Excellent Enantiocontrol Research Articles

Highly Enantioselective Synthesis of N-Unprotected Unnatural α-Amino Acid Derivatives by Ruthenium-Catalyzed Direct Asymmetric Reductive Amination.

An unprecedented highly enantioselective Ru-catalyzed direct asymmetric reductive amination of α-keto amides with ammonium salts has been disclosed, efficiently offering valuable enantioenriched N-unprotected unnatural α-amino acid derivatives bearing a broad range of aryl or alkyl α-substituents. This protocol features easily accessible substrates, good functional-group tolerance and excellent enantiocontrol, making it a good complementary approach to the known methods. Moreover, this method is also applicable to the preparation of N-unprotected unnatural α-amino acid derivatives containing an additional stereogenic center at the β-position through a dynamic kinetic resolution (DKR) process. Convenient transformations of the obtained products into chiral N-unprotected unnatural α-amino acids, drug intermediates, peptides, and organocatalysts/ligands further showcase the utility of this method.

Development of Axially Chiral Styrene-Type Carboxylic Acid Ligands via Palladium-Catalyzed Asymmetric C-H Alkynylation.

A weakly coordinated carboxylate-directed palladium-catalyzed atroposelective C-H alkynylation method for the development of novel axially chiral styrene-type carboxylic acids is disclosed. This transformation exhibits good yields (up to 85%), excellent enantiocontrol (up to 99% ee), and mild conditions. Notably, the synthetic utility of the resulting alkynyl carboxylic acid derivatives was demonstrated by various derivatizations as well as their potential as chiral ligands in asymmetric C-H activations.

Chiral Phosphoric Acid-Catalyzed Remote Control of Axial Chirality at Boron-Carbon Bond.

The previously elusive catalytic enantioselective construction of axially chiral B-aryl-1,2-azaborines with a C-B stereogenic axis has been realized through a chiral phosphoric acid-catalyzed desymmetrization strategy reported herein. The electrophilic aromatic substitution reaction of 3,5-disubsituted phenols with diazodicarboxamides could afford these axially chiral structures in good efficiency with excellent enantiocontrol. The efficient long-range stereochemical control is achieved by multiple well-defined H-bonding interactions between chiral phosphoric acid and both substrates. Meanwhile, the reaction duration could be markedly shortened with weakly acidic N-H in 1,2-azaborine acting as H-bond donor. The scalability of the reaction and facile cleavage of the N-N bond in the product further demonstrated the practicality of this method.

Nickel-Catalyzed Reductive Asymmetric Aryl-Acylation and Aryl-Carbamoylation of Unactivated Alkenes

Nickel-Catalyzed Reductive Asymmetric Aryl-Acylation and Aryl-Carbamoylation of Unactivated Alkenes

Catalytic reductive desymmetrization of malonic esters.

Desymmetrization of fully substituted carbons with a pair of enantiotopic functional groups is a practical strategy for the synthesis of quaternary stereocentres, as it divides the tasks of enantioselection and C-C bond formation. The use of disubstituted malonic esters as the substrate of desymmetrization is particularly attractive, given their easy and modular preparation, as well as the high synthetic values of the chiral monoester products. Here, we report that a dinuclear zinc complex with a tetradentate ligand can selectively hydrosilylate one of the carbonyls of malonic esters to give α-quaternary β-hydroxyesters, providing a promising alternative to the desymmetric hydrolysis using carboxylesterases. The asymmetric reduction features excellent enantiocontrol that can differentiate sterically similar substituents and high chemoselectivity towards the diester motif of substrates. Together with the versatile preparation of malonic ester substrates and post-reduction derivatization, the desymmetric reduction has enabled the synthesis of a diverse array of quaternary stereocentres with distinct structural features.

Enantioselective Hydrogenation of Tetrasubstituted α,β‐Unsaturated Carboxylic Acids Enabled by Cobalt(II) Catalysis: Scope and Mechanistic Insights

AbstractChiral carboxylic acids are important compounds because of their prevalence in pharmaceuticals, natural products and agrochemicals. Asymmetric hydrogenation of α,β‐unsaturated carboxylic acids has been widely recognized as one of the most efficient synthetic approaches to afford such compounds. Although related asymmetric hydrogenation of di‐ and trisubstituted unsaturated acids with noble metals is well established, asymmetric hydrogenation of challenging tetrasubstituted α,β‐unsaturated carboxylic acids is rarely reported. We demonstrate enantioselective hydrogenation of cyclic and acyclic tetrasubstituted α,β‐unsaturated carboxylic acids via cobalt(II) catalysis. This protocol showed broad substrate scope and gave chiral carboxylic acids in good yields with excellent enantiocontrol (up to 98 % yield and 99 % ee). Combined experimental and computational mechanistic studies support a CoII catalytic cycle involving migratory insertion and σ‐bond metathesis processes. DFT calculations reveal that enantioselectivity may originate from the steric effect between the phenyl groups of the ligand and the substrate.

Enantioselective Hydrogenation of Tetrasubstituted α,β-Unsaturated Carboxylic Acids Enabled by Cobalt(II) Catalysis: Scope and Mechanistic Insights.

Chiral carboxylic acids are important compounds because of their prevalence in pharmaceuticals, natural products and agrochemicals. Asymmetric hydrogenation of α,β-unsaturated carboxylic acids has been widely recognized as one of the most efficient synthetic approaches to afford such compounds. Although related asymmetric hydrogenation of di- and trisubstituted unsaturated acids with noble metals is well established, asymmetric hydrogenation of challenging tetrasubstituted α,β-unsaturated carboxylic acids is rarely reported. We demonstrate enantioselective hydrogenation of cyclic and acyclic tetrasubstituted α,β-unsaturated carboxylic acids via cobalt(II) catalysis. This protocol showed broad substrate scope and gave chiral carboxylic acids in good yields with excellent enantiocontrol (up to 98 % yield and 99 % ee). Combined experimental and computational mechanistic studies support a CoII catalytic cycle involving migratory insertion and σ-bond metathesis processes. DFT calculations reveal that enantioselectivity may originate from the steric effect between the phenyl groups of the ligand and the substrate.

Iridium-Catalyzed Asymmetric Cascade Allylation/Pictet-Spengler Cyclization Reaction for the Enantioselective Synthesis of 1,3,4-Trisubstituted Tetrahydroisoquinolines.

An iridium-catalyzed trifluoroacetic acid-promoted asymmetric cascade allylation/Pictet-Spengler cyclization reaction of azomethine ylides with aromatic allylic alcohols is reported. This protocol provides a facile and scalable method for the construction of 1,3,4-trisubstituted tetrahydroisoquinolines containing two stereogenic centers in good yields (up to 96%) with generally excellent diastereo- and enantioselectivities (up to >20:1 dr and >99% ee). Furthermore, a series of aromatic heterocycle-fused piperidines were also obtained with excellent enantiocontrol by this methodology.

Enantioselective vinylogous Mukaiyama aldol reaction of α-ketoesters under bifunctional organocatalysis.

A highly enantioselective vinylogous Mukaiyama aldol reaction to ketoesters catalysed by a hydrogen-bond-donor-based bifunctional organocatalyst is presented. The addition of silyloxy dienol ether gives rise to multifunctional chiral tertiary alcohols bearing a versatile α,β-unsaturated aldehyde with excellent enantiocontrol.

Organocatalytic asymmetric synthesis of α-amino esters from sulfoxonium ylides.

Described here is the first organocatalytic asymmetric N–H insertion reaction of α-carbonyl sulfoxonium ylides. Without a metal catalyst, this reaction represents an attractive complement to the well-established carbene insertion reactions. As a stable surrogate of diazocarbonyl compounds, sulfoxonium ylides reacted with a range of aryl amines to provide efficient access to α-aryl glycines with excellent enantiocontrol in the presence of a suitable chiral phosphoric acid catalyst. The high stability and weak basicity of sulfoxonium ylides not only enable this protocol to be user-friendly and practically useful, but also preclude catalyst decomposition, which is crucial to the excellent amenability to electron-poor amine nucleophiles. Detailed mechanistic studies indicated that the initial protonation is reversible and the C–N bond formation is rate-determining.

C2‐Symmetric Cinchona Alkaloid Derivatives: Versatile Catalysts for the Enantioselective C−C Bond Forming Conjugate Addition of Nucleophiles to Simple α,β‐Unsaturated Acyl Pyrazoles

AbstractA single C2‐symmetric squaramide catalyst system allows the facile addition of either malononitrile or benzyl nitroacetate to simple pyrazole‐based Michael acceptors with excellent enantiocontrol and at lower catalyst loadings than previously possible. The latter reactions are not diastereoselective, however facile hydrogenolysis leads to decarboxylation and formation of the formal adduct from the addition of nitromethane (a very recalcitrant nucleophile in this chemistry) with excellent yield and enantiocontrol.

Ni-Catalyzed Regiodivergent and Stereoselective Hydroalkylation of Acyclic Branched Dienes with Unstabilized C(sp3) Nucleophiles.

Two complementary regiodivergent [(P,N)Ni]-catalyzed hydroalkylations of branched dienes are reported. When amides are employed as unstabilized C(sp3) nucleophiles, a highly regioselective 1,4-addition process is favored. The addition products are obtained in high yield and with excellent stereocontrol of the internal olefin. With use of a chiral ligand and imides as carbon nucleophiles, a 3,4-addition protocol was developed, enabling construction of two contiguous tertiary stereocenters in a single step with moderate to high levels of diastereocontrol and excellent enantiocontrol. Both methods operate under mild reaction conditions, display a broad scope, and show excellent functional group tolerance. The synthetic potential of the 3,4-hydroalkylation reaction was established via a series of postcatalytic modifications.

Isothiourea‐Catalyzed Functionalization of Pyrrolyl‐ and Indolylacetic Acid: Enantioselective Synthesis of Dihydropyridinones and One‐pot Synthesis of Pyridinones

AbstractA protocol for the isothiourea‐catalyzed enantioselective functionalization of pyrrolyl‐ and indolylacetic acids has been developed. Stereodefined dihydropyridinones are accessed through formal [4+2] cycloaddition of an in situ generated isothiouronium enolate with α,β‐unsaturated ketimines. The dihydropyridinones are obtained in moderate to excellent yield (26–97%), excellent diastereocontrol (all >95 : 5 dr) and moderate to excellent enantiocontrol (75 : 25–99 : 1 er). An unusual elimination of pyrrole or indole from the dihydropyridinone to access achiral pyridinones was observed and could be selectively promoted. A further one‐pot synthesis using an acyl imidazole was developed to give pyridinones in good to excellent yields (67–91%).

P-Stereogenic N-Phosphine-Phosphite Ligands for the Rh-Catalyzed Hydrogenation of Olefins.

We have identified a successful family of simple P-stereogenic N-phosphine-phosphite ligands for the Rh-catalyzed asymmetric hydrogenation of olefins. These catalysts show excellent enantiocontrol for α-dehydroamino acid derivatives and α-enamides (ee's up to >99%) and promising results for the more challenging β-analogues (ee's up to 80%). The usefulness of these catalytic systems was further demonstrated with the synthesis of several valuable precursors for pharmacologically active compounds, with ee's at least as high as the best ones reported previously (up to >99%).

Chiral Phosphoric Acid Catalyzed Atroposelective C-H Amination of Arenes.

N-arylcarbazole structures are important because of their prevalence in natural products and functional OLED materials. C-H amination of arenes has been widely recognized as the most efficient approach to access these structures. Conventional strategies involving transition-metal catalysts suffer from confined substrate generality and the requirement of exogenous oxidants. Organocatalytic enantioselective C-N chiral axis construction remains elusive. Presented here is the first organocatalytic strategy for the synthesis of novel axially chiral N-arylcarbazole frameworks by the assembly of azonaphthalenes and carbazoles. This reaction accommodates broad substrate scope and gives atropisomeric N-arylcarbazoles in good yields with excellent enantiocontrol. This approach not only offers an alternative to metal-catalyzed C-N cross-coupling, but also brings about opportunities for the exploitation of structurally diverse N-aryl atropisomers and OLED materials.

Chiral Phosphoric Acid Catalyzed Atroposelective C−H Amination of Arenes

AbstractN‐arylcarbazole structures are important because of their prevalence in natural products and functional OLED materials. C−H amination of arenes has been widely recognized as the most efficient approach to access these structures. Conventional strategies involving transition‐metal catalysts suffer from confined substrate generality and the requirement of exogenous oxidants. Organocatalytic enantioselective C–N chiral axis construction remains elusive. Presented here is the first organocatalytic strategy for the synthesis of novel axially chiral N‐arylcarbazole frameworks by the assembly of azonaphthalenes and carbazoles. This reaction accommodates broad substrate scope and gives atropisomeric N‐arylcarbazoles in good yields with excellent enantiocontrol. This approach not only offers an alternative to metal‐catalyzed C–N cross‐coupling, but also brings about opportunities for the exploitation of structurally diverse N‐aryl atropisomers and OLED materials.

Organocatalytic Asymmetric Synthesis of Indole-Based Chiral Heterocycles: Strategies, Reactions, and Outreach.

Indole-based chiral heterocycles constitute a class of important heterocyclic compounds that are found in numerous pharmaceuticals, functional materials, and chiral catalysts or ligands. Catalytic asymmetric synthesis, for which the 2001 Nobel Prize in Chemistry was awarded, has been demonstrated to be the most efficient method for accessing chiral compounds. Therefore, the catalytic asymmetric synthesis of indole-based chiral heterocycles has attracted great interest from the scientific community. However, the strategies toward this goal are rather limited, and great challenges remain in this field, such as metal contamination in the products, the limited number of platform molecules with versatile reactivity, and the limited number of catalytic asymmetric reactions that offer high step economy, atom economy, and excellent enantiocontrol. Therefore, novel strategies for the catalytic asymmetric synthesis of indole-based chiral heterocycles are urgently needed. To achieve this goal, our group has developed a series of unique strategies, such as designing and developing versatile platform molecules and their corresponding organocatalytic asymmetric reactions to access indole-based chiral heterocycles. In this Account, we describe our efforts to address the remaining challenges in this research field. Namely, we have designed and developed vinylindoles, indolylmethanols, arylindoles and indole derivatives as versatile platform molecules for the construction of indole-based chiral heterocyclic scaffolds with structural diversity and complexity. Based on the reactivities of these platform molecules, we have designed and accomplished a series of organocatalytic asymmetric cycloaddition, cyclization, addition and dearomatization reactions with a high step economy, atom economy and excellent enantiocontrol. Using these strategies, a wide range of indole-based chiral heterocycles, including five-membered to seven-membered heterocycles, axially chiral heterocycles and tetrasubstituted heterocycles, have been synthesized with high efficiency and excellent enantioselectivity. In addition, we have investigated the properties of some indole-based chiral heterocycles, including their bioactivities and catalytic activities, and showed that these chiral heterocycles have potent anticancer activities and promising catalytic activities in asymmetric catalysis. These results help elucidate the potential applications of indole-based chiral heterocycles in drug development and chiral catalysts. The organocatalytic asymmetric synthesis of indole-based chiral heterocycles has undoubtedly become and will continue to be a hot topic in the field of asymmetric catalysis and synthesis. Our efforts, summarized in this Account, will not only open a window for the future development of innovative strategies toward organocatalytic asymmetric synthesis of indole-based chiral heterocycles but also inspire chemists worldwide to confront the remaining challenges in this field and prompt further advances.

Organocatalytic Enantioselective Functionalization of Unactivated Indole C(sp3)−H Bonds

AbstractDescribed here is a direct catalytic asymmetric functionalization of unactivated alkyl indoles using organocatalysis. In the presence of an effective chiral urea catalyst and a phosphoric acid additive, the intermolecular C−C bond formation between alkyl indoles and trifluoropyruvates proceeded with high efficiency and enantiocontrol. Unlike previous asymmetric C(sp3−H) functionalizations of α‐azaarenes, this process does not require the use of either a strong base or an electron‐deficient substrate. The excellent enantiocontrol is particularly noteworthy in view of the severe background reaction as well as the complete inability of other types of catalysts evaluated. Control experiments, kinetic studies, and DFT calculations provided important insights into the mechanism.

Organocatalytic Enantioselective Functionalization of Unactivated Indole C(sp3)−H Bonds

Described here is a direct catalytic asymmetric functionalization of unactivated alkyl indoles using organocatalysis. In the presence of an effective chiral urea catalyst and a phosphoric acid additive, the intermolecular C-C bond formation between alkyl indoles and trifluoropyruvates proceeded with high efficiency and enantiocontrol. Unlike previous asymmetric C(sp3 -H) functionalizations of α-azaarenes, this process does not require the use of either a strong base or an electron-deficient substrate. The excellent enantiocontrol is particularly noteworthy in view of the severe background reaction as well as the complete inability of other types of catalysts evaluated. Control experiments, kinetic studies, and DFT calculations provided important insights into the mechanism.

Enantioselective Conjugate Azidation of α,β‐Unsaturated Ketones under Bifunctional Organocatalysis by Direct Activation of TMSN3

AbstractAn enantioselective organocatalytic conjugate azidation of α,β‐unsaturated ketones is presented. A bifunctional organocatalyst activates TMSN3, triggering the nucleophilic addition of the azido group to enones in absence of external promoters and avoiding the direct use or the pre‐formation of highly toxic and explosive hydrazoic acid. This protocol proceeds with excellent enantiocontrol under mild conditions. DFT calculations and mechanistic trials have been performed in order to demonstrate the direct activation performed by the bifunctional organocatalyst.magnified image