An enantioselective intramolecular allylic C-H oxidation to generate optically active chromans has been accomplished under the cooperative catalysis of a palladium complex of chiral phosphoramidite ligand and 2-fluorobenzoic acid. Mechanistic studies suggest that this reaction commences with a Pd-catalyzed allylic C-H activation event and then undergoes asymmetric allylic alkoxylation. The synthetic significance of the method has been embodied by concisely building up a key chiral intermediate to access (+)-diversonol.

The asymmetric allylic alkylation (AAA), which features employing active allylic substrates, has historical significance in organic synthesis. The allylic C−H alkylation is principally more atom-and step-economic than the classical allylic functionalizations and thus can be considered a transformative variant. However, asymmetric allylic C−H alkylation reactions are still scarce and yet underdeveloped. Herein, we have found that Z/E-and regioselectivities in the Pd-catalyzed asymmetric allylic C−H alkylation of 1,4-dienes are highly dependent on the type of nucleophiles. A highly stereoselective allylic C−H alkylation of 1,4-dienes with azlactones has been established by palladium-chiral phosphoramidite catalysis. The protocol proceeds under mild conditions and can accommodate a wide scope of substrates, delivering structurally divergent α,αdisubstituted α-amino acid surrogates in high yields and excellent levels of diastereo-, Z/E-, regio-, and enantioselectivities. Notably, this method provides key chiral intermediates for an efficient synthesis of lepadiformine marine alkaloids. Experimental and computational studies on the reaction mechanism suggest a novel concerted proton and two-electron transfer process for the allylic C−H cleavage and reveal that the Z/E-and regioselectivities are governed by the geometry and coordination pattern of nucleophiles.

The first enantioselective α-allylation of aldehydes with terminal alkenes has been realized by combining asymmetric counteranion catalysis and palladium-catalyzed allylic C-H activation. This method can tolerate a wide scope of α-branched aromatic aldehydes and terminal alkenes, thus affording allylation products in high yields and with good to excellent levels of enantioselectivity. Importantly, the findings suggest a new strategy for the future creation of enantioselective C-H/C-H coupling reactions.

A highly enantioselective allylic C-H alkylation reaction of allylarenes with pyrazol-5-ones has been established by the cooperative catalysis of a chiral palladium complex and chiral Brønsted acid to afford a wide spectrum of functionalized chiral N-heterocycles with an all-carbon quaternary stereogenic center in high yields and with high levels of enantioselectivity (up to 96% ee), wherein the chiral ligand and phosphoric acid showed synergistic effect on the control of stereoselectivity. In addition, a palladium-catalyzed asymmetric allylic C-H alkylation of 1,4-pentadienes with pyrazol-5-ones has been realized to furnish highly functionalized pyrazol-5-ones in high enantioselectivities. In this case, the chiral ligand controls the stereoselectivity while the achiral Bronsted acid, 2-fluorobenzoic acid, turns out to be a better cocatalyst than the chiral phosphoric acid. The installation of electron-deficient substituents at 3,3'-positions of binaphthyl backbone of chiral phosphoramidites is actually beneficial to the allylic C-H oxidation due to their survival in the presence of quinone derivative oxidants. These allylic C-H alkylation reactions undergo smoothly under mild conditions and tolerate a wide range of substrates. The resultant highly functionalized chiral pyrazol-5-ones have been applied to the preparation of more structurally diverse heterocycles by classical transformations.

Metrics & MoreArticle Recommendations 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 Pdcatalyzed 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 Pdcatalyzed 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 bondforming 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,αdisubstituted 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.

Allylamines are important building blocks in the synthesis of bioactive compounds. The direct coupling of allylic CÀ H bonds and commonly available amines is a major synthetic challenge. An allylic CÀ H amination of 1,4-dienes has been accomplished by palladium catalysis. With aromatic amines, branchselective allylic aminations are favored to generate thermodynamically unstable Z-allylamines. In addition, more basic aliphatic cyclic amines can also engage in the reaction, but linear dienyl allylic amines are the major products.

The hybrid Au(I)/Brønsted acid binary catalyst system enables enynes to serve as latent 1,3-silyloxydienes capable of participating in the first cascade hydrosiloxylation of an enynyl silanol/asymmetric Diels-Alder reaction. A variety of polycyclic compounds bearing multistereogenic centers were obtained in high yields and excellent enantioselectivities from the relay catalytic cascade reaction between (2-(but-3-en-1-ynyl)phenyl) silanols and quinones catalyzed by the combined achiral gold complex and chiral N-triflyl phosphoramide.

A palladium-catalyzed, enantioselective allylic C-H alkylation of 1,4-pentadienes with 5 H-thiazol-4-ones has been developed. Under the cooperative catalysis of a palladium complex of chiral phosphoramidite ligand and an achiral Brønsted acid, a broad range of substituted 5 H-thiazol-4-ones bearing sulfur-containing tertiary chiral centers were accessed from the allylic C-H alkylation in high levels of yields and enantioselectivities. Alkyl and aryl 1,4-pentadienes led to linear and branched allylation products, respectively.