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.
A palladium‐catalyzed asymmetric intramolecular allylic C−H amination controlled by a chiral phosphoramidite ligand was established for the preparation of various substituted chiral ...hydropyrimidinones, the precursors of hydropyrimidines, in high yields with high enantioselectivities. In particular, dienyl sodium N‐sulfonyl amides bearing an arylethene‐1‐sulfonyl group underwent a sequential allylic C−H amination and intramolecular Diels–Alder (IMDA) reaction to produce chiral fused tricyclic tetrahydropyrimidinone frameworks in high yields and with high levels of stereoselectivity. Significantly, this method was used as the key step in an asymmetric synthesis of letermovir.
Getting to the core of it: An asymmetric palladium‐catalyzed intramolecular allylic C−H amination controlled by a chiral phosphoramidite ligand was used to provide efficient access various substituted chiral hydropyrimidines. This methodology was successfully applied to the asymmetric synthesis of letermovir (see scheme; IMDA=intramolecular Diels–Alder reaction).
Allylamines are important building blocks in the synthesis of bioactive compounds. The direct coupling of allylic C−H bonds and commonly available amines is a major synthetic challenge. An allylic ...C−H amination of 1,4‐dienes has been accomplished by palladium catalysis. With aromatic amines, branch‐selective 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.
A Pd‐catalyzed branch‐ and Z‐selective allylic C−H amination from 1,4‐dienes and aromatic amines has been established for the efficient synthesis of thermodynamically unstable Z‐allylamines. In addition, more basic aliphatic cyclic amines also smoothly engage in the allylic C−H amination reaction without any Lewis acid additive, preferentially giving linear‐selective allylamines as the major regioisomers.
Branched selectivity in asymmetric allylic C−H alkylation is enabled by using 2‐acylimidazoles as nucleophiles in the presence of a chiral phosphoramidite‐palladium catalyst. A wide range of terminal ...alkenes, including 1,4‐dienes and allylarenes, are nicely tolerated and provide chiral 2‐acylimidazoles in moderate to high yields and with high levels of regio‐, and enantio‐, and E/Z‐selectivities. Mechanistic studies using density‐functional theory calculations suggest a nucleophile‐coordination‐enabled inner‐sphere attack mode for the enantioselective carbon–carbon bond‐forming event.
Branching out: Palladium‐chiral phosphoramidite catalysis is used for an unprecedented branched‐selective asymmetric allylic C−H alkylation by using 2‐acylimidazoles as model coordinating nucleophiles. Density‐functional theory calculations suggest an unusual inner‐sphere mechanism for the carbon–carbon bond‐forming process.
A light-mediated asymmetric dicarbofunctionalization of enamides with carboxylic-acid-derived redox-active esters (RAEs) and indoles has been established by using chiral lithium phosphate catalysis ...in the presence or absence of photoredox catalyst. This reaction features mild reaction conditions and broad substrate scopes, delivering a wide range of highly functionalized chiral amine derivatives. Mechanistic studies suggest that chiral lithium phosphate can serve as a pocket to accelerate the aggregation of enamide and RAE through hydrogen-bonding and coordination interaction, enabling the formation of a charge-transfer complex (CTC). Either enamide or CTC can be excited by direct irradiation or Ru(II)-mediated photosensitization to furnish chiral iminium intermediates for the asymmetric Friedel–Crafts reaction of indole.
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,α-disubstituted 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 CH 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 CH/CH coupling reactions.
Go with the combo: The title reaction is realized by combining asymmetric counteranion catalysis and palladium‐catalyzed allylic CH activation. This method tolerates 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.
Enantioconvergent catalysis enables the conversion of racemic molecules into a single enantiomer in perfect yield and is considered an ideal approach for asymmetric synthesis. Despite remarkable ...advances in this field, enantioconvergent transformations of inert tertiary C−H bonds remain largely unexplored due to the high bond dissociation energy and the surrounding steric repulsion that pose unparalleled constraints on bond cleavage and formation. Here, we report an enantioconvergent Pd‐catalyzed alkylation of racemic tertiary allylic C−H bonds of α‐alkenes, providing a unique approach to access a broad range of enantioenriched γ,δ‐unsaturated carbonyl compounds featuring quaternary carbon stereocenters. Mechanistic studies reveal that a stereoablative event occurs through the rate‐limiting cleavage of tertiary allylic C−H bonds to generate σ‐allyl‐Pd species, and the achieved E/Z‐selectivity of σ‐allyl‐Pd species effectively regulates the diastereoselectivity via a nucleophile coordination‐enabled SN2′‐allylation pathway.
A Pd‐chiral phosphoramidite‐catalyzed intermolecular enantioconvergent alkylation of racemic tertiary allylic C−H bonds provides facile access to a range of enantioenriched allylic compounds featuring quaternary carbon stereocenters. The deracemization has been accomplished through a rate‐limiting cleavage of racemic tertiary allylic C−H bonds to generate σ‐allyl‐Pd species, and the obtained E/Z‐selectivity of σ‐allyl‐Pd species markedly regulates the diastereoselectivity via a nucleophile coordination‐enabled SN2′‐allylation pathway.
Comprehensive Summary
Pd‐catalyzed asymmetric allylic C—H functionalization has emerged as a powerful tool to access chiral, densely functionalized molecules from easily accessible alkenes, enabling ...the increase of the step‐ or atom‐economy by minimizing functional group manipulations for preparing allylating reagents. Due to the inadequacy of stereoselection strategies, the asymmetric allylic C—H functionalization is still in the early stage. In this essay, we will describe our journey to identification of asymmetric catalytic systems, mechanism of allylic C—H activation, control of stereo‐ and regioselectivity, and applications in asymmetric synthesis.
What is the most favorite and original chemistry developed in your research group?
The establishment of asymmetric organo/transition‐metal cooperative catalysis to enable enantioselective reactions.
How do you get into this specific field? Could you please share some experiences with our readers?
We initially attempted to expand the chiral enamine/Pd cooperative catalysis to create asymmetric allylic C—H alkylation of α‐olefins. Although this idea turned out to be unsuccessful, we finally accomplished an asymmetric allylic C—H alkylation of allylarenes enabled by cooperative catalysis of achiral amine, chiral phosphoric acid and palladium, marking a starting point to deeply get involved in this field.
How do you supervise your students?
I am basically strict with students in regulation and technique, but respect them very much. They are always my co‐workers and have equal authority in chemistry if they like.
What is the most important personality for scientific research?
Hardworking and critical thinking always pay off. What are your hobbies? What's your favorite book(s)?
I have ever enjoyed learning martial arts and playing basketball, but now enjoy reading history books.
Who influences you mostly in your life?
So many people influence me so much in my life, it's really hard to say who mostly does. I heard the story of Hua Loo‐Keng (Hua Luo‐Geng), an eminent mathematician, in my childhood and his legend always motivates me to keep working hard.
What is your favorite journal(s)?
So many journals I keep reading every day, if I have to say, J. Am. Chem. Soc. may be my favorite, because it publishes, so far, my most representative work. Of course, Chin. J. Chem. is among the favorite journals.
Could you please give us some advices on improving Chinese Journal of Chemistry?
Keep disseminating the journal in international community and improve the diversity in authorship and contents to make it really international.
This essay presents recent advances in Pd‐catalyzed asymmetric allylic C—H functionalization in our lab, including the development of asymmetric catalytic systems, the mechanism of allylic C—H activation and the control of stereo‐ and regioselectivity. A diverse range of α‐alkenes have been active allylic reagents to engage in the reactions to access synthetically useful building blocks, enabling the asymmetric synthesis of a range of natural products and biologically molecules.
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.
