control chirality including the use of chiral auxiliaries, reagents, solvents, and catalysts documented in literature and textbooks. Among them, asymmetric catalysts are normally divided into homogeneous and heterogeneous catalysis. In this report, we present a new type of asymmetric control-asymmetric catalysis via chiral aggregates that would not belong to the above categories. This new strategy is represented by catalytic asymmetric dihydroxylation reaction of olefins in which chiral ligands are aggregated by taking advantage of typical aggregation-induced emission systems containing tetrahydrofuran and H2O cosolvents. It was proven that the chiral induction can be enhanced from er of 78:22 to 97:3 simply by changing the ratios of these 2 cosolvents. The formation of chiral aggregates of asymmetric dihydroxylation ligands, (DHQD)2PHAL and (DHQ)2PHAL, has been proven by aggregation-induced emission and a new analytical tool-aggregation-induced polarization established by our laboratory. In the meanwhile, chiral aggregates were found to be formed either by adding NaCl into tetrahydrofuran/H2O systems or by increasing concentrations of chiral ligands. The present strategy also showed promising reverse control of enantioselectivity in the Diels-Alder reaction. This work is anticipated to be extended broadly to general catalysis, especially to asymmetric catalysis in the future.