The Combination of Lewis Acid with N-Heterocyclic Carbene (NHC) Catalysis

catalysts

Review The Combination of Lewis Acid with N-Heterocyclic Carbene (NHC) Catalysis

Qianfa Jia 1 , Yaqiong Li 1, Yinhe Lin 1 and Qiao Ren 2,*

1 Chongqing Key Laboratory of Inorganic Special Functional Materials, College of Chemistry and Chemical Engineering, Yangtze Normal University, Fuling, Chongqing 408100, China; [email protected] (Q.J.); [email protected] (Y.L.); [email protected] (Y.L.) 2 College of Pharmaceutical Science, Southwest University, Chongqing 400715, China * Correspondence: [email protected]; Tel.: +86-23-6825-1225

Received: 16 September 2019; Accepted: 14 October 2019; Published: 16 October 2019

Abstract: In the last ten years, the combination of Lewis acid with N-heterocyclic carbene (NHC) catalysis has emerged as a powerful strategy in a variety of important asymmetric synthesis, due to the ready availability of starting materials, operational simplicity and mild reaction conditions. Recent findings illustrate that Lewis acid could largely enhance the efficiency and enantioselectivity, reverse the diastereoselectivity, and even influence the pathway of the same reaction partners. Herein, this review aims to reveal the recent advances in NHC-Lewis acid synergistically promoted enantioselective reactions for the expeditious assembly of versatile biologically important chiral pharmaceuticals and natural products.

Keywords: N-heterocyclic carbenes (NHC); Lewis acid; cooperative catalysis; asymmetric synthesis; umpolung

1. Introduction N-heterocyclic carbenes (NHCs) are roughly categorized into three sections in accordance with their properties and applications: (i) excellent ligands for transition metals; (ii) coordination to p-block elements and (iii) organocatalysts [1–7]. The ﬁrst N-heterocyclic carbene stabilized by two bulky adamantyl substituents was isolated and characterized by the Arduengo group in 1991 [8], which opened up an intriguing class of organic compounds for investigation. So far, a variety of novel carbenes have been revealed and synthesized, for instance, the dominant thiazolium-, imidazolium- and triazolium-based carbenes [9–12]. As powerful and eﬃcient organocatalysts, they have been employed successfully for the synthesis of highly complex molecular architectures [13–18]. However, the stereoselectivities and/or regioselectivities of assembled products were limited for the single mode of activation during NHC catalyzed processes. Inspired by the importance and advantages of the cooperative catalysis strategy [19–25], which could activate the starting materials simultaneously with satisfying enantio- and stereoselectivities, N-heterocyclic carbenes as an important class of Lewis bases can cooperate with various Lewis acids to enhance yield and reverse selectivity or regioselectivity [26]. This strategy has emerged as a powerful approach for the direct access to various carbocyclic and heterocyclic compounds [27–32]. The recent developments in NHC/Lewis acid cooperative catalysis for the synthesis of some important enantioenriched molecules will be discussed in this review. They are categorized into several sections according to the species of the Lewis acid, including LiCl, Mg(Ot-Bu)2, Sc(OTf)3, La(OTf)3, Ti(Oi-Pr)4, etc. Due to the unique umpolung capacity, NHCs are widely applied in a variety of asymmetric transformations, resulting in the construction of versatile active acyl anions, enolates, homoenolates and α,β-unsaturated acylazolium equivalents from the corresponding carbonyl

Catalysts 2019, 9, 863; doi:10.3390/catal9100863 www.mdpi.com/journal/catalysts Catalysts 2019, 9, 863 2 of 23 Catalysts 2019, 9, x FOR PEER REVIEW 2 of 23 compoundscarbonyl compounds (Scheme1 )[(Scheme33–41], 1) while [33–41 Lewis], while acids Lewis as co-catalysts acids as co improve-catalysts the improve reactivities the reactivities or activate inactiveor activate electrophiles. inactive The electrophiles. related exciting The discoveriesrelated exciting involving discoveries NHCs/ Lewis involving acid cooperativeNHCs/Lewis catalysis acid arecooperative presented catalysis herein. are presented herein.

SchemeScheme 1. 1. CarbonylCarbonyl compounds compounds and corresponding and corresponding N-heterocyclic carbeneN-heterocyclic (NHC)-bound carbene (NHC)-bound intermediates. intermediates.

2.2. Cooperative Cooperative NHCNHC/Mg/Mg CatalysisCatalysis ThoughThough NHCs NHCs have have been been proved proved to to be be good good ligands ligands for for many many transition transition metals metals on accounton account of their of strongtheir strong donor properties,donor properties the Scheidt, the Scheidt group reported group repo a pioneeringrted a pioneering investigation investigation and made and an importantmade an breakthrough,important breakthrough which defies, conventionalwhich defies wisdom conventional with respect wisdom to the potential with respect incompatibility to the potential of Lewis acidsincompatibility and bases. ofγ-lactam Lewis acids derivatives and bases. 2 with γ- highlactam enantioselectivities derivatives 2 with and high diastereoselectivities enantioselectivities wereand obtaineddiastereoselectivit by a formalies [3were+ 2] obtained cycloaddition by a formal of N-acyl [3 +hydrazones 2] cycloaddition 1 and cinnamaldehydeof N-acyl hydrazones (Scheme 1 and2). Thecinnamaldehyde results indicated (Scheme that the 2) employment. The results of Mg(O indicatedt-Bu) 2 thatcould the increase employment the yield of of Mg(γ-lactamOt-Bu) distinctly2 could fromincrease 31% the to yield 78% andof γ-lactam enhance distinctly the enantioselectivity from 31% to 78% slightly and enhance in the the presence enantioselectivity of 5 mol% slightly of NHC catalyst.in the presence Subsequently, of 5 mol% the substratesof NHC catalyst. scope was Subsequently, surveyed and the asubstrates broad range scope of functionalitieswas surveyed turnedand a outbroad to be range well of accommodated. functionalities turned In these out processes, to be we carbenell accommodated. precursor AIn was these deprotonated processes, carbene by the baseprecursor 1,5,7-triazabicyclo[4.4.0]dec-5-ene A was deprotonated by the (TBD) base 1,5,7 followed-triazabicycl by additiono[4.4.0 to]decα,β-5-unsaturated-ene (TBD) followed aldehyde by to produceaddition homoenolate to α,β-unsaturated equivalent aldehyde 4 by to raising produce the homoenolate HOMO energy. equivalent Simultaneously, 4 by raising magnesium the HOMO (II) di-energy.tert-butoxide Simultaneously, was selected magnesium as the optimal (II) di-tert Lewis-butoxide acid towas activate selectedN-acyl as thehydrazones optimal Lewis by lowering acid to theactivate LUMO N- energy.acyl hydrazones Further kineticby lowering studies the indicated LUMO energy. that the Further reaction kinetic initial-rate studies emerged indicated an that inverse the first-orderreaction initial relation-rate for emerge Mg (II)d an concentration inverse first- [order42]. relation for Mg (II) concentration [42]. TheThe Zhao Zhaogroup group reportedreported thethe pioneeringpioneering work on the kinetic resolution resolution of of tertiary tertiary alcohols alcohols 6 6 by by NHC-catalyzedNHC-catalyzed esterificationesterification underunder oxidativeoxidative conditionsconditions (Scheme(Scheme3 3).). TheThe presencepresence ofof Mg(OTf)Mg(OTf)22 andand NaBFNaBF44in in thisthis catalyticcatalytic systemsystem turnedturned out to be eefficientfficient to improve both selectivity selectivity and and reaction reaction rate. rate. AA broad broad range range of of substrates substrates was was investigated investigated and and displayed displayed the the practicability practicability of this of protocol.this protocol In most. In cases,most the cases, unreacted the unreacted starting tertiary starting alcohols tertiary 8were alcohols recovered 8 were in high recovered to excellent in highenantioselectivities. to excellent Theenantioselectivit proposed mechanismies. The proposed revealed mechanism that the Lewis revealed acid that Mg(OTf) the Lewis2 may acid activate Mg(OTf) the2 substratemay activate in a cooperativethe substrate way in to a benefit cooperative the presumable way to benefit attack of the tertiary presumable alcohol attack on acyl of azolium tertiaryintermediate alcohol on acyl from theazolium opposite intermediate side of the catalyst’s from the chiral opposite backbone. side of However, the catalyst the oxindole’s chiral structure backbone. was However, proved to the be criticaloxindole for structure this system was to proved work smoothly to be critical [43 ].for this system to work smoothly [43].

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Scheme 2. NHC/Mg(Ot-Bu)2 strategy for the stereoselective synthesis of γ-lactams. SchemeScheme 2. NHC/Mg(ONHC/Mg(Ot-Bu)-Bu)2 sstrategytrategy for the s stereoselectivetereoselective synthesis of γ--lactams.lactams.

SchemeScheme 3. 3.Kinetic Kinetic resolutionresolution ofof tertiarytertiary alcoholsalcohols by NHC and Lewis acid. Scheme 3. Kinetic resolution of tertiary alcohols by NHC and Lewis acid.

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InIn 2018, 2018, Wang Wang and and co-workers co-workers discloseddisclosed aa [3 [3+ + 3]3] atroposelective atroposelective annulation annulation of of alkynylalkynyl acyl acyl azoliumsazoliums 1515 withwith 1,3-dicarbonyls1,3-dicarbonyls 1212 (Scheme (Scheme4 ).4) 3,3. 3,3′0,5,5,5,5′0-tetratert-butyldiphenoquinone-tetratert-butyldiphenoquinone (DQ)(DQ) asas anan externalexternal oxidant,oxidant, acted acted as as a two-electrona two-electron acceptor acceptor to deliverto deliver the the Breslow Breslow intermediate intermediate 14 to 14 alkynyl to alkynyl acyl azoliumacyl azolium 15. This 15 approach. This approach accessed access an arrayed anof axially array chiral of axially pyranones chiral 13 pyranones in a good to13 excellentin a good level to ofexcellent enantioselectivities. level of enantioselectivit The Lewis acidies. Mg(OTf)The Lewis2 was acid proved Mg(O toTf) be2 was critical proved to promote to be critical the ketoenolate’s to promote ‘C’the attack ketoenolate’s to alkynyl ‘C’ acyl attack azolium to alkynyl instead acyl of the azolium direct ‘O’instead attack. of the Further direct transformation ‘O’ attack. Further of the axiallytransformation chiral pyranone-aryls of the axially successfullychiral pyranone afforded-aryls the successfully commonly afforded used axial the biaryls commonly via Diels-Alder used axial reaction.biaryls via It is Diels worth-Alder mentioning reaction. thatIt is the worth key intermediate mentioning that alkynyl the acyl key azoliums intermediate 15 derived alkynyl from acyl ynalsazoliums were 15 discovered derived for from the firstynals time were in NHCdiscovered catalysis for [44 the]. Encouraged first time byin the NHC initial catalysis exploration [44]. ofEncouraged the alkynyl by acylazolium the initial intermediates, exploration of they the reported alkynyl anotheracylazolium formal intermediates [3 + 3] annulation, they reported of ynals withanother amidines formal to [3 aff +ord 3] a annulation series of functionalized of ynals with 1,2,6-trisubstituted amidines to afford pyrimidin-4-ones a series of functionalized under mild reaction1,2,6-trisubstituted conditions. pyrimidin Notably,- the4-ones chemical under yields mild ofreaction pyrimidin-4-ones conditions. Notably, were increased the chemical significantly yields withof pyrimidin the addition-4-ones of Mg(OTf) were increased2, which significantly activated the withN-substituted the addition amidines of Mg(O andTf)2 alkynyl, which acylactivate azoliumd the intermediatesN-substituted simultaneouslyamidines and alkynyl [45]. acyl azolium intermediates simultaneously [45].

SchemeScheme 4.4. EnantioselectiveEnantioselective [3[3 ++ 3] atroposelective annulationannulation catalyzedcatalyzed byby NN-heterocyclic-heterocyclic carbenes.carbenes.

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3. Cooperative NHC/Ti Catalysis 3. Cooperative NHC/Ti Catalysis The Scheidt group found that an appropriate Lewis acid could reverse the diastereoselectivity The Scheidt group found that an appropriate Lewis acid could reverse the diastereoselectivity in NHC-catalyzed enals with chalcones 20 through preorganization of the reactants (Scheme 5) [46]. inThough NHC-catalyzed the Bode enalsgroup with previously chalcones reported 20 through that NHC preorganization-catalyzed reactions of the reactants of chalcone (Scheme derivatives5)[ 46]. Thoughand enals the provided Bode group trans previously-cyclopentene reported products, that cis NHC-catalyzed-cyclopentenes reactions21 were also of chalconeobtained derivativesonly using and(E)- enalsethyl provided 4-oxo-2-butenoatetrans-cyclopentene as the partner products, of substrates.cis-cyclopentenes Optically 21 were active also cis obtained1,3,4-trisubstituted only using (E)cyclopentenes-ethyl 4-oxo-2-butenoate were observed as when the partner employing of substrates. titanium tetraisopropoxide Optically active ascis the1,3,4-trisubstituted Lewis acid and cyclopentenesinvolving homoenolates were observed 22 whengenerated employing by NHC titanium catalysis. tetraisopropoxide While other asLewis the Lewis acids acidsuch and as involvingmagnesium, homoenolates zinc or scandium 22 generated triflate by NHCcompletely catalysis. inhibited While homoenolateother Lewis acids addition, such as the magnesium, usage of zincMg(O ort scandium-Bu)2 afforded triﬂate predominately completely inhibited the trans homoenolate cyclopentenes addition, in moderate the usage yield. of It Mg(O is noteworthyt-Bu)2 aﬀorded that predominatelythe catalytic amounts the trans ofcyclopentenes isopropyl alcohol in moderate could improv yield.e Itboth is noteworthy the yield and that the the rate catalytic by separating amounts ofthe isopropyl titanium alcohol catalyst could from improve the intermediate both the yield easily. and the In rate the by exploration separating the of titaniummechanism, catalyst Scheidt from theproposed intermediate that the easily. titanium In the Lewis exploration acid promotes of mechanism, the generation Scheidt proposed of homoenolate that the equivalents titanium Lewis 22, and acid promotesthen activates the generation the chalcone of homoenolate to coordinate equivalents with 22, the and homoenolate then activates-titanium the chalcone intermediate to coordinate 23. withSubsequently, the homoenolate-titanium two successive intermediateC–C bond formation, 23. Subsequently, acylation two and successive decarboxylation C–C bond provides formation, the acylationcyclopentene. and decarboxylation Density functional provides theory the (DFT cyclopentene.) studies by Density Domingo functional illustrated theory that (DFT) the studies titanium by Domingocomplex could illustrated not only that accelerate the titanium the complexannulation could reaction not onlyby lowing accelerate the Gibbs the annulation free energy, reaction but also by lowingfavor pre the-organizing Gibbs free energy,the spatial but alignment also favor pre-organizingof homoenolate the and spatial chalcone, alignment in line ofwith homoenolate the proposed and chalcone,reaction pathway in line with [47]. the proposed reaction pathway [47].

Scheme 5. NHC/Ti(Oi-Pr) strategy for the synthesis of optically active cis cyclopentenes. Scheme 5. NHC/Ti(Oi-Pr)44 strategy for the synthesis of optically active cis cyclopentenes. To extend the scope of substrates, Scheidt et al. developed the enantioselective dimerization of To extend the scope of substrates, Scheidt et al. developed the enantioselective dimerization of enals using cooperative catalysis NHC/Ti(Oi-Pr)4 (Scheme6). The NHC /titanium-mediated 1,4-addition enals using cooperative catalysis NHC/Ti(Oi-Pr)4 (Scheme 6). The NHC/titanium-mediated of1,4 homoenolate-addition of equivalents homoenolate to equivalents enals was favored to enals over was the favored traditional over 1,2-addition,the traditional resulting 1,2-addition in the, γ formationresulting in of the-lactones formation [48 ].of γ-lactones [48].

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Scheme 6. NHC-catalyzed enantioselective enal dimerization. SchemeScheme 6.6. NHC-catalyzedNHC-catalyzed enantioselective enal enal dimerization. dimerization. Meanwhile, the Scheidt group uncovered the β,γ-unsaturated α-ketoesters 28 as a suitable class Meanwhile, the Scheidt group uncovered the β,γ-unsaturated α-ketoesters 28 as a suitable class of homoenolateMeanwhile, acceptorsthe Scheidt with group enals uncovered to give the the highly β,γ-unsaturated functionalized α-ketoesters cyclopentanes 28 as 29a suitable (Scheme class 7) ofof homoenolate homoenolate acceptors acceptors with with enals enals to to give give the the highly highly functionalized functionalized cyclopentanes cyclopentanes 29 (Scheme29 (Scheme7)[ 497) ]. [49]. Importantly, the Lewis acid Ti(Oi-Pr)4 played a crucial role in the initial coordination to the Importantly, the Lewis acid Ti(Oi-Pr) played4 a crucial role in the initial coordination to the enals, [4enals9]. Importantly,, which promote the Lewisd the acid formation Ti(O4 i- Pr) of extendedplayed a crucial Breslow role intermediate in the initial 30 coordination and subsequent to the whichenalscoordination, promotedwhich to promote the another formationd enalthe formation or of the extended β,γ -unsaturated of Breslow extended intermediate α Breslow-ketoester. intermediate The 30 and high subsequent enantiopure 30 and coordination subsequent products β γ α tocoordinationwere another received enal to orthrough another the ,the enal-unsaturated C– C or bond the β,γformation,--ketoester.unsaturated protonation/tautomerization, The α-ketoester. high enantiopure The high products enantiopureintramolecular were products received aldol throughwerereaction received the and C–C thenthrough bond acylation/elimination formation, the C–C bond protonation formation, or transe/tautomerization, protonation/tautomerization,sterification. intramolecular In addition, no aldol intramolecular reaction reaction happened and aldol then acylationreactiondrastically /elimination and without then acylation/elimination the or transesterification.titanium (IV) iso- propoxide, or In transe addition,sterification which no reactionconfirmed. In addition,happened the significance no drastically reaction of the without happened Lewis the titaniumdrasticallyacid during (IV) without isothe-propoxide, process the titanium. which (IV) confirmed iso-propoxide, the significance which confirmed of the Lewis the significance acid during of the the process. Lewis acid during the process.

Scheme 7. NHC-catalyzed addition of homoenolates to β,γ-unsaturated α-ketoesters.

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In 2013, Snyder group disclosed a one-stepone-step cooperative NHCNHC/Lewis/Lewis acid catalysis to forge the entire tricyclic butenolide cores,cores, which belong to securinega alkaloids and exhibit various intriguing biological activities (Scheme(Scheme8 8).). AA linearlinear enynalenynal 3535 waswas selectedselected asas thethe appropriateappropriate precursorprecursor forfor thethe in-situin-situ generatedgenerated homoenolatehomoenolate equivalent, equivalent which, which underwent underwent an an intramolecular intramolecular addition addition to ketone to ketone and followedand followed by lactonization by lactonization to a ﬀtoord afford the desiredthe desired product. product The. The reaction reaction conditions conditions were were optimized optimized by investigatingby investigating diﬀ erent different NHC NHC catalyst catalyst structures, structures, species species of Lewis of acid Lewis or the acid concentration or the concentration of solutions. of Eventually,solutions. Eventually, the tricyclic the butenolide tricyclic 36butenolide product was36 product isolated was by slowly isolated adding by slowly starting adding material starting into amaterial suspension into aof suspension catalyst and of Ti(O catalysti-Pr) 4 andin tolueneTi(Oi-Pr) with4 in toluenethe concentration with the concentration of 0.03 M. Surprisingly, of 0.03 M. anSurprisingly, exogenous an base exogenous was not base necessary, was not probably necessary, due probably to the Ti(O duei- Pr)to the4 was Ti(O basici-Pr) enough4 was basic to facilitate enough theto facilitate generation the ofgeneration the active of carbene. the active In thiscarbene. dual catalysisIn this dual strategy, catalysis ynals strategy were used, ynals as were nucleophilic used as homoenolatenucleophilic homoenolate precursors to precursors synthesize to securinega synthesizealkaloids securinega in alkaloids only nine in steps only from nine commercialsteps from materials,commercial which materials, could provide which opportunitiescould provide for the opportunities further development for the offurther NHC-catalyzed development reactions of inNHC total-catalyzed synthesis reactions of fused in bicyclic total synthesis butenolide of domainsfused bicyclic [50]. butenolide domains [50].

SchemeScheme 8.8. NHC/Ti(ONHC/Ti(Oii-Pr)-Pr)44 strategy for the synthesis of securinega alkaloids.

Later on, on, Cheng Cheng group group reported reported the the NHC/Ti(O NHC/Ti(Oi-Pr)i-Pr)4 4co-catalyzedco-catalyzed dimerization dimerization of of2-formylcinnamates 2-formylcinnamates 37 for 37the access for the to isochromenone access to isochromenone derivatives 38 via derivatives an unexpected 38 pathway. via an unexpectedHowever, a mixture pathway. of two diastereoisomers However, a mixture with cis- and of trans two-isochrome diastereoisomersno[4,3-c]isochromene with cis-- and trans6,12-diacetates-isochromeno[4,3-c]isochromene-6,12-diacetates were isolated in the absence of Ti(Oi-Pr) were4 (Scheme isolated 9). The in the combination absence ofof Ti(ONHCi-Pr) and4 (SchemeTi(Oi-Pr)94). changed The combination the reaction of NHC path andway Ti(O ofi-Pr) the4 changed dimerization the reaction completely pathway [5 of1]. the The dimerization proposed completelymechanism [revealed51]. The that proposed the Breslow mechanism intermediate revealed 39 thatwas thefirstly Breslow generated intermediate via the deprotonation, 39 was ﬁrstly generatednucleophilic via addition the deprotonation, and proton nucleophilic transfer. It then addition underwent and proton the second transfer. nucleophilic It then underwent addition the to second2-formylcinnamates nucleophilic to addition generate to α 2-formylcinnamates-hydroxyl ketones 40 to, which generate wasα activated-hydroxyl by ketones titanium(IV) 40, which and wasunderwent activated the by aerob titanium(IV)ic oxidation and to underwent afford the the 1,2 aerobic-diketone oxidation 42. Intriguingly, to aﬀord the 1,2-diketone nucleophilic 42.addition Intriguingly, of NHC theto the nucleophilic carbonyl of addition 1,2-diketone of NHC, the to following the carbonyl intramolecular of 1,2-diketone, rearrangement the following and intramolecularcopy rearrangement rearrangement produced and the copy peroxide rearrangement intermediates produced 45. 1,8- theDiazabicyclo[5.4.0]und peroxide intermediatesec-7-ene 45. 1,8-Diazabicyclo[5.4.0]undec-7-ene(DBU) as a powerful nucleophile attacked (DBU) as the a powerful peroxide nucleophile intermediate attacked to facilitate the peroxide the cleavage intermediate of O– toO facilitatebond and the eliminat cleavageion of of O–O the acetate bond and moiety elimination resulting of thein the acetate formation moiety of resulting the enolates in the 46 formation. At last, ofthe the intramolecular enolates 46. lactonization At last, the intramolecular and release of lactonizationthe NHC delivered and release the isochromenone of the NHC delivered derivatives the isochromenone38. In this case, derivatives the Lewis 38.acid In changed this case, the the reaction Lewis acid pathway changed and the provided reaction pathway opportunities and provided for the opportunitiesapplication of forNHC/Lewis the application acid cooperative of NHC/Lewis catalysis. acid cooperative catalysis.

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SchemeScheme9. 9. DimerizationDimerization ofof 2-formylcinnamates2-formylcinnamates by NHC/ NHC/Lewis a acidcid c cooperativeooperative c catalysis.atalysis.

Moreover,Moreover, the the Cheng Cheng group group has systematically has systematically studied the studied chiral N- theheterocyclic chiral carbene/LewisN-heterocyclic carbeneacid /Lewis co-catalyzed acid co-catalyzed intermolecular intermolecular dimerization dimerization of of 22-aroylvinylcinnamaldehydes,-aroylvinylcinnamaldehydes, 2-aroylvinylcinnamaldehydes2-aroylvinylcinnamaldehydes 47 47 with with aromatic aromatic aldehydes aldehydes 48 and48 and 2-(aroylvinyl)benzaldehydes 2-(aroylvinyl)benzaldehydes 51 with 51 enalswith (Scheme enals 10(Scheme). A variety 10 of). synthetically A variety unavailable of synthetically functionalized unavailable chiral indeno[1,2-c]furan-1-ones functionalized chiral 49,indeno[1,2 tetrahydroindeno[1,2-c]furan-1-ones-c]furan-1-ones 49, 50, 4,5-dihydro-1,4-methanobenzo[c]oxepin-3-onestetrahydroindeno[1,2-c]furan-1-ones 52 and50, 2,8-dihydrocyclopenta[4,5-dihydro-1,4-methanobenzo[c]oxepina]indenes 53 were-3 synthesized-ones 52 and with 2,8 good-dihydrocyclopenta[ yields, excellenta enantioselectivities]indenes 53 were andsynthesized high diastereoselectivities. with good yields, excellent The Lewis enantioselectivities acid Ti(Oi-Pr)4 as and a co-catalyst high diastereoselectivities. has been exempliﬁed The byLewis activating acid Ti(O thei-Pr) reaction4 as a co partners-catalyst simultaneously has been exemplified and then by act inducingivating the reaction stereoselectivities partners preferentiallysimultaneously [52 and–54]. then inducing the stereoselectivities preferentially [52–54].

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SchemeScheme 10. 10.The The reactions reactions of of 2-aroylvinylcinnamaldehydes 2-aroylvinylcinnamaldehydes or or 2-(aroylvinyl)benzaldehydes 2-(aroylvinyl)benzaldehydes involved involved in NHCin NHC/Ti(O/Ti(Oi-Pr)i4-Pr)cooperate4 cooperate catalysis. catalysis.

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Zhao and co-workers developed a divergent annulation reaction of heterocyclic enones 64 with enalsZhao to synthesis and co-workers ε-lactones developed 65 or spiro a divergent-heterocycles annulation (Scheme reaction 11). Ti(O of heterocyclici-Pr)4 as the optimal enones 64Lewis with enalsacid to was synthesis surveyedε-lactones to enhance 65 or spiro-heterocyclesthe conversion of (Scheme the catalytic 11). Ti(O systemi-Pr)4 andas the deliver optimal the Lewis [3 + acid 4] wasannulation surveyed product to enhance ε-lactone thes conversion 65 in good of yield the catalyticand excellent system chemo and- deliver and stereo the [3-selectivities+ 4] annulation [55]. productSurprisingly,ε-lactones the indole 65 in good-based yield enones and afforded excellent the chemo- indole and-fused stereo-selectivities ε-lactones as a [single55]. Surprisingly, diastereomer, the indole-basedpotentially due enones to a theﬀorded control the indole-fusedof chiral catalystε-lactones. This as work a single disp diastereomer,layed the catalyst potentially-controlled due to thechemoselective control of chiral process catalyst. in This NHC work catalysis displayed and the extended catalyst-controlled the capability chemoselective of NHC/Lewis process acid in NHCcooperative catalysis catalysis. and extended the capability of NHC/Lewis acid cooperative catalysis.

SchemeScheme11. 11. StereoselectiveStereoselective synthesissynthesis of ε-lactones-lactones by NHC NHC-catalyzed-catalyzed annulation annulation.. 4. Cooperative NHC/Li Catalysis 4. Cooperative NHC/Li Catalysis Since the combination of NHC catalysis with Lewis acids demonstrated high efficiency to facilitate Since the combination of NHC catalysis with Lewis acids demonstrated high efficiency to synthetic transformations, the Scheidt group has made a number of pioneer works and reported the facilitate synthetic transformations, the Scheidt group has made a number of pioneer works and first cooperative catalytic system consisting of achiral NHC and LiCl to promote an intermolecular reported the first cooperative catalytic system consisting of achiral NHC and LiCl to promote an conjugate addition of primary and secondary alcohols with activated alkenes (Scheme 12). The impact intermolecular conjugate addition of primary and secondary alcohols with activated alkenes of(Scheme lithium cation12). The was impact probed of that lithium the addition cation of was 1.0 equivalent probed that of 12-crown-4 the addition leaded of 1.0 a decreased equivalent yield. of β Therefore,12-crown- LiCl4 leaded was a added decreased to generate yield. Therefore, the desired LiCl-alkoxy was added ketone to 68generate in 95% the yield. desired Unfortunately, β-alkoxy theketone enantioselective 68 in 95% yield. versions Unfortunately, with the chiral the NHCenantioselective/LiCl co-catalysis versions were with carried the chiral out resulting NHC/LiCl in racemicco-catalysis products were carried or low outee values resulting even in racemic if high yields.products The or low mechanism ee values investigationeven if high yields. illustrated The thatmechanism the free investigationN-heterocyclic illustrated carbene that derived the free from N- IMesheterocyclic acted as carb a Brønstedene derived base from and IMes accessed acted theas NHC-alcohola Brønsted base complex and accessed 69 as a crucialthe NHC intermediate.-alcohol complex Remarkably, 69 as a crucial no oligomerization intermediate. products Remarkably, were observedno oligomerization presumably products because were the lithium observed chloride presumably as a Lewis because acid the activated lithium the chloride enones as toward a Lewis the 1,4-additonacid activated of the the alcohols. enones toward Ultimately, the 1,4 the-additon overall yieldof the was alcohols. improved Ultimately, [56]. the overall yield was improvedSubsequently, [56]. Scheidt and coworkers reported an enantioselective annulation of isatins 71 with enals forSubsequently, accessing spirooxindole Scheidt and lactones coworkers 72 in goodreported yields an and enantioselective high enantioselectivities annulation (Scheme of isatins 13)[ 5771]. Soonwith later, enals Sunoj for accessingand coworkers spirooxindole focused on lactones the mechanism 72 in good and origin yields of and stereoselectivity high enantioselect in theivities chiral NHC(Scheme/Lewis 13) acid [57]. co-catalyzed Soon later, synthesis Sunoj and of spirooxindole coworkers focused lactones. on the The mechanism addition of and chiral origin NHC of to αs,tereoselectivityβ-unsaturated in aldehydes the chiral generates NHC/Lewis the acid homoenolate co-catalyzed equivalent synthesis as of nucleophilic spirooxindole species lactone ands. The then inductsaddition the of enantioselectivity chiral NHC to α, of β the-unsaturated annulation aldehydes process. Ongenerate the others the hand, homoenolate the lithium equivalent counterion as interactsnucleophilic with species both the and 1,2-dicarbonyl then inducts the of theenantioselectivity isatin and the NHC-boundof the annulation homoenolate, process. On resulting the other in anhand, enantioselective the lithium addition counterion of the interactsre face with with the both enhancement the 1,2-dicarbonyl on the level of of theenantioselectivity, isatin and the in lineNHC with-bound the experimental homoenolate, observations resulting in [58 ]. an At enantioselective last, this approach addition was successfully of the re appliedface with into the the conciseenhancement synthesis on ofthe maremycin level of enantioselectivity, B, which contains in a line 3-hydroxy with the indole experimental structure observations scaffold and [5 exhibits8]. At thelast, excellent this approach anticancer was activity successfully [57]. applied into the concise synthesis of maremycin B, which contains a 3-hydroxy indole structure scaffold and exhibits the excellent anticancer activity [57].

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SchemeScheme 12. NHC-catalyzedNHC-catalyzed conjugate additions of alcohols. Scheme 12. NHC-catalyzed conjugate additions of alcohols.

Scheme 13. NHC/LiCl strategy for the stereoselective synthesis of spirooxindole lactones. ScheSchememe 1 13.3. NHC/LiClNHC/LiCl strategy for the stereoselective synthesis of spirooxindole lactones.lactones. The appropriate Lewis acid has a significant influence on the NHC-catalyzed umpolung The appropriate Lewis acid has a signiﬁcant inﬂuence on the NHC-catalyzed umpolung reactions. reactions.The appropriate In 2013, the Lewis She group acid h reportedas a significant an elegant influence work that on the the NHC NHC/Lewis-catalyzed acid umpolung catalytic In 2013, the She group reported an elegant work that the NHC/Lewis acid catalytic system mediated the reactions.system mediated In 2013, the the [3 +She 2] annulation group reported of alkynyl an elegant aldehydes work 73 thatwith theβ,γ - NHC/Lewisunsaturated α acid-ketoester catalytic 74 [3 + 2] annulation of alkynyl aldehydes 73 with β,γ-unsaturated α-ketoester 74 (Scheme 14). No desired system(Scheme mediated 14). No thedesired [3 + 2]product annulation was observedof alkynyl in aldehydes initial studies 73 with employing β,γ-unsatu onlyrated NHC α-ketoester-catalyst 74in product was observed in initial studies employing only NHC-catalyst in the absence of the Lewis acid. (theScheme absence 14). of No the desired Lewis productacid. Notably, was observed the yields in initialof butenolides studies employing were enhanced only NHCand the-catalyst starting in Notably, the yields of butenolides were enhanced and the starting materials were consumed completely thematerials absence were of the consumed Lewis acid. completely Notably, in the a yields short timeof butenolides in the presence were enhanced of LiCl. and In addition, the starting the in a short time in the presence of LiCl. In addition, the enantioselective studies of this methodology materialsenantioselective were consumedstudies of this completely methodology in a shortwere timecarried in out the by presence screening of several LiCl. In available addition, chiral the were carried out by screening several available chiral carbenes to realize the asymmetric version of this enanticarbenesoselective to realize studies the asymmetric of this methodology version of were this carriedformal [3out + by2] cyclization.screening several Although available a moderate chiral formal [3 + 2] cyclization. Although a moderate enantioselectivity was observed, this result prompted carbenesenantioselectivity to realize was the observed,asymmetric this version result ofprompted this formal further [3 + 2]exploration cyclization. on Although the NHC/Lewis a moderate acid further exploration on the NHC/Lewis acid mediated enantioselective reactions [59]. Shortly thereafter, enantioselectivitymediated enantioselective was observed, reactions this result[59]. prompted Shortly thereafter further e, xplorationScheidt andon the co -NHC/Lewisworkers further acid Scheidt and co-workers further explored a chiral NHC-catalyzed cascade reaction of α,β-alkynals mediatedexplored a enantioselective chiral NHC-catalyzed reactions cascade [59] .reaction Shortly of thereafter α,β-alkynals, Scheidt with α and-ketoesters co-workers by using further the with α-ketoesters by using the same cooperative catalysis strategy. The enantioselectivity of this exploredsame cooperative a chiral NHCcatalysis-catalyzed strateg y. cascade The enantioselectivity reaction of α,β- alkynalsof this formal with [3 α- ketoesters+ 2] annulation by using reaction the formal [3 + 2] annulation reaction was induced by a saturated imidazolium J (SImes Cl) and chiral samewas induced cooperative by a catalysissaturated strateg imidazoliumy. The enantioselectivity J (SImes·Cl) and ofchiral this phosphoricformal [3 + 2]acid. annulation Remarkably,· reaction the phosphoric acid. Remarkably, the introduction of lithium cation organized the transition state by means wasintroduction induced ofby lithiuma saturated cation imidazolium organized theJ (SImes·Cl) transition and state chiral by means phosphoric of activating acid. Remarkably, the phosphate the of activating the phosphate and α-ketoesters simultaneously [60]. Du and Lu group reported another introductionand α-ketoesters of lithium simultaneously cation organized [60]. Du theand transition Lu group statereported by means another of formalactivating [3 + the2] annulations phosphate formal [3 + 2] annulations of alkynyl aldehydes with isatins. A variety of spirooxindole butenolides andof alkynyl α-ketoesters aldehydes simultaneously with isatins. [60] . ADu variety and Lu ofgroup spirooxindole reported another butenolides formal and[3 + 2] spirooxindole annulations andof alkynyl spirooxindole aldehydes furan-3(2H)-ones with isatins. were A variety formed of by spirooxindole the NHC/LiCl butenolidesco-catalyzed and transformation spirooxindole3 via3 furan3-3(2H)3 -ones were formed by the NHC/LiCl1 1 co-catalyzed transformation via the a -d the a -d umpolung of alkynyl aldehydes and a -d umpolung process respectively. The asymmetric3 3 furanumpolung-3(2H) of-ones alkynyl were aldehydes formed and by a the1-d 1 umpolung NHC/LiCl process co-catalyzed respectively. transformation The asymmetric via the version a -d version of this formal [3 + 2] cyclization1 1 reaction has also been realized using the chiral carbene umpolungof this formal of alkynyl[3 + 2] cyclization aldehydes reactionand a -d has umpolung also been process realized respectively. using the chiral The asymmetriccarbene precursor version I ofas thiscatalyst, formal and [3 the + 2] spirooxi cyclizationndole reaction butenolide has alsoas a beensingle realized regioisomer using was the affordedchiral carbene in 78% precursor yield and I as catalyst, and the spirooxindole butenolide as a single regioisomer was afforded in 78% yield and

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Catalysts 2019, 9, x FOR PEER REVIEW 12 of 23 precursor I as catalyst, and the spirooxindole butenolide as a single regioisomer was aﬀorded in 78% 73% ee value [61]. In short, the common nature of these elegant studies is the umpolung of the yield and 73% ee value [61]. In short, the common nature of these elegant studies is the umpolung of the β-position of alkynyl aldehydes by N-heterocyclic carbenes to afford a unique “allenolate” β-position of alkynyl aldehydes by N-heterocyclic carbenes to aﬀord a unique “allenolate” nucleophile, nucleophile, whilst LiCl as the optimal Lewis acid activates the carbonyl of various electrophilic whilstreagents. LiCl as the optimal Lewis acid activates the carbonyl of various electrophilic reagents.

Scheme 14. NHC-catalyzed/Lewis acid mediated conjugate umpolung of alkynyl aldehydes. Scheme 14. NHC-catalyzed/Lewis acid mediated conjugate umpolung of alkynyl aldehydes. Studer et al. reported the cooperative NHC/LiCl catalyzed the conjugate additions of tertiary Studer et al. reported the cooperative NHC/LiCl catalyzed the conjugate additions of tertiary prochiral C-nucleophiles to α,β-unsaturated acyl azolium in situ generated from the oxidation of the prochiral C-nucleophiles to α,β-unsaturated acyl azolium in situ generated from the oxidation of Breslow intermediate (Scheme 15). β-diketones, β-ketoesters, and malonates 76 bearing a β-oxyalkyl the Breslow intermediate (Scheme 15). β-diketones, β-ketoesters, and malonates 76 bearing a substituent at the α position reacted smoothly with enals to aﬀord highly substituted cyclopentanes 77 β-oxyalkyl substituent at the α position reacted smoothly with enals to afford highly substituted in high yields and excellent diastereo- and enantioselectivities. The proposed mechanism revealed that cyclopentanes 77 in high yields and excellent diastereo- and enantioselectivities. The proposed this organic cascade process consisted of the deprotonation of NHC precursor K, Michael addition and mechanism revealed that this organic cascade process consisted of the deprotonation of NHC subsequentprecursor K asynchronous, Michael addition formal and [2 +subsequent2] aldol lactonization asynchronous with formal the regeneration [2 + 2] aldol of lactonization the NHC catalyst with β tothe give regeneration the desired of highly the NHC substituted catalyst to-lactones give the desired [62]. highly substituted β-lactones [62].

SchemeScheme 15. 15Asymmetric. Asymmetric synthesis synthesis of highly of highly substituted substitutedβ-lactones β-lactones through through oxidative oxidative carbene c catalysisarbene withcatalysis LiCl aswith cooperative LiCl as cooperative Lewis acid. Lewis acid.

InIn 2015, 2015, Studer Studer and and Ye Ye reported reported the the similar similar results results that that the the cooperative cooperative oxidative oxidative NHC NHC/Lewis/Lewis acid enantioselectiveacid enantioselective catalysis catalysis gave gave highly highly substituted substitutedδ-lactones δ-lactones 79 through 79 through the reactions the reactions of enals of enals with ε-oxo-with γ ε,δ-oxo-malonates-γ,δ-malonates 78 containing 78 containing two Michael two acceptors Michael (Scheme acceptors 16 ).(Scheme The suggested 16). The mechanism suggested of thesemechanism two cascade of these reaction two demonstrated cascade reaction that the demonstrated oxidation of vinyl that the Breslow oxidation intermediate of vinyl aﬀ orded Breslow the αintermediate,β-unsaturated afforded acyl azolium the α,β intermediate,-unsaturated acyl which azolium was then intermediate, attacked by which the deprotonated was then attacked malonates by tothe give deprotonated the enolate intermediate. malonates to Subsequently, give the enolate the second intermediate. intramolecular Subsequently, Michael-type the cyclization second andintramolecular lactonization Michael aﬀorded-type thecyclopentane- cyclization and cyclohexane-fused lactonization affordedδ-lactones the with cyclopentane the release- ofand the catalyst.cyclohexane Meanwhile,-fused δ the-lactones LiClwas with likely the releaseto coordinate of the with catalyst. the enolate Meanwhile, of malonates the LiCl and was the likely oxygen to atomcoordinate of the withα,β-unsaturated the enolate of acylazolium malonates and intermediate the oxygen by atom lowering of the the α,β LUMO-unsaturated energy. acylazolium Therefore, LiClintermediate turned out by to be lowering essential the for LUMOfacilitating energy. the formation Therefore, of new LiClC–C turned bond out and t theo be outcome essential of high for yieldsfacilitating and excellent the formation stereoselectivities of new C [63–C,64 bond]. and the outcome of high yields and excellent stereoselectivities [63,64].

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Scheme 16. Enantioselective synthesis of bicyclic δ-lactones via NHC-catalyzed cascade reaction.

InScheme Sche 2016,me Zhong16. 16. EnantioselectiveEnantioselective reported an synthesissynthesis enantioselective of b bicyclicicyclic δ δ- annulation-lactoneslactones via via NHC NHC-catalyzedof α,β-catalyzed-unsaturated c cascadeascade aldehydes r reaction.eaction. with 1,3-dicarbonyl compounds 80 by cooperative N-heterocyclic carbene/Lewis acid catalysis strategy α β (SchemeInIn 2016, 2016,17). LiCl Zhong Zhong and reported reported 4Å molecular an an enantioselective enantioselective sieves were found annulation to be the of of α,βbest, --unsaturatedunsaturated in the optimization aldehydes aldehydes studies. with with 1,3-dicarbonylThe1,3- dicarbonylee value of compounds compoundsthe desired 8080dihydropyranone byby cooperativecooperative N81-heterocyclic- heterocyclicwas improved carbene/Lewis carbene distinctly/Lewis from acid acid 60% catalysis catalysis to 87% strategy strategy in the (Schemepresence(Scheme 17 of1).7 LiCl.). LiCl LiCl It and andwas 4Å 4Ånoteworthy molecular molecular sievesthat sieves the were ambientwere found found air to actedto be be the asthe best the best insole thein othe optimizationxidant optimization in this studies.asymmetric studies. The eeThevalue ee value of the of desired the desired dihydropyranone dihydropyranone 81 was 81 improved was improved distinctly distinctly from 60% from to 87%60% into the87% presence in the annulation reaction. Some control experiments were carried out to illustrate that the molecular O2 ofindeedpresence LiCl. It could of was LiCl. noteworthy promote It was noteworthy the that oxidation the ambient that ofthe air homoenolateambient acted as air the acted sole equivalent as oxidant the sole to in o this thexidant asymmetric α,β in-unsaturated this asymmetric annulation acyl reaction.triazolium.annulation Some reaction. In control this regards,Some experiments control the aerobicexperiments were carried oxidative were out tocarried NHC/Lewis illustrate out thatto acidillustrate the molecularcatalyzed that the O enantioselective 2molecularindeed could O2 α β promoteannulationsindeed the could oxidationprovided promote ofanhomoenolate efficient, the oxidation concise equivalent of and homoenolate green to the version, -unsaturated equivalent in asymmetric to acyl the triazolium. synthesis α,β-unsaturated [6 In5 this]. Then, regards, acyl Du triazolium. In this regards, the aerobic oxidative NHC/Lewis acid catalyzed enantioselective theand aerobic Zheng oxidative independently NHC /Lewis reported acid the catalyzed formal enantioselectiveNHC/Lewis acid annulations catalyzed [3 provided + 3] annulation an efficient, of annulations provided an efficient, concise and green version in asymmetric synthesis [65]. Then, Du concise1,3-dicarbonyl and green versioncompounds in asymmetric with synthesisisatin-derived [65]. Then, 2-bromoenals Du and Zheng and independently β-cyano- reportedsubstituted the and Zheng independently reported the formal NHC/Lewis acid catalyzed [3 + 3] annulation of formalα,β-unsaturated NHC/Lewis aldehydes acid catalyzed, respectively [3 + 3] annulation[66]. Compared of 1,3-dicarbonyl with the isatin compounds-derived with enals, isatin-derived which was 1,3-dicarbonyl compounds with isatin-derived 2-bromoenals and β-cyano-substituted 2-bromoenalsunstable under and airβ -cyano-substituted and always difficultα,β -unsaturated to separate aldehydes, from the Z/E respectively mixtures, [66 the]. Compared isatin-derived with α,β-unsaturated aldehydes, respectively [66]. Compared with the isatin-derived enals, which was the-bromoenals isatin-derived were enals, proved which to was be unstablemore stable under under air and air always and reacted difficult well to separate with 1,3 from-dicarbonyl the Z/E unstable under air and always difficult to separate from the Z/E mixtures, the isatin-derived mixtures,compounds the under isatin-derived NHC/base 2-bromoenals conditions. were However, proved to it bewas more still stable ambiguous under air that and whether reacted well the -bromoenals were proved to be more stable under air and reacted well with 1,3-dicarbonyl withβ-cyano 1,3-dicarbonyl-substituted compoundsα,β-unsaturated under aldehydes NHC/base could conditions. be attacked However, by the it NHC was stillcatalyst ambiguous or not. thatThe compounds under NHC/base conditions. However, it was still ambiguous that whether the whetherenantioselective the β-cyano-substituted annulations of α β,-βcyano-unsaturated-substituted aldehydes α,β-unsaturated could be attacked aldehydes by the with NHC malonates catalyst β-cyano-substituted α,β-unsaturated aldehydes could be attacked by the NHC catalyst or not. The orwere not. investigated The enantioselective under NHC annulations-catalyzed oxidative of β-cyano-substituted conditions. In theseα,β-unsaturated two reactions, aldehydes the addition with enantioselective annulations of β-cyano-substituted α,β-unsaturated aldehydes with malonates malonatesof LiCl enhanced were investigated the reaction under yields NHC-catalyzed and stereoselectivities oxidative conditions. significantly In these to twogive reactions, the desired the were investigated under NHC-catalyzed oxidative conditions. In these two reactions, the addition additionspirooxindole of LiCl δ- enhancedlactones and the reactiondihydropyran yields-4 and-carbonitrile stereoselectivities compound significantlys [67]. Then, to giveDong, the Du desired and of LiCl enhanced the reaction yields and stereoselectivities significantly to give the desired spirooxindolecolleagues reportedδ-lactones the first and application dihydropyran-4-carbonitrile of esters as alkynyl compoundsacyl azolium [ 67precursors]. Then, Dong,that have Du been and spirooxindole δ-lactones and dihydropyran-4-carbonitrile compounds [67]. Then, Dong, Du and colleaguesutilized to reported undergo the first a application formal [2 of esters + 3] as annulation alkynyl acyl azolium with amidomalonates precursors that havethrough been utilizedcolleagues to undergo reported a the formal first [2 application+ 3] annulation of esters with as amidomalonates alkynyl acyl azolium through precursors dimethylaminopyridine that have been dimethylaminopyridineutilized to undergo (DMAP)/LiCl a formal [2 and + NHC/ 3] annulationLiCl coop erative with catalysis. amidomalonates A wide rangethrough of (DMAP)/LiCl and NHC/LiCl cooperative catalysis. A wide range of (Z)-5-amino-3-furanones was (Zdimethylaminopyridine)-5-amino-3-furanones was (DMAP)/LiCl synthesized and with NHC/ moderateLiCl coop to higherative yields catalysis. (41%– 99%A wideyield) rangeand high of synthesized with moderate to high yields (41%–99% yield) and high regioselectivities [68]. regioselectivit(Z)-5-amino-3ies-furanones [68]. was synthesized with moderate to high yields (41%–99% yield) and high regioselectivities [68].

SchemeScheme 17.17. NHC/LewisNHC/Lewis a acidcid c catalyzedatalyzed enantioselectiveenantioselective aerobicaerobic annulationannulation of of α α,β,β-unsaturated-unsaturated aldehydesaScheldehydesme 1 with7. NHC/Lewis 1,3-dicarbonyl1,3-dicarbonyl acid compounds.c ompoundscatalyzed .e nantioselective aerobic annulation of α,β-unsaturated aldehydes with 1,3-dicarbonyl compounds. Compared with with enals, enals, the carboxylic the carboxylic acids are acids more are readily more available readily and available stable. They and could stable. be TheyeasilyCompared activated could be withand easily inenals, situ the converted activated carboxylic to and acids the key inare NHCmore situ- readilybound converted intermediatesavailable to and the stablewith key . theThey NHC-bound assist could of be an intermediatesarrayeasily activated of with andcoupling thein situ assist converted of reagents an array to , the of keysuch coupling NHC -bound reagents,as intermediates carbonyldiimidazole such as with carbonyldiimidazole the assist of(CDI), an (CDI),2array-(7-aza 2-(7-aza-1H-benhexaﬂuorophoszotriazole-1-yl)-1,1,3,3-tetramethyluroniumphate-1H- ofbenhexafluorophoszotriazole coupling reagents-,1 -yl)-1,1,3,3such -tetramethyluroniumphateas carbonyldiimidazole (HATU), (HATU), (CDI), and α β pivaloyl2-(7-aza -1H chloridechloride.-benhexafluorophoszotriazole. Yao Yao and and co co-workers-workers reported-1 reported-yl)-1,1,3,3 that that-tetramethyluroniumphate α,β-,unsaturated-unsaturated carboxylic carboxylic (HATU), acids acids could couldand be be transformed into α,β-unsaturated acyl azolium in the presence of HATU via the in situ pivaloyl chloride. Yao and co-workers reported that α,β-unsaturated carboxylic acids could be

Catalysts 2019, 9, x FOR PEER REVIEW 14 of 23

Catalysts 2019, 9, x FOR PEER REVIEW 14 of 23 transformed into α,β-unsaturated acyl azolium in the presence of HATU via the in situ activation Catalysts 2019, 9, 863 14 of 23 transformedstrategy. Moreover, into α,β -unsaturated the introduction acyl azolium of LiCl in the could presence improve of HATU the via enantioselectivit the in situ activationies of strategy.dihydropyranone Moreover, products the introduction[69]. In 2017, of theLiCl Bijucould group improve demonstrated the enantioselectivit an intramolecularies of activationdihydropyranoneNHC-catalyzed strategy. aldol products Moreover,-lactonization [69 the]. introductionIn of ketoacids 2017, the of 82Biju LiClusing group could the improvedynamic demonstrated the kinetic enantioselectivities an resolution intramolecular (DKR of) dihydropyranoneNHCstrategy-catalyzed (Scheme aldol products18).- lactTheonization [ 69kinetics]. In 2017, s oftudy the ketoacids Bijuindicate group 82d demonstratedthatusing the the reaction dynamic an intramolecular proceed kineticed resolutionvia NHC-catalyzed DKR process (DKR) aldol-lactonizationstrategybecause (moreScheme than 1 of8) .ketoacids 50%The kineticsβ-lactones 82 using study were the indicate dynamic obtainedd that kinetic in the 6resolution reactionh. Further proceed (DKR) transformation strategyed via DKR (Scheme process of 18 the). Thebecausecyclopentane kinetics more study-fused than indicatedβ -lactone 50% β that-productslactones the reaction 83were with proceededobtained primary amines in via 6 DKRh resulted. Further process in becausesuccinimide transformation more derivatives than of 50% the βcyclopentanecontaining-lactones werefour-fused obtained contiguous β-lactone in 6 stereocenters h.products Further 83 transformation with in excellent primary of yieldamines thes cyclopentane-fused and resulted diastereoselectivit in succinimideβ-lactoneies derivatives and products good 83containingenantiopurit with primary fouries [ 70 amines contiguous]. resulted stereocenters in succinimide in excellent derivatives yield containings and diastereoselectivit four contiguousies stereocenters and good inenantiopurit excellent yieldsies [70 and]. diastereoselectivities and good enantiopurities [70].

Scheme 18. NHC-catalyzed aldol-lactonization of ketoacids via dynamic kinetic resolution. SchemeScheme 18.18. NHCNHC-catalyzed-catalyzed a aldol-lactonizationldol-lactonization of k ketoacidsetoacids via dynamicdynamic kinetickinetic resolution.resolution. In 2017, Huang and Fu Group reported an oxidative amidation of aldimine 84 by NHC In 2017, Huang and Fu Group reported an oxidative amidation of aldimine 84 by NHC catalysis catalysisIn 2017, with LiCl Huang as c andooperative Fu Group Lewis reported acid under an ambient oxidative air amidation (Scheme 1 of9). aldimineThe proposed 84 by reaction NHC with LiCl as cooperative Lewis acid under ambient air (Scheme 19). The proposed reaction pathway catalysispathway with indicated LiCl as that cooperative the NHC Lewis-bounded acid under aldimine ambient intermediat air (Schemee was 1 9 produced). The proposed firstly reaction by the indicated that the NHC-bounded aldimine intermediate was produced firstly by the umpolung of pathwayumpolung indicated of aldimine that under the NHC- catalysisbounded with aldimine the assistance intermediat of thee was LiCl, produced and the structure firstly by of the aldimine under NHC catalysis with the assistance of the LiCl, and the structure of the intermediate umpolungintermediate of aldimine was confirmed under NHC by X catalysis-ray diffracti with onthe analysisassistance. Then of the theLiCl, intermediate and the structure underwent of the was confirmed by X-ray diffraction analysis. Then the intermediate underwent dearomatization and intermediatedearomatization was and confirmed deprotonation by X -processray diffracti to formon an analysis imine-. derivedThen theBreslow intermediate intermediate underwent, which deprotonation process to form an imine-derived Breslow intermediate, which then added to dioxygen dearomatizationthen added to dioxygen and deprotonation from the air process and cleaved to form the an i Omine–O bond-derived under Breslow basic intermediate condition to, whichafford from the air and cleaved the O–O bond under basic condition to afford amides 85 with the expulsion of thenamides added 85 with to dioxygenthe expulsion from of the the air free and carbene. cleaved O verall,the O –aOn economical bond under and basic efficient condition methodology to afford the free carbene. Overall, an economical and efficient methodology was developed for the synthesis of amideswas developed 85 with thefor expulsion the synthesis of the of free some carbene. biological Overall, molecules an economical by the cooperativeand efficient catalysismethodology with some biological molecules by the cooperative catalysis with ambient air or O as the sole oxidant [71]. wasambient developed air or O 2for as the sole synthesis oxidant of [7 some1]. biological molecules by the cooperative2 catalysis with ambient air or O2 as the sole oxidant [71].

SchemeScheme 19.19. AccessAccess to to a amidemide from from a aldimineldimine via a aerobicerobic o oxidativexidative carbenecarbene catalysiscatalysis and LiCl as cooperativeSchecooperativeme 19. LewisAccess acid.a cid to . amide from aldimine via aerobic oxidative carbene catalysis and LiCl as cooperative Lewis acid. Later, thethe samesame authorsauthors employedemployed potassiumpotassium 2-oxo-3-enoates2-oxo-3-enoates 86 as outstandingoutstanding and practical surrogates for α,β-unsaturated aldehydes in NHC-catalyzed asymmetric reactions. These salts surrogatesLater, the for same α,β-unsaturated authors employed aldehydes potassium in NHC 2--oxocatalyzed-3-enoates asymmetric 86 as outstanding reactions. and These practical salts could be prepared at scale and puriﬁed to undergo NHC-catalyzed reactions with enones 87, isatins surrogatescould be prepared for α,β at-unsaturated scale and purified aldehydes to undergo in NHC NHC-catalyzed-catalyzed asymmetric reactions with reactions. enones These 87, isatins salts 89, and 1,3-dicarbonyl compounds 91 respectively, aﬀording various corresponding cyclopentenes could89, and be 1,3 prepared-dicarbonyl at scale compounds and purified 91 respectively, to undergo NHCafford-catalyzeding various reactions corresponding with enones cyclopentenes 87, isatins 88, spirooxindole lactones 90 and lactones 92 with broad substrate scopes and good to excellent 8988, and spirooxindole 1,3-dicarbonyl lactones compounds 90 and lactones91 respectively, 92 with afford broading substrate various scopescorresponding and good cyclopentenes to excellent enantioselectivities [72]. In 2019, this group further developed a novel NHC-catalyzed [3 + 3] 88enantioselectivities, spirooxindole lactones [72]. In 90 2019, and th lactonesis group 92 furtherwith broad developed substrate a novel scopes NHC and -catalyzed good to excellent [3 + 3] annulation of potassium 2-oxo-3-enoates 86 with 2-ethylidene 1,3-indandione 93 to give 2,2-diacyl enantioselectivitiesannulation of potassium [72]. 2 In-oxo 2019,-3-enoates this group 86 with further 2-ethylidene developed 1,3 - aindandione novel NHC 93- catalyzedto give 2,2 [3-diacyl + 3] spirocyclohexanones 94 in good to excellent yields. Lewis acid LiCl was added in these reactions to annulation of potassium 2-oxo-3-enoates 86 with 2-ethylidene 1,3-indandione 93 to give 2,2-diacyl activate the potassium 2-oxo-3-enoates via the collaborative strategy (Scheme 20)[73].

Catalysts 2019, 9, x FOR PEER REVIEW 15 of 23

Catalystsspirocyclohexanones2019, 9, 863 94 in good to excellent yields. Lewis acid LiCl was added in these reactions15 of to 23 activate the potassium 2-oxo-3-enoates via the collaborative strategy (Scheme 20) [73].

SchemeScheme 20.20. Potassium 22-oxo-3-enoates-oxo-3-enoates as e ffectiveﬀective and versatileversatile surrogatessurrogates for for α α,β,β-unsaturated-unsaturated aldehydesaldehydes inin NHC-catalyzedNHC-catalyzed asymmetricasymmetric reactions.reactions.

InIn 2018, 2018, the the Enders Enders group group reported reported a new a new NHC-catalyzed NHC-catalyzed domino domino process process of enals of with enals reactive with malonatesreactive malonates 98 (Scheme 98 ( Scheme21). The 21 huge). The challengehuge challenge of this of cascade this cascade reaction reaction was howwas how to control to control the reactivitiesthe reactivities of multifold of multifold nucleophilic nucleophilic and electrophilic and electrophilic of the substrates of the substrates [74]. Hence [74 the]. Hence malonates the bearingmalonates an bearing ortho-hydroxy an ortho phenyl-hydroxy group phenyl and enalsgroup were and selectedenals were as startingselected materials as starting to materials validate the to feasibilityvalidate the of the feasibili dominoty of processes. the domino Gratifyingly, processes. the Gratifyingly, desired cyclopenta[c]-fused the desired cyclopenta[c] chromenones-fused 99 werechromenones isolated in99an were acceptable isolated yields in an and acceptable high enantioselectivities yields and high with enantioselectivit the assistanceies of LiClwith as the a cooperativeassistance of Lewis LiCl acid. as a Since cooperative there are Lewis two possible acid. Since mechanisms there areto illuminate two possible the reaction mechanism pathway,s to DFTilluminate calculations the reaction and control pathway, experiments DFT calculations were carried andout to control verify that experiments the reaction were has carriedbeen subjected out to toverify the dominothat the Michaelreaction/ aldolhas been/lactonization subjected/ dehydrationto the domino process. Michael/aldol/lactonization/dehydration Notably, low chemical yields and eeprocess.values Notably, were obtained low chemical in the absence yields of and LiCl. ee values This domino were obtain reactioned clearly in the absenceshowed theof LiCl. power This of NHCdomino/Lewis reaction acid cooperative clearly showed catalysis the involving power of reactive NHC/Lewis reagents. acid cooperative catalysis involving reactive reagents.

Catalysts 2019, 9, 863 16 of 23 Catalysts 2019, 9, x FOR PEER REVIEW 16 of 23 Catalysts 2019, 9, x FOR PEER REVIEW 16 of 23

SchemeScheSchememe 21.2121.. NHCNHCNHC-catalyzed--catalyzedcatalyzed quadruple quadruple domino domino reactions: reactions: asymmetric asymmetric asymmetric synthesis synthesis of of of cyclopenta[c]chromenones.cyclopenta[c]chromenones.cyclopenta[c]chromenones.

Recently,RecentlyRecently, Naumann,, NaumannNaumann Buchmeiser,, BuchmeiserBuchmeiser and co-workersand co--workers established establishedestablished an NHC / anLiCl an NHC/LiCl NHC/LiClcooperative cooperative catalysiscooperative for thecatalysiscatalysis synthesis for for ofthethe linear synthesissynthesis poly(oxazolidin-2-one)s ofof linearlinear poly(oxazolidin (POxa)--22 102--one)sone)s (Scheme (POxa)(POxa) 22 ). 102102 Diepoxides ( (SchemeScheme 22 101,22).) .Diepoxides aromaticDiepoxides as 101 well101, , asaromaticaromatic aliphatic as as diisocyanates well well as as aliphatic aliphatic 100, and diisocyanates NHC-CO2 adducts100,, and wered NHC NHC employed--COCO22 adductsadducts in the polymerizationwere were employed employed reaction. inin the the Morepolymerizationpolymerization importantly, reaction.reaction. the Lewis MoreMore acid importantly, LiCl was selectedthe LewisLewis as acidacid cocatalyst LiClLiCl waswas to selectedselected secure high-molecular-weightas as cocatalyst cocatalyst to to secure secure POxahighhigh--molecular andmolecular control--weightweight the polymerization POxaPOxa and control in a reasonablethe polymerization degree [ 75 inin ]. aa reasonablereasonable degree degree [ 7[755].] .

SchemeScheSchememe 22.22 22.. Synthesis Synthesis ofof linearlinear poly(oxazolidin-2-one)spoly(oxazolidin-2--one)s by by cooperative cooperative catalysis catalysiscatalysis based basedbased on onon NHC/L NHCNHC/L/LiCl.iCliCl. .

5. Cooperative NHC/Sc Catalysis 5.5. Cooperative Cooperative NHC/ScNHC/Sc CatalysisCatalysis In 2012, the scandium-based Lewis acid was first applied in the cooperative NHC catalysis by InIn 2012,2012, thethe scandiumscandium--basedbased Lewis acid was first appliedapplied inin thethe cooperativecooperative NHC NHC catalysis catalysis by by thethe Chi Chi group group [76 ]. [76 The]. The authors authors successfully successfully circumvented circumvented the di ffi theculties difficulties in improving in improving the reactivity the the Chi group [76]. The authors successfully circumvented the difficulties in improving the andreactivity enantioselectivity and enantioselectivity of the remote of γthe-carbon remote of γ enals-carbon (Scheme of enals 23). (Schemeβ-phenyl 23 substituted). β-phenyl butenalsubstituted was reactivity and enantioselectivity of the remote γ-carbon of enals (Scheme 23). β-phenyl substituted chosenbutenal as was the chosen starting as material the starting to avoid material the competing to avoid the pathway competing of the pathway NHC-mediated of the NHC enal-mediated reactions. butenal was chosen as the starting material to avoid the competing pathway of the NHC-mediated Theenal combination reactions. The of Sc(OTf)combination3 and of Mg(OTf) Sc(OTf)2 3o andffered Mg(OTf) a small2 butoffered consistent a small additional but consistentee enhancement. additional enal reactions. The combination of Sc(OTf)3 and Mg(OTf)2 offered a small but consistent additional Remarkably,ee enhancement. only Remarkably 5%–23% ee were, only observed 5%–23% inee allwere cases observed when thein all reactions cases when were the conducted reactions without were ee enhancement. Remarkably, only 5%–23% ee were observed in all cases when the reactions were Sc(OTf)conducted3, which without demonstrated Sc(OTf)3, which that the demonstrated potential coordination that the potential of Sc(OTf) coordination3 played aof critical Sc(OTf) role3 pla inyed the conducted without Sc(OTf)3, which demonstrated that the potential coordination of Sc(OTf)3 played chirala critical induction. role in the chiral induction. a critical role in the chiral induction.

Catalysts 2019, 9, 863 17 of 23 Catalysts 2019, 9, x FOR PEER REVIEW 17 of 23

SchemeScheme 23.23. OxidativeOxidative γ-additionγ-addition of enals of to enals trifluoromethyl to triﬂuoromethyl ketones by ketones NHC/Sc(OTf) by NHC3 cooperative/Sc(OTf)3 cooperativecatalysis. catalysis.

InspiredInspired by by these these results, results, Wang Wang and and co-workers co-workers reported reported an enantioselective i intermolecularntermolecular dynamicdynamic kinetic kinetic resolution resolution (DKR) (DKR) catalyzed catalyzed by an Nby-heterocyclic an N-heterocyclic carbene andcarbene a Lewis and acid a cooperatively Lewis acid (Schemecooperatively 24)[77 (].Scheme The enantiomerically 24) [77]. The enantiomerically pure DKR products pure σ DKR-lactones products 106 were σ-lactones isolated 106 from were the reactionisolated of fromβ-phenyl the reaction substituted of butenal β-phenyl and substitutedβ-halo-α-ketoesters butenal and 105 underβ-halo- oxidativeα-ketoesters conditions 105 under with excellentoxidative enantio- conditions and with diastereocontrol. excellent enantio The- postulated and diastereocontrol. reaction pathway The postulated was illustrated reaction that pathway the key intermediatewas illustrated vinyl that enolate the key 109 intermediate arose from the vinylγ-deprotonation enolate 109 ofarose the oxidativelyfrom the γ- generateddeprotonation unsaturated of the acyloxidatively azolium intermediate generated unsaturated 108. Then, this acyl intermediate azolium underwentintermediate the 108 nucleophilic. Then, additionthis intermediate to activate ketones,underwent resulting the nucleophilic in the regioselective addition toγ -additionactivate ketones, and construction resulting in of the cyclizationregioselective products. γ-addition The Lewisand construction acid Sc(OTf) of3 theor Mg(OTf)cyclization2 were products. known The to Lewis exhibit acid good Sc( aOTf)ﬃnities3 or Mg(OTf) for carbonyl2 were oxygen known and to carboxylates,exhibit good and affinities potentially for carbonyl involved oxygen in the multisite and carboxylates, coordination and to bringpotentially the ketone involved electrophile in the intomultisite close proximity coordination with to vinyl bring enolate the ketone intermediate. electrophile In general, into close the eproximityﬀect of this with coordination vinyl enolate may amplifyintermediate. the otherwise In general, weak the chiral effect induction of this by coordination the chiral NHC may catalyst. amplify the otherwise weak chiral induction by the chiral NHC catalyst.

Catalysts 2019, 9, 863 18 of 23 Catalysts 2019, 9, x FOR PEER REVIEW 18 of 23

SchemeScheme 24. 24.Intermolecular Intermolecular dynamicdynamic kinetickinetic resolutionresolution cooperatively catalyzed by by an an NN--heterocyclicheterocyclic carbenecarbene and and a a Lewis Lewis acid. acid.

6.6. Miscellaneous Miscellaneous

InIn 2014, 2014, Yao Yao and and coworkers coworkers reported reported a a novel novel Lewis Lewis acid La(OTf)33 asas a a co co-catalyst-catalyst in in the the NHC-catalyzedNHC-catalyzed [4 [4+ +2] 2] annulation annulation of of 2-bromo-2-enals 2-bromo-2-enals with with isatin isatin derivatives derivatives 112 11 (Scheme2 (Scheme 25). 2 This5). Th dualis catalysisdual catalysis process process was initiated was initiated by the by addition the addition of the NHC of the to NHC 2-bromo-2-enals to 2-bromo-2 to-enals give tothe give Breslow the 3 3 intermediate,Breslow intermediate, which then which underwent then a underwentto d umpolung a3 to d and3 umpolung debromination and debromination to generate α,β -unsaturated to generate acylα,β- azoliumunsaturated intermediate acyl azolium without intermediate the addition ofwithout external theoxidant. addition The α, ofβ-unsaturated external oxidant. acyl azolium The wasα,β- thenunsaturated deprotonated acyl azolium at the γwas-position then deprotonated to provide the at the vinyl γ-position enolate intermediate.to provide the Subsequently,vinyl enolate theintermediate. nucleophilic Subsequently, addition and the intramolecular nucleophilic lactonization addition and occurred intramolecul betweenar lactonization the vinyl enolate occurred and isatinbetween 112. Spirocyclic the vinyl oxindole-dihydropyranones enolate and isatin 112. Spirocyclic 113 were prepared oxindole in-dihydropyranones good yields and with 11 excellent3 were enantioselectivities.prepared in good yields Similar and to with Chi’s excellent and Wang’s enantioselectivities. report (vide supra), Similar only to 19–41% Chi’s andee were Wang’ observeds report in all(vide cases supra in the), only absence 19% of–41% Lewis ee were acid La(OTf)observed3 asin aall co-catalyst cases in the [78 absence]. of Lewis acid La(OTf)3 as a co-catalyst [78].

Catalysts 2019, 9, 863 19 of 23 CatalystsCatalysts 20192019,, 99,, xx FORFOR PEERPEER REVIEWREVIEW 1919 ofof 2323

Scheme 25. NHC/La(OTf)3 strategy for the stereoselective synthesis of ScheSchememe 2255.. NHC/La(OTf)NHC/La(OTf)3 sstrategytrategy3 for for the the sstereoselectivetereoselective ssynthesisynthesis of of sspirocyclicpirocyclic spirocyclicooxindolexindole--dd oxindole-dihydropyranones.ihydropyranonesihydropyranones.. Ye and colleagues investigated the reactions of α,β-unsaturated carboxylic acids with isatin-derived YeYe and and colleagues colleagues investigatedinvestigated thethe reaction reactionss ofof α,βα,β--unsaturatedunsaturated carboxyliccarboxylic acid acidss withwith ketamines under NHC catalysis. Initially, the desired spirocyclic oxindolodihydropyridinone product isatinisatin--derivedderived ketamine ketaminess underunder NHC NHC catalysis catalysis.. Initially,Initially, the the desired desired spirocyclic spirocyclic ee wasoxindolodihydropyridinoneoxindolodihydropyridinone isolated in low yield with product product only 7%waswas isolatedisolatedin the absence in in low low yield yield of Lewis with with acid. only only 7% Notably,7% eeee inin the the absence absenceLewis acid of of La(OTf) performed well to improve the yield and3 enantioselectivity [79]. In 2017, Huang and LewisLewis 3 acid. acid. Notably,Notably, t thehe Lewis Lewis acid acid La(OTf) La(OTf)3 performedperformed well well toto improve improve the the yield yield and and β co-workersenantioselectivityenantioselectivity presented [[7799] an].. InIn enantioselective 2017,2017, HuangHuang andand-protonation coco--workersworkers presentedpresented of enals via anan a enantioselectiveenantioselective shuttling strategy ββ--protonationprotonation (Scheme 26 ). Aofof variety enals enals ofvia via Lewis a a shuttling shuttling acids have strategy strategy been ((Scheme screenedScheme 22 and66)).. AA displayed variety variety of of a strong Lewis Lewis impact acid acidss haha onveve the beenbeen enantioselectivity. screened screened and and Finally, Cu(OTf) resulted in the highest yield and ee value. The2 Lewis acid could coordinate displayeddisplayed aa strongstrong2 impactimpact onon thethe enantioselectivityenantioselectivity.. Finally,Finally, Cu(OTf)Cu(OTf)2 resultedresulted inin thethe highhighestest yieldyield withandand enalseeee value.value. and TT mercaptanshehe Lewis Lewis acid acid 114 couldcould through coordinatecoordinate not only with with stabilizing en enalsals andand a homoenolate mercaptans mercaptans 1111 intermediate44 throughthrough notnot but only only also facilitatingstabilizstabilizinging protonationaa homoenolatehomoenolate by intermediateintermediate increasing the butbut acidityalsoalso facilitatfacilitat of theinging thiol. protonationprotonation In a word, byby increasingincreasing the combination thethe acidityacidity of ofof a chiralthethe thiol.thiol.N-heterocyclic InIn aa word,word, thethe carbene combinationcombination (NHC) ofof catalyst aa chiralchiral and NN--heterocyclicheterocyclic a strong Brønsted carbenecarbene/ Lewis (NHC)(NHC) acid catalystcatalyst cocatalyst andand aa strongstrong solved theBrønsted/LewisBrønsted/Lewis longstanding challenge acid acid cocatalyst cocatalyst of enantioselective solved solved thethe longstandingremote longstandingβ-protonation challenge challenge of homoenolates of of enantioselective enantioselective with excellentremoteremote reactivityββ--protonationprotonation and enantioselectivity ofof homohomoenolatesenolates withwith [80]. excellentexcellent reactivityreactivity andand enantioselectivityenantioselectivity [[8080]]..

SchemeScheSchememe 26. 226.6. Enantioselective EnantioselectiveEnantioselective ββ--protonation-protonationprotonation ofof enalsenals via via a a shuttlingshuttling shuttling strategystrategy strategy... 7. Conclusions 7.7. ConclusionsConclusions In this review, a number of catalytic applications have demonstrated that the combination of InIn thisthis review,review, aa numbernumber ofof catalyticcatalytic applicationsapplications havehave demonstrateddemonstrated thatthat thethe combinationcombination ofof NHCNHCNHC catalysis catalysiscatalysis with withwith Lewis LewisLewis acid acidacid isisis aaa uniqueunique andand efficient eefficientﬃcient strategy strategy forfor accessaccess toto to aa a widewide wide rangerange range ofof of highlyhighly highly functionalizedfunctionalizedfunctionalized complex complexcomplex andandand enantiomericallyenantiomericallyenantiomerically enriched enriched structural structural motifs.motifs. motifs. TheThe The useuse use ofof of aa a LewisLewis Lewis acidacid acid inin in combinationcombinationcombination with with with a NHCa a NHC NHC catalyst catalyst catalyst enable enableenable us tousus (1) totoincrease ((1)1) inc increaserease the yield thethe yield andyield enantioselectivity, and and enantioselectivity, enantioselectivity, (2) reverse ((2)2) diastereo-reversereverse diastereodiastereo and regioselectivity,-- andand regioselectivity,regioselectivity, (3) change ((3)3) the changechange reaction thethe reactionreaction pathway pathwaypathway and (4) activateandand ((4)4) activateactivate a previous aa previousprevious inactive electrophileinactiveinactive electrophile electrophile in NHC-generated in in NHC NHC--generatedgenerated processes. processes. processes. Overall, the Overall, Overall, dual catalytic the the dual dual approaches catalytic catalytic approaches approaches would expand would would the utilityexpandexpand of NHC the the utili/ utiliLewistyty ofacid of NHC/Lewis NHC/Lewis methodology acid acid and methodology methodology construct other and and synthetically construct construct useful other other products synthetically synthetically with diverseuseful useful particularlyproductsproducts with with important diverse diverse skeletons. particularly particularly Further important important development skeletons. skeletons. of the Further Further cooperative development development catalysis in of of the the the total cooperative cooperative synthesis ofcatalysiscatalysis natural in productsin thethe totaltotal and synthesissynthesis pharmaceuticals ofof naturalnatural will productsproducts be the andand target pharmaceuticalspharmaceuticals of future studies. willwill bebe thethe tatargetrget ofof futurefuture studies.studies.

Catalysts 2019, 9, 863 20 of 23

Author Contributions: Q.J. and Q.R. wrote the manuscript. Y.L. (Yaqiong Li) and Y.L. (Yinhe Lin) contributed to discussions and edited the manuscript. Funding: The project is funded by the National Natural Science Foundation of China (No. 21602179) and Science Foundation of Yangtze Normal University (No. 2017KYQD123, 2018QNRC17). Conﬂicts of Interest: The authors declare no conﬂict of interest.

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