Abstract
1,3-Dienes are easily accessible chemicals that participate in a series of reactions acting on the carbon–carbon double bonds. Catalytic difunctionalization of 1,3-dienes provides a wide ...scope of functionalized chemicals. Pd(0) catalysts provide a diverse set of principles for the creation of asymmetric catalytic reactions, which are initiated with the oxidative addition and then undergo insertion reaction with one of double bonds of the 1,3-diene to become a π-allyl palladium species that is reactive toward nucleophilic attack. This review summarizes typical advances on the Pd(0)-catalyzed difunctionalization of 1,3-dienes in recent decades, particularly emphasizing the concepts that enable the switch from a racemic reaction to an enantioselective version.
1 Introduction
2 Amination
3 Boration
4 Carbonation
5 Hydrogenation
6 Oxygenation
7 Silylation
8 Conclusion and Outlook
Conspectus Asymmetric functionalization of inert C–H bonds is undoubtedly a synthetically significant yet challenging bond-forming process, allowing for the preparation of densely functionalized ...molecules from abundantly available feedstocks. In the past decade, our group and others have found that trivalent phosphorus ligands are capable of facilitating Pd-catalyzed allylic C–H functionalization of α-alkenes upon using p-quinone as an oxidant. In these reactions, a 16-electron Pd(0) complex bearing a monodentate phosphorus ligand, a p-quinone, and an α-alkene has been identified as a key intermediate. Through a concerted proton and two-electron transfer process, electrophilic π-allylpalladium is subsequently generated and can be leveraged to forge versatile chemical bonds with a wide range of nucleophiles. This Account focuses on describing the origin, evolution, and synthetic applications of Pd-catalyzed asymmetric allylic C–H functionalization reactions, with an emphasis on the fundamental mechanism of the concerted proton and two-electron transfer process in allylic C–H activation. Enabled by the cooperative catalysis of the palladium complex of triarylphosphine, a primary amine, and a chiral phosphoric acid, an enantioselective α-allylation of aldehydes with α-alkenes is established. The combination of chiral phosphoric acid and a palladium complex of a chiral phosphoramidite ligand allows the allylic C–H alkylation of α-alkenes with pyrazol-5-ones to give excellent enantioselectivities, wherein the chiral ligand and chiral phosphoric acid synergistically control the stereoselectivity. Notably, the palladium–phosphoramidite complexes are also efficient catalysts for allylic C–H alkylation, with a wide scope of nucleophiles. In the case of 1,4-dienes, the geometry and coordination pattern of the nucleophile are able to vary the transition states of bond-forming events and thereby determine the Z/E-, regio-, and stereoselectivities. These enantioselective allylic C–H functionalization reactions are tolerant of a wide range of nucleophiles and α-alkenes, providing a large library of optically active building blocks. Based on enantioselective intramolecular allylic C–H oxidation, the formal synthesis of (+)-diversonol is accomplished, and enantioselective intramolecular allylic C–H amination can enable concise access to letermovir. In particular, the asymmetric allylic C–H alkylation of 1,4-dienes with azlactones offers highly enantioenriched α,α-disubstituted α-amino acid derivatives that are capable of serving as key building blocks for the enantioselective synthesis of lepadiformine alkaloids. In addition, a tachykinin receptor antagonist and (−)-tanikolide are also synthesized with chiral molecules generated from the corresponding allylic C–H alkylation reactions.
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The present work demonstrates a CuCl and anionic chiral cobalt(III)‐catalyzed enantioselective ring‐opening reaction. The small‐size, ligand‐free copper species enabled the cross‐coupling of iodonium ...salts with a series of bulky aromatic amines in high ee values. The chiral cobalt(III) anion causes appreciable chemical shift changes of cyclic diaryliodoniums in 1H NMR spectra.
A CuCl and anionic chiral cobalt(III) complex co‐catalyzed asymmetric ring‐opening reaction of cyclic diaryliodonium salts was realized. The chiral anion catalysis gave a small size catalytic active copper species, which enabled the cross‐coupling of very bulky aromatic amines.
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As a special family of cyclopropanes, alkylidenecyclopropanes (ACPs), exhibit outstanding physical and chemical activities, which provide opportunities to participate in fascinating chemical ...transformations to access cyclopropane‐containing units without ring‐opening processes and other unavailable compounds through conventional routes with ring‐opening processes owing to their strain‐driven reactivity and synthetic accessibility. Nowadays, intramolecular reactions of methylenecyclopropanes (MCPs) or ACPs with adjacent functionalities have emerged as a powerful synthetic protocol for the construction of a variety of polycyclic and heterocyclic compounds with different sized skeletons through catalytic methods. Recently, we put forward the concept of functional alkylidenecyclopropanes (FACPs) and in this Minireview, we will summarize the reactions of FACPs after 2016 including several important early works from three aspects: 1) reactions with distal C−C bond cleavage, 2) reactions with proximal C−C bond cleavage (including ring‐expansion reactions), and 3) reactions without C−C bond cleavage.
Polycycles: During the past few years, functionalized alkylidenecyclopropanes (FACPs) have been widely used for molecular complexity. This Minireview mainly focuses on the advances of this area after 2016 classified by C−C bond cleavage (see scheme).
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Optically pure nitrogenous compounds, and especially nitrogen-containing heterocycles, have drawn intense research attention because of their frequent isolation as natural products. These compounds ...have wide-ranging biological and pharmaceutical activities, offering potential as new drug candidates. Among the various synthetic approaches to nitrogenous heterocycles, the use of asymmetric multicomponent reactions (MCRs) catalyzed by chiral phosphoric acids has recently emerged as a particularly robust tool. This method combines the prominent merits of MCRs with organocatalysis, thus affording enantio-enriched nitrogenous heterocyclic compounds with excellent enantioselectivity, atom economy, bond-forming efficiency, structural diversity, and complexity. In this Account, we discuss a variety of asymmetric MCRs catalyzed by chiral phosphoric acids that lead to the production of structurally diverse nitrogenous heterocycles. In MCRs, three or more reagents are combined simultaneously to produce a single product containing structural contributions from all the components. These one-pot processes are especially useful in the construction of heterocyclic cores: they can provide a high degree of both complexity and diversity for a targeted set of scaffolds while minimizing the number of synthetic operations. Unfortunately, enantioselective MCRs have thus far been relatively underdeveloped. Particularly lacking are reactions that proceed through imine intermediates, which are formed from the condensation of carbonyls and amines. The concomitant generation of water in the condensation reaction can deactivate some Lewis acid catalysts, resulting in premature termination of the reaction. Thus, chiral catalysts typically must be compatible with water for MCRs to generate nitrogenous compounds. Recently, organocatalytic MCRs have proven valuable in this respect. Brønsted acids, an important class of organocatalysts, are highly compatible with water and thereby offer great potential as chiral catalysts for multicomponent protocols that unavoidably release water molecules during the course of the reaction. We present a detailed investigation of several MCRs catalyzed by chiral phosphoric acids, including Biginelli and Biginelli-like reactions; 1,3-dipolar cycloadditions; aza Diels–Alder reactions; and some other cyclization reactions. These approaches have enabled the facile preparation of 3,4-dihydropyrimidinones, pyrrolidines, piperidines, and dihydropyridines with high optical purity. The synthetic applications of these new protocols are also discussed, together with theoretical studies of the reaction transition states that address the regio- and stereochemistry. In addition, we briefly illustrate the application of a recently developed strategy that involves relay catalysis by a binary system consisting of a chiral phosphoric acid and a metal complex. This technique has provided access to new reactions that generate structurally diverse and complex heterocycles. Enantioselective organocatalytic MCRs remain a challenge, but we illustrate success on several fronts with chiral phosphoric acids as the primary catalysts. Further progress will undoubtedly provide even better access to the chiral nitrogen-containing heterocycles that are not only prevalent as natural products but also serve as key chiral building blocks in organic synthesis.
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An asymmetric catalytic decarboxylative 4+2 annulation of 4‐ethynyl dihydrobenzooxazinones and carboxylic acids has been established by cooperative copper and nucleophilic Lewis base catalysis. A C1 ...ammonium enolate and copper–allenylidene complex, each catalytically generated from different substrates, underwent a cascade asymmetric propargylation and lactamization process to yield optically active 3,4‐dihydroquinolin‐2‐one derivatives with excellent levels of stereoselectivity (up to 99 % ee, 95:5 d.r.).
A team effort: An asymmetric 4+2 annulation of C1 ammonium enolates with copper–allenylidenes catalytically generated from carboxylic acids and 4‐ethynyl dihydrobenzooxazinones, respectively, led to optically active 3,4‐dihydroquinolin‐2‐one derivatives with excellent levels of stereoselectivity.
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A hybrid palladium catalyst assembled from a chiral phosphoric acid (CPA) and thioamide enables a highly efficient and enantioselective β‐C(sp3)−H functionalization of thioamides (up to 99 % yield, ...97 % ee). A kinetic resolution of unsymmetrical thioamides by intermolecular C(sp3)−H arylation can be achieved with high s‐factors. Mechanistic investigations have revealed that stereocontrol is achieved by embedding the substrate in a robust chiral cavity defined by the bulky CPA and a neutral thioamide ligand.
Bulk up: A Pd‐catalyzed enantioselective β‐C(sp3)−H functionalization of thioamides has been developed using a chiral phosphoric acid (CPA) as the chiral auxiliary. Mass spectrometry studies and DFT analysis elucidate the role of the bulky CPA and the assistance of the thioamide ligand, which define a robust chiral cavity for achieving a high level of stereocontrol.
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Since its advent two decades ago, asymmetric organo/transition-metal combined catalysis (AOMC), including cooperative catalysis and relay catalysis, has leveraged redistribution of chemical bonds to ...build up molecular complexity and enantio-differentiation to form individual enantiomers with activations from versatile organocatalysts and transition-metal complexes. The goal of this perspective is to provide readers with the fundamental attributes of AOMCorthogonality, kinetics, mechanism, and selectivityto understand how an organocatalyst and a transition-metal complex would collaborate to enable fruitful new reaction development and what are the intrinsic pathways of unproductive events, such as catalyst self-quenching. In closing, future opportunities of AOMC have been directed toward the prediction of effective catalyst combination, introducing enzyme catalysis, and a focus on transient radical intermediate, to animate this area in the years to come.
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Dysregulated prefrontal control over amygdala is engaged in the pathogenesis of psychiatric diseases including depression and anxiety disorders. Here we show that, in a rodent anxiety model induced ...by chronic restraint stress (CRS), the dysregulation occurs in basolateral amygdala projection neurons receiving mono-directional inputs from dorsomedial prefrontal cortex (dmPFC→BLA PNs) rather than those reciprocally connected with dmPFC (dmPFC↔BLA PNs). Specifically, CRS shifts the dmPFC-driven excitatory-inhibitory balance towards excitation in the former, but not latter population. Such specificity is preferential to connections made by dmPFC, caused by enhanced presynaptic glutamate release, and highly correlated with the increased anxiety-like behavior in stressed mice. Importantly, low-frequency optogenetic stimulation of dmPFC afferents in BLA normalizes the enhanced prefrontal glutamate release onto dmPFC→BLA PNs and lastingly attenuates CRS-induced increase of anxiety-like behavior. Our findings thus reveal a target cell-based dysregulation of mPFC-to-amygdala transmission for stress-induced anxiety.
Catalytic kinetic resolution (KR) and dynamic kinetic asymmetric transformation (DyKAT) are alternative and complementary avenues to access chiral stereoisomers of both starting materials and ...reaction products. The development of highly efficient chiral catalytic systems for kinetically controlled processes has therefore been one of the linchpins in asymmetric synthesis. N‐heterocyclic carbene (NHC)/copper cooperative catalysis has enabled highly efficient KR and DyKAT of racemic N‐tosylaziridines by 3+3 annulation with isatin‐derived enals, leading to highly enantioenriched N‐tosylaziridine derivatives (up to >99 % ee) and a large library of spirooxindole derivatives with high structural diversity and stereoselectivity (up to >95:5 d.r., >99 % ee). Mechanistic studies suggest that the NHC can bind reversibly to the copper catalyst without compromising its catalytic activity and regulate the catalytic activity of the copper complex to switch the chemoselection between KR and DyKAT.
Highly efficient kinetic resolution and dynamic kinetic asymmetric transformation of racemic N‐tosylaziridines with isatin‐derived enals have been achieved by the cooperative catalysis of chiral N‐heterocyclic carbene (NHC) and copper complexes, leading to highly enantioenriched N‐tosylaziridines and spirooxindole derivatives with high structural diversity.
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