catalysts

Review OrganocatalysisReview and Beyond: Activating Reactions withOrganocatalysis Two Catalytic and Species Beyond: Activating Reactions with Two Catalytic Species Arianna Sinibaldi 1, Valeria Nori 1, Andrea Baschieri 1, Francesco Fini 2, Antonio Arcadi 1 and ArmandoArianna Sinibaldi Carlone 1,1*, Valeria Nori 1 , Andrea Baschieri 1 , Francesco Fini 2, Antonio Arcadi 1 1, and1 Department Armando of Carlone Physical *and Chemical Sciences, Università degli Studi dell’Aquila, via Vetoio, 1 67100Department L’Aquila, of Italy; Physical arianna.sinibaldi and [email protected] Sciences, Università (A.S.);degli [email protected] dell’Aquila, via Vetoio, (V.N.); [email protected] L’Aquila, Italy; [email protected] (A.B.); [email protected] (A.A.) (A.S.); [email protected] (V.N.); 2 [email protected] of Life Sciences, (A.B.);Università [email protected] degli Studi di Modena (A.A.) e Reggio Emilia, via G. Campi 103, 2 41125Department Modena, of Italy; Life Sciences,[email protected] Università degli Studi di Modena e Reggio Emilia, via G. Campi 103, * Correspondence:41125 Modena, Italy;armando.ca francesco.fi[email protected]@univaq.it; +39-0862-433-036 *Received:Correspondence: 18 October 2019; [email protected]; Accepted: 1 November Tel.:2019;+ Published:39-0862-433-036 date



 Abstract:Received: 18Since October the beginning 2019; Accepted: of the 1 November millennium, 2019; orga Published:nocatalysis 6 November has been 2019 gaining a predominant role in asymmetric synthesis and it is, nowadays, a foundation of catalysis. Synergistic catalysis, Abstract: Since the beginning of the millennium, organocatalysis has been gaining a predominant combining two or more different catalytic cycles acting in concert, exploits the vast knowledge role in asymmetric synthesis and it is, nowadays, a foundation of catalysis. Synergistic catalysis, acquired in organocatalysis and other fields to perform reactions that would be otherwise combining two or more different catalytic cycles acting in concert, exploits the vast knowledge impossible. Merging organocatalysis with photo-, metallo- and organocatalysis itself, researchers acquired in organocatalysis and other fields to perform reactions that would be otherwise impossible. have ingeniously devised a range of activations. This feature review, focusing on selected Merging organocatalysis with photo-, metallo- and organocatalysis itself, researchers have ingeniously synergistic catalytic approaches, aims to provide a flavor of the creativity and innovation in the area, devised a range of activations. This feature review, focusing on selected synergistic catalytic approaches, showing ground-breaking examples of organocatalysts, such as proline derivatives, hydrogen aims to provide a flavor of the creativity and innovation in the area, showing ground-breaking bond-mediated, Cinchona alkaloids or phosphoric acids catalysts, which work cooperatively with examples of organocatalysts, such as proline derivatives, hydrogen bond-mediated, Cinchona alkaloids different catalytic partners. or phosphoric acids catalysts, which work cooperatively with different catalytic partners. Keywords: organocatalysis; metallocatalysis; photocatalysis; synergistic; cooperative; asymmetric; Keywords: organocatalysis; metallocatalysis; photocatalysis; synergistic; cooperative; asymmetric; catalysis catalysis

1. Introduction 1. Introduction The origins of asymmetric organocatalysis date back to the intuitive experiment of two remarkable The origins of asymmetric organocatalysis date back to the intuitive experiment of two scientists, Bredig and Fiske, during the first decade of the 1900s. They reported the first enantioselective remarkable scientists, Bredig and Fiske, during the first decade of the 1900s. They reported the first addition reaction of HCN to benzaldehyde 1 mediated by Cinchona alkaloids as organocatalyst [1] enantioselective addition reaction of HCN to benzaldehyde 1 mediated by Cinchona alkaloids as (Scheme1). organocatalyst [1] (Scheme 1).

Catalyst:

H

O OH N HCN H * CN HO H Ia 1 2 N Ia

Scheme 1. AdditionAddition of of HCN HCN to to benzaldehyde benzaldehyde 1,1, performedperformed by Bredig and Fiske. In hindsight, the results obtained were a breakthrough as it was the first use of a small organic molecule as a catalyst. For several reasons, however, asymmetric organocatalysis was not born; Catalysts 2019, 9, x; doi: FOR PEER REVIEW www.mdpi.com/journal/catalysts Catalysts 2019, 9, 928; doi:10.3390/catal9110928 www.mdpi.com/journal/catalysts Catalysts 2019, 9, x FOR PEER REVIEW 2 of 36 Catalysts 2019, 9, 928 2 of 35 In hindsight, the results obtained were a breakthrough as it was the first use of a small organic molecule as a catalyst. For several reasons, however, asymmetric organocatalysis was not born; it was it was probably only at the beginning of the new millennium that the field was mature enough to probably only at the beginning of the new millennium that the field was mature enough to bloom. bloom. This is testified by the fact that two ground breaking pioneers in the field of organic chemistry, This is testified by the fact that two ground breaking pioneers in the field of organic chemistry, Benjamin List [2] (Scheme2a) and David MacMillan [ 3] (Scheme2b), simultaneously reported two Benjamin List [2] (Scheme 2a) and David MacMillan [3] (Scheme 2b), simultaneously reported two different, albeit complementary, activations with aminocatalysts, giving birth to a “Gold Rush” in different, albeit complementary, activations with aminocatalysts, giving birth to a “Gold Rush” in organocatalysis [4]. In particular, their studies highlighted the possibility of carrying out asymmetric organocatalysis [4]. In particular, their studies highlighted the possibility of carrying out asymmetric reactions with organocatalysts based on enamine or iminium ion or activation. reactions with organocatalysts based on enamine or iminium ion or activation.

Scheme 2. (a) Ketone activation via aminocatalysis, performed by List; and (b) aldehyde activation via Scheme 2 (a) Ketone activation via aminocatalysis, performed by List; and (b) aldehyde activation via aminocatalysis, performed by MacMillan. aminocatalysis, performed by MacMillan. The main advantage of using organocatalysts derives from their user-friendliness: No anhydrous conditionsThe main are required; advantage they of are using highly organocatalysts stable in a broad derives range of temperaturesfrom their user-friendliness: and in most common No anhydrouschromatographic conditions and reactionare required; conditions; they are and highly moreover, stable their in a wastebroad disposal range of operation temperatures has aand lower in mostenvironmental common impactchromatographic respect to other and catalysts.reaction conditions; and moreover, their waste disposal operationInspired has bya lower this new environmental technology platform,impact respect several to scientists other catalysts. discovered a large variety of catalysts, whichInspired directly by came this from new the technology chiral pool platform, or undergo seve syntheticral scientists modifications discovered to generatea large analogousvariety of catalysts,compounds which positively directly impacting came from the the economy chiral po ofol the or entireundergo process, synthetic thanks modifications to the availability to generate and analogousaffordability compounds of the starting positively materials impacting [5]. the economy of the entire process, thanks to the availabilityAn incredible and affordability range of organocatalysts of the starting capable materials of promoting [5]. enantioselective reactions were found, enablingAn incredible transformations range of thanks organocatalysts to different activations,capable of promoting via iminium enantioselective ion or enamine reactions activation were [6], viafound, protonation enabling or transformations deprotonation (chiralthanks basic to diff [1] orerent acidic activations, catalysts [via7]), coordinationiminium ion viaor hydrogenenamine activationbond [8,9], [6], and via via protonation steric hindrance or deprotonation [6,10,11] (Figure (chi1ral). The basic combination [1] or acidic of catalysts the di fferent [7]), activationscoordination in viaone hydrogen catalyst to bond interact [8,9], with and di viafferent steric reaction hindrance partners [6,10,11] is noteworthy; (Figure 1).a The bifunctional, combination or multifunctional, of the different activationscatalyst is ain molecule one catalyst which to interact exhibits with more differ thanent one reaction functional partners group is noteworthy; capable of interacting a bifunctional, and ororientating multifunctional, with two catalyst different is a substrates molecule duringwhich aexhibits catalytic more process than [ 12one]. functional group capable of interacting and orientating with two different substrates during a catalytic process [12].

Catalysts 2019, 9, 928 3 of 35 Catalysts 2019, 9, x FOR PEER REVIEW 3 of 36

Figure 1. Different methods of substrate activation. Figure 1. Different methods of substrate activation. With the purpose of imitating the perfect performance of enzymes, chemists began to synthesize a With the purpose of imitating the perfect performance of enzymes, chemists began to synthesize few bifunctional catalysts able to bring together the different reaction partners. a few bifunctional catalysts able to bring together the different reaction partners. These compounds have different multiple catalytic sites spaced out by a linker or spacer, which These compounds have different multiple catalytic sites spaced out by a linker or spacer, which confer to its structure a proper dimension, rigidity and geometry in order to perform the reaction in a confer to its structure a proper dimension, rigidity and geometry in order to perform the reaction in stereoselective way. The benefit of this modus operandi is directly linked to entropic energy: keeping a stereoselective way. The benefit of this modus operandi is directly linked to entropic energy: the activated reacting partners in proximity and orientating them in a specific way to obtain the desired keeping the activated reacting partners in proximity and orientating them in a specific way to obtain product with stereocontrol. the desired product with stereocontrol. A remarkable deficiency of this process is correlated to the many synthetic steps needed to obtain A remarkable deficiency of this process is correlated to the many synthetic steps needed to obtain these catalysts. As an alternative and complementary approach, some research groups focused on these catalysts. As an alternative and complementary approach, some research groups focused on synergistic catalysis, a relatively new technology platform which allows the simultaneous activation of synergistic catalysis, a relatively new technology platform which allows the simultaneous activation both reaction partners by two distinct catalytic cycles. The reduction of the ∆E(HOMO-LUMO) causes of both reaction partners by two distinct catalytic cycles. The reduction of the ΔE(HOMO-LUMO) a substantial decrease in the activation energy of the desired reaction, which increases the constant rate causes a substantial decrease in the activation energy of the desired reaction, which increases the driving the desired pathway compared to possible side reactions (Figure2). constant rate driving the desired pathway compared to possible side reactions (Figure 2).

Figure 2. Synergistic catalysis. Figure 2. Synergistic catalysis. The activated species can rapidly react, making reactions possible that would otherwise be ineffiThecient activated or even impossiblespecies can with rapidly traditional react, making mono-catalysis reactions methods. possible Thethat reaction would otherwise between two be inefficientintermediates or even present impossible in low sub-stoichiometricwith traditional mono-catalysis concentrations methods. should The be, reaction in principle, between diffi cult;two intermediateshowever, considering present kineticin low aspects,sub-stoichiometric the reaction concentrations between two activatedshould be, intermediates in principle, should difficult; be promisinghowever, considering due to the narrowing kinetic aspects, of the HOMO-LUMO,the reaction between which two causes activated a large decreaseintermediates in the should activation be promisingenergy and, due as ato consequence, the narrowing increases of the HOMO-LUMO, the rate constant which to drive causes the a desiredlarge decrease synthetic in the pathway. activation energyWhile and, nature as a consequence, takes advantage increases from physicalthe rate separationconstant to between drive the catalytic desired moieties synthetic in pathway. the enzymes activeWhile sites, nature a synergistic takes advantage catalytic system from couldphysical undergo separation self-quenching, between catalytic rendering moieties both catalysts in the enzymesinactive. Foractive this sites, reason, a synergistic research groups catalytic interested system in could catalysis undergo involving self-quenching, two or more rendering catalytic cycles both whichcatalysts act inactive. in cooperation, For this need reason, to select research the catalystsgroups interested combination in catalysis judiciously. involving Synergistic two catalysisor more catalyticopens the cycles possibility which to screenact in several cooperation, combinations need ofto aselect wide rangethe catalysts of catalysts combination for a particular judiciously. reaction. SynergisticIn this scenario, catalysis synergistic opens the catalysis possibility attracted to screen increasing several interest combinations in the academic of a wide community. range of catalysts for aIn particular this review reaction. we will In focus this onscenario, selected synergis strategiestic catalysis and reports attracted that exploit increasing synergistic interest catalysis in the withacademic disrupting community. innovation; the cooperation of organocatalysts with other catalytic species of different nature,In this such review as organo-, we will metal- focus or on photo-catalysts, selected strate willgies be and discussed. reports that exploit synergistic catalysis with disrupting innovation; the cooperation of organocatalysts with other catalytic species of different nature, such as organo-, metal- or photo-catalysts, will be discussed.

Catalysts 2019, 9, 928 4 of 35 Catalysts 2019, 9, x FOR PEER REVIEW 4 of 36

2. Proline-Derivatives Catalysis 2. Proline-Derivatives Catalysis Proline is the only natural α-amin oacid with a secondary amine; its nitrogen, part of the Proline is the only natural α-amin oacid with a secondary amine; its nitrogen, part of the pyrrolidine pyrrolidine heterocycle, has an increased pKa with respect to other amin oacids. Thanks to the heterocycle, has an increased pKa with respect to other amin oacids. Thanks to the carboxylic acid carboxylic acid moiety, proline can also behave as a bifunctional catalyst: The nitrogen can act as a moiety, proline can also behave as a bifunctional catalyst: The nitrogen can act as a Lewis base while Lewis base while the carboxylate portion as a general Brønsted acid. Following condensation of the the carboxylate portion as a general Brønsted acid. Following condensation of the nitrogen with nitrogen with carbonyl compounds, proline activates reagents via the corresponding enamine or carbonyl compounds, proline activates reagents via the corresponding enamine or iminium ion [2]. iminium ion [2]. Proline can be used to functionalise α,β-unsaturated aldehyde 9 with nucleophiles, Proline can be used to functionalise α,β-unsaturated aldehyde 9 with nucleophiles, via iminium ion, via iminium ion, or saturated aldehydes 10 with electrophiles via enamine (Scheme 3). When proline or saturated aldehydes 10 with electrophiles via enamine (Scheme3). When proline itself is used as a itself is used as a catalyst, the carboxylic moiety will aid in imparting stereoselectivity by orienting catalyst, the carboxylic moiety will aid in imparting stereoselectivity by orienting the approaching the approaching reaction partner via an intermolecular hydrogen bond. reaction partner via an intermolecular hydrogen bond.

Scheme 3. Proline activation modes: (a) via iminium ion, (b) via enamine. Scheme 3. Proline activation modes: (a) via iminium ion, (b) via enamine. To improve enantioselectivity and to expand the applicability of proline beyond H-bond acceptors, prolineTo derivativesimprove enantioselectivity bearing steric hinderedand to expand groups, the or longerapplicability alkyl chainsof proline were beyond prepared H-bond [6,9]. Catalyticacceptors, equivalents proline derivatives of proline, bearing such as steric imidazolidinone-based hindered groups, or MacMillan longer alkyl catalysts chains or were prolinamides prepared derivatives,[6,9]. Catalytic also equivalents proved extremely of proline, successful such [3 ,as4]. imidazolidinone-based MacMillan catalysts or prolinamidesProline and derivatives, its derivatives also effectivelyproved extremely catalyze asuccessful multitude [3,4]. of reactions; an interesting example is the asymmetricProline intramolecular and its derivatives aldol reaction, effectively a breakthrough catalyze a report multitude by Hajos-Parrish-Eder-Sauer-Wiechert of reactions; an interesting example[13,14]. Thisis the reaction asymmetric was used intramolecular by two distinct aldol industrial reaction, research a breakthrough groups who report discovered by Hajos-Parrish-Eder-Sauer- a synthetic strategy to obtainWiechert a very [13,14]. versatile This intermediate reaction was in used organic by synthesis,two distinct the Wieland–Miescherindustrial research ketone groups [15 who]. discovered a syntheticProline wasstrategy also usedto obtain in asymmetric a very versatile synthesis intermediate to obtain compounds in organic of natural synthesis, or pharmacological the Wieland– interest,Miescher such ketone as steroids [15]. [16], or eritromicine antibiotics [17]. It was also exploited in different and more versatileProline reaction was pathways, also used such in as asymmetric the cyclisation synt of racemichesis to diketones obtain [comp18], orounds to eff ectof Knoevenagelnatural or condensationpharmacological [19 ,interest,20], Mannich such reactions,as steroids and [16], many or eritromicine more [21]. antibiotics [17]. It was also exploited in different and more versatile reaction pathways, such as the cyclisation of racemic diketones [18], 2.1.or to Synergistic effect Knoevenagel Catalysis with condensation Proline-Based [19, Catalysts20], Mannich reactions, and many more [21].

2.1.1. Combination with Transition Metal-Based Catalysts The combination of transition metal catalysis and organocatalysis gained increasing recognition, improving several reactions [22]. One of the first groundbreaking examples of metal- and organo-catalysis working in concert was reported by the Cordova research group in 2006 [23].

Catalysts 2019, 9, x FOR PEER REVIEW 5 of 36 Catalysts 2019, 9, x FOR PEER REVIEW 5 of 36 2.1. Synergistic Catalysis with Proline-Based Catalysts 2.1. Synergistic Catalysis with Proline-Based Catalysts 2.1.1. Combination with Transition Metal-Based Catalysts 2.1.1. Combination with Transition Metal-Based Catalysts The combination of transition metal catalysis and organocatalysis gained increasing recognition, CatalystsThe2019 combination, 9, 928 of transition metal catalysis and organocatalysis gained increasing recognition,5 of 35 improving several reactions [22]. One of the first groundbreaking examples of metal- and organo- improving several reactions [22]. One of the first groundbreaking examples of metal- and organo- catalysis working in concert was reported by the Cordova research group in 2006 [23]. They proposed catalysis working in concert was reported by the Cordova research group in 2006 [23]. They proposed Theya direct proposed catalytic a direct allylic catalytic alkylation allylic of alkylationaldehydes of and aldehydes cyclic andketones. cyclic The ketones. intermolecular The intermolecular α-allylic a direct catalytic allylic alkylation of aldehydes and cyclic ketones. The intermolecular α-allylic αalkylation-allylic alkylation reaction, reaction, which whichhas the has advantage the advantage of being of being highly highly chemo- chemo- and and regio-selective, regio-selective, was alkylation reaction, which has the advantage of being highly chemo- and regio-selective, was performed through an unprecedented combination of palladium and enamine mediated catalysis. performed through an unprecedented combination of palladium and enamine mediated catalysis. They described the reaction of 3-phenylpropionaldehyde (11,, 3 equiv.) with allyl acetate acetate ( (12,, 1 1 equiv.) equiv.) They described the reaction of 3-phenylpropionaldehyde (11, 3 equiv.) with allyl acetate (12, 1 equiv.) inin the presence presence of of a a catalytic catalytic amount amount of of palladium palladium catalyst catalyst [Pd(PPh [Pd(PPh3)4] 3(5)4 ]mol%) (5 mol%) and andpyrrolidine pyrrolidine VIII in the presence of a catalytic amount of palladium catalyst [Pd(PPh3)4] (5 mol%) and pyrrolidine VIII VIII(10 mol%)(10 mol%) in dimethyl in dimethyl sulfoxide sulfoxide at room at room temperature. temperature. The corresponding The corresponding α-benzylicα-benzylic alcohol alcohol 14 was14 (10 mol%) in dimethyl sulfoxide at room temperature. The corresponding α-benzylic alcohol 14 was wasisolated isolated in 72% in 72% yield yield after after 16 16h by h by reduction reduction with with NaBH NaBH4 4ofof the the αα-allylic-allylic alkylated alkylated aldehyde 13 isolated in 72% yield after 16 h by reduction with NaBH4 of the α-allylic alkylated aldehyde 13 (Scheme(Scheme4 4).). (Scheme 4).

Scheme 4. Synergistic catalysis mediated by palladium and pyrrolidine. Scheme 4. Synergistic catalysis mediated by palladium and pyrrolidine. Merging two powerful powerful catalytic catalytic cycles cycles enables enables both both electrophilic electrophilic and and nucleophilic nucleophilic activation. activation. As Merging two powerful catalytic cycles enables both electrophilic and nucleophilic activation. As Asdepicted depicted in Scheme in Scheme 5, 5the, the C–C C–C bond bond formation formation is is allowed allowed by by the the catalytic catalytic enamine intermediateintermediate 11a depicted in Scheme 5, the C–C bond formation is allowed by the catalytic enamine intermediate 11a generated in situ, which attacks the catalytically generated electrophilic palladium π-allyl complexes generated in situ, which attacks the catalytically generated electrophilic palladium π-allyl complexes 12a12a.. ReductiveReductive eliminationelimination and subsequentsubsequent hydrolysis ofof thethe iminiumiminium intermediateintermediate regeneratesregenerates thethe 12a. Reductive elimination and subsequent hydrolysis of the iminium intermediate regenerates the Pd(0) and the amine catalyst VIIIVIII,, andand yieldsyields thethe αα-allylic-allylic alkylatedalkylated aldehydealdehyde 1313.. Pd(0) and the amine catalyst VIII, and yields the α-allylic alkylated aldehyde 13.

Scheme 5. Mechanistic insight in synergistic palladiumpalladium and pyrrolidine-based catalysis. Scheme 5. Mechanistic insight in synergistic palladium and pyrrolidine-based catalysis. The reaction proved to work smoothly with a range of aldehydes 15 (Scheme6a) and ketones 18 (Scheme6b) with high chemoselectivity. Unfortunately, the catalytic asymmetric variant provided the α-allylic alkylated alcohol 17 or ketone 19 with high enantioselectivity, but in moderate yields (yields 25% and 20%, ee 74% and 88%, respectively). Catalysts 2019, 9, x FOR PEER REVIEW 6 of 36 Catalysts 2019, 9, x FOR PEER REVIEW 6 of 36 The reaction proved to work smoothly with a range of aldehydes 15 (Scheme 6a) and ketones 18 The reaction proved to work smoothly with a range of aldehydes 15 (Scheme 6a) and ketones 18 (Scheme 6b) with high chemoselectivity. Unfortunately, the catalytic asymmetric variant provided (Scheme 6b) with high chemoselectivity. Unfortunately, the catalytic asymmetric variant provided the α-allylic alkylated alcohol 17 or ketone 19 with high enantioselectivity, but in moderate yields Catalyststhe α-allylic2019, 9 ,alkylated 928 alcohol 17 or ketone 19 with high enantioselectivity, but in moderate yields6 of 35 (yields 25% and 20%, ee 74% and 88%, respectively). (yields 25% and 20%, ee 74% and 88%, respectively).

Scheme 6. General α-allylation of of aldehydes ( (a)) or ketones ( b) via synergistic catalysis mediated by Scheme 6. General α-allylation of aldehydes (a) or ketones (b) via synergistic catalysis mediated by palladium and pyrrolidine. palladium and pyrrolidine. Since then, several synergistic catalytic approa approachesches based on transition metal catalysis and Since then, several synergistic catalytic approaches based on transition metal catalysis and aminocatalysis were developed. Pr Promptedompted by the great results obtain obtaineded through synergistic catalysis aminocatalysis were developed. Prompted by the great results obtained through synergistic catalysis and their growing interest in natural product-like compound synthesissynthesis [[24–26].24–26]. Wu et al. described a and their growing interest in natural product-like compound synthesis [24–26]. Wu et al. described a novel and promising one-pot combination of silver tr triflateiflate and proline catalysis provided an efficient efficient novel and promising one-pot combination of silver triflate and proline catalysis provided an efficient route for the the synthesis synthesis of of 1,2- 1,2-dihydroisoquinolinedihydroisoquinoline derivatives derivatives 2222 viavia multicomponent multicomponent reactions reactions of of2- route for the synthesis of 1,2-dihydroisoquinoline derivatives 22 via multicomponent reactions of 2- alkynylbenzaldehydes2-alkynylbenzaldehydes 2020, amines, amines 2121, and, and ketones ketones 1818 [27][27 (Scheme] (Scheme 7).7). alkynylbenzaldehydes 20, amines 21, and ketones 18 [27] (Scheme 7).

Scheme 7. SynergisticSynergistic catalysis mediated by silver-based and proline catalysis. Scheme 7. Synergistic catalysis mediated by silver-based and proline catalysis. Merging two powerful catalytic cycles enables both electrophilic and nucleophilic activation. activation. Merging two powerful catalytic cycles enables both electrophilic and nucleophilic activation. The mild metal metal Lewis Lewis acids acids tested, tested, such such as as silver silver,, coordinate coordinate the the triple triple bond bond of ofthe the starting starting 2- The mild metal Lewis acids tested, such as silver, coordinate the triple bond of the starting 2- alkynylbenzaldehyde2-alkynylbenzaldehyde 20,20 making, making it more it more electrophilic, electrophilic, while while proline proline simultaneously simultaneously generates generates the alkynylbenzaldehyde 20, making it more electrophilic, while proline simultaneously generates the nucleophilicthe nucleophilic enamine enamine intermediate. intermediate. nucleophilic enamine intermediate. Together with silver, goldgold waswas usedused asas thethe metalmetal partner.partner. The firstfirst example of Au(I)-enamine Together with silver, gold was used as the metal partner. The first example of Au(I)-enamine synergistic catalysis catalysis was was reported reported in in 2008 2008 by by Kirsh Kirsh et et al. al. [28]. [28 ].The The authors authors performed performed a cyclisation a cyclisation of synergistic catalysis was reported in 2008 by Kirsh et al. [28]. The authors performed a cyclisation of theof the alkyne alkyne aldehydes aldehydes 2323 to to2424 oror 2525 providingproviding racemic racemic products products with with excellent excellent yields yields (Scheme (Scheme 88a).a). the alkyne aldehydes 23 to 24 or 25 providing racemic products with excellent yields (Scheme 8a). The proposed proposed mechanism mechanism features features a asimultaneous simultaneous enamine enamine formation formation at the at theterminal terminal aldehyde aldehyde and The proposed mechanism features a simultaneous enamine formation at the terminal aldehyde and aand π-acid a π -acidactivation activation at the triple at the bond. triple This bond. protocol, This however, protocol, comes however, with an comes inherent with challenge: an inherent If R a π-acid activation at the triple bond. This protocol, however, comes with an inherent challenge: If R ischallenge: H, the Au(I)-catalysed If R is H, the cyclisation Au(I)-catalysed results cyclisation in an exocyclic results terminal in an exocyclic alkene after terminal protodeauration, alkene after is H, the Au(I)-catalysed cyclisation results in an exocyclic terminal alkene after protodeauration, protodeauration,which spontaneously which isomerizes spontaneously to the isomerizes thermodynamically to the thermodynamically more stable more compound stable compound 25. This which spontaneously isomerizes to the thermodynamically more stable compound 25. This isomerization25. This isomerization removes removesthe new stereogenic the new stereogenic center created center during created the during carbon-carbon the carbon-carbon bond formation bond isomerization removes the new stereogenic center created during the carbon-carbon bond formation step.formation If R is step. a methyl If R isgroup, a methyl a quat group,ernary a quaternarystereocenter stereocenter bearing product bearing 24 productis created24 inis up created to 72% in upstep. to If 72% R is yield. a methyl An enantioselectivegroup, a quaternary version stereocenter of this reaction bearing was product later reported 24 is created by Jørgensen in up to et72% al.

(Scheme 8b) [ 29]. They exploited the sterically bulky Jørgensen-Hayashi catalyst X to induce the attack of 26 to an α,β-unsaturated aldehyde 9 via iminium-ion activation. The first Michael addition creates Catalysts 2019, 9, x FOR PEER REVIEW 7 of 36

yield. An enantioselective version of this reaction was later reported by Jørgensen et al. (Scheme 8b) [29]. They exploited the sterically bulky Jørgensen-Hayashi catalyst X to induce the attack of 26 to an α,β-unsaturatedCatalysts 2019, 9, x FORaldehyde PEER REVIEW 9 via iminium-ion activation. The first Michael addition7 createsof 36 an Catalystsintermediate,2019, 9, 928which undergoes synergistic enamine/Au(I) catalysis to obtain the carbocyclisation7 of 35 yield. An enantioselective version of this reaction was later reported by Jørgensen et al. (Scheme 8b) reaction with high enantio-enrichment of 28 in good to excellent yields. [29]. They exploited the sterically bulky Jørgensen-Hayashi catalyst X to induce the attack of 26 to an an intermediate,α,β-unsaturated which aldehyde undergoes 9 via iminium-ion synergistic enamineactivation./Au(I) The catalysisfirst Michael to obtain addition the carbocyclisationcreates an reactionintermediate, with high which enantio-enrichment undergoes synergistic of 28 enamine/in goodAu(I) to excellent catalysis yields. to obtain the carbocyclisation reaction with high enantio-enrichment of 28 in good to excellent yields.

Scheme 8. General α-allylation of aldehydes (a) or ketones (b) via synergistic catalysis mediated by Scheme 8. General α-allylation of aldehydes (a) or ketones (b) via synergistic catalysis mediated by palladiumScheme and8. General pyrrolidine. α-allylation of aldehydes (a) or ketones (b) via synergistic catalysis mediated by palladiumpalladium and and pyrrolidine. pyrrolidine.

Inspired by metal-associated enzymes, Kudo’s re researchsearch group designed a biomimetic catalysis, exploitingInspired the cooperation by metal-associated of a resin-supported enzymes, Kudo’s peptide research catalyst group anddesigned Fe-based a biomimetic metal catalyst. catalysis, exploitingexploiting the the cooperation cooperation of of a a resin-supportedresin-supported peptide peptide catalyst catalyst and and Fe-based Fe-based metal metal catalyst. catalyst. The combination of the peptide containing polyleucine and FeCl2 in two catalytic cycles was highly TheThe combination combination of the of peptide the peptide containing containing polyleucine polyleucine and FeCl and2 in two FeCl catalytic2 in two cycles catalytic was highly cycles was efficient to allow the asymmetric oxyamination of aldehydes in aqueous media [30] (Scheme 9). highlyefficient efficient to allow to allow the asymmetric the asymmetric oxyamination oxyamination of aldehydes of aldehydes in aqueous in media aqueous [30] media (Scheme [30 9).] (Scheme9).

Scheme 9. Synergistic iron- and peptide-mediated catalysis. Scheme 9. Synergistic iron- and peptide-mediated catalysis. Scheme 9. Synergistic iron- and peptide-mediated catalysis. The oxyamination of 3-phenylpropanal 11 is performed with TEMPO 29 using iron(III) chloride The oxyamination of 3-phenylpropanal 11 is performed with TEMPO 29 using iron(III) chloride inThe the oxyaminationpresence of the of peptide 3-phenylpropanal catalyst. The 11reaction is performed is carried with out TEMPOin THF/H 292O using1/2 (v /iron(III)v) at room chloride in the presence of the peptide catalyst. The reaction is carried out in THF/H2O 1/2 (v/v) at room in thetemperature; presence increasingof the peptide the amount catalyst. of water The inreaction the system is carried THF/H 2outO from in THF/H1/1 to 1/22O increases1/2 (v/v )the at room temperature;hydrophobic increasing effect and causes the amount an acceleration of water of inthe the desired system product THF formation./H2O from The 1/ best1 to results 1/2 increases were the temperature; increasing the amount of water in the system THF/H2O from 1/1 to 1/2 increases the hydrophobic effect and causes an acceleration of the desired product formation. The best results were hydrophobicobtained by effect introducing and causes a polyleucine an acceleration chain between of the desiredthe terminal product prolyl formation. residue of Thepeptide best catalyst results were obtainedand its by support. introducing This structural a polyleucine change chain enhances between the reaction the terminal rate and prolyl increases residue the enantioselectivity of peptide catalyst and obtained by introducing a polyleucine chain between the terminal prolyl residue of peptide catalyst its support.[31]. This structural change enhances the reaction rate and increases the enantioselectivity [31]. and its support. This structural change enhances the reaction rate and increases the enantioselectivity Following studies showed that the amount of iron(III) chloride could be decreased to catalytic [31]. amount using dioxygen as the oxidant [32]. The best improvement is achieved by performing the reaction with iron(II) chloride under an air atmosphere; the oxyaminated product is obtained within 1 h, without using an oxidazing agent. This reaction system proved to be efficient enough that the loading Catalysts 2019,, 9,, xx FORFOR PEERPEER REVIEWREVIEW 8 of 36

Following studies showed that the amount of iron(III) chloride could be decreased to catalytic Catalystsamount2019 using, 9, 928 dioxygen as the oxidantidant [32].[32]. TheThe bestbest improvementimprovement isis achievedachieved byby performingperforming8 of thethe 35 reaction with iron(II) chloride under an air atmosphere; the oxyaminated product is obtained within 1 h, without using an oxidazing agent. This reaction systemsystem provedproved toto bebe efficientefficient enoughenough thatthat thethe of the peptide catalyst could be reduced to 3 mol% without any loss in yield and enantioselectivity, loadingloading ofof thethe peptidepeptide catalystcatalyst couldcould bebe reducedreduced toto 33 mol%mol% withoutwithout anyany lossloss inin yieldyield andand by increasing the reaction time. enantioselectivity, by increasing the reaction time. Based on this concept, in 2018 Rios et al. reported the first synergistic organocascade reaction for Based on this concept, in 2018 Rios et al. reported the first synergistic organocascade reaction for the synthesis of cyclopropanes 32 with an unusual cis configuration between the benzoxazole and the the synthesis of cyclopropanes 32 withwith anan unusualunusual ciscis configurationconfiguration betweenbetween thethe benzoxazolebenzoxazole andand substituted phenyl ring with good yields and steroselectivities [33] (Scheme 10). the substituted phenyl ring with good yields andand steroselectivitiessteroselectivities [33][33] (Scheme(Scheme 10).10).

Scheme 10. Synergistic catalysis mediated by palladium and Jørgensen-Hayashi catalyst. Scheme 10. Synergistic catalysis mediated by palladium and Jørgensen-Hayashi catalyst. The reaction proceeds via a simultaneous organocatalytic activation of enals with a secondary amineThe catalyst reaction and proceeds the metal via Lewis a simultaneous acid-based organocatalytic activation of benzoxazoles; activation of theenals stereocontrol with a secondary in this protocolamine catalyst is imparted and the by metal the chiral Lewis organocatalyst, acid-based activation thus avoiding of benzoxazoles; the need of expensivethe stereocontrol chiral ligands in this protocolfor the metal. is imparted The palladium by the chiral catalyst organocatalyst, coordinates thus to the avoiding nitrogen the atom need of of the expensive heterocycle, chiral increasing ligands forthe the acidity metal. of The the adjacentpalladium alkyl catalyst chain, coordinates while the to Jørgensen-Hayashi the nitrogen atom catalystof the heterocycle,X activates increasing the enals, thegenerating acidity of an the electrophilic adjacent alkyl iminium-ion chain, while intermediate; the Jørgensen-Hayashi these two species catalyst can X then activates react rapidlythe enals, to generatinggenerate a newan electrophilic C–C bond in iminium-ion the cyclopropane intermediate; precursor these (Scheme two 11 species). can then react rapidly to generate a new C–C bond in the cyclopropane precursor (Scheme 11).

Scheme 11. Mechanistic insight in the synthesis of the cyclopropane precursor to compounds 32a and 32b. Scheme 11. Mechanistic insight in the synthesis of thethe cyclopropanecyclopropane precursorprecursor toto compoundscompounds 32a andand 32bThe.. same research group reported another interesting example by merging organocatalysis via iminium-ion with ytterbium-based metal catalysis to prepare dihydroacridines [34]. The reaction The same research group reported another interesting example by merging organocatalysis via proceeds via the activation of quinolines derivatives 33 with Yb(OTf) and the concurrent enals iminium-ioniminium-ion withwith ytterbium-basedytterbium-based metalmetal catalysiscatalysis to prepare dihydroacridines3 [34]. The reaction activation via iminium-ion by the TMS-protected diaryl prolinol X (Scheme 12). proceeds via the activation of quinolines derivatives 33 withwith Yb(OTf)Yb(OTf)3 andand thethe concurrentconcurrent enalsenals The metal Lewis acid coordinates the aromatic nitrogen and increases the nucleophilicity of activation via iminium-ion by the TMS-protected diaryl prolinol X (Scheme(Scheme 12).12). the α-methylene that can react with the iminium-ion generated from the enal. The formed enolate The metal Lewis acid coordinates the aromatic nitrogen and increases the nucleophilicity of the intermediate undergoes an intramolecular aldol reaction with the carbaldehyde. The subsequent α-methylene that can react with the iminium-ion generated from the enal. The formed enolate 6-exo-trig cyclisation, followed by a dehydration, yields the desired dihydroacridine 34.

Catalysts 2019, 9, x FOR PEER REVIEW 9 of 36 intermediate undergoes an intramolecular aldol reaction with the carbaldehyde. The subsequent 6- exo-trig cyclisation, followed by a dehydration, yields the desired dihydroacridine 34.

CatalystsCatalysts 20192019,, 99,, xx FORFOR PEERPEER REVIEWREVIEW 99 ofof 3636 intermediateintermediate undergoesundergoes anan intramolecularintramolecular aldolaldol reactionreaction withwith thethe carbaldehyde.carbaldehyde. TheThe subsequentsubsequent 6-6- Catalysts 2019, 9, 928 9 of 35 exo-trig cyclisation, followed by a dehydration, yields the desired dihydroacridine 34. exo-trig cyclisation, followed by a dehydration, yields the desired dihydroacridine 34. Scheme 12. Merging organocatalysis via iminium-ion with ytterbium-based metal catalysis.

2.1.2. Combination with Other Organocatalysts In 2007, Hong et al. reported an interesting method to access a precursor employed in the total synthesis of (+)-palitantine (Scheme 13) [35]. The reaction is a formal self-dimerization [4 + 2] addition of (E)-4-acetoxycrotonaldehyde activated by L-proline in presence of a trialkyl amine as a co-catalyst. Given the type of reaction, the pathway can only evolve if the reagent is activated in two different ways by the same catalyst. This is, fortunately, the case, given the complementary types of activation that proline can effect. While Scheme 12. Merging organocatalysis via iminium-ion with ytterbium-based metal catalysis. one aldehydeScheme is 12.activated Merging via organocatalysis an electrophilic via iminium-ion iminium-ion with intermediate, ytterbium-based the metal other catalysis. one proceeds 2.1.2.through Combination a nucleophilic with dienamine Other Organocatalysts intermediate. At this point, the electronic rearrangement will 2.1.2. Combination with Other Organocatalysts produce2.1.2. Combination the intermediate with Other compound Organocatalysts 37 with the formation of two new C–C bonds. Triethylamine In 2007, Hong et al. reported an interesting method to access a precursor employed in the total was addedIn 2007, as Hong a co-catalyst et al. reported to improve an interesting the reaction method time and to accessthe yield; a precursor this way, employed the reaction in couldthe total be synthesisIn 2007, of ( +Hong)-palitantine et al. reported (Scheme an 13 interesting)[35]. method to access a precursor employed in the total synthesiscarriedsynthesis out ofof at (+)-palitantine(+)-palitantine a lower temperature, (Scheme(Scheme providing 13)13) [35].[35]. a higher enantiomeric excess. TheThe reactionreaction isis aa formalformal self-dimerizationself-dimerization [4[4 ++ 2]2] additionaddition ofof ((EE)-4-acetoxycrotonaldehyde)-4-acetoxycrotonaldehyde activatedactivated byby LL-proline-proline inin presencepresence ofof aa trialkyltrialkyl amineamine asas aa co-catalyst.co-catalyst. GivenGiven thethe typetype ofof reaction,reaction, thethe pathwaypathway cancan onlyonly evolveevolve ifif thethe reagentreagent isis activatedactivated inin twotwo differentdifferent waysways byby thethe samesame catalyst.catalyst. ThisThis is,is, fortunately,fortunately, thethe case,case, givengiven thethe complementarycomplementary tytypespes ofof activationactivation thatthat prolineproline cancan effect.effect. WhileWhile oneone aldehydealdehyde isis activatedactivated viavia anan electrophilicelectrophilic iminium-ioniminium-ion intermediate,intermediate, thethe otherother oneone proceedsproceeds throughthrough aa nucleophilicnucleophilic dienaminedienamine intermediate.intermediate. AtAt thisthis point,point, thethe electronicelectronic rearrangementrearrangement willwill produceproduce thethe intermediateintermediate compoundcompound 3737 withwith thethe formationformation ofof twotwo newnew C–CC–C bonds.bonds. TriethylamineTriethylamine waswas addedadded asasScheme aa co-catalystco-catalyst 13. Formation toto improveimprove of new thethe C–C reactionreaction bonds titi mediatedmeme andand thethe by proline yield;yield; this andthis way, triethylamine.way, thethe reactionreaction couldcould bebe Scheme 13. Formation of new C–C bonds mediated by proline and triethylamine. carriedcarried outout atat aa lowerlower temperature,temperature, providingproviding aa higherhigher enantiomericenantiomeric excess.excess. The reaction is a formal self-dimerization [4 + 2] addition of (E)-4-acetoxycrotonaldehyde activated by L-prolineWhile Hong in presence presented of a trialkyl a synergistic amine as activation a co-catalyst. using Given the thesame type catalyst of reaction, to activate the pathway the two can onlyreaction evolve partners, if the reagent Xu et isal. activated reported in an two enanti differentoselective ways bydomino the same oxa-Michael-Mannich catalyst. This is, fortunately, reaction thebetween case, givensalicylaldehyde the complementary 38 and typescyclohexenones of activation 39 that, activating proline can the eff ect.reaction While partners one aldehyde with isa activatedcombination via anof a electrophilic primary and iminium-ion a secondary intermediate, chiral amine the (Scheme other one14) proceeds[36]. through a nucleophilic dienamine intermediate. At this point, the electronic rearrangement will produce the intermediate compound 37 with the formation of two new C–C bonds. Triethylamine was added as a co-catalyst to improve the reaction time and the yield; this way, the reaction could be carried out at a lower temperature,Scheme providingScheme 13.13. aFormationFormation higher enantiomeric ofof newnew C–CC–C bondsbonds excess. mediatedmediated byby prolineproline andand triethylamine.triethylamine. While Hong presented a synergistic activation using the same catalyst to activate the two reaction While Hong presented a synergistic activation using the same catalyst to activate the two partners,While Xu Hong et al. presented reported a an synergistic enantioselective activation domino using oxa-Michael-Mannich the same catalyst to reactionactivate betweenthe two reaction partners, Xu et al. reported an enantioselective domino oxa-Michael-Mannich reaction salicylaldehydereaction partners,38 andXu et cyclohexenones al. reported an39 ,enanti activatingoselective the reaction domino partners oxa-Michael-Mannich with a combination reaction of a between salicylaldehyde 38 and cyclohexenones 39, activating the reaction partners with a primarybetween andsalicylaldehyde a secondary chiral 38 and amine cyclohexenones (Scheme 14)[36 39]. , activating the reaction partners with a combinationcombination ofof aa primaryprimary andand aa secondarysecondary chiralchiral amineamine (Scheme(Scheme 14)14) [36].[36].

Scheme 14. Synergistic catalysis based on a primary and a secondary amines activation. Catalysts 2019, 9, x FOR PEER REVIEW 10 of 36 Catalysts 2019, 9, 928 10 of 35 Scheme 14. Synergistic catalysis based on a primary and a secondary amines activation. The amino acid, a primary amine, condenses with salicylaldehyde 38 to form imine 38a. A proline The amino acid, a primary amine, condenses with salicylaldehyde 38 to form imine 38a. A derivative XI generates an iminium-ion intermediate reacting with cyclohexenones 39 (Scheme 15). proline derivative XI generates an iminium-ion intermediate reacting with cyclohexenones 39 The intermediates formed with the two different catalysts can then react via an oxa-Michael-Mannich (Scheme 15). The intermediates formed with the two different catalysts can then react via an oxa- reaction. The depicted transition state was confirmed by Fourier-transform ion cyclotron resonance Michael-Mannich reaction. The depicted transition state was confirmed by Fourier-transform ion mass spectroscopy. cyclotron resonance mass spectroscopy.

Scheme 15. Mechanistic insight in the enantioselective domino oxa-Michael-Mannich reaction. Scheme 15. Mechanistic insight in the enantioselective domino oxa-Michael-Mannich reaction. 2.1.3. Combination with Photocatalysts 2.1.3. Combination with Photocatalysts Photochemical reactions, together with enzymatically catalysed reactions, are generally considered as thePhotochemical beginning of the reactions, green chemistry together concept with forenzy syntheticmatically chemistry catalysed [37]. Solarreactions, light isare undoubtedly generally theconsidered cleanest as source the beginning of energy of and the the green photon chemistry is considered concept a for traceless synthetic regent chemistry [38]. Photocatalysis [37]. Solar light with is visibleundoubtedly light [39 the] is cleanest undoubtedly source one of of energy the emerging and the strategies photon to is meet considered the increasing a traceless demand regent for more[38]. sustainablePhotocatalysis chemical with visible processes. light [39] is undoubtedly one of the emerging strategies to meet the increasingA number demand of powerful for more methods sustainable has beenchemical recently processes. developed applying organometallic complexes 2+ + suchA as [Ru(bpy)number 3of] powerfuland [Ir(ppy) methods2(dtb-bpy)] has wherebeen re bpycently= 2,2 developed0-bipyridine, applying ppy = 2-phenylpyridine organometallic 3 2+ 2 + andcomplexes dtb-bpy such= 4,4 0as-di-tertbutyl-2,2 [Ru(bpy) ] 0and-bipyridine [Ir(ppy) [40(dtb-bpy)],41]. The redox where potential bpy = of2,2 the′-bipyridine, metal complexes ppy = can 2- bephenylpyridine readily fine-tuned and bydtb-bpy ligand = modification.4,4′-di-tertbutyl-2,2′-bipyridine [40,41]. The redox potential of the metalHowever, complexes due can to be the readily high cost fine and-tuned potential by ligand toxicity modification. of the ruthenium and iridium salts, as well as theirHowever, limited availability, due to the organic high cost dyes and could potential also betoxici successfullyty of the ruthenium used in photoredox and iridium catalysis salts, insteadas well ofas atheir metal limited catalyst availability, [42]. organic dyes could also be successfully used in photoredox catalysis insteadOf particularof a metal notecatalyst is the [42]. cooperative combination of photocatalysis with an organocatalytic cycle, offeringOf particular catalytic methodsnote is the for cooperative the enantioselective combinationα of-alkylation photocatalysis [41], αwith-perfluoroalkylation an organocatalytic [ 43cycle,] or αoffering-benzylation catalytic [44 ]methods of aldehydes for the (Scheme enantioselective 16). α-alkylation [41], α-perfluoroalkylation [43] or α- benzylationIn the first[44] of case, aldehydes in particular, (Scheme the 16). authors proposed two interwoven catalytic cycles that simultaneously generate an electron-rich enamine from the condensation of an aldehyde with the chiral amine catalyst and an electron-deficient alkyl radical via reduction of an alkyl bromide with a 2+ Ru(II) photoredox catalyst. It is well known that [Ru(bpy)3] will readily accept a photon from a light 2+ source to populate the *[Ru(bpy)3] metal to ligand charge transfer (MLCT) excited states. These high energy intermediates remove a single electron from a sacrificial quantity of enamine to form Ru(I) that react via single-electron transfer with the α-bromocarbonyl substrate to furnish the reactive alkyl radical (and Ru(II)) able to react with the enamine formed in the complementary organocatalytic cycle.

Catalysts 2019, 9, 928 11 of 35 Catalysts 2019, 9, x FOR PEER REVIEW 11 of 36

Scheme 16. Synergistic catalysis of proline derivative working in combination with photocatalysis Scheme 16. Synergistic catalysis of proline derivative working in combination with photocatalysis performedperformed by the by MacMillan the MacMillan research research group. group.

The sameIn the reaction first case, of αin-alkylation particular, ofthe aldehydes authors proposed was proposed two interwoven by Zeitler catalytic et al. cycles in 2011, that using a metal-freesimultaneously cooperative generate asymmetric an electron-rich organophotoredox enamine fromcatalysis the condensation approach of an mediated aldehyde bywith luminescent the organicchiral dyes amine [42]. catalyst and an electron-deficient alkyl radical via reduction of an alkyl bromide with a Ru(II) photoredox2+ catalyst. It is well known that [Ru(bpy)3]2+ will readily accept a photon from a light [Ru(bpy)3] has been replaced with eosin EY that acts as a photoredox catalyst. After its source to populate the *[Ru(bpy)3]2+ metal to ligand charge transfer (MLCT) excited states. These high excitation with visible light and the population of its more stable triplet state (3EY*), the eosin excited energy intermediates remove a single electron from a sacrificial quantity of enamine to form Ru(I) state followsthat react areductive via single-electron quenching. transfer The with oxidation the α-bromocarbonyl of a catalytic substrate amount to furnish of enamine the reactive occurs alkyl to form – EY , whichradical subsequently (and Ru(II)) able reacts to react via with single-electron the enamine formed transfer in (SET)the complementary with alkyl halideorganocatalytic to provide the · electron-deficientcycle. alkyl radical (RAD). The additionThe same of reaction this radical of α-alkylation to the electron-richof aldehydes was olefin proposed of the by enamineZeitler et al. that in 2011, is simultaneously using a generatedmetal-free within cooperative the organocatalytic asymmetric organophotoredox cycle merges both catalysis activation approach pathways. mediated Inby theluminescent catalytic cycle, organic dyes [42]. the subsequent oxidation of the amino radical to the iminium species provides the electron for the [Ru(bpy)3]2+ has been replaced with eosin EY that acts as a photoredox catalyst. After its 3 reductiveCatalystsexcitation quenching 2019 with, 9, x FORvisible of PEER the light dyeREVIEW and excited the population state EY of* its (Scheme more stable 17). triplet state (3EY*), the eosin excited12 of 36 state follows a reductive quenching. The oxidation of a catalytic amount of enamine occurs to form EY⋅–, which subsequently reacts via single-electron transfer (SET) with alkyl halide to provide the electron-deficient alkyl radical (RAD). The addition of this radical to the electron-rich olefin of the enamine that is simultaneously generated within the organocatalytic cycle merges both activation pathways. In the catalytic cycle, the subsequent oxidation of the amino radical to the iminium species provides the electron for the reductive quenching of the dye excited state 3EY* (Scheme 17).

SchemeScheme 17. Mechanistic 17. Mechanistic insight insight in in the the reportedreported pr prolineoline and and photo-synergistic photo-synergistic catalysis. catalysis.

3. Hydrogen Bonding Catalysis Hydrogen bonding is an electrostatic interaction, so the typical value of bond energy between the catalyst and a substrate is around 10–30 kJ/mol. Asymmetric catalysts that can form hydrogen bonds are able to orient reagents, since the hydrogen bond is extremely directional. Moreover, by exalting acidity of the reaction partner, these kinds of catalyst affect the reactivity of the chemical species which they coordinate. In 1990, Kelly reported a reactivity study based on the Diels-Alder reaction between an α,β-unsaturated aldehyde as a dienophile, and different dienes. Bis-phenol derivatives act as catalysts and establish a double hydrogen bond with the oxygen on the dienophile; this implies that the gap in energy between the HOMO-LUMO orbitals decreases and, therefore, the speed of the desired reaction increases [45]. Usually a catalyst that exploits only hydrogen bonds to activate the reagents is not enough to establish the required stereocontrol; in fact, in general, an additional chiral catalyst or a bifunctional catalyst is needed. For example, Tsogoeva et al. reported the use of chiral diamino-compounds (XV– XVIII) as stoichiometric additives, besides a dipeptide catalyst (XIX–XX), to increase the efficiency of a conjugate addition of 2-nitropropane 46 to 2-cyclohexen-1-one 39 (Scheme 18).

Catalysts 2019, 9, 928 12 of 35

3. Hydrogen Bonding Catalysis Hydrogen bonding is an electrostatic interaction, so the typical value of bond energy between the catalyst and a substrate is around 10–30 kJ/mol. Asymmetric catalysts that can form hydrogen bonds are able to orient reagents, since the hydrogen bond is extremely directional. Moreover, by exalting acidity of the reaction partner, these kinds of catalyst affect the reactivity of the chemical species which they coordinate. In 1990, Kelly reported a reactivity study based on the Diels-Alder reaction between an α,β-unsaturated aldehyde as a dienophile, and different dienes. Bis-phenol derivatives act as catalysts and establish a double hydrogen bond with the oxygen on the dienophile; this implies that the gap in energy between the HOMO-LUMO orbitals decreases and, therefore, the speed of the desired reaction increases [45]. Usually a catalyst that exploits only hydrogen bonds to activate the reagents is not enough to establish the required stereocontrol; in fact, in general, an additional chiral catalyst or a bifunctional catalyst is needed. For example, Tsogoeva et al. reported the use of chiral diamino-compounds (XV–XVIII) as stoichiometric additives, besides a dipeptide catalyst (XIX–XX), to increase the efficiency Catalystsof a conjugate 2019, 9, xaddition FOR PEERof REVIEW 2-nitropropane 46 to 2-cyclohexen-1-one 39 (Scheme 18). 13 of 36

Scheme 18. ChiralChiral diamino-compounds as stoichiometric additive to a dipeptide catalyst. Bifunctional catalysts tend to be widely used since the spatial proximity of the catalytic units, Bifunctional catalysts tend to be widely used since the spatial proximity of the catalytic units, generating two types of interaction with the reagents, may promote a controlled transition state generating two types of interaction with the reagents, may promote a controlled transition state giving rise to high enantioselectivity. Jacobsen et al. reported ground-breaking examples in the area, giving rise to high enantioselectivity. Jacobsen et al. reported ground-breaking examples in the area, with chiral thiourea bifunctional catalysts [9]; it was established that the presence of two m-CF3 groups with chiral thiourea bifunctional catalysts [9]; it was established that the presence of two m-CF3 on the aromatic ring improves the efficiency of the reaction [8,12,46]. groups on the aromatic ring improves the efficiency of the reaction [8,12,46]. A related group of bifunctional catalysts is the squaramide-derived one, introduced by Rawal. A related group of bifunctional catalysts is the squaramide-derived one, introduced by Rawal. Thanks to the higher efficiency shown, this type of catalyst is proving increasingly successful Thanks to the higher efficiency shown, this type of catalyst is proving increasingly successful (Scheme 19) [47]. Moreover, thiosquaramides show superior performance compared to thioureas, as described by Wheeler and et al. [48].

Scheme 19. The addition to nitrostyrene catalyzed of squaramide-derived catalyst, introduced by Rawal.

Hydrogen bonding is very relevant in biological systems for several reasons; indeed, the architecture of hydrogen bonding bifunctional catalysts is inspired by the interactions within the cavity of enzymes. For example, Malkov reported an interesting study about the activation of two

Catalysts 2019, 9, x FOR PEER REVIEW 13 of 36

Scheme 18. Chiral diamino-compounds as stoichiometric additive to a dipeptide catalyst.

Bifunctional catalysts tend to be widely used since the spatial proximity of the catalytic units, generating two types of interaction with the reagents, may promote a controlled transition state giving rise to high enantioselectivity. Jacobsen et al. reported ground-breaking examples in the area, with chiral thiourea bifunctional catalysts [9]; it was established that the presence of two m-CF3 groups on the aromatic ring improves the efficiency of the reaction [8,12,46]. Catalysts 2019, 9, 928 13 of 35 A related group of bifunctional catalysts is the squaramide-derived one, introduced by Rawal. Thanks to the higher efficiency shown, this type of catalyst is proving increasingly successful (Scheme (Scheme19) [47]. Moreover, 19)[47]. Moreover,thiosquaramides thiosquaramides show superior show performance superior performance compared to compared thioureas, toas thioureas,described byas describedWheeler and by Wheeleret al. [48]. and et al. [48].

Scheme 19.19. TheThe addition addition to to nitrostyrene nitrostyrene catalyzed catalyzed of squaramide-derived of squaramide-derived catalyst, catalyst, introduced introduced by Rawal. by Rawal. Hydrogen bonding is very relevant in biological systems for several reasons; indeed, theCatalysts architectureHydrogen 2019, 9, x FORbonding of PEER hydrogen REVIEW is very bonding relevant bifunctional in biological catalysts systems is inspired for several by the reasons; interactions indeed, within14 ofthe 36 architecturethe cavity of of enzymes. hydrogen For bonding example, bifunctional Malkov reported catalysts an is interesting inspired by study the interactions about the activation within the of reagents by dipeptide-derivatives XXIIXXII in an enantioselective reaction of ketimines 51 using cavitytwo reagents of enzymes. by dipeptide-derivatives For example, Malkov reportedin an an enantioselective interesting study reaction about of the ketimines activation ofusing two trichlorosilane.trichlorosilane. The The complementarity between between the the re reagentsagents and the “catalytic site”, along with thethe weak weak interactioninteraction established, established, recalls recalls an enzyme.an enzyme. In the In transition the transition state 51a state, three 51a non-covalent, three non-covalent contacts arecontacts established are established between thebetween catalyst the and catalyst the two an reagents,d the two two reagents, hydrogen two bonds hydrogen and one bondsπ-π andinteraction one π- (Schemeπ interaction 20), thus(Scheme emphasizing 20), thus emphasizing the importance the of importance non-covalent of non-covalent bonds [49]. Therefore,bonds [49]. synergistic Therefore, activationssynergistic thatactivations exploit that the hydrogenexploit the bond hydrogen can help bond when can weakhelp when interactions weak interactions are not enough are not for successfulenough for activation. successful activation.

SchemeScheme 20.20. Enantioselective reduction of ketimines to the correspondingcorresponding secondary amines with aa dipeptide-deriveddipeptide-derived catalyst.catalyst. 3.1. Synergistic Catalysis with Hydrogen Bonding Catalysts 3.1. Synergistic Catalysis with Hydrogen Bonding Catalysts 3.1.1. Combination with Transition Metal-Based Catalysts 3.1.1. Combination with Transition Metal-Based Catalysts A catalytic system, combining Cinchona alkaloid-derived squaramide-based catalyst with AgSbF6 was reportedA catalytic by Zhao,system, Shi combining et al. to perform Cinchona a highly alkaloid-derived diastereo- and squaramide-based enantio-selective formalcatalyst [3 with+ 2] cycloadditionAgSbF6 was reported of α-aryl by isocyanoacetates Zhao, Shi et al. 52to withperformN-aryl-substituted a highly diastereo- maleimides and enantio-selective54 (Scheme 21 formal)[50]. [3 + 2] cycloaddition of α-aryl isocyanoacetates 52 with N-aryl-substituted maleimides 54 (Scheme 21) [50].

Scheme 21. Synergistic catalysis combining a Cinchona alkaloid-derived squaramide-based catalyst

with AgSbF6.

The high stereocontrol is provided by the synergistic catalytic system, in which one carbonyl group of the maleimide is hydrogen-bonded to the squaramide motif; at the same time, Ag(I) chelates to the terminal carbon of the isocyano group, enhancing the acidity of the isocyanoacetate proton that can, therefore, be deprotonated by the quinuclidine nitrogen of the Cinchona catalyst. This multifunctional, well-designed, transitional state orients the isocyanoacetate enolate to attack the maleimide; subsequently, a 5-endo-dig cyclisation takes place, forming the product 55 with a third stereocentre.

Catalysts 2019, 9, x FOR PEER REVIEW 14 of 36 reagents by dipeptide-derivatives XXII in an enantioselective reaction of ketimines 51 using trichlorosilane. The complementarity between the reagents and the “catalytic site”, along with the weak interaction established, recalls an enzyme. In the transition state 51a, three non-covalent contacts are established between the catalyst and the two reagents, two hydrogen bonds and one π- π interaction (Scheme 20), thus emphasizing the importance of non-covalent bonds [49]. Therefore, synergistic activations that exploit the hydrogen bond can help when weak interactions are not enough for successful activation.

Scheme 20. Enantioselective reduction of ketimines to the corresponding secondary amines with a dipeptide-derived catalyst.

3.1. Synergistic Catalysis with Hydrogen Bonding Catalysts

3.1.1. Combination with Transition Metal-Based Catalysts A catalytic system, combining Cinchona alkaloid-derived squaramide-based catalyst with AgSbF6 was reported by Zhao, Shi et al. to perform a highly diastereo- and enantio-selective formal [3 + 2] cycloaddition of α-aryl isocyanoacetates 52 with N-aryl-substituted maleimides 54 (Scheme 21)Catalysts [50].2019 , 9, 928 14 of 35

Scheme 21. Synergistic catalysis combining a Cinchona alkaloid-derived squaramide-based catalyst Scheme 21. Synergistic catalysis combining a Cinchona alkaloid-derived squaramide-based catalyst with AgSbF6. with AgSbF6. The high stereocontrol is provided by the synergistic catalytic system, in which one carbonyl The high stereocontrol is provided by the synergistic catalytic system, in which one carbonyl group of the maleimide is hydrogen-bonded to the squaramide motif; at the same time, Ag(I) group of the maleimide is hydrogen-bonded to the squaramide motif; at the same time, Ag(I) chelates chelates to the terminal carbon of the isocyano group, enhancing the acidity of the isocyanoacetate to the terminal carbon of the isocyano group, enhancing the acidity of the isocyanoacetate proton that proton that can, therefore, be deprotonated by the quinuclidine nitrogen of the Cinchona catalyst. can, therefore, be deprotonated by the quinuclidine nitrogen of the Cinchona catalyst. This This multifunctional, well-designed, transitional state orients the isocyanoacetate enolate to attack multifunctional, well-designed, transitional state orients the isocyanoacetate enolate to attack the the maleimide; subsequently, a 5-endo-dig cyclisation takes place, forming the product 55 with a maleimide; subsequently, a 5-endo-dig cyclisation takes place, forming the product 55 with a third thirdCatalysts stereocentre. 2019, 9, x FOR PEER REVIEW 15 of 36 stereocentre. Oh and Kim developed a domino aldol-cyclisation reaction between aldehydes 10 and methyl α-isocyanoacetateOh and Kim developed56 [51]. This a domino synergistic aldol-cy catalysisclisation exploits reaction a chiral between cobalt aldehydes complex, which 10 and works methyl in concertα-isocyanoacetate with an achiral 56 [51]. thiourea This synergistic (Scheme 22 catalysis). exploits a chiral cobalt complex, which works in concert with an achiral thiourea (Scheme 22).

Scheme 22. Domino aldol-cyclisation reaction between aldehydes 9 and methyl α-isocyanoacetate 56 Scheme 22. Domino aldol-cyclisation reaction between aldehydes 9 and methyl α-isocyanoacetate 56 catalysed by cobalt and thiourea catalysts. catalysed by cobalt and thiourea catalysts.

3.1.2. Combination with other Organocatalysts In 2011, Jacobsen reported a novel and elegant synergistic strategy to obtain tricyclic structures by [5 + 2] dipolar cycloaddition using a dual catalytic system [52]. The system consists of two different types of thiourea-based catalysts; while XXIV exploits the primary amino group for enamine activation, XXIII activates the other reaction partner via a H-bond. The synergistic catalysis was demonstrated with a series of reactions run with different bifunctional chiral catalysts in the presence and absence of XXIII; this way, a clear and dramatic cooperative effect was observed (Scheme 23).

Scheme 23. Synergistic catalysis mediated by two different thiourea-based catalysts.

The authors propose that XXIII induce ionization to the pyrylium ion and acts as a carboxylate- binding agent to generate, cooperatively with XXIV whose amine condenses with the ketone to yield

Catalysts 2019, 9, x FOR PEER REVIEW 15 of 36

Oh and Kim developed a domino aldol-cyclisation reaction between aldehydes 10 and methyl α-isocyanoacetate 56 [51]. This synergistic catalysis exploits a chiral cobalt complex, which works in concert with an achiral thiourea (Scheme 22).

CatalystsScheme2019, 9 ,22. 928 Domino aldol-cyclisation reaction between aldehydes 9 and methyl α-isocyanoacetate 5615 of 35 catalysed by cobalt and thiourea catalysts.

3.1.2. Combination with Other Organocatalysts 3.1.2. Combination with other Organocatalysts In 2011, Jacobsen reported a novel and elegant synergistic strategy to obtain tricyclic structures by In 2011, Jacobsen reported a novel and elegant synergistic strategy to obtain tricyclic structures [5 + 2] dipolar cycloaddition using a dual catalytic system [52]. by [5 + 2] dipolar cycloaddition using a dual catalytic system [52]. The system consists of two different types of thiourea-based catalysts; while XXIV exploits the The system consists of two different types of thiourea-based catalysts; while XXIV exploits the primary amino group for enamine activation, XXIII activates the other reaction partner via a H-bond. primary amino group for enamine activation, XXIII activates the other reaction partner via a H-bond. The synergistic catalysis was demonstrated with a series of reactions run with different bifunctional The synergistic catalysis was demonstrated with a series of reactions run with different bifunctional chiral catalysts in the presence and absence of XXIII; this way, a clear and dramatic cooperative effect chiral catalysts in the presence and absence of XXIII; this way, a clear and dramatic cooperative effect was observed (Scheme 23). was observed (Scheme 23).

Scheme 23. Synergistic catalysis mediated by two different thiourea-based catalysts. Scheme 23. Synergistic catalysis mediated by two different thiourea-based catalysts. The authors propose that XXIII induce ionization to the pyrylium ion and acts as a carboxylate-bindingThe authors propose agent that to generate,XXIII induce cooperatively ionization withto theXXIV pyryliwhoseum ion amine and acts condenses as a carboxylate- with the ketonebinding to agent yield to dienamine generate, cooperatively after tautomerisation, with XXIV the whose reactive amine ion pair condenses that undergoes with the intramolecularketone to yield cycloaddition. The initial substrate condensation with the primary amine function present on catalyst XXIV generates an electron delocalization, which involves a C–C bond breaking, also leaving a positive charge on the oxygen atom. The second catalyst XXIII, by forming a hydrogen bond, assists the leaving group on the substrate. In this regard, the dipolarophile cycloaddition may occur. Pihko developed a three-component reaction yielding a β,γ-functionalized aldehyde exploiting the synergy of a chiral secondary amine catalyst and a multiple-hydrogen-bond catalyst. This synthesis is a versatile strategy to avoid self-condensation of aldehydes and the whole study exemplifies the importance of evaluating the reactivity of each reaction partner during the synthesis design [53]. During the first reaction step, an aliphatic aldehyde 10, activated as iminium-ion by the amine catalyst, undergoes condensation with nitromethane 60, activated by the multiple H-bond donor catalyst XXV, providing a nitro-olefin 61. The nitro-olefin can then be activated by the H-bond catalyst and reacts with the nucleophilic aldehyde activated via enamine by the secondary amine catalyst, to yield the β,γ-functionalised aldehyde 62 (Scheme 24). Catalysts 2019, 9, x FOR PEER REVIEW 16 of 36 dienamine after tautomerisation, the reactive ion pair that undergoes intramolecular cycloaddition. The initial substrate condensation with the primary amine function present on catalyst XXIV generates an electron delocalization, which involves a C–C bond breaking, also leaving a positive charge on the oxygen atom. The second catalyst XXIII, by forming a hydrogen bond, assists the leaving group on the substrate. In this regard, the dipolarophile cycloaddition may occur. Pihko developed a three-component reaction yielding a β,γ-functionalized aldehyde exploiting the synergy of a chiral secondary amine catalyst and a multiple-hydrogen-bond catalyst. This synthesis is a versatile strategy to avoid self-condensation of aldehydes and the whole study exemplifies the importance of evaluating the reactivity of each reaction partner during the synthesis design [53]. During the first reaction step, an aliphatic aldehyde 10, activated as iminium-ion by the amine catalyst, undergoes condensation with nitromethane 60, activated by the multiple H-bond donor catalyst XXV, providing a nitro-olefin 61. The nitro-olefin can then be activated by the H-bond catalyst and reacts with the nucleophilic aldehyde activated via enamine by the secondary amine Catalysts 2019, 9, 928 16 of 35 catalyst, to yield the β,γ-functionalised aldehyde 62 (Scheme 24).

SchemeScheme 24.24. SynergisticSynergistic catalysis catalysis mediated mediated by aby chiral a chiral secondary secondary amine amine catalyst catalyst and a multiple and a hydrogenmultiple hydrogenbond thiourea-based bond thiour catalyst.ea-based catalyst. 3.1.3. Combination with Photocatalyst 3.1.3. Combination with Photocatalyst Photoredox catalysis has emerged recently as a powerful tool for the generation of synthetically Photoredox catalysis has emerged recently as a powerful tool for the generation of synthetically useful high-energy organic intermediates such as free radicals [54] and radical anions and cations [55,56]. useful high-energy organic intermediates such as free radicals [54] and radical anions and cations Successful efforts to induce enantioselective catalytic control in such photocatalysed processes have [55,56]. Successful efforts to induce enantioselective catalytic control in such photocatalysed relied, thus far, on covalent organocatalysis, and only recently on chiral anion-binding catalysts [57]. processes have relied, thus far, on covalent organocatalysis, and only recently on chiral anion-binding Stephenson et al. describe the successful development of a dual catalyst strategy with a chiral catalysts [57]. 2+ H-bond donor catalyst XXVI in combination with [Ru(bpy)3] , for the enantioselective oxidative Stephenson et al. describe the successful development of a dual catalyst strategy with a chiral alkylation of tetrahydroisoquinolines 63 with silyl ketene acetals 64 via enantioselective oxidative H-bond donor catalyst XXVI in combination with [Ru(bpy)3]2+, for the enantioselective oxidative Mannich reactions, to yield tetrahydroisoquinoline-derived β-amino esters 65 [58]. alkylation of tetrahydroisoquinolines 63 with silyl ketene acetals 64 via enantioselective oxidative An accurate screening of the reaction conditions, suitable for both transformations, allowed the Mannich reactions, to yield tetrahydroisoquinoline-derived β-amino esters 65 [58]. combination of two very different methodologies for obtaining products with high enantiomeric excess An accurate screening of the reaction conditions, suitable for both transformations, allowed the in good yields (Scheme 25). combination of two very different methodologies for obtaining products with high enantiomeric The asymmetric reduction of 1,2-diketones provides enantiomerically enriched α-hydroxy ketones, excess in good yields (Scheme 25). which are very useful as organic frameworks building blocks and as important intermediates in the pharmaceutical industry [59]. Based on the first work of Knowles et al. [60], where the presence of a hydrogen-bonding interaction between a Brønsted acid catalyst XXVII and the ketyl intermediate was

verified, Jiang et al. reported the first example of asymmetric photoredox reduction of 1,2-diketones through a dual catalysis platform using a H-bonding organocatalyst [61]. In an attempt to work without using metals as catalysts, they tested a dicyanopyrazine-derived chromophore (DPZ) as the photoredox catalyst instead of ruthenium derivatives. The reaction worked with 0.5 mol% of DPZ, 1.0 equiv of THIQ-2 (2-naphthyl N-substituted tetrahydroisoquinolines), 10 mol% guanidinium salt XXVII and 10 mol% of NaBArF in PhCl solvent at 0 ◦C and under irradiation with a 3 W blue LED, giving chiral secondary alcohols 67. All tested 1,2-diketones react completely, providing optically active α-hydroxy ketones in 60%–99% yields with 80%–98% ee (Scheme 26). Catalysts 2019, 9, x FOR PEER REVIEW 17 of 36

Catalysts 2019, 9, 928 17 of 35 Catalysts 2019, 9, x FOR PEER REVIEW 17 of 36

Scheme 25. Synergistic catalysis mediated by hydrogen bond thiourea-based catalyst and Ru-based photocatalyst.

The asymmetric reduction of 1,2-diketones provides enantiomerically enriched α-hydroxy ketones, which are very useful as organic frameworks building blocks and as important intermediates in the pharmaceutical industry [59]. Based on the first work of Knowles et al. [60], where the presence of a hydrogen-bonding interaction between a Brønsted acid catalyst XXVII and the ketyl intermediate was verified, Jiang et al. reported the first example of asymmetric photoredox reduction of 1,2-diketones through a dual catalysis platform using a H-bonding organocatalyst [61]. In an attempt to work without using metals as catalysts, they tested a dicyanopyrazine-derived chromophore (DPZ) as the photoredox catalyst instead of ruthenium derivatives. The reaction worked with 0.5 mol% of DPZ, 1.0 equiv of THIQ-2 (2-naphthyl N-substituted tetrahydroisoquinolines), 10 mol% guanidinium salt XXVII and 10 mol% of NaBArF in PhCl solvent at 0 °C and under irradiation with a 3 W blue LED, giving chiral secondary alcohols 67. All tested 1,2- diketones react completely, providing optically active α-hydroxy ketones in 60%–99% yields with 80%–98%Scheme ee (Scheme 25.25. Synergisticcatalysismediatedbyhydrogenbondthiourea-basedcatalystandRu-basedphotocatalyst.Synergistic 26). catalysis mediated by hydrogen bond thiourea-based catalyst and Ru-based photocatalyst.

The asymmetric reduction of 1,2-diketones provides enantiomerically enriched α-hydroxy ketones, which are very useful as organic frameworks building blocks and as important intermediates in the pharmaceutical industry [59]. Based on the first work of Knowles et al. [60], where the presence of a hydrogen-bonding interaction between a Brønsted acid catalyst XXVII and the ketyl intermediate was verified, Jiang et al. reported the first example of asymmetric photoredox reduction of 1,2-diketones through a dual catalysis platform using a H-bonding organocatalyst [61]. In an attempt to work without using metals as catalysts, they tested a dicyanopyrazine-derived chromophore (DPZ) as the photoredox catalyst instead of ruthenium derivatives. The reaction Scheme 26. Hydrogen-bond based catalyst working in concert with photocatalysis [60]. worked withScheme 0.5 26. Hydrogen-bondmol% of DPZ, based catalyst1.0 equiv working of in concertTHIQ-2 with photocatalysis(2-naphthyl [60].N-substituted tetrahydroisoquinolines),The possibility to select 10 amol% chiral guanidinium Brønsted acid salt for XXVII proton and shuttle 10 mol% permits of NaBArF two distinct in PhCl reductions, solvent throughat 0 °CThe and highlypossibility under enantioselective irradiation to select a with chiral protonation, a 3Brønsted W blue LED, andacid allows forgiving proton thechiral synthesisshuttle secondary permits of diverse alcohols two anddistinct 67 valuable. All reductions, tested chiral 1,2- throughαdiketones-hydroxy highly react ketones enantioselectivecompletely, with high providingee values.protonation, optically and active allows α the-hydroxy synthesis ketones of diverse in 60%–99% and valuable yields chiral with α80%–98%-hydroxy ee ketones (Scheme with 26). high ee values. 4. Cinchona Alkaloids Organocatalysis Cinchona alkaloids are a complex mixture of organic compounds derived from the bark of Cinchona and used for the treatment of malaria fever. This class of compounds presents five chiral centers and two different heterocycles, quinuclidine and a quinolinic one. (Figure3) Cinchona alkaloids are bifunctional catalysts (Figure4); the nitrogen atom in the quinuclidinic ring works as a base activator site which can deprotonate and activate through a base-catalyzed mechanism a nucleophile having a pKa = up to 10–11. After deprotonation, a tight ion pair is formed between the protonated catalyst and the deprotonated nucleophile, enabling a better enantiocontrol thanks to the steric hindrance. The 9-OH acts as a H-bond donor activating the electrophilic species [62] (Figure4 ). Cinchona alkaloids can be functionalized on the 9-OH with a range of functional groups, to obtain Scheme 26. Hydrogen-bond based catalyst working in concert with photocatalysis [60]. modular catalysts according to operative needs. In addition, their versatility derives from the fact that they can be easily functionalized as required in other positions, for example on the C5’ position, [63] The possibility to select a chiral Brønsted acid for proton shuttle permits two distinct reductions, or the nitrogen atom of the quinuclidinic portion can be quaternized to provide, for example, PTC through highly enantioselective protonation, and allows the synthesis of diverse and valuable chiral catalysts that enable the activation of nucleophilic substrates with a pK values between 11 and 21 α-hydroxy ketones with high ee values. a (Scheme 27).

Catalysts 2019, 9, x FOR PEER REVIEW 18 of 36

4. Cinchona Alkaloids Organocatalysis Cinchona alkaloids are a complex mixture of organic compounds derived from the bark of Cinchona and used for the treatment of malaria fever. This class of compounds presents five chiral centers and two different heterocycles, quinuclidine and a quinolinic one. (Figure 3)

Catalysts 2019, 9, x FOR PEER REVIEW 18 of 36

4. Cinchona Alkaloids Organocatalysis Cinchona alkaloids are a complex mixture of organic compounds derived from the bark of CatalystsCinchona2019 and, 9, 928used for the treatment of malaria fever. This class of compounds presents five 18chiral of 35 centers and two different heterocycles, quinuclidine and a quinolinic one. (Figure 3)

Figure 3. Cinchona alkaloids.

Cinchona alkaloids are bifunctional catalysts (Figure 4); the nitrogen atom in the quinuclidinic ring works as a base activator site which can deprotonate and activate through a base-catalyzed mechanism a nucleophile having a pKa = up to 10–11. After deprotonation, a tight ion pair is formed between the protonated catalyst and the deprotonated nucleophile, enabling a better enantiocontrol thanks to the steric hindrance. The 9-OH acts as a H-bond donor activating the electrophilic species [62] (Figure 4). Figure 3. Cinchona alkaloids. Figure 3. Cinchona alkaloids.

Cinchona alkaloids are bifunctional catalysts (Figure 4); the nitrogen atom in the quinuclidinic ring works as a base activator site which can deprotonate and activate through a base-catalyzed mechanism a nucleophile having a pKa = up to 10–11. After deprotonation, a tight ion pair is formed between the protonated catalyst and the deprotonated nucleophile, enabling a better enantiocontrol thanks to the steric hindrance. The 9-OH acts as a H-bond donor activating the electrophilic species [62] (Figure 4). Catalysts 2019, 9, x FOR PEER REVIEW 19 of 36

PTC catalysts that enable the activation of nucleophilic substrates with a pKa values between 11 and 21 (Scheme 27). Figure 4. Cinchona alkaloids as bifunctional catalysts. Figure 4. Cinchona alkaloids as bifunctional catalysts.

Cinchona alkaloids can be functionalized on the 9-OH with a range of functional groups, to obtain modular catalysts according to operative needs. In addition, their versatility derives from the fact that they can be easily functionalized as required in other positions, for example on the C5’ position, [63] or the nitrogen atom of the quinuclidinic portion can be quaternized to provide, for example,

Figure 4. Cinchona alkaloids as bifunctional catalysts.

Cinchona alkaloids can be functionalized on the 9-OH with a range of functional groups, to obtain modular catalysts according to operative needs. In addition, their versatility derives from the fact that they can be easily functionalized as required in other positions, for example on the C5’ position, [63] or the nitrogen atom of the quinuclidinic portion can be quaternized to provide, for example,

Scheme 27. Quinuclidinic proton quaternarization.

Cinchona alkaloids were first employed in organic chemistry in 1859 as a chiral auxiliary by Pasteur for the resolution of the racemate of tartaric acid [64]. The first asymmetric reaction employing Cinchona alkaloids was reported in 1912 by Bredig and Fiske [1]. Cinchonine Ia deprotonates HCN, forming a tight chiral ion pair that directs the attack of cyanide onto the benzaldehyde enantioselectively (Scheme 28).

HCN O OH N HO H HCN CN H * CN O N Ia N HO Ph H 2 Chiral ion pair 1 B*-R 1 Ia Catalyst: N H

OH N HO O N H CN * CN HO H 2 Ph H N Chiral ion pair B*- (Sub-R) N Ia

Scheme 28. First asymmetric reaction employing cinchonine Ia as catalysts.

Furthermore, Wynberg and Hiemstra developed, in 1981, an enantioselective 1,4-addition of thiols to unsaturated ketones [65,66] (Scheme 29).

Catalysts 2019, 9, x FOR PEER REVIEW 19 of 36

PTC catalysts that enable the activation of nucleophilic substrates with a pKa values between 11 and 21 (Scheme 27).

Catalysts 2019, 9, 928 19 of 35 Scheme 27. Quinuclidinic proton quaternarization. Cinchona alkaloids were first employed in organic chemistry in 1859 as a chiral auxiliary by Cinchona alkaloids were first employed in organic chemistry in 1859 as a chiral auxiliary by Pasteur for the resolution of the racemate of tartaric acid [64]. The first asymmetric reaction employing Pasteur for the resolution of the racemate of tartaric acid [64]. The first asymmetric reaction Cinchona alkaloids was reported in 1912 by Bredig and Fiske [1]. Cinchonine Ia deprotonates HCN, employing Cinchona alkaloids was reported in 1912 by Bredig and Fiske [1]. Cinchonine Ia forming a tight chiral ion pair that directs the attack of cyanide onto the benzaldehyde enantioselectively deprotonates HCN, forming a tight chiral ion pair that directs the attack of cyanide onto the (Scheme 28). benzaldehyde enantioselectively (Scheme 28).

HCN O OH N HO H HCN CN H * CN O N Ia N HO Ph H 2 Chiral ion pair 1 B*-R 1 Ia Catalyst: N H

OH N HO O N H CN * CN HO H 2 Ph H N Chiral ion pair B*- (Sub-R) N Ia Scheme 28. First asymmetric reaction employing cinchonine Ia as catalysts. Scheme 28. First asymmetric reaction employing cinchonine Ia as catalysts. Furthermore, Wynberg and Hiemstra developed, in 1981, an enantioselective 1,4-addition of thiols CatalystsFurthermore, 2019, 9, x FOR WynbergPEER REVIEW and Hiemstra developed, in 1981, an enantioselective 1,4-addition20 of of36 to unsaturated ketones [65,66] (Scheme 29). thiols to unsaturated ketones [65,66] (Scheme 29).

Scheme 29. Enantioselective 1,4-addition of thiols to unsaturated ketones. Scheme 29. Enantioselective 1,4-addition of thiols to unsaturated ketones. Since then, Cinchona alkaloids have been used extensively in organocatalysis. The most common derivativesSince then, are functionalizedCinchona alkaloids atthe have C9 been position, used extensivel with eithery in bulky organocatalysis. groups, H-bonding The most moieties,common orderivatives primary aminesare functionalized able to condense at the with C9 position, carbonyls with (Figure either5)[ bulky67,68]. groups, H-bonding moieties, or primary amines able to condense with carbonyls (Figure 5) [67,68].

Figure 5. Cinchona alkaloids derivatives functionalized at the C9 position.

4.1. Synergistic Catalysis with Cinchona Alkaloids

4.1.1. Combination with Transition Metal-Based Catalysts A remarkable example of Cinchona-derived bifunctional catalysts in combination with metal- catalysts exploits copper(I) triflate to perform an asymmetric Conia-ene reaction of β-ketoesters 70 [69] (Scheme 30).

Catalysts 2019, 9, x FOR PEER REVIEW 20 of 36

Scheme 29. Enantioselective 1,4-addition of thiols to unsaturated ketones.

Since then, Cinchona alkaloids have been used extensively in organocatalysis. The most common derivatives are functionalized at the C9 position, with either bulky groups, H-bonding moieties, or Catalysts 2019 9 primary amines, , 928 able to condense with carbonyls (Figure 5) [67,68]. 20 of 35

Figure 5. Cinchona alkaloids derivatives functionalized at the C9 position. Figure 5. Cinchona alkaloids derivatives functionalized at the C9 position. 4.1. Synergistic Catalysis with Cinchona Alkaloids 4.1. Synergistic Catalysis with Cinchona Alkaloids 4.1.1. Combination with Transition Metal-Based Catalysts 4.1.1. Combination with Transition Metal-Based Catalysts A remarkable example of Cinchona-derived bifunctional catalysts in combination with metal-catalystsA remarkable exploits example copper(I) of Cinchona triflate to-derived perform bifunctional an asymmetric catalysts Conia-ene in combination reaction of βwith-ketoesters metal- 70catalystsCatalysts[69] (Scheme2019 exploits, 9, x FOR 30 copper(I)). PEER REVIEW triflate to perform an asymmetric Conia-ene reaction of β-ketoesters21 of 7036 [69] (Scheme 30).

Scheme 30. Synergistic catalysis mediated by Cinchona-derived bifunctional catalysts in combination Scheme 30. Synergistic catalysis mediated by Cinchona-derived bifunctional catalysts in combination with copper(I) triflate. with copper(I) triflate. The organocatalyst acts as a Brønsted base and as a ligand for the copper enolate, imparting high The organocatalyst acts as a Brønsted base and as a ligand for the copper enolate, imparting high levels of enantiocontrol. In a preliminary study, the thiourea-based organocatalysts derived from levels of enantiocontrol. In a preliminary study, the thiourea-based organocatalysts derived from 9-amino-9-deoxyepicinchonidine were tested in synergy with transition-metal ions [70–72]. 9-amino-9-deoxyepicinchonidine were tested in synergy with transition-metal ions [70–72]. Lectka et al. reported a high-yielding diastero- and enantio-selective synthesis of β-lactam products exploiting a synergistic catalytic system, in which a chiral nucleophile organic molecule works in concert with an achiral Lewis acidic metal salt [73–78] (Scheme 31).

Scheme 31. β-lactams synthesis thanks to benzoylquinine and indium cooperative catalysis.

According to their mechanistic studies, the pure organocatalytic pathway with Cinchona catalyst activates acyl chlorides, providing ketene-derived zwitterionic enolates that subsequently add to electrophilic imines 73, giving rise to β-lactam four-members rings 74 with excellent enantiomeric excess (over 95%), albeit in modest yields from 40% to 65%. Aiming to improve the yields and suppressing the formation of undesired by-products, they proposed the addition of a Lewis acid catalyst to activate the imine. The combination of In(OTf)3, as a Lewis acid, and benzoylquinine XXX, as a Brønsted base, proved to be the optimal one for the synthesis of β-lactams, using a powerful synergistic strategy maintaining high levels of diastero- and enantio-selectivity, while improving the yields (Scheme 32).

Catalysts 2019, 9, x FOR PEER REVIEW 21 of 36

Scheme 30. Synergistic catalysis mediated by Cinchona-derived bifunctional catalysts in combination with copper(I) triflate.

CatalystsThe2019 organocatalyst, 9, 928 acts as a Brønsted base and as a ligand for the copper enolate, imparting21 high of 35 levels of enantiocontrol. In a preliminary study, the thiourea-based organocatalysts derived from 9-amino-9-deoxyepicinchonidine were tested in synergy with transition-metal ions [70–72]. Lectka et al. reported a high-yielding diastero- and enantio-selective synthesis of β-lactam Lectka et al. reported a high-yielding diastero- and enantio-selective synthesis of β-lactam products exploiting a synergistic catalytic system, in which a chiral nucleophile organic molecule products exploiting a synergistic catalytic system, in which a chiral nucleophile organic molecule works in concert with an achiral Lewis acidic metal salt [73–78] (Scheme 31). works in concert with an achiral Lewis acidic metal salt [73–78] (Scheme 31).

Scheme 31. β-lactams synthesis thanks to benzoylquinine and indium cooperative catalysis. Scheme 31. β-lactams synthesis thanks to benzoylquinine and indium cooperative catalysis. According to their mechanistic studies, the pure organocatalytic pathway with Cinchona catalyst According to their mechanistic studies, the pure organocatalytic pathway with Cinchona catalyst activates acyl chlorides, providing ketene-derived zwitterionic enolates that subsequently add to activates acyl chlorides, providing ketene-derived zwitterionic enolates that subsequently add to electrophilic imines 73, giving rise to β-lactam four-members rings 74 with excellent enantiomeric electrophilic imines 73, giving rise to β-lactam four-members rings 74 with excellent enantiomeric excess (over 95%), albeit in modest yields from 40% to 65%. excess (over 95%), albeit in modest yields from 40% to 65%. Aiming to improve the yields and suppressing the formation of undesired by-products, Aiming to improve the yields and suppressing the formation of undesired by-products, they they proposed the addition of a Lewis acid catalyst to activate the imine. The combination of proposed the addition of a Lewis acid catalyst to activate the imine. The combination of In(OTf)3, as In(OTf)3, as a Lewis acid, and benzoylquinine XXX, as a Brønsted base, proved to be the optimal one a Lewis acid, and benzoylquinine XXX, as a Brønsted base, proved to be the optimal one for the for the synthesis of β-lactams, using a powerful synergistic strategy maintaining high levels of diastero- synthesis of β-lactams, using a powerful synergistic strategy maintaining high levels of diastero- and andCatalysts enantio-selectivity, 2019, 9, x FOR PEERwhile REVIEW improving the yields (Scheme 32). 22 of 36 enantio-selectivity, while improving the yields (Scheme 32).

Scheme 32. Mechanistic insight in the β-lactams synthesis exploiting synergistic catalysis. Scheme 32. Mechanistic insight in the β-lactams synthesis exploiting synergistic catalysis.

4.1.2. Combination with Other Organocatalysts An asymmetric Michael reaction between 1-azido-2-(2-nitrovinyl)benzene 76 and acetone 3, catalyzed by a combination of an amino acid with a Cinchona-derived bifunctional catalyst XXIX, was reported by Ramachary [79]. As depicted in Scheme 33, the proposed transition state features a network of hydrogen bonds between the thiourea catalyst XXIX with the azido- and nitro-group on the electrophile 76. Acetone 3, on the other hand, is activated via enamine by the amino acid XIIIe, which is also part of the H- bond network with the quinuclidinic nitrogen. The proximal effect influenced the facial approach between both activated reagents.

Scheme 33. Asymmetric Michael reaction catalyzed by a combination of amino acid XIIIe with the Cinchona-derived bifunctional catalyst XXIX.

Catalysts 2019, 9, x FOR PEER REVIEW 22 of 36

Catalysts 2019, 9, 928 22 of 35

4.1.2. Combination with Other Organocatalysts An asymmetricScheme Michael 32. Mechanistic reaction insight between in the β-lactams 1-azido-2-(2-nitrovinyl)benzene synthesis exploiting synergistic catalysis.76 and acetone 3, catalyzed4.1.2. by a Combination combination with ofOther an Organocatalysts amino acid with a Cinchona-derived bifunctional catalyst XXIX, was reported byAn Ramacharyasymmetric Michael [79]. reaction between 1-azido-2-(2-nitrovinyl)benzene 76 and acetone 3, As depictedcatalyzed inby Schemea combination 33, theof an proposed amino acid with transition a Cinchona state-derived features bifunctional a network catalyst of XXIX hydrogen, was bonds between thereported thiourea by Ramachary catalyst [79].XXIX with the azido- and nitro-group on the electrophile 76. Acetone 3, on the other hand,As depicted is activated in Scheme via 33, enamine the proposed by thetransiti aminoon state acid featuresXIIIe a, network which of is hydrogen also part bonds of the H-bond between the thiourea catalyst XXIX with the azido- and nitro-group on the electrophile 76. Acetone network with3, on thethe other quinuclidinic hand, is activated nitrogen. via enamine The proximal by the amino effect acid influenced XIIIe, which the is also facial part approach of the H- between both activatedbond network reagents. with the quinuclidinic nitrogen. The proximal effect influenced the facial approach between both activated reagents.

Scheme 33.SchemeAsymmetric 33. Asymmetric Michael Michael reaction reaction catalyzed catalyzed by by a acombination combination of amino of aminoacid XIIIe acid withXIIIe the with the Cinchona-derivedCinchona-derived bifunctional bifunctional catalyst catalystXXIX. XXIX. Catalysts 2019, 9, x FOR PEER REVIEW 23 of 36 Enantioselective additions of aldehydes to nitro-olefins, catalyzed by a combination of proline Enantioselective additions of aldehydes to nitro-olefins, catalyzed by a combination of proline and a quinidine-thiourea catalyst and developed by Zhao (Scheme 34)[80,81], were recently further and a quinidine-thiourea catalyst and developed by Zhao (Scheme 34) [80,81], were recently further investigated by Sunoj [82]. The two original research papers are a Michael addition of butanone 78 investigated by Sunoj [82]. The two original research papers are a Michael addition of butanone 78 to to nitrostyrene 49 and a tandem Michael-Michael cascade reaction. The proline condenses with the nitrostyrene 49 and a tandem Michael-Michael cascade reaction. The proline condenses with the aldehyde 80 to form a nucleophilic enamine, while the Cinchona alkaloid activates the nitro-olefin via a aldehyde 80 to form a nucleophilic enamine, while the Cinchona alkaloid activates the nitro-olefin via H-bond network. In the tandem cascade reaction, the condensation of proline occurs more rapidly a H-bond network. In the tandem cascade reaction, the condensation of proline occurs more rapidly with the aldehyde than with the ketone, given the difference in reactivity (Scheme 34). with the aldehyde than with the ketone, given the difference in reactivity (Scheme 34).

Scheme 34. Michael addition reaction between nitrostyrene and ketone 78 (a) or α,β-unsaturated dicarbonylicScheme 34. Michael compound addition80 (b). reaction between nitrostyrene and ketone 78 (a) or α,β-unsaturated dicarbonylic compound 80 (b).

The Cinchona catalyst XXIX establishes a tight H-bond network, with a well-defined geometry; the thiourea coordinates with the proline carboxylate group while the protonated quinuclidinic ring with the nitrostyrene. Following the first Michael addition, and several rearrangements of hydrogen bonds, the intermediate is oriented in such a way that the electronic deficiency on the carbon adjacent to the nitro-group is near the electrophilic position, so that a new Michael addition can occur to yield the cyclic product 81 after hydrolysis (Scheme 35).

Catalysts 2019, 9, 928 23 of 35

The Cinchona catalyst XXIX establishes a tight H-bond network, with a well-defined geometry; the thiourea coordinates with the proline carboxylate group while the protonated quinuclidinic ring with the nitrostyrene. Following the first Michael addition, and several rearrangements of hydrogen bonds, the intermediate is oriented in such a way that the electronic deficiency on the carbon adjacent to the nitro-group is near the electrophilic position, so that a new Michael addition can occur to yield Catalyststhe cyclic 2019 product, 9, x FOR81 PEERafter REVIEW hydrolysis (Scheme 35). 24 of 36

Scheme 35. MechanisticMechanistic insights insights in in the the en enantioselectiveantioselective addition of aldehydes to nitro-olefins. nitro-olefins.

4.1.3. Combination with Photocatalysts 4.1.3. Combination with Photocatalysts Asymmetric alkylation of cyclic ketones with alkyl bromides, to obtain of α-alkylated products, Asymmetric alkylation of cyclic ketones with alkyl bromides, to obtain of α-alkylated products, has been studied by Melchiorre et al., with high levels of regio-, diastereo-, and enantioselectivity [83]. has been studied by Melchiorre et al., with high levels of regio-, diastereo-, and enantioselectivity Cyclohexanone derivatives 82 were reacted with substituted benzyl bromide 83 using quinine-derived [83]. Cyclohexanone derivatives 82 were reacted with substituted benzyl bromide 83 using quinine- primary amines Ig or Ii as catalyst. derived primary amines Ig or Ii as catalyst. The process is confirmed as photochemical since it requires light in order to proceed. The process is confirmed as photochemical since it requires light in order to proceed. The The experiments were conducted using a household full-spectrum 23 W compact fluorescent lightbulb experiments were conducted using a household full-spectrum 23 W compact fluorescent lightbulb (CFL). The electron-rich enamine 82a, formed from the condensation of ketones 82 (or aldehydes) with (CFL). The electron-rich enamine 82a, formed from the condensation of ketones 82 (or aldehydes) a chiral secondary amine Ig/I (Cinchona-based catalyst), and the electron-accepting alkyl bromide 83 with a chiral secondary amine Ig/I (Cinchona-based catalyst), and the electron-accepting alkyl form the coloured EDA complexes by means of molecular aggregations, which occur in the ground bromide 83 form the coloured EDA complexes by means of molecular aggregations, which occur in state of both compounds [84]. Light irradiation induced an electron transfer from the enamine to the the ground state of both compounds [84]. Light irradiation induced an electron transfer from the bromide and a facile radical fragmentation of the latter. The ion pair radical puts the two reagents into enamine to the bromide and a facile radical fragmentation of the latter. The ion pair radical puts the two reagents into a geometrically restricted chiral space and into very close proximity. This condition facilitated a stereo controlled radical combination within the solvent cage to form a new carbon– carbon bond and the α-carbonyl stereogenic centre of the final product 84 (Scheme 36).

Catalysts 2019, 9, 928 24 of 35 a geometrically restricted chiral space and into very close proximity. This condition facilitated a stereo controlled radical combination within the solvent cage to form a new carbon–carbon bond and the Catalystsα-carbonyl 2019, stereogenic9, x FOR PEER centre REVIEW of the final product 84 (Scheme 36). 25 of 36

Scheme 36. Mechanistic insights in the intermolecular asymmetric alkylation of cyclic ketones with Scheme 36. Mechanistic insights in the intermolecular asymmetric alkylation of cyclic ketones with alkyl bromides, mediated by Cinchona alkaloids-based catalysis merged with photocatalysis. alkyl bromides, mediated by Cinchona alkaloids-based catalysis merged with photocatalysis. In this, the photocatalyst is not present but the photochemically reactive species is the adduct formedIn this, by molecular the photocatalyst aggregation is not of thepresent two reagentsbut the photochemically with the chiral catalyst. reactive species is the adduct formedAnother by molecular example aggregation of synergistic of the photoredox two reagents activation with the for chiral the directcatalyst.β-arylation of ketones in combinationAnother withexampleCinchona of synergisticalkaloids phot is presentedoredox activation by MacMillan for the [85 direct]. The β authors-arylation showed of ketones the use in combination with Cinchona alkaloids is presented by MacMillan [85]. The authors showed the use of of [Ir(ppy)3] as a photocatalyst to promote a single-electron transfer with 1,4-dicyanobenzene 85 to [Ir(ppy)afford the3] as corresponding a photocatalyst arene to radicalpromote anion. a single-electron Iridium complexes transfer havewith a1,4-dicyanobenzene strong absorption in85the to afford the corresponding arene radical anion. Iridium complexes have a strong absorption in the visible range, allowing them to accept a photon from a variety of light sources to populate the *Ir(ppy)3 visiblemetal-to-ligand range, allowing charge transfer them to excited accept state, a photon which from has strong a variety reductant of light properties. sources to populate the *Ir(ppy)In combination3 metal-to-ligand with charge this photoredox transfer excited step, cyclohexanonestate, which has82 strongshould reductant condense properties. with the amine groupInof combination a Cinchona-derived with this organocatalyst photoredox step,Ik to cyclohexanone form the electron-rich 82 should enamine. condense with the amine groupAt of this a Cinchona juncture-derived the photoredox organocatalyst and organocatalytic Ik to form the cycles electron-rich would merge, enamine. as the electron-deficient IV At this juncture the photoredox and organocatalytic cycles would merge, as the electron- Ir (ppy)3 intermediate should readily accept an electron, via SET, from the electron-rich enamine IV deficientto generate Ir (ppy) the3 corresponding intermediate should radical readily cation accept and subsequentan electron, viaβ-enamine SET, from radical the electron-rich formation, enamine to generate the corresponding radical cation and subsequent β-enamine radical formation, eventually giving the β-arylation product 86 with promising levels of enantioselectivity (82% yield, 50% ee) (Scheme 37).

Catalysts 2019, 9, 928 25 of 35 eventually giving the β-arylation product 86 with promising levels of enantioselectivity (82% yield, Catalysts50% ee) 20192019 (Scheme,, 99,, xx FORFOR 37 ).PEERPEER REVIEWREVIEW 2626 ofof 3636

Scheme 37. EnantioselectiveEnantioselective ββ-arylation-arylation-arylation ofof of cyclohexanonecyclohexanone cyclohexanone explexpl exploitingoiting synergistic synergistic catalysis of Cinchona alkaloidsalkaloids and and photocatalyst. photocatalyst. 5. Phosphoric Acids Catalysis 5. Phosphoric Acids Catalysis A powerful class of chiral catalyst used in asymmetric synthesis is represented by BINOL-derived A powerful class of chiral catalyst used in asymmetric synthesis is represented by BINOL- phosphoric acids used as Brønsted acids in electrophilic catalysis, imitating what nature does with derived phosphoric acids used as Brønsted acids in electrophilicelectrophilic catalysis,catalysis, imitatingimitating whatwhat naturenature doesdoes enzymes. The phosphoric acid group can decrease the energy of the LUMO orbital of an electrophilic with enzymes. The phosphoric acid group can decrease the energy of the LUMO orbital of an substrate through the formation of an intermolecular hydrogen bond. Thanks to the high steric hindered electrophilicelectrophilic substratesubstrate throughthrough thethe formationformation ofof anan intermolecularintermolecular hydrogenhydrogen bond.bond. ThanksThanks toto thethe highhigh substituents, substrates are confined to an extremely limited space, enabling stereocontrol. Thanks to stericsteric hinderedhindered substituents,substituents, substratessubstrates areare coconfined to an extremely limited space, enabling the Brønsted acid and Lewis base sites, and to the potential steric hindrance, BINOL derivatives can stereocontrol.stereocontrol. ThanksThanks toto thethe BrønstBrønsteded acidacid andand LewisLewis basebase sites,sites, andand toto thethe potentialpotential stericsteric hindrance,hindrance, have multiple modes of activation (Figure6). BINOL derivatives can have multiple modesmodes ofof activationactivation (Figure(Figure 6).6).

Figure 6. Activation modes of substrates by phosphoric acids. Figure 6. Activation modes of substrateses byby phosphoricphosphoric acids.acids. In 1975, Cornforth used a similar catalyst derived from phosphinic acid for the hydration reaction InIn 1975,1975, CornforthCornforth usedused aa similarsimilar catalystcatalyst derivedderived fromfrom phosphinicphosphinic acidacid forfor thethe hydrationhydration of alkenes, paving the way for the study of chiral phosphoric catalyst [86,87]. Despite the early reactionreaction ofof alkenes,alkenes, pavingpaving thethe wayway forfor thethe studystudy ofof chiralchiral phosphoricphosphoric catalystcatalyst [86,87].[86,87]. DespiteDespite thethe reports by Cornforth, it was only several decades later that chiral phosphoric acids were used as earlyearly reportsreports byby Cornforth,Cornforth, itit waswas onlyonly severalseveral decadecades later that chiral phosphoric acids were used catalysts; in 2004, Akiyama [88] and Terada [89] simultaneously developed a Mannich reaction using as catalysts; in 2004, Akiyama [88] and Terada [89] simultaneously developed a Mannich reaction two different BINOL-derived catalysts, a phosphoric acid and a phosphoramide, respectively [90] using two different BINOL-derived catalysts, a phosphoric acid and a phosphoramide, respectively (Scheme 38). [90][90] (Scheme(Scheme 38).38).

Catalysts 2019, 9, 928 26 of 35 Catalysts 2019, 9, x FOR PEER REVIEW 27 of 36

Scheme 38. Mannich reaction performed using BINOL-derived catalysts. 5.1. Synergistic Catalysis with Phosphoric Acids 5.1. Synergistic Catalysis with Phosphoric Acids 5.1.1. Combination with Transition Metal-Based Catalysts 5.1.1. Combination with Transition Metal-Based Catalysts Beller et al. developed an asymmetric hydrogenation of imines, using an inexpensive metal catalyst Beller et al. developed an asymmetric hydrogenation of imines, using an inexpensive metal and ligandBeller et in combinational. developed with an asymmetric TRIP [91], mimicking hydrogenation well-known of imines, biocatalysts, using an suchinexpensive as iron-based metal catalyst and ligand in combination with TRIP [91], mimicking well-known biocatalysts, such as iron- hydrogenasescatalyst and ligand [92]. in The combination iron complex with catalyst TRIP [91],XXXII mimickingand chiral well-known acid XXXI biocatalysts,work synergistically such as iron- in a based hydrogenases [92]. The iron complex catalyst XXXII and chiral acid XXXI work synergistically cooperativebased hydrogenases manner, [92]. enabling The iron enantioselective complex catalyst hydrogenation XXXII and (Scheme chiral acid 39). XXXI work synergistically in a cooperative manner, enabling enantioselective hydrogenation (Scheme 39).

Scheme 39. Asymmetric hydrogenation of imines using iron-based catalyst XXXII synergistically with Scheme 39. Asymmetric hydrogenation of imines using iron-based catalyst XXXII synergistically TRIPSchemeXXXI. 39. Asymmetric hydrogenation of imines using iron-based catalyst XXXII synergistically with TRIP XXXI. The Brønsted acid (S)-TRIP protonates the starting imine to form the corresponding chiral ion-pair.The Brønsted This intermediate acid (S)-TRIP accepts protonates the hydride the starting from Knölker imine complex,to form the producing corresponding enantioenriched chiral ion- secondarypair. This amines.intermediate accepts the hydride from Knölker complex, producing enantioenriched secondary amines. Luo et al. developed the first regio- and enantio-selective hetero-Diels-Alder reaction of 3 cyclopentadienes employing a chiral phosphoric acid/InBr3 catalytic system (Scheme 40) [93].

Catalysts 2019, 9, x FOR PEER REVIEW 28 of 36

The chiral phosphoric acid XXXIII proved to be unable to catalyse the reaction; by combining it withCatalysts a 2019transition, 9, 928 metal Lewis acid, the synergistic catalytic system is competent in activating27 ofthe 35 reaction partners towards the hetero-Diels-Alder pathway with good results in terms of both reactivity (99% yield) and enantioselectivity (ee 99%). It was shown that the free InBr3 favours the DA Luo et al. developed the first regio- and enantio-selective hetero-Diels-Alder reaction of pathway rather than HDA, demonstrating that the synergistic combinations of phosphoric acid and cyclopentadienes employing a chiral phosphoric acid/InBr catalytic system (Scheme 40)[93]. metal Lewis acid was needed for effective catalysis. 3

Scheme 40. Enantioselective hetero-Diels–Alder reaction of cyclopentadienes exploiting a chiral Scheme 40. Enantioselective hetero-Diels–Alder reaction of cyclopentadienes exploiting a chiral phosphoric acid/InBr3 catalytic system. phosphoric acid/InBr3 catalytic system. The chiral phosphoric acid XXXIII proved to be unable to catalyse the reaction; by combining 5.1.2.it with Combination a transition with metal other Lewis Organocatalysts acid, the synergistic catalytic system is competent in activating the reactionAn partnerselegant asymmetric towards the fluorination hetero-Diels-Alder of carbonyl pathway compounds, with good carried results out in terms in a biphasic of both reactivity system, was(99% reported yield) and by enantioselectivityToste [94]. (ee 99%). It was shown that the free InBr3 favours the DA pathway ratherThe than sodium HDA, salt demonstrating of the chiral that phosphoric the synergistic acid XXXIV combinations acts as ofa PTC, phosphoric transporting acid and Selectfluor metal Lewis 96 asacid a double was needed chiral for ionic effective pair, at catalysis. the interphase; the carbonyl compound present in the organic phase is activated via enamine by the primary amine function of aminoacid derived XXXV. The two activated5.1.2. Combination substrates with can other then Organocatalystsreact at the interphase, where an additional weak interaction is establishedAn elegant between asymmetric the amino fluorination group and ofone carbonyl of the oxygens compounds, of XXXIV carried (Scheme out in 41). a biphasic system, was reported by Toste [94]. The sodium salt of the chiral phosphoric acid XXXIV acts as a PTC, transporting Selectfluor 96 as a double chiral ionic pair, at the interphase; the carbonyl compound present in the organic phase is activated via enamine by the primary amine function of aminoacid derived XXXV. The two activated substrates can then react at the interphase, where an additional weak interaction is established between the amino group and one of the oxygens of XXXIV (Scheme 41). To avoid disrupting the well-balanced H-bond network, it was necessary to protect the carboxylic moiety of the amino acid. A direct asymmetric γ-alkylation of α-substituted linear α,β-unsaturated aldehydes 98 with secondary alcohols 99 was reported by Melchiorre (Scheme 42)[95]. The reaction is formally a SN1 reaction that proceeds through nucleophile attack of the activated 98 compound to the carbocation generated from 99. The activate-nucleophile species is the dienamine, generated from the condensation between 60-hydroxy-9-amino-9-deoxy-epiquinidine and the α,β-unsaturated aldehyde. The phosphoric acid protonates the pro-electrophile generating a stabilized carbocation that can be intercepted by the dienamine. A complex mechanistic model is proposed where the Cinchona catalyst coordinates with two phosphoric acids, on one hand via the 60-OH and on the other hand with the protonated quinuclidinic nitrogen. The mechanistic model is supported by the fact that a 60-OH group is needed for high enantiomeric excess. Catalysts 2019, 9, 928 28 of 35 Catalysts 2019, 9, x FOR PEER REVIEW 29 of 36

Scheme 41. Asymmetric fluorination of α-branched cyclohexanones exploiting the combination of CatalystsScheme 2019, 9 ,41. x FOR Asymmetric PEER REVIEW fluorination of α-branched cyclohexanones exploiting the combination 30of of 36 chiralchiral anion anion phase-transfer phase-transfer and and enamine enamine catalysis. catalysis. H To avoid disrupting the well-balanced H-bond network, it was necessary to protect the O carboxylicO moiety of the amino acid.OH Im 20mol% Bn H A direct asymmetric+ γ-alkylation of α-substitutedXXXVI or XXXVI linear30mol% α,β-unsaturated aldehydes 98 with secondary alcohols 99 was reported by Melchiorre (Scheme 42) [95]. Me2N NMe2 CHCl3 0.1M Bn 50 °C, 16 h Me2N NMe2 98 99 100

Catalysts:

H R1

N O O H N P 2 H O OH HO R1 N R= H XXXVI Im R= 4-NO2C6H4 XXXVII

γ α α β SchemeScheme 42. 42.Asymmetric Asymmetric -alkylationγ-alkylation ofof α-substituted-substituted linear linear α,β-unsaturated, -unsaturated aldehydes aldehydes with with

secondarysecondary alcohols. alcohols.

The reaction is formally a SN1 reaction that proceeds through nucleophile attack of the activated 98 compound to the carbocation generated from 99. The activate-nucleophile species is the dienamine, generated from the condensation between 6′-hydroxy-9-amino-9-deoxy-epiquinidine and the α,β-unsaturated aldehyde. The phosphoric acid protonates the pro-electrophile generating a stabilized carbocation that can be intercepted by the dienamine. A complex mechanistic model is proposed where the Cinchona catalyst coordinates with two phosphoric acids, on one hand via the 6′-OH and on the other hand with the protonated quinuclidinic nitrogen. The mechanistic model is supported by the fact that a 6′-OH group is needed for high enantiomeric excess.

5.1.3. Combination with Photocatalysts Stereocontrol in light-driven photochemical reactions still remains one of the most ambitious goals [96]. To achieve this goal, many dual catalytic systems based on the contemporary use of transition-metal photosensitizers and stereocontrollers have been successfully introduced, leading to the establishment of highly stereoselective protocols for the assembly of chiral molecules [60,97]. Phipps et al. disclose the direct Minisci-type addition of α-amino alkyl radicals 102 to the 2- position of basic heteroarenes 101, with excellent control of both enantioselectivity and regioselectivity, by virtue of a combination of asymmetric Brønsted acid catalysis and photoredox catalysis [98]. Protonation significantly reduces the energy of the LUMO of the heteroarene, and the conjugate anion of the chiral acid remain associated with the pyridinium cation through electrostatic and hydrogen-bonding interactions. Therefore, the substrate is activated by a chiral environment. They use RAEs (Redox Active Ester), as precursors to N-acyl α-amino alkyl radicals, which are prochiral and nucleophilic radicals that possess hydrogen bond donor functionality. Breaking into several fragments of the RAE is induced via electron transfer from an Ir(II) species generated after irradiation of photocatalyst [Ir(dF(CF3)ppy)2(dtbpy)]PF6, with dF(CF3)ppy = 2-(2,4-difluorophenyl)- 5-(trifluoromethyl)-pyridinyl and dtbpy = 4,4′-bis(tert-butyl)-bipyridine, with blue LEDs. The chiral Brønsted acid were (R)-TRIP XXXI or (R)-TCYP XXXVIII (Scheme 43).

Catalysts 2019, 9, 928 29 of 35

5.1.3. Combination with Photocatalysts Stereocontrol in light-driven photochemical reactions still remains one of the most ambitious goals [96]. To achieve this goal, many dual catalytic systems based on the contemporary use of transition-metal photosensitizers and stereocontrollers have been successfully introduced, leading to the establishment of highly stereoselective protocols for the assembly of chiral molecules [60,97]. Phipps et al. disclose the direct Minisci-type addition of α-amino alkyl radicals 102 to the 2-position of basic heteroarenes 101, with excellent control of both enantioselectivity and regioselectivity, by virtue of a combination of asymmetric Brønsted acid catalysis and photoredox catalysis [98]. Protonation significantly reduces the energy of the LUMO of the heteroarene, and the conjugate anion of the chiral acid remain associated with the pyridinium cation through electrostatic and hydrogen-bonding interactions. Therefore, the substrate is activated by a chiral environment. They use RAEs (Redox Active Ester), as precursors to N-acyl α-amino alkyl radicals, which are prochiral and nucleophilic radicals that possess hydrogen bond donor functionality. Breaking into several fragments of the RAE is induced via electron transfer from an Ir(II) species generated after irradiation of photocatalyst [Ir(dF(CF3)ppy)2(dtbpy)]PF6, with dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-(trifluoromethyl)-pyridinyl and dtbpy = 4,40-bis(tert-butyl)-bipyridine, Catalystswith blue 2019 LEDs.,, 9,, xx FORFOR The PEERPEER chiral REVIEWREVIEW Brønsted acid were (R)-TRIP XXXI or (R)-TCYP XXXVIII (Scheme 3143 of). 36

α Scheme 43. Minisci-typeMinisci-type addition addition of of α-amino-amino alkyl alkyl radicals radicals to to the the 2- 2-positionposition of basic heteroarenes performed thanks to a combination of Brønsted acid catalysis and photoredox catalysis. performed thanks to a combination of Brønsted acidacid catalysiscatalysis andand phphotoredox catalysis. Ooi et al., instead, developed a highly enantioselective α-coupling of N-arylaminomethanes Ooi et al., instead, developed a highly enantioselective α-coupling of N-arylaminomethanes 105 105 with N-sulfonyl aldimines 104 using a chiral tetraaminophosphonium ion XXXIX and Ir-centred with N-sulfonyl aldimines 104 using a chiral tetraaminophosphonium ion XXXIX and Ir-centred photosensitizer with visible light irradiation [99]. They adopted N-sulfonyl imines as the precursors of photosensitizer with visible light irradiation [99]. They adopted N-sulfonyl imines as the precursors anion radicals due to their affinity to the hydrogen-bond donor catalyst (Scheme 44). of anion radicals due to their affinity to the hydrogen-bond donor catalyst (Scheme 44).

Scheme 44. Enantioselective α-coupling of N-arylaminomethanes catalyzed by chiral tetraaminophosphonium Scheme 44. Enantioselective α-coupling of N-arylaminomethanes catalyzed by chiral ion and Ir-centred photosensitizer. tetraaminophosphoniumtetraaminophosphonium ionion andand Ir-centred photosensitizer.

The iridium complex [Ir(ppy)2(bpy)]BArF (where Hppy = 2-phenylpyridine, bpy = 2,2′′- bipyridine, HBArF = tetrakis [3,5-bis(trifluoromethyl)phenyl]-borate) was reversibly promoted to its excited state, under visible light irradiation.irradiation. SubsequentSubsequent reductivereductive quenchingquenching ofof thethe *Ir(III)*Ir(III) speciesspecies with 105 leadlead toto thethe formationformation ofof electronicallyelectronically neutralneutral Ir(II)Ir(II) complexcomplex andand thethe cation-radicalcation-radical ofof 105 inin presence of the counterion BArF−.. TheThe Ir(II)Ir(II) complexcomplex givesgives anan electronelectron toto thethe imineimine 104 toto formform thethe corresponding anion-radical that should be spontaneously paired with the positively charged of the Ir(III) complex. This complex would undergo prompt ion exchange with the catalysis, to afford the parent photosensitizer and the adduct between the imineimine anion-radicalanion-radical andand thethe BrønstedBrønsted acidacid XXXIX..

At the same time, an aminomethyl radical is formed via deprotonation of the Ph2NMe cation-radical by a basic species. Then, a coupling reaction between the imine anion-radical and the aminomethyl radical take place by means of the chiral catalyst to enantioselectively produce the 1,2-diamine derivatives 106..

6. Conclusions Synergistic catalysis evolved from organocatalysisorganocatalysis combinedcombined withwith otherother typestypes ofof catalysiscatalysis toto access new activation modes. As discussed, there is a range of different combinations that have been discovered and many more that still need to be designed. We believe that this relatively new field of catalysis holds high potential and will greatly contribute to synthetic chemistry, both in academia and in industry.

Catalysts 2019, 9, 928 30 of 35

The iridium complex [Ir(ppy)2(bpy)]BArF (where Hppy = 2-phenylpyridine, bpy = 2,20-bipyridine, HBArF = tetrakis [3,5-bis(trifluoromethyl)phenyl]-borate) was reversibly promoted to its excited state, under visible light irradiation. Subsequent reductive quenching of the *Ir(III) species with 105 lead to the formation of electronically neutral Ir(II) complex and the cation-radical of 105 in presence of the counterion BArF−. The Ir(II) complex gives an electron to the imine 104 to form the corresponding anion-radical that should be spontaneously paired with the positively charged of the Ir(III) complex. This complex would undergo prompt ion exchange with the catalysis, to afford the parent photosensitizer and the adduct between the imine anion-radical and the Brønsted acid XXXIX. At the same time, an aminomethyl radical is formed via deprotonation of the Ph2NMe cation-radical by a basic species. Then, a coupling reaction between the imine anion-radical and the aminomethyl radical take place by means of the chiral catalyst to enantioselectively produce the 1,2-diamine derivatives 106.

6. Conclusions Synergistic catalysis evolved from organocatalysis combined with other types of catalysis to access new activation modes. As discussed, there is a range of different combinations that have been discovered and many more that still need to be designed. We believe that this relatively new field of catalysis holds high potential and will greatly contribute to synthetic chemistry, both in academia and in industry.

Author Contributions: A.S. and V.N. contributed equally to this work. A.S., V.N., A.B., F.F., A.A. and A.C. all collectively conceived the project, drafted and revised the manuscript. Funding: This research received no external funding. Acknowledgments: Aurora Cacciapuoti (http://www.auroracacciapuoti.com) is gratefully acknowledged for the graphical abstract illustration. Cristian De Luca and Francesca Della Penna are gratefully acknowledged for their support. Conflicts of Interest: The authors declare no conflict of interest.

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