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 Theelectrophiles. related exciting The discoveriesrelated exciting involving discoveries NHCs/ Lewisinvolving 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 potentialwith 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(Oindicatedt-Bu) 2thatcould 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 berange well of accommodated. functionalities turned In these out processes, to be we carbenell accommodated. precursor AIn wasthese 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 thecases, unreacted the unreacted starting tertiary starting alcohols tertiary 8were alcohols recovered 8 were in high recovered to excellent in high enantioselectivities. 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 benefitcooperative the presumable way to benefit attack ofthe tertiary presumable alcohol attack on acyl of azolium tertiaryintermediate alcohol on acyl from theazolium opposite intermediate side of the catalyst’sfrom the chiralopposite backbone. side of However, the catalyst the oxindole’s chiral structurebackbone. was However, proved tothe be criticaloxindole for structure this system was to proved work smoothly to be critical [43 ].for this system to work smoothly [43]. Catalysts 2019, 9, 863 3 of 23 CatalystsCatalysts 2019 2019, 9, ,9 x, xFOR FOR PEER PEER REVIEW REVIEW 33 of of 23 23 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. Catalysts 2019, 9, 863 4 of 23 Catalysts 2019, 9, x FOR PEER REVIEW 4 of 23 InIn 2018,2018, WangWang andand co-workersco-workers discloseddisclosed aa [3[3+ + 3]3] atroposelectiveatroposelective annulationannulation ofof alkynylalkynyl acylacyl 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