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Asymmetric organocatalysis involving double activation

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    1 Equally contributed to this work.
    Zhi Chen
    Footnotes
    1 Equally contributed to this work.
    Affiliations
    Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
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  • Author Footnotes
    1 Equally contributed to this work.
    Qian-Qian Yang
    Footnotes
    1 Equally contributed to this work.
    Affiliations
    State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
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  • Wei Du
    Correspondence
    Corresponding author.
    Affiliations
    Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
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  • Ying-Chun Chen
    Correspondence
    Corresponding author.
    Affiliations
    Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
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Open AccessPublished:May 26, 2022DOI:https://doi.org/10.1016/j.tchem.2022.100017

      Abstract

      Asymmetric organocatalysis contributed tremendously to the field of organic synthesis since year 2000. Considering the diversity of organocatalysts and their activation modes, chemists developed the double activation strategy, in which two distinct catalysts simultaneously interact with a single substrate, thus enabling effective transformations that might be too challenging or even unattainable under a sole catalytic system. This review summarized the asymmetric reactions via double activation catalysis involving different Lewis bases (aminocatalysts, N-heterocyclic carbenes, isothioureas, N,N-dimethyl-4-aminopyridine, tertiary amines/phosphines, or even thiols), Brønsted bases (including phase transfer catalysts), Brønsted acids, and a few examples combining organocatalysts and metal catalysts or photocatalysts were also discussed. In most cases, compared to those with a single catalyst, better reactivity and stereoselectivity, or even completely different regioselectivity or chemoselectivity were observed under double activation catalysis, demonstrating the power and superiority of this promising strategy. Some key intermediates as well as the mechanisms have been presented to provide insights into the activation processes, which might inspire the development of new double activation systems and more interesting work in the future.

      Graphical abstract

      Keywords

      1. Introduction

      Asymmetric organocatalysis, typically featuring low cost, air/water stability, availability from renewable resources, and environmentally friendliness, represents one of the most powerful strategies for the construction of enantioenriched substances [
      • Houk K.N.
      • List B.
      Asymmetric organocatalysis.
      ,
      • MacMillan D.W.C.
      The advent and development of organocatalysis.
      ,
      • Seayad J.
      • List B.
      ]. It has received extensive interest since year 2000, and two important pioneers in this field, Benjamin List and David MacMillan, were awarded the Nobel Prize in Chemistry in 2021. Within several different types of organocatalysts in the magic toolbox, mainly consisting of Lewis bases [
      • Vedejs E.
      • Denmark S.E.
      Lewis Base Catalysis in Organic Synthesis.
      ,
      • Denmark S.E.
      • Beutner G.L.
      Lewis base catalysis in organic synthesis.
      ], Brønsted acids [
      • Rueping M.
      • Kuenkel A.
      • Atodiresei I.
      Chiral Brønsted acids in enantioselective carbonyl activations-activation modes and applications.
      ,
      • Akiyama T.
      • Itoh J.
      • Fuchibe K.
      Recent progress in chiral Brønsted acid catalysis.
      ], Brønsted bases [
      • Palomo C.
      • Oiarbide M.
      • López R.
      Asymmetric organocatalysis by chiral Brønsted bases: implications and applications.
      ,
      • Ting A.
      • Goss J.M.
      • McDougal N.T.
      • Schaus S.E.
      Brønsted Base Catalysts.
      ] (including phase transfer catalysts) [
      • Maruoka K.
      Practical aspects of recent asymmetric phase-transfer catalysis.
      ,
      • Shirakawa S.
      • Maruoka K.
      Recent developments in asymmetric phase-transfer reactions.
      ], great development and breakthrough have been achieved over the past two decades, providing efficient access towards a variety of chiral compounds with broad structural and functional diversity, even for the construction of natural products, bioactive and pharmaceutical substances.
      Furthermore, multi-catalytic systems, in which two (or more) catalysts work cooperatively in a reaction through diverse activation modes, can facilitate many difficult or even unattainable transformations with a sole catalyst [
      • Wende R.C.
      • Schreiner P.R.
      Evolution of asymmetric organocatalysis: multi- and retrocatalysis.
      ,
      • Allen A.E.
      • MacMillan D.W.C.
      Synergistic catalysis: a powerful synthetic strategy for new reaction development.
      ,
      • Zhou J.
      Multicatalyst System in Asymmetric Catalysis.
      ]. Based on the activation models, there are several different types of multi-catalytic systems. The “relay catalysis” is a one-pot cascade process in which individual reactions are independently promoted by distinct catalysts (Scheme 1A) [
      • Wang P.-S.
      • Chen D.-F.
      • Gong L.-Z.
      Recent progress in asymmetric relay catalysis of metal complex with chiral phosphoric acid.
      ]. The “cooperative catalysis”, also named as “synergistic catalysis”, in which both substrates are simultaneously activated by different catalysts (Scheme 1B), has been well-documented in several reviews [
      • Afewerki S.
      • Córdova A.
      Combinations of aminocatalysts and metal catalysts: a powerful cooperative approach in selective organic synthesis.
      ,
      • Peters R.
      Cooperative Catalysis: Designing Efficient Catalysts for Synthesis.
      ,
      • Inamdar S.M.
      • Shinde V.S.
      • Patil N.T.
      Enantioselective cooperative catalysis.
      ]. In the “assisted catalysis” model, one catalyst severs as an activator for another catalyst to significantly enhance the reactivity and/or stereoselectivity, rather than interacting with any substrates (Scheme 1C) [
      • Wang H.-Y.
      • Zheng C.-W.
      • Chai Z.
      • Zhang J.-X.
      • Zhao G.
      Asymmetric cyanation of imines via dipeptide-derived organophosphine dual-reagent catalysis.
      ,
      • Lin S.
      • Jacobsen E.N.
      Thiourea-catalysed ring opening of episulfonium ions with indole derivatives by means of stabilizing non-covalent interactions.
      ]. In this review, we focus on the development of a unique model, “double activation catalysis”, defined as two distinct catalysts working together to activate a single substrate (Scheme 1D), especially for asymmetric reactions with organocatalysis. The contents will be chaptered based on different catalytic systems via the double activation strategy, involving different Lewis bases (aminocatalysts, N-heterocyclic carbenes, isothioureas, N,N-dimethyl-4-aminopyridine, tertiary amines/phosphines, or even thiols), and Brønsted acids. Some studies combining organocatalysts and metal catalysts or photocatalysts also will be discussed. The key intermediates and reaction pathways will be detailed for some cases, trying to provide insights into the relevant activation modes.
      Scheme 1
      Scheme 1Typical models of multi-catalytic systems.

      2. Double activation catalysis involving aminocatalysts

      Chiral Lewis bases, holding lone electron pairs, can attack the substrates with a suitable electrophilic group covalently, thus increasing either the nucleophilicity or electrophilicity of the resultant intermediates. The diversity as well as easy structural modifications of Lewis base catalysts (typically aminocatalysts, N-heterocyclic carbenes, isothioureas, tertiary amines/phosphines) renders fruitful achievements in organic synthesis. Moreover, higher reactivity, better selectivity and even some challenging transformations have been realized through double activation combining Lewis bases and other catalysts.
      Primary and secondary amines can activate aldehydes/ketones by increasing the HOMO (Highest Occupied Molecular Orbital) energy or decreasing the LUMO (Lowest Occupied Molecular Orbital) energy via the formation of enamine or iminium ion intermediates, respectively [
      • Melchiorre P.
      • Marigo M.
      • Carlone A.
      • Bartoli G.
      Asymmetric aminocatalysis—gold rush in organic chemistry.
      ,
      • Mukherjee S.
      • Yang J.W.
      • Hoffmann S.
      • List B.
      Asymmetric enamine catalysis.
      ,
      • Erkkilä A.
      • Majander I.
      • Pihko P.M.
      Iminium catalysis.
      ]. In addition, acidic additives are usually required, as they can enhance the electrophilicity of the carbonyl substrates via H-bonding interaction for the subsequent attack by amine catalysts [
      • Hong L.
      • Sun W.
      • Yang D.
      • Li G.
      • Wang R.
      Additive effects on asymmetric catalysis.
      ]. In addition, for the reactions via iminium ion catalysis, both amine catalysts and acidic additives work concertedly on the unsaturated carbonyl substrates to form chiral iminium ion pairs, which would react with suitable nucleophiles (Scheme 2).
      Scheme 2
      Scheme 2Iminium ion catalysis in the presence of amines and acids.
      Based on the classic activation mode of iminium ion catalysis, the Xu group [
      • Wang Y.
      • Yu T.-Y.
      • Zhang H.-B.
      • Luo Y.-C.
      • Xu P.-F.
      Hydrogen-bond-mediated supramolecular iminium ion catalysis.
      ,
      • Gu Y.
      • Wang Y.
      • Yu T.-Y.
      • Liang Y.-M.
      • Xu P.-F.
      Rationally designed multifunctional supramolecular iminium catalysis: direct binylogous Michael addition of unmodified linear dienol substrates.
      ] established a strategy of supramolecular iminium ion catalysis, in which a thiourea was employed as an additional H-bonding donor to separate the iminium ion pair to some extent through interaction with the counteranion. As a result, the supramolecular iminium ion from unsaturated aldehyde 1 and assembly C2 exhibited better reactivity compared to that of traditional amine salt C1. Higher efficacy was similarly observed in the Friedel−Crafts reaction of cinnamaldehyde 3 and indole 4 catalyzed by assembly C3 (Scheme 3).
      Scheme 3
      Scheme 3Examples via supramolecular iminium ion catalysis.
      Beside of iminium ion catalysis, acid additives could work with enamine intermediates in a double activation system. The Huang group [
      • Li L.
      • Chen B.
      • Chen J.
      • Huang Y.
      Enantioselective intramolecular [2,3]-sigmatropic rearrangement of aldehydes via a sulfonium enamine intermediate.
      ] reported an enantioselective organocatalytic [
      • MacMillan D.W.C.
      The advent and development of organocatalysis.
      ,
      • Seayad J.
      • List B.
      ]-sigmatropic rearrangement reaction of sulfur-containing aldehydes 6, which underwent halogenation in the presence of N-iodosuccinimide (NIS) followed by a substitution reaction, finally furnishing chiral sulfur-heterocycles 7 bearing a tetrasubstituted stereogenic center with high optical purity after a sigmatropic rearrangement process (Scheme 4). Interestingly, the protocol was not only compatible with the substrates bearing an allyl group, but also for those with an alkynyl or allenyl moiety, affording the products with an allene or diene motif, respectively.
      Scheme 4
      Scheme 4Chiral amine/CPA catalyzed enantioselective [
      • MacMillan D.W.C.
      The advent and development of organocatalysis.
      ,
      • Seayad J.
      • List B.
      ]-sigmatropic rearrangement.

      3. Double activation catalysis involving N-heterocyclic carbenes (NHCs)

      N-Heterocyclic carbenes are well-known for their application in umpolung reactions by generating the Breslow intermediates with aldehydes [
      • Chen X.
      • Wang H.
      • Jin Z.
      • Chi Y.R.
      N-heterocyclic carbene organocatalysis: activation modes and typical reactive intermediates.
      ,
      • Flanigan D.M.
      • Romanov-Michailidis F.
      • White N.A.
      • Rovis T.
      Organocatalytic reactions enabled by N-heterocyclic carbenes.
      ]. In spite of the intrinsic Brønsted basicity of NHCs, they could coexist with Brønsted acids with retained reactivity. Based on this characteristic, the catalytic system of NHC/Brønsted acid has been developed for asymmetric transformations of carbonyl compounds [
      • Wang M.H.
      • Scheidt K.A.
      Cooperative catalysis and activation with N-heterocyclic carbenes.
      ].
      A pioneering work on the asymmetric [4 ​+ ​2] annulations between chalcones 8 and enals 9 via double activation of NHC and Brønsted acid was reported by Chi (Scheme 5) [
      • Fu Z.
      • Sun H.
      • Chen S.
      • Tiwari B.
      • Li G.
      • Robin Chi Y.
      Controlled β-protonation and [4+2] cycloaddition of enals and chalcones via N-heterocyclic carbene/acid catalysis: toward substrate independent reaction control.
      ]. The homoenolates generated from enals 9 and C6 could undergo annulations with chalcones 8 to give cyclopentenes 10 after the release of CO2. However, when HOAc was added as a co-catalyst, the homoenolates were protonated first, and the resultant enolates participated in [4 ​+ ​2] annulations with the identical chalcones in high selectivity. A similar double activation system was applied to another asymmetric [4 ​+ ​2] annulation reaction of cinnamaldehydes with imidazolidinones via β-protonation, providing a distinct approach to potentially bioactive imidazoles with high levels of stereoselectivity [
      • McCusker E.O.B.
      • Scheidt K.A.
      Enantioselective N-heterocyclic carbene catalyzed annulation reactions with imidazolidinones.
      ].
      Scheme 5
      Scheme 5Switchable annulations via double NHC/Brønsted acid catalysis.
      Beside of the direct β-protonation pathway, the carboxylic acids could serve as H-bonding donors in the double activation system with NHC catalysis. The Glorius group [
      • Li J.-L.
      • Sahoo B.
      • Daniliuc C.-G.
      • Glorius F.
      Conjugate umpolung of β,β-disubstituted enals by dual catalysis with an N-heterocyclic carbene and a Brønsted acid: facile construction of contiguous quaternary stereocenters.
      ] reported an efficient stereoselective [3 ​+ ​2] annulation reaction of isatin 12a and β,β-disubstituted enal 13a catalyzed by NHC C7 and 2-F-BzOH (Scheme 6). Both reactivity and stereoselectivity were highly dependent on the acid co-catalyst, probably because of the double H-bonding interactions of the acid with the Breslow intermediate and isatin 12a. The spirocyclic oxindole 14 bearing vicinal quaternary carbon centers was produced with good enantioselectivity. In addition, similar substrates could undergo an asymmetric [4 ​+ ​2] annulation reaction via NHC/Brønsted acid double activation, by generating the dienolate species after oxidation of the Breslow intermediate [
      • Lin Y.
      • Yang L.
      • Deng Y.
      • Zhong G.
      Cooperative catalysis of N-heterocyclic carbene and Brønsted acid for a highly enantioselective route to unprotected spiro-indoline-pyrans.
      ].
      Scheme 6
      Scheme 6Asymmetric annulation reactions via double NHC/carboxylic acid activation.
      Chiral phosphoric acids (CPAs) are applicable for the double activation with NHC catalysis as well. In 2016, the Rovis group [
      • Chen D.-F.
      • Rovis T.
      N-heterocyclic carbene and chiral Brønsted acid cooperative catalysis for a highly enantioselective [4+2] annulation.
      ] realized a highly enantioselective [4 ​+ ​2] reaction between functionalized benzaldehydes 16 and activated ketones 17 by using the combination of chiral NHC C8 and CPA C9 (Scheme 7). The Breslow intermediate formed in-situ in the presence of C8 extruded a bromide to give a dearomatized dienolate, which might transform to an ion pair with C9 as a chiral counterion, finally affording isochroman derivatives 18 with good to excellent enantioselectivity. Since improved ee values and a matched phenomenon of both catalysts were observed for the double activation system, it was speculated that the chiral ion pair played an important role in the stereocontrol.
      Scheme 7
      Scheme 7Asymmetric [4 ​+ ​2] annulation through double NHC/CPA catalysis.
      More H-bonding donors are compatible in NHC catalysis. In 2015, the Scheidt group [
      • Wang M.H.
      • Cohen D.T.
      • Schwamb C.B.
      • Mishra R.K.
      • Scheidt K.A.
      Enantioselective β-protonation by a cooperative catalysis strategy.
      ] reported a highly enantioselective β-protonation reaction of β,β-disubstituted enals 19, providing an easy access to enantioenriched succinate derivatives 21 (Scheme 8). The initial attempts resulted in moderate enantioselectivity with sole NHC catalysis, while the addition of squaramide C11 significantly enhanced the selectivity. It was proposed that C11 might coordinate to the Breslow intermediate and provide additional steric interaction near the β-position, thus increasing the facial selectivity. Inspired by this work, Huang and Chen employed CPAs as proton-shuttling catalysts in combination with NHC catalysis for asymmetric β-protonation of enals, giving diverse β-functionalized carboxylic derivatives in good to excellent stereoselectivity [
      • Yuan P.
      • Chen J.
      • Zhao J.
      • Huang Y.
      Enantioselective hydroamidation of enals by trapping of a transient acyl species.
      ,
      • Zhang L.
      • Yuan P.
      • Chen J.
      • Huang Y.
      Enantioselective cooperative proton-transfer catalysis using chiral ammonium phosphates.
      ].
      Scheme 8
      Scheme 8Enantioselective β-protonation via double NHC/squaramide catalysis.
      Although the strong donor property of NHCs renders them as good ligands for transition metals, early metals would bind with NHCs loosely and the dissociation would occur easily. Accordingly, fruitful results have been achieved with the double and concerted activation system of NHCs and Lewis acids [
      • Jia Q.
      • Li Y.
      • Lin Y.
      • Ren Q.
      The combination of Lewis acid with N-heterocyclic carbene (NHC) catalysis.
      ]. In 2010, the Scheidt group [
      • Cardinal-David B.
      • Raup D.E.A.
      • Scheidt K.A.
      Cooperative N-heterocyclic carbene/Lewis acid catalysis for highly stereoselective annulation reactions with homoenolates.
      ] reported a pioneering work on an asymmetric [3 ​+ ​2] annulation reaction between chalcones 8 and enals 9 under the catalysis of NHC C12/Ti(Oi-Pr)4, constructing cis-cyclopentenes 10 in moderate to good yields with excellent stereocontrol (Scheme 9). Without the Lewis acid, trans-products were mainly obtained with low diastereoselectivity. In contrast, when Ti(Oi-Pr)4 was added, the diastereoselectivity was switched and cis-products 10 was afforded exclusively. It was proposed that Ti(Oi-Pr)4 was coordinated to enals 9 and facilitated subsequent attack of C12 to the carbonyl group, and the resultant extended Ti-Breslow intermediates were also bound to chalcones 8, thus controlling the diastereoselectivity for the conjugate addition step. The role of Ti(IV) through pre-organizing the spatial alignment of homoenolates and chalcones was confirmed by DFT (density functional theory) studies [
      • Domingo L.R.
      • Zaragozá R.J.
      • Arnó M.
      Understanding the cooperative NHC/LA catalysis for stereoselective annulation reactions with homoenolates. A DFT study.
      ]. Subsequently, the double activation systems combining NHCs and diverse Lewis acids have been extensively utilized in the annulation reactions of enals or ynals, providing efficient access towards enantioenriched cyclic frameworks or even axially chiral architectures [
      • Mo J.
      • Chen X.
      • Chi Y.R.
      Oxidative γ-addition of enals to trifluoromethyl ketones: enantioselectivity control via Lewis acid/N-Heterocyclic carbene cooperative catalysis.
      ,
      • Cohen D.T.
      • Cardinal-David B.
      • Scheidt K.A.
      Lewis acid activated synthesis of highly substituted cyclopentanes by the N-heterocyclic carbene catalyzed addition of homoenolate equivalents to unsaturated ketoesters.
      ,
      • Wu Z.
      • Li F.
      • Wang J.
      Intermolecular dynamic kinetic resolution cooperatively catalyzed by an N-heterocyclic darbene and a Lewis acid.
      ,
      • Zhao C.
      • Guo D.
      • Munkerup K.
      • Huang K.-W.
      • Li F.
      • Wang J.
      Enantioselective [3+3] atroposelective annulation catalyzed by N-heterocyclic carbenes.
      ].
      Scheme 9
      Scheme 9Stereoselective annulations via chiral NHC/Lewis acid catalysis.

      4. Double activation catalysis involving isothioureas

      Chiral isothioureas, as an important class of Lewis base catalysts, have been widely employed as efficient acyl transfer or ammonium enolate-type catalysts for asymmetric transformations of carboxylic acid derivatives [
      • Merad J.
      • Pons J.-M.
      • Chuzel O.
      • Bressy C.
      Enantioselective catalysis by chiral isothioureas.
      ].
      Among different isothioureas, benzotetramisole (BTM), first developed by Birman in 2006 [
      • Birman V.B.
      • Li X.
      Benzotetramisole: a remarkably enantioselective acyl transfer catalyst.
      ], showed prominent activity as well as stereoselectivity for kinetic resolution reactions. It could attack activated carboxylic acid derivatives to afford acyl ammonium intermediates, which could be stabilized by adding suitable acid catalysts to form chiral ion pairs (Scheme 10). Several groups have demonstrated that the in-situ generated chiral ion pairs in a BTM/Brønsted acid double activation system exhibited higher efficacy and even better stereocontrol in asymmetric reactions. Birman [
      • Yang X.
      • Lu G.
      • Birman V.B.
      Benzotetramisole-catalyzed dynamic kinetic resolution of azlactones.
      ,
      • Bumbu V.D.
      • Birman V.B.
      Kinetic resolution of N-acyl-β-lactams via benzotetramisole-catalyzed enantioselective alcoholysis.
      ] utilized a dual catalytic system of BTM and benzoic acid to realize dynamic kinetic resolution of azlactones 22 and kinetic resolution of N-acyl-β-lactams 24 via alcoholysis. The acid might also play an important role in the ring opening process of these carboxylic acid derivatives.
      Scheme 10
      Scheme 10BTM/Brønsted acid catalyzed dynamic kinetic resolution and kinetic resolution.
      A similar catalytic system, combining BTM analogue C13 and diphenyl phosphate, was developed for the asymmetric annulation reaction between bench-stable α,β-unsaturated aryl esters 26 and enamines 27 by the Gong group (Scheme 11) [
      • Zhang Y.-C.
      • Geng R.-L.
      • Song J.
      • Gong L.-Z.
      Isothiourea and Brønsted acid cooperative catalysis: enantioselective construction of dihydropyridinones.
      ]. A key α,β-unsaturated acyl ammonium intermediate was probably involved in the reaction, and the corresponding ion pair with diphenylphosphinate played dual roles in terms of both reactivity and enantioselectivity. A variety of functionalized 3,4-dihydropyridin-2-ones 28 were obtained in high yields with excellent enantioselectivity after a cascade Michael addition/cyclization process.
      Scheme 11
      Scheme 11Asymmetric [3 ​+ ​3] annulations via Brønsted acid/BTM analogue.

      5. Double activation catalysis involving N,N-dimethyl-4-aminopyridine

      Like isothioureas, N,N-dimethyl-4-aminopyridine (DMAP) and its chiral analogues are good acyl transfer catalysts as well [
      • Wurz R.P.
      Chiral dialkylaminopyridine catalysts in asymmetric synthesis.
      ,
      • Mandai H.
      • Fujii K.
      • Suga S.
      Recent topics in enantioselective acyl transfer reactions with dialkylaminopyridine-based nucleophilic catalysts.
      ], and have been applied for the dynamic kinetic resolution reactions by forming similar acyl ammonium ion pairs with acid catalysts [
      • Liang J.
      • Ruble J.C.
      • Fu G.C.
      Dynamic kinetic resolutions catalyzed by a planar-chiral derivative of DMAP: enantioselective synthesis of protected α-amino acids from racemic azlactones.
      ].
      In addition to the ion pair catalysis, anion binding approach represents another promising strategy for the DMAP involved double activation catalysis. The Seidel group utilized chiral thioureas C14 or C15 as H-bonding donors, together with achiral DMAP or its analogue C16, and realized kinetic resolution for benzylic amines 29 [
      • De C.K.
      • Klauber E.G.
      • Seidel D.
      Merging nucleophilic and hydrogen bonding catalysis: an anion binding approach to the kinetic resolution of amines.
      ], propargylic amines 30 [
      • Klauber E.G.
      • De C.K.
      • Shah T.K.
      • Seidel D.
      Merging nucleophilic and hydrogen bonding catalysis: an anion binding approach to the kinetic resolution of propargylic amines.
      ] and allylic amines 31 [
      • Klauber E.G.
      • Mittal N.
      • Shah T.K.
      • Seidel D.
      A dual-catalysis/anion-binding approach to the kinetic resolution of allylic amines.
      ] (Scheme 12). Furthermore, a desymmetrization reaction of meso-1,2-diaryl-1,2-diaminoethanes 32 has been accomplished similarly [
      • De C.K.
      • Seidel D.
      Catalytic enantioselective desymmetrization of meso-diamines: a dual small-molecule catalysis approach.
      ]. In these reactions, benzoic anhydride was used as the electrophile, and it was converted to an acyl pyridinium cation, which was paired with benzoic anion binding to the thiourea in the double activation system.
      Scheme 12
      Scheme 12Kinetic resolution and desymmetrization of various amines via dual activation catalysis of DMAP/thiourea.
      This approach has been applied to other acyl transfer reactions. In 2011, Seidel [
      • De C.K.
      • Mittal N.
      • Seidel D.
      A dual-catalysis approach to the asymmetric steglich rearrangement and catalytic enantioselective addition of o-acylated azlactones to isoquinolines.
      ] reported an asymmetric Steglich rearrangement of O-acylated azlactones 37 under dual catalysis of DMAP and thiourea C17, providing α,α-disubstituted amino acid derivatives 38 in moderate yields with high enantioselectivity (Scheme 13). A key intermediate featuring an N-acylpyridinium cation and an enolate anion coordinated with thiourea C18 via H-bonding interaction was proposed for the high stereocontrol. A highly enantioselective acylation of silyl ketene acetals 39 with acyl fluorides 40 was similarly realized by Jacobsen [
      • Birrell J.A.
      • Desrosiers J.-N.
      • Jacobsen E.N.
      Enantioselective acylation of silyl ketene acetals through fluoride anion-binding catalysis.
      ], with C16 and C18 as the catalysts, furnishing α,α-disubstituted butyrolactone products 41 in good results.
      Scheme 13
      Scheme 13Asymmetric acyl transfer reaction through a DMAP/thiourea mediated anion-binding approach.

      6. Double activation catalysis involving tertiary amines/phosphines

      Tertiary amines and phosphines are good Lewis base catalysts for activating electron-deficient systems, such α,β-unsaturated carbonyls/allenates, thus enabling a variety of classic reactions, including Morita–Baylis–Hillman (MBH) reaction [
      • Wei Y.
      • Shi M.
      Recent advances in organocatalytic asymmetric Morita–Baylis–Hillman/aza-Morita–Baylis–Hillman reactions.
      ], Rauhut–Currier (RC) reaction [
      • Aroyan C.E.
      • Dermenci A.
      • Miller S.J.
      The Rauhut–Currier reaction: a history and its synthetic application.
      ], and Lu's [3 ​+ ​2] cycloaddition reaction [
      • Wei Y.
      • Shi M.
      Lu's [3+2] cycloaddition of allenes with electrophiles: discovery, development and synthetic application.
      ].
      4-Diazabicyclo- [
      • MacMillan D.W.C.
      The advent and development of organocatalysis.
      ,
      • MacMillan D.W.C.
      The advent and development of organocatalysis.
      ,
      • MacMillan D.W.C.
      The advent and development of organocatalysis.
      ]octane (DABCO) features two bridge-headed tertiary amines, showing high nucleophilicity. Its application in asymmetric transformations is limited since it could not induce chiral information itself. Thus chemists developed double activation systems of DABCO with another chiral H-bonding donor as the co-catalyst to enhance the stereoselectivity. These reactions were generally initiated by a conjugate addition of DABCO to an activated alkene, and subsequently the resultant zwitterionic intermediate would be captured and stabilized by a chiral co-catalyst, typically a thiourea/urea, through H-bonding interaction, finally facilitating the attack towards electrophiles under appropriate chiral environments (Scheme 14).
      Scheme 14
      Scheme 14Double activation mode combining DABCO and H-bonding donor.
      In 2004, Nagasawa [
      • Sohtome Y.
      • Tanatani A.
      • Hashimoto Y.
      • Nagasawa K.
      Development of bis-thiourea-type organocatalyst for asymmetric Baylis–Hillman reaction.
      ] reported an enantioselective MBH reaction of aldehydes 42 and 2-cyclohexenone 43 under the catalysis of DABCO and bis(thiourea) catalyst C14, affording chiral allylic alcohols 44 in moderate to good results (Scheme 15). The H-bonding donor not only controlled the stereoselectivity, but also improved the yield significantly. When DABCO was replaced by DMAP, even better results were obtained.
      Scheme 15
      Scheme 15DABCO/chiral thiourea catalyzed enantioselective MBH reaction.
      In addition, a similar asymmetric MBH reaction of 2-cyclohexenone 43 was investigated under the double activation catalytic systems of tertiary phosphines and H-bonding donors. In 2003, Schaus [
      • McDougal N.T.
      • Schaus S.E.
      Asymmetric Morita−Baylis−Hillman reactions catalyzed by chiral Brønsted acids.
      ] employed simple Et3P as the Lewis base catalyst, in combination with (R)-H8-BINOL C19 or C20, providing an efficient access to chiral allylic alcohols ent-44 via the H-bonding donor-bound phosphonium enolate (Scheme 16). Since large amounts of Et3P were used, modifications on both catalysts had been conducted to improve the reactivity and stereocontrol [
      • Garnier J.-M.
      • Anstiss C.
      • Liu F.
      Enantioselective trifunctional organocatalysts for rate- enhanced aza-Morita–Baylis–Hillman reactions at room temperature.
      ,
      • Yang Y.-L.
      • Wei Y.
      • Shi M.
      New multifunctional chiral phosphines and BINOL derivatives co-catalyzed enantioselective aza-Morita–Baylis–Hillman reaction of 5,5-disubstituted cyclopent-2-enone and N-sulfonated imines.
      ,
      • Duan Z.
      • Zhang Z.
      • Qian P.
      • Han J.
      • Pan Y.
      Asymmetric Morita–Baylis–Hillman reaction of isatins with α,β-unsaturated γ-butyrolactam as the nucleophile.
      ].
      Scheme 16
      Scheme 16Tertiary phosphine/chiral diol catalyzed enantioselective MBH reaction.
      Cinchona alkaloids [
      • Song C.E.
      Cinchona Alkaloids in Synthesis and Catalysis: Ligands, Immobilization and Organocatalysis.
      ] bearing a quinuclidine motif are excellent surrogates of DABCO, which are extensively used as chiral Lewis bases for different asymmetric transformations of activated alkenes, allenes, MBH adducts, etc. In 2009, Zhu and co-workers [
      • Abermil N.
      • Masson G.
      • Zhu J.
      Invertible enantioselectivity in 6′-Deoxy-6′-acylamino-β-isocupreidine-catalyzed asymmetric aza-Morita−Baylis−Hillman reaction: key role of achiral additive.
      ] uncovered an asymmetric aza-MBH reaction of N-sulfonylimine 45 with methyl vinyl ketone (MVK) 46 catalyzed by β-isocupreidine (β-ICD) derivative C21, and allylic amine (R)-47 was isolated (Scheme 17). Interestingly, the configuration of the product was reversed by adding 2-naphthol C23 as the co-catalyst, indicating the power of the double activation catalysis. Furthermore, Chen and co-workers [
      • Yao Y.
      • Li J.-L.
      • Zhou Q.-Q.
      • Dong L.
      • Chen Y.-C.
      Enantioselective aza-Morita–Baylis–Hillman reaction with ketimines and acrolein catalyzed by organic assemblies.
      ] developed an aza-MBH reaction between imines of β,γ-unsaturated α-ketoesters 48 and acrolein 49 catalyzed by a combined catalytic system of β-ICD C22 and (S)-BINOL C24, and a self-assembled reaction model among substrates and catalysts were proposed. It is notable that the reaction showed excellent regioselectivity of the 1,2-addition (aza-MBH pathway) to 50 rather than 1,4-addition (RC pathway), thus constructing a series of chiral amino products 50 with dense functionalities with moderate to excellent enantioselectivity.
      Scheme 17
      Scheme 17Tertiary amine/phenol co-catalyzed enantioselective aza-MBH reaction.
      Apart from the catalytic system of Lewis base/H-bonding donor, aminocatalysis could cooperate with Lewis base catalysis for asymmetric MBH reactions. The pioneering work of Shi indicated a double activation catalytic system of (l)-proline and tertiary amine was effective for the MBH reaction, and imidazole gave even better results, but no stereocontrol was achieved [
      • Shi M.
      • Jiang J.-K.
      • Li C.-Q.
      Lewis base and l-proline co-catalyzed Baylis–Hillman reaction of arylaldehydes with methyl vinyl ketone.
      ]. Later, the Miller group [
      • Imbriglio J.E.
      • Vasbinder M.M.
      • Miller S.J.
      Dual catalyst control in the amino acid-peptide-catalyzed enantioselective Baylis−Hillman reaction.
      ] developed an asymmetric MBH reaction between aldehydes 42 and MVK 46 by employing methyl-histidine containing peptide C25 together with (l)-proline as the catalyst (Scheme 18). It was assumed that the high reactivity and better enantioselectivity might result from an enamine tethered imidazolium intermediate. A similar double activation mode was extended to an intramolecular version [
      • Aroyan C.E.
      • Vasbinder M.M.
      • Miller S.J.
      Dual catalyst control in the enantioselective intramolecular Morita−Baylis−Hillman reaction.
      ].
      Scheme 18
      Scheme 18Amine/Lewis base catalyzed enantioselective MBH reaction.
      It should be noted that it is much more challenging for the activation of enals or enones with a β-substitution by traditional Lewis bases, probably due to the steric hindrance. Barbas [
      • Utsumi N.
      • Zhang H.
      • Tanaka F.
      • Barbas III, C.F.
      A way to highly enantiomerically enriched aza-Morita–Baylis–Hillman–type products.
      ] reported an alternative strategy to synthesize formal aza-MBH type products 54 from β-substituted enals 52 and imino ester 53 by using (l)-proline and imidazole (Scheme 19). Different from the above cases, dienamine intermediates were generated in the presence of (l)-proline, followed by a Mannich-type reaction/isomerization sequence with the assistance of imidazole.
      Scheme 19
      Scheme 19Proline/imidazole catalyzed formal aza-MBH reaction of β-substituted enals.
      Although the double activation catalytic systems combining Lewis bases and Brønsted acids have been greatly developed, it should be noticed that the reaction type is mainly limited to asymmetric acyl transfer or MBH reaction. Therefore, new activation modes as well as new reaction patterns are desirable.

      7. Double activation catalysis involving thiols

      Thiolates exhibit extremely high nucleophilicity after deprotonation of thiols, thus thiols could serve as Lewis base catalyst precursors. However, their application in catalytic asymmetric reactions is rather limited. Until 2007, Miller and co-workers [
      • Aroyan C.E.
      • Miller S.J.
      Enantioselective Rauhut−Currier reactions promoted by protected cysteine.
      ] developed the first asymmetric intramolecular RC reaction catalyzed by a cysteine derivative. However, stoichiometric chiral thiol and excess strong base were required to give better conversions.
      The Chen group has made significant contributions to the thiol-based double activation catalysis. While an intriguing γ,β′-[6 ​+ ​2] cycloaddition reaction of α′-alkylidene-2-cyclopentenones 55 and 3-olefinic oxindoles 56 was observed under the catalysis of cinchonine-derived primary amine C26 and salicylic acid C29 by forming 4-aminofulvene intermediates, a highly enantioselective α,γ-regioselective [4 ​+ ​2] reaction from the identical sets of substrates was switched by using 2-mercaptobenzoic acid C30 as the acid additive (Scheme 20) [
      • Zhou Z.
      • Wang Z.-X.
      • Zhou Y.-C.
      • Xiao W.
      • Ouyang Q.
      • Du W.
      • Chen Y.-C.
      Switchable regioselectivity in amine-catalysed asymmetric cycloadditions.
      ]. The mechanism study indicated that a direct β′-regioselective sulfur-Michael addition of C30 to 55 would occur to give racemic enones after C C bond isomerization, followed by the assembly with chiral amine C27 to deliver active dienamine species. The subsequent asymmetric [4 ​+ ​2] cycloaddition with activated alkenes 56 would take place to give the regiodivergent products 58. It should be noted the ortho-carboxylic group was crucial for this thiol-based catalysis, probably through facilitating the elimination of the thiol substance, and the analogous meta- or para-mercaptobenzoic acid could not be similarly utilized.
      Scheme 20
      Scheme 20Switchable regiodivergent cycloadditions via double amine/thiol catalysis.
      Such a double amine/thiol catalysis could be applicable to more types of enone substrates [
      • Wang Z.-X.
      • Zhou Z.
      • Xiao W.
      • Ouyang Q.
      • Du W.
      • Chen Y.-C.
      Double activation catalysis for α′-alkylidene cyclic enones with chiral amines and thiols.
      ]. While the α′-alkylidene cyclic enones 59 proved to be poor Michael acceptors by forming the polyconjugated iminium ions under the catalysis of chiral amine C31, significantly improved reactivity and enantioselectivity were obtained by using malononitriles or indoles as the nucleophiles after adding thiol C30 as the co-catalyst (Scheme 21). It was suggested that different interrupted iminium ions would be generated via β′-regioselective sulfur addition, resulting in better reactivity and enantiocontrol in the subsequent Michael process.
      Scheme 21
      Scheme 21Double activation catalysis by forming interrupted iminium ions.
      Simple 2-cyclopentenone 61 also could be activated via a similar double activation strategy by forming interrupted enamine intermediate with amine C32 and thiol C30, which exhibited a more negative natural population analysis (NPA) charge (−0.324 VS −0.337) as well as higher nucleophilicity at the α′-position than that of traditional cross dienamine species [
      • Yang Q.-Q.
      • Xiao W.
      • Du W.
      • Ouyang Q.
      • Chen Y.-C.
      Asymmetric [4+2] annulations to construct norcamphor scaffolds with 2-cyclopentenone via double amine–thiol catalysis.
      ]. As outlined in Scheme 22, apparently increased reactivity was observed in the asymmetric [4 ​+ ​2] cycloadditions of 2-cyclopentenone 61 and different types of activated alkenes 62 under the double activation catalysis, and a series of bicycle[2,2,1]heptane scaffolds 63 were efficiently furnished in good to excellent yields with high enantioselectivity.
      Scheme 22
      Scheme 22Enhanced reactivity of 2-cyclopentenone via double activation catalysis.
      The MBH alcohols 64 condensed from 2-cyclopentenone and aldehydes have been employed in an unusual asymmetric α′,γ-regioselective formal [5 ​+ ​3] cycloaddition with cyclic azomethine imines 65 under the co-catalysis of amine C28, thiol C30, and acid C33, further strengthening the efficacy and compatibility of such a double activation system for multifunctional carbonyl substrates [
      • Yang Q.-Q.
      • Yin X.
      • He X.-L.
      • Du W.
      • Chen Y.-C.
      Asymmetric formal [5+3] cycloadditions with unmodified Morita–Baylis–Hillman alcohols via double cctivation catalysis.
      ]. As proposed in Scheme 23, the addition of 2-mercaptobenzoic acid C30 prompted the dehydration of MBH alcohol 64, generating the key cross-dienamine intermediate with amine C28. Subsequently, an α′-regioselective Mannich-type reaction occurred with azomethine imines 65. The ortho-carboxylic group of C30 might serve as an intramolecular H-bonding donor to facilitate the γ-deprotonation and sequential release of thiol C30. The final isomerization and intramolecular aza-Michael addition at the γ-position would furnish the formal [5 ​+ ​3] products 66.
      Scheme 23
      Scheme 23Asymmetric formal [5 ​+ ​3] annulations via amine/thiol catalysis.
      Thiol catalysts are well compatible with Brønsted bases or phase transfer catalysts (PTCs), and their combination for the double activation of α,β-unsaturated alkenes has been developed [
      • Jiang Y.
      • Yang Y.
      • He Q.
      • Du W.
      • Chen Y.-C.
      Asymmetric intramolecular Rauhut–Currier reaction and its desymmetric version via double thiol/phase-transfer catalysis.
      ]. An asymmetric intramolecular RC reaction of linear bis(enones) 67, including a newly designed desymmetric version, has been accomplished under the co-catalysis of thiols (C34C36) and sterically hindered chiral PTCs (C37C39) (Scheme 24). A broad spectrum of enantioenriched cyclohexene and cyclopentene derivatives 68 were efficiently constructed with moderate to excellent enantioselectivity. It was speculated that the reversible sulfur-addition of thiol catalysts to prochiral bis(enones) 67 would lead to the desymmetric generation of enolate ion intermediates, which could form compact chiral ion-pairs with PTCs to undertake the key asymmetric Michael addition.
      Scheme 24
      Scheme 24Asymmetric intramolecular RC reaction via double thiol/PTC catalysis.
      The intermolecular version of 2-cyclopentenone 61 with activated alkenes 69 has been realized under the double activation of thiols and chiral PTCs or Brønsted bases (tertiary amines) (Scheme 25) [
      • Zhou Z.
      • He Q.
      • Jiang Y.
      • Ouyang Q.
      • Du W.
      • Chen Y.-C.
      Double thiol-chiral Brønsted base catalysis: asymmetric cross Rauhut–Currier reaction and sequential [4+2] annulation for assembly of different activated olefins.
      ]. Notably, the resultant chiral RC adducts 70 possess an acidic proton, thus enabling deprotonation and sequential Michael addition/cyclization with nitroolefins 71 to furnish highly enantioenriched cyclohexane derivatives 72. Nevertheless, 2-cyclohexenone 43 showed much lower reactivity and enantioselectivity under similar catalytic conditions.
      Scheme 25
      Scheme 25Asymmetric RC reaction initiated [4 ​+ ​2] annulations via double thiol/Brønsted base catalysis.
      The double activation system combining thiol C30 and quinine was further applied to the asymmetric intermolecular RC of α′-alkylidene 2-cyclohexenones 59 and (7-aza)isatinylidene malononitriles 73 by generating the dienolate ion pair intermediates (Scheme 26) [
      • He Q.
      • Yang Z.-H.
      • Yang J.
      • Du W.
      • Chen Y.-C.
      Enantioselective formal arylation of (7-aza)isatylidene malononitriles with α′-alkylidene-2-cyclohexenones.
      ]. After releasing thiol C30, a deprotonation of the chiral RC adduct occurred with the assistance of quinine, and the resultant dienolate intermediates proceeded through a Pinner-type cyclization/[
      • Houk K.N.
      • List B.
      Asymmetric organocatalysis.
      ,
      • Seayad J.
      • List B.
      ]-H shift reaction, finally affording the formal 3-arylated spiro(7-aza)oxindole derivatives 74 with fair to excellent enantioselectivity.
      Scheme 26
      Scheme 26Enantioselective formal arylation via thiol/Brønsted base catalysis.
      Thiols as a type of Lewis base precursors have not shown satisfactory performance in asymmetric reactions independently; in contrast, the above-mentioned cases well demonstrated the power of thiols in double activation catalysis. These strategies also significantly expanded the reaction patterns and substrate scope of Lewis base catalysis, probably owing to the high nucleophilicity and less congested structure of thiolates. Nevertheless, 2-mercaptobenzoic acid, as an achiral compound, was commonly employed with the combination of another chiral organocatalyst in most cases, while other types of chiral thiols have not been well designed and utilized [
      • Jiang Y.
      • Yang Y.
      • He Q.
      • Du W.
      • Chen Y.-C.
      Asymmetric intramolecular Rauhut–Currier reaction and its desymmetric version via double thiol/phase-transfer catalysis.
      ]. Therefore, further structure modifications are in high demand for the development of chiral thiol-based Lewis base catalysis with high efficacy.

      8. Double activation catalysis involving two Brønsted acids

      Two different Brønsted acid catalysts can be used together for activating one substrate, thus significantly enhancing the electrophilicity for subsequent asymmetric reactions. In 2010, Jacobsen [
      • Xu H.
      • Zuend S.J.
      • Woll M.G.
      • Tao Y.
      • Jacobsen E.N.
      Asymmetric cooperative catalysis of strong Brønsted acid-promoted reactions using chiral ureas.
      ] uncovered an enantioselective Povarov reaction of N-aryl imines 75, electron-rich olefins 76 and 87 under the catalysis of a double activation system of chiral urea C41 and strong Brønsted acid C42 (Scheme 27). The DFT calculations and experimental results implied that an ion pair of the protonated imine cation with the urea bound anion would be crucial for the observed high enantioselectivity. In addition, the sulfinamide moiety of urea C41 might coordinate to the iminium ion formyl proton via an H-bond, leading to pronounced effects on the asymmetric Povarov reaction. Apart from the strong Brønsted acid, some Lewis acids were also employed for the asymmetric transformations of carbonyls in combination with these H-bonding donors [
      • Kim H.Y.
      • Oh K.
      Highly diastereo- and enantioselective aldol reaction of methyl α-isocyanoacetate: a cooperative catalysis approach.
      ].
      Scheme 27
      Scheme 27Asymmetric Povarov reaction mediated by non-covalent interactions via Brønsted acid/chiral urea catalysis.
      On the other hand, fluorinated alcohols have been widely used in synthetic chemistry as a kind of effective additives, due to their strong H-bonding donor ability and low nucleophilicity [
      • An X.-D.
      • Xiao J.
      Fluorinated alcohols: magic reaction medium and promoters for organic synthesis.
      ]. Very recently, the Shi group [
      • Li T.-Z.
      • Liu S.-J.
      • Sun Y.-W.
      • Deng S.
      • Tan W.
      • Jiao Y.
      • Zhang Y.-C.
      • Shi F.
      Regio- and enantioselective [3+3] cycloaddition of nitrones with 2-indolylmethanols enabled by cooperative organocatalysis.
      ] reported a regio- and enantioselective [3 ​+ ​3] annulation of 2-indolymethanols 80 with nitrones 81 under the cooperative catalysis of hexafluoroisopropanol (HFIP) and CPA C43, and a series of indole-fused six-membered heterocycles 82 were synthesized in high yields with excellent stereoselectivity (Scheme 28). Moreover, control experiments and theoretical calculations elucidated the role of the co-catalyst HFIP in the assistance of CPA for stabilizing the key transition state and creating a chiral environment via multiple hydrogen-bonding interactions, thus accelerating the reaction and improving the enantiocontrol.
      Scheme 28
      Scheme 28Stereoselective [3 ​+ ​3] annulations via CPA/HFIP catalysis.

      9. Miscellaneous double activation systems of organocatalysis

      Beside of the double activation systems of merging different types of organocatalysts, some other catalytic systems, such as transition metal catalysis and photocatalysis, also have been utilized in combination with organocatalysis.
      The combination of metal catalysis and organocatalysis has greatly broadened the substrate scope of organic synthesis via diverse activation strategies, and some elegant works have been reported by Carreira [
      • Krautwald S.
      • Sarlah D.
      • Schafroth M.A.
      • Carreira E.M.
      Enantio- and diastereodivergent dual catalysis: α-allylation of branched aldehydes.
      ], Córdova [
      • Ma G.
      • Afewerki S.
      • Deiana L.
      • Palo-Nieto C.
      • Liu L.
      • Sun J.
      • Ibrahem I.
      • Córdova A.
      A palladium/chiral amine co-catalyzed enantioselective dynamic cascade reaction: synthesis of polysubstituted carbocycles with a quaternary carbon stereocenter.
      ], Takemoto [
      • Nakoji M.
      • Kanayama T.
      • Okino T.
      • Takemoto Y.
      Chiral phosphine-free Pd-mediated asymmetric allylation of prochiral enolate with a chiral phase-transfer catalyst.
      ], Gong [
      • Chen D.-F.
      • Han Z.-Y.
      • Zhou X.-L.
      • Gong L.-Z.
      Asymmetric organocatalysis combined with metal catalysis: concept, proof of concept, and beyond.
      ] et al., in a cooperative catalysis manner or a relay catalysis pattern [
      • Wang P.-S.
      • Chen D.-F.
      • Gong L.-Z.
      Asymmetric Organocatalysis Combined with Metal Catalysis.
      ,
      • Chen D.-F.
      • Gong L.-Z.
      Organo/transition-metal combined catalysis rejuvenates both in asymmetric synthesis.
      ]. In contrast, the examples via double activation catalysis of organocatalysts and transition metals have been much less disclosed. In 2007, the List group [
      • Mukherjee S.
      • List B.
      Chiral counteranions in asymmetric transition-metal catalysis: highly enantioselective Pd/Brønsted acid-catalyzed direct α-allylation of aldehydes.
      ] utilized the double activation catalytic system of Pd/CPA in a highly enantioselective α-allylation reaction of branched aldehydes 83 (Scheme 29). It was proposed that aldehydes 83 were condensed with allylamines 84 under the catalysis of CPA C44, and the resultant enamonium phosphate salts would undergo an oxidative addition in the presence of Pd(PPh3)4 to give enamines and π-allylpalladium species assembled by the phosphate anion. CPA C44 had a dual catalytic function in the transformation, acting both as a proton source and as a counterion for the cationic π-allylpalladium complex, thus guaranteeing high reactivity and stereocontrol for the formation of aldehydes 85 possessing an all-carbon quaternary stereogenic center.
      Scheme 29
      Scheme 29Asymmetric α-allylation of branched aldehydes via Pd/CPA catalysis.
      With the development of asymmetric allylic alkylation reactions, the zwitterionic dipoles containing a π-allylmetal complex moiety have been extensively employed for the construction of various chiral cyclic frameworks [
      • De N.
      • Yoo E.J.
      Recent advances in the catalytic cycloaddition of 1,n-dipoles.
      ]. However, some dipoles are inactive, since the anionic group might bind to the π-allylmetal complex moiety intramolecularly and the attack toward the electrophiles might be prohibited. Aggarwal [
      • Lowe M.A.
      • Ostovar M.
      • Ferrini S.
      • Chen C.C.
      • Lawrence P.G.
      • Fontana F.
      • Calabrese A.A.
      • Aggarwal V.K.
      Palladium-mediated annulation of vinyl aziridines with michael acceptors: stereocontrolled synthesis of substituted pyrrolidines and its application in a formal synthesis of (−)-α-Kainic acid.
      ] found that the addition of nBu4NCl significantly enhanced the nucleophilicity of the dipole generated from 86, probably by forming ion pairs (Scheme 30). The Chen group [
      • Yang Y.
      • Zhu B.
      • Zhu L.
      • Jiang Y.
      • Guo C.-L.
      • Gu J.
      • Ouyang Q.
      • Du W.
      • Chen Y.-C.
      Combining palladium and ammonium halide catalysts for Morita–Baylis–Hillman carbonates of methyl vinyl ketone: from 1,4-carbodipoles to ion pairs.
      ] further developed this double activation catalytic system by employing chiral ammonium salts and chiral palladium complexes, and accomplished an asymmetric [4 ​+ ​2] annulation reaction of simple MBH carbonates 87 with activated alkenes 88, affording a variety of spirocyclic products 89 with excellent enantioselectivity. The addition of ammonium salt C45 resulted in apparent improvement for the reactivity, and the regioselectivity could be controlled by tuning the substitution patterns of MBH carbonate 87. More importantly, different combinations of ammonium salts and ligands with independent stereogenic information led to switchable diastereoselectivity. The authors assumed that the 1,4-carbodiples generated from MBH carbonates 87 under the catalysis of Pd might be converted to inactive Pd-ligated 5-membered species, whereas compact chiral ion pairs embedding an electronically neutral Pd complex would be formed by adding ammonium halides, thus facilitating the subsequent attack on activated alkenes 89 with high stereocontrol.
      Scheme 30
      Scheme 30Enantioselective [4 ​+ ​2] annulations catalyzed by Pd/ammonium halides.
      Photocatalysis has attracted increasing interest in recent years, as light could trigger numerous unique transformations as a renewable and ample energy source. However, it is challenging to achieve highly stereoselective control in a photochemical reaction process due to the high reactivity of radicals generated via light irradiation. One approach is to employ dual catalytic systems by merging an achiral photocatalyst with a chiral small-molecular organic catalyst. In 2008, MacMillan [
      • Nicewicz D.A.
      • MacMillan D.W.C.
      Merging photoredox catalysis with organocatalysis: the direct asymmetric alkylation of aldehydes.
      ] uncovered the first example by combining photocatalysis and enamine catalysis, which laid the foundation for asymmetric photocatalysis. Significant progress has been achieved over the following decade, and several groups, including Riovs [
      • DiRocco D.A.
      • Rovis T.
      Catalytic asymmetric α-acylation of tertiary amines mediated by a dual catalysis mode: N-heterocyclic carbene and photoredox catalysis.
      ], Melchiorre [
      • Murphy J.J.
      • Bastida D.
      • Paria S.
      • Fagnoni M.
      • Melchiorre P.
      Asymmetric catalytic formation of quaternary carbons by iminium ion trapping of radicals.
      ], Ooi [
      • Uraguchi D.
      • Kinoshita N.
      • Kizu T.
      • Ooi T.
      Synergistic catalysis of ionic Brønsted acid and photosensitizer for a redox neutral asymmetric α-coupling of N-arylaminomethanes with aldimines.
      ], Bach [
      • Alonso R.
      • Bach T.
      A chiral thioxanthone as an organocatalyst for enantioselective [2+2] photocycloaddition reactions induced by visible light.
      ], Knowles and Miller [
      • Shin N.Y.
      • Ryss J.M.
      • Zhang X.
      • Miller S.J.
      • Knowles R.R.
      Light-driven deracemization enabled by excited-state electron transfer.
      ] et al., have made great contributions by introducing NHCs, amines, Brønsted acids and other organocatalysts into photocatalysis. It should be noticed that cooperative catalysis or relay catalysis was involved in most examples, which have been well summarized in related reviews [
      • Yao W.
      • Bazan-Bergamino E.A.
      • Ngai M.-Y.
      Asymmetric photocatalysis enabled by chiral organocatalysts.
      ,
      • Silvi M.
      • Melchiorre P.
      Enhancing the potential of enantioselective organocatalysis with light.
      ,
      • Liu Y.-Y.
      • Liu J.
      • Lu L.-Q.
      • Xiao W.-J.
      Organocatalysis combined with photocatalysis.
      ]. On the other hand, those based on a double activation strategy were much less disclosed. In 2013, the MacMillan group further extended the multicatalytic strategy, by using a double activation system of aminocatalyst C26 and photocatalyst Ir(ppy)3, accomplishing a direct asymmetric β-functionalization of cyclohexanone 90 (Scheme 31) [
      • Pirnot M.T.
      • Rankic D.A.
      • Martin D.B.C.
      • MacMillan D.W.C.
      Photoredox activation for the direct β-arylation of ketones and aldehydes.
      ]. In the aminocatalytic cycle, an electron-rich enamine intermediate was generated from 90 in the presence of C26, and it was oxidized by the active Ir(IV) formed in the photoredox cycle, affording a 5π-electron intermediate after the loss of a proton. Finally, the β-arylation product 92 was furnished via a coupling reaction with the dicycno arene radical anion followed by the elimination of a cyanide and hydrolysis. It should be noted that the reaction site, β-position of cyclohexanone 90, was relatively far from the chiral center of the catalyst (compared to the well-established α-functionalization of carbonyls), thus only moderate enantioselectivity was achieved. Apart from photoredox catalysis, the Jørgensen group [
      • Næsborg L.
      • Corti V.
      • Leth L.A.
      • Poulsen P.H.
      • Jørgensen K.A.
      Catalytic asymmetric oxidative γ-coupling of α,β-unsaturated aldehydes with air as the terminal oxidant.
      ] further disclosed a novel single electron oxidation system by using a catalytic amount of Cu(II) salts and air as the terminal oxidant, which oxidized dienamine intermediates generated from ɑ,β-unsaturated aldehydes in the presence of a chiral amine catalyst, and the resulting dienamine radical cation intermediates underwent asymmetric γ-homo-coupling or highly selective γ-hetero-coupling reactions with another molecular ɑ,β-unsaturated aldehydes.
      Scheme 31
      Scheme 31Asymmetric β-arylation of cyclohexanone via amine/photoredox catalysis.
      Very recently, the Luo group [
      • Huang M.
      • Zhang L.
      • Pan T.
      • Luo S.
      Deracemization through photochemical E/Z isomerization of enamines.
      ] developed an interesting deracemization of α-branched aldehydes 93 through an E/Z-isomerization strategy by using aminocatalyst C46 and photosensitizer Ir(ppy)3, providing a simple but efficient approach towards enantioenriched branched aldehydes from the corresponding racemic ones (Scheme 32). Mechanism studies and DFT calculations suggested the photochemical perturbation proceeded through energy transfer, and a triplet-state transition state was involved. Under the photocatalytic conditions, the E-configured enamines generated from the stereochemically matched enantiomers with C46, continuously isomerized to disfavored Z-configured isomers via energy transfer, and they were facially selectively protonated to the mismatched R-enantiomers. Finally, the consumption of the matched S-enantiomers and the accruement of mismatched R-enantiomers resulted in effective deracemization.
      Scheme 32
      Scheme 32Deracemization of branched aldehydes via photochemical isomerization of enamine intermediates.
      In contrast to the well-developed electron pair transfer processes catalyzed by NHCs, the single electron transfer processes represent another strategy which has been rapidly developed in recent years, especially in combination with photochemistry. Two major pathways are involved in the formation of radical intermediates from carbonyls via NHC catalysis, one is the single electron oxidation of Breslow intermediates to give radical cations, and the other is the single electron transfer reduction to generate ketyl radicals [
      • Li Q.-Z.
      • Zeng R.
      • Han B.
      • Li J.-L.
      Single-electron transfer reactions enabled by N-heterocyclic carbene organocatalysis, Chem.
      ,
      • Liu J.
      • Xing X.-N.
      • Huang J.-H.
      • Lu L.-Q.
      • Xiao W.-J.
      Light opens a new window for N-heterocyclic carbene catalysis.
      ] (Scheme 33). Some elegant examples have been uncovered based on both strategies, unfortunately, usually in a racemic manner [
      • Meng Q.-Y.
      • Döben N.
      • Studer A.
      Cooperative NHC and photoredox catalysis for the synthesis of β-trifluoromethylated alkyl aryl ketones.
      ,
      • Liu K.
      • Studer A.
      Direct α-acylation of alkenes via N-heterocyclic carbene, sulfinate, and photoredox cooperative triple catalysis.
      ,
      • Huang H.
      • Dai Q.-S.
      • Leng H.-J.
      • Li Q.-Z.
      • Yang S.-L.
      • Tao Y.-M.
      • Zhang X.
      • Qi T.
      • Li J.-L.
      Suzuki-type cross-coupling of alkyl trifluoroborates with acid fluoride enabled by NHC/photoredox dual catalysis.
      ]. High levels of stereocontrol seem to be challenging probably because of the limitations of available chiral NHC catalysts and hyperactive radical-radical coupling reactions. A preliminary attempt for the asymmetric reductive single-electron alkylation of acyl azoliums from acyl imidazole 94 via the double activation of NHC C47 and photoredox catalyst C48 was conducted by Scheidt [
      • Bay A.V.
      • Fitzpatrick K.P.
      • Betori R.C.
      • Scheidt K.A.
      Combined photoredox and carbene catalysis for the synthesis of ketones from carboxylic acids.
      ]. The radical-radical coupling between the ketyl radical generated from the acyl triazolium intermediate via single-electron reduction and the benzyl radical from Hantzsch ester 95 through a fragmentation process, afforded ketone 96 with a fair ee value. This work demonstrated asymmetric induction via the double activation of NHC and photocatalysis is feasible.
      Scheme 33
      Scheme 33Double activation to generate radical via NHC/photoredox catalysis.
      Apart from aminocatalysis and NHC catalysis, photoredox catalysis has also been utilized in combination with CPA catalysis. In 2013, the Knowles group [
      • Rono L.J.
      • Yayla H.G.
      • Wang D.Y.
      • Armstrong M.F.
      • Knowles R.R.
      Enantioselective photoredox catalysis enabled by proton-coupled electron transfer: development of an asymmetric aza-pinacol cyclization.
      ] realized the first asymmetric aza-pinacol-type reductive cyclization of 97 embedding a ketone and a hydrazone moiety via a double activation system, furnishing syn-1,2-amino alcohols 98 with high enantioselectivity (Scheme 34). The combination of CPA C49 and photoredox catalyst Ir(ppy)2(dtbpy)PF6 trigged the formation of the ketyl radical intermediates through a concerted proton-couped electron transfer (PCET) process. More importantly, the neutral ketyl radicals tightly coordinated with the phosphate anion via H-bond interaction, thus guaranteeing higher stereocontrol during the cyclization step. This work indicated that the weak interactions with the non-covalent catalysts represent a promising strategy for radical chemistry, which provided inspiration for future studies [
      • Gentry E.C.
      • Knowles R.R.
      Synthetic applications of proton-coupled electron transfer.
      ,
      • Li S.
      • Xiang S.-H.
      • Tan B.
      Chiral phosphoric acid creates promising opportunities for enantioselective photoredox catalysis.
      ].
      Scheme 34
      Scheme 34Asymmetric aza-pinacol-type cyclization via CPA/photoredox catalysis.

      10. Summary

      Along with the development of organocatalysis over the past decades, tremendous progress has been made by using the unique double activation strategy with two or more catalysts. Different types of small organic molecules independently or cooperatively interact with one of the multifunctional reaction partners. Moreover, their combination with transition metal catalysis and photocatalysis has been proven to be successful. The double activation strategy represents a miraculous solution for some problematic and challenging, or even unattainable reactions. As a result, higher reactivity and better stereoselectivity are often realized, and even switchable regioselectivity, diastereoselectivity and chemoselectivity could be accomplished in some cases.
      Nevertheless, the application of double activation catalysis is still relatively limited, especially compared with the well-developed cooperative or relay catalysis. One possible reason is that deliberate design of the multifunctional substrates is often required, and at least two different functional groups which would interact with distinct catalysts simultaneously, are usually installed in a single substrate. In addition, judicious selection of the assembly of different catalysts is another key factor, though some organocatalysts show good compatibility and high tolerance with each other or even with metals. Besides, the double activation mechanism has not been fully elucidated in some cases because of the multiple interaction modes, thus detailed theoretical calculations might be helpful for better understanding the relevant reactions and inspiring new reaction designs. On the other hand, though photocatalysis and electrocatalysis are powerful tools for the generation of reactive radical intermediates, their integration with organocatalysis is still in infancy [
      • Yao W.
      • Bazan-Bergamino E.A.
      • Ngai M.-Y.
      Asymmetric photocatalysis enabled by chiral organocatalysts.
      ,
      • Margarita C.
      • Lundberg H.
      Recent advances in asymmetric catalytic electrosynthesis.
      ]. Besides, the combination of organocatalysis and biocatalysis remains underdeveloped [
      • Bering L.
      • Thompson J.
      • Micklefield J.
      New reaction pathways by integrating chemo- and biocatalysis.
      ], especially considering that multienzymatic systems have been widely witnessed in nature. Therefore, more studies by selecting the finely positioned multifunctional substrates, which could be applied in novel double activation modes with high compatibility, are highly expected. We believe that with the activation versatility and structural diversity of the abundant organocatalysts, the relevant double activation strategies would find more application in organic synthesis for the rapid construction of enantioenriched architectures.

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgement

      We are grateful for the financial support from the NSFC (21961132004 and 21931006).

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