Non-Covalent Interactions in Enantioselective Organocatalysis

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Review Non-Covalent Interactions in Enantioselective Organocatalysis: Theoretical and Mechanistic Studies of Reactions Mediated by Dual H-Bond Donors, Bifunctional Squaramides, Thioureas and Related Catalysts

Ana Maria Faisca Phillips 1,* , Martin H. G. Prechtl 1 and Armando J. L. Pombeiro 1,2

1 Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal; [email protected] (M.H.G.P.); [email protected] (A.J.L.P.) 2 Research Institute of Chemistry, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia * Correspondence: [email protected]; Tel.: +351-21-841-9225

Abstract: Chiral bifunctional dual H-bond donor catalysts have become one of the pillars of organocatalysis. They include squaramide, thiosquaramide, thiourea, urea, and even selenourea- based catalysts combined with chiral amines, cinchona alkaloids, sulfides, phosphines and more. They can promote several types of reactions affording products in very high yields and excellent stereoselectivities in many cases: conjugate additions, cycloadditions, the aldol and Henry reactions, the Morita–Baylis–Hilman reaction, even cascade reactions, among others. The desire to understand mechanisms and the quest for the origins of stereoselectivity, in attempts to find guidelines for Citation: Phillips, A.M.F.; Prechtl, M.H.G.; Pombeiro, A.J.L. developing more efficient catalysts for new transformations, has promoted many mechanistic and Non-Covalent Interactions in theoretical studies. In this review, we survey the literature published in this area since 2015. Enantioselective Organocatalysis: Theoretical and Mechanistic Studies Keywords: asymmetric synthesis; H-bonding; nonbonding interactions; density functional theory of Reactions Mediated by Dual calculations; Michael addition; cycloadditions; anion-binding catalysis; cascade reactions; transition H-Bond Donors, Bifunctional states; organocatalysis Squaramides, Thioureas and Related Catalysts. Catalysts 2021, 11, 569. https://doi.org/10.3390/catal11050569 1. Introduction Academic Editor: Cristina Trujillo The activation of reactants by hydrogen bonding and other noncovalent interactions has enabled the development of an enormous variety of reactions in recent years, and Received: 14 April 2021 Accepted: 26 April 2021 consequently, the production of chiral substances for several applications. This was possible Published: 29 April 2021 due to the discovery of an array of very efficient chiral bifunctional catalysts, mostly thiourea- or squaramide-based, usually combined with chiral amines or cinchona alkaloids,

Publisher’s Note: MDPI stays neutral and more recently also amides, phosphines or sulfides [1–4]. Urea, thiosquaramide and with regard to jurisdictional claims in even selenosquaramide chiral bifunctional catalysts are also starting to appear. They are published maps and institutional affil- usually assembled on a modular basis, which allows for easy structural modifications and iations. optimization of the results. The hydrogen bond-donors differ in duality, rigidity, H-bond spacing, H-bond angle, and pKa, which influence their catalytic behavior [1,5]. The average distance between the N–H groups in these substances is shown in Figure1a. Squaramides are distinct from the ureas in their hydrogen bond donor and acceptor character since, upon hydrogen bond Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. formation, aromaticity is enhanced in the latter. The cyclobutadienone ring contains two 2 This article is an open access article coplanar carbonyls and two NHs that are almost coplanar and essentially sp hybridized distributed under the terms and so that the lone pairs are available for conjugation into the π-system orthogonal plane [6]. conditions of the Creative Commons Similarly, the ability of thioureas to recognize cations is also more limited [6]. As Attribution (CC BY) license (https:// a result of their ambivalent hydrogen bonding characteristics, squaramides also form creativecommons.org/licenses/by/ dimeric species. 4.0/).

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Catalysts 2021, 11, 569 2 of 54 Similarly, the ability of thioureas to recognize cations is also more limited [6]. As a result of their ambivalent hydrogen bonding characteristics, squaramides also form dimeric species. The distancedistance betweenbetween the the N–H N–H groups groups is largeris larger in squaramidesin squaramides than than in thioureas. in thioureas. Due Dueto the to geometry the geometry of the of cyclobutenedione the cyclobutenedione ring, ring, the N–H the N–H groups groups are also are oriented also oriented towards to- ◦ wardseach other each byother ~6 by, a ~6°, characteristic, a characteristic, which which is absent is absent in the in amido/thioamidothe amido/thioamido groups groups of ofureas/thioureas ureas/thioureas [7 ].[7]. This This property property may may result result in in increased increased linearity linearity in in hydrogen hydrogen bonding bond- withing with some some substrates substrates and and provide provide different different binding binding properties properties in the in transitionthe transition state. state.

Figure 1. (a) DualityDuality inin hydrogenhydrogen bondingbonding inin squaramidessquaramides andand H-bondH-bond spacingspacing distancesdistances inin H-bondH-bond donordonor catalystscatalysts andand ((b)) thethe ppKaa value acidity scales of typical thiourea and squaramide-based catalysts [[7,8].7,8].

The determination determination of of the the p pKKa avaluesvalues has has been been the the subject subject of ofsome some studies. studies. Since, Since, ac- cordingaccording to tothe the proton proton affinity–p afﬁnity–pKKa aequalizationequalization principle, principle, the the strength strength of of hydrogen hydrogen bonds can be approximated by the pKa valuesvalues of the the donor donor and the a acceptorcceptor species, these values can be used to characterize the catalytic activity and allow predictions to be made that are useful for developing novel catalysts [8]. The higher the acidity of a hydrogen-bonding donor, the stronger is the resulting hydrogen bond, and therefore, introducing stronger hydrogen-bonding donor groups in a catalyst should result in higher catalytic activity. In

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addition, the formation of a strong hydrogen bond should also help with stereocontrol and enantioselectivity. Figure1b shows the p Ka values of some well-known thiourea- and squaramide-based catalysts, determined by applying the classical overlapping indicator method in DMSO through UV spectrophotometric titrations [5,8–10]. Comparing the pKa values of related catalysts, it was found that the pKa values of squaramides are lower than those of their thiourea analogs, with a gap of 0.13–1.97 pKa units [8]. The actual value itself depends on the nature of other groups attached to the thiourea/squaramide group. However, since squaramides are more acidic than thioureas, they form stronger hydrogen bonds, which may explain why squaramides can often be used at lower catalytic loadings and display higher activity in a range of reactions. Li, Cheng and coworkers found, from a plot of pKa values of thioureas versus the pKa values of the analog squaramides, that there is a good correlation, two good straight lines with R values of 0.995 and 0.932 were obtained, which implies that if desired, the pKa values of squaramides might be roughly estimated from those of the corresponding thioureas, which have been more studied [8]. In addition, the linear free energy relationship (LEFR) between the acidity and activity of thiourea catalysts was determined with the Michael addition of diethyl malonate to nitrostyrene as a model reaction. Excellent LEFRs were observed for the stereoselectivity correlated with the pKa values of the corresponding thioureas. Although there were significant differences between the catalysts, the slopes of the LFERs between pKa values and enantioselectivities were almost identical, which suggests a similar process for forming the transition states of these reactions, and hence that the catalysts react by similar mechanisms. Lu and Wheeler demonstrated that thiosquaramides provide even stronger hydrogen- bonding interactions, and since the introduction of chiral bifunctional catalysts containing this motif by Rawal, they are gaining more interest [11,12]. The literature on mechanistic and density functional theory (DFT) studies concerning hydrogen-bonding organocatalysts has been reviewed occasionally [13]. In many cases, the B3LYP method was used since it has become a favorite in organocatalysis, as it yields accurate geometries and energies. Although we are still far from predicting exactly what will be the stereochemical outcome of a reaction, these studies aim to clarify the mode of action of the catalysts, and to reveal the nature of asymmetric induction, the factors responsible for it, so that better and more efficient catalysts can be designed for future applications. In this review, we survey the information published since 2015, when the last general overview of the field was reported [13]. The review is divided into the following sections: 1. Introduction; 2. Michael and other conjugate addition reactions; 3. Cycloaddition reactions; 4. Aldol and Henry reactions; 5. Miscellaneous reactions involving anion-binding catalysis; 6. Miscellaneous; 7. Conclusions.

2. Michael and Other Conjugate Addition Reactions 2.1. Additions to Nitroalkenes The largest number of papers encountered covering studies falling within the scope of this review were developments on the Michael addition reaction and its variants [14,15]. The ﬁrst report on utilizing a bifunctional thiourea-based organocatalyst in synthesis was by Takemoto and coworkers in 2003 [16]. It involved a Michael addition of malonates (1) to nitrooleﬁns (2) that were achieved with high yields and ees with catalyst C1 in toluene at room temperature (rt) (Figure2a). Catalytic asymmetric versions of this reaction were known at the time but required either metal catalysis or strict reaction conditions. This reaction opened the way to intensive research, and soon after, this and other thiourea- based bifunctional catalysts were applied in several reactions, e.g., the aza–Henry reaction, Catalysts 2021, 11, x FOR PEER REVIEW 4 of 55

at room temperature (rt) (Figure 2a). Catalytic asymmetric versions of this reaction were

Catalysts 2021, 11, 569 known at the time but required either metal catalysis or strict reaction conditions.4 This of 54 reaction opened the way to intensive research, and soon after, this and other thiourea- based bifunctional catalysts were applied in several reactions, e.g., the aza–Henry reaction, dynamic kinetic resolution of aza-lactones, Michael addition to α,β-unsaturated im- dynamicides, the aldol kinetic reaction, resolution sp2 of-alkylations, aza-lactones, spiro-ketal Michael addition formation to αand,β-unsaturated many others imides, [1–4]. The the aldolauthors reaction, showed sp through2-alkylations, experiments spiro-ketal using formation only either and the many amine others or the [1 –thiourea4]. The authorsas cata- showedlysts thatthrough for any significant experiments amount using of only product either 3 to the be amineobtained or and the for thiourea high enantiomeric as catalysts thatexcesses for anyto be signiﬁcant achieved, amountthe simultaneous of product presen3 to bece of obtained both units and in for the high catalyst enantiomeric molecule excesseswas essential. to be achieved,Kinetic studies the simultaneous to elucidate presencethe reaction of bothmechanism units in suggested the catalyst that molecule the ac- wastive essential.catalyst is Kinetic a monomeric studies tospecies, elucidate and the a bifunctional reaction mechanism mode of suggested activation that of both the active reac- catalysttants was is proposed a monomeric [17]. species,The catalytic and a cycle bifunctional (Figure mode2b) begins of activation with the ofdeprotonation both reactants of wasthe diester proposed by the [17 ].tertiary The catalytic amine moiety cycle (Figure of the2 catalystb) begins and with the the formation deprotonation of complex of the 4. diesterEnolate by addition the tertiary takes amine place moietypreferentially of the catalyst on the Si and face the of formation the nitronate of complex via TS2,4 affording. Enolate additioncomplex takes5. Proton place transfer preferentially to theon nitronate the Si face yields of the the nitronate product via (3a TS2,) and affording regenerates complex the 5catalyst.. Proton transfer to the nitronate yields the product (3a) and regenerates the catalyst.

Figure 2. The first ﬁrst bifunctional thiourea-catalyzedthiourea-catalyzed reaction ((aa)) andand itsits mechanismmechanism ((bb)[) [16,17].16,17].

Soon after, twotwo theoreticaltheoretical studiesstudies werewere reportedreported withwith conflictingconflicting results.results. Liu andand coworkers identified, identified, through through DFT DFT calculations, calculations, proton proton transfer transfer to to the the nitronate nitronate carbon carbon of ofcomplex complex 5 as5 as the the rate-determining rate-determining step step in in the the ca catalytictalytic cycle cycle [18]. [18]. Papái Papái and coworkerscoworkers identifiedidentified two possible binding modes, A and B, for TS2, in whichwhich eithereither thethe nitronatenitronate bonds to the thiourea moiety and the diester to the tertiary amine (binding mode A) or vice versa (binding mode B) (Figure3)[ 19]. It was calculated that binding mode B is −1 energetically favored by 2.7 kcal mol and that carbon–carbon bond formation is the rate-determining step. Other studies have been performed on this reaction and other bifunctional thiourea-based organocatalyzed Michael additions since then, but only the Catalysts 2021, 11, x FOR PEER REVIEW 5 of 55 Catalysts 2021, 11, x FOR PEER REVIEW 5 of 55

bonds to the thiourea moiety and the diester to the tertiary amine (binding mode A) or bonds to the thiourea moiety and the diester to the tertiary amine (binding mode A) or vice versa (binding mode B) (Figure 3) [19]. It was calculated that binding mode B is en- Catalysts 2021, 11, 569 vice versa (binding mode B) (Figure 3) [19]. It was calculated that binding mode B5 is of en- 54 ergetically favored by 2.7 kcal mol−1 and that carbon–carbon bond formation is the rate- ergetically favored by 2.7 kcal mol−1 and that carbon–carbon bond formation is the rate- determining step. Other studies have been performed on this reaction and other bifunc- determining step. Other studies have been performed on this reaction and other bifunctional thiourea-based organocatalyzed Michael additions since then, but only the more tional thiourea-based organocatalyzed Michael additions since then, but only the more morerecent recent literature literature is reviewed is reviewed here. here. NMR, NMR, crystallographic, crystallographic, and and computational computational studies studies on recent literature is reviewed here. NMR, crystallographic, and computational studies on onrelated related systems systems have have revealed revealed that that in the in thelowest lowest energy-binding energy-binding conformation, conformation, the cata- the related systems have revealed that in the lowest energy-binding conformation, the cata- catalystlyst displays displays a “syn, a “syn, anti anti” configuration” configuration of the of thethiourea thiourea functional functional group group and and not notthe thetra- lyst displays a “syn, anti” configuration of the thiourea functional group and not the tra- traditionalditional thiourea thiourea “anti, “anti, anti anti” ”configuration configuration shown shown in in Figure Figure 44aa [[20–23].20–23]. Generally, therethere ditional thiourea “anti, anti” configuration shown in Figure 4a [20–23]. Generally, there areare threethree main main activation activation modes modes possible possible to to explain explain thiourea-tertiary thiourea-tertiary amine amine organocatalysis, organocatal- are three main activation modes possible to explain thiourea-tertiary amine organocatal- namelyysis, namely mode mode A, attributed A, attributed to Takemoto to Takemoto et al. [et17 al.], mode[17], mode B, attributed B, attributed to Pá paito Pápai et al. et [19 al.] ysis, namely mode A, attributed to Takemoto et al. [17], mode B, attributed to Pápai et al. and[19] modeand mode C, attributed C, attributed to Wang to Wang et al. et [al.24 ][24] (Figure (Figure4b). 4b). These These three three possible possible modes modes of of [19] and mode C, attributed to Wang et al. [24] (Figure 4b). These three possible modes of activationactivation areare usuallyusually takentaken intointo considerationconsideration inin thisthis fieldfield inin theoreticaltheoretical studiesstudies whenwhen aa activation are usually taken into consideration in this field in theoretical studies when a searchsearch isis donedone forfor thethe transitiontransition state,state, whichwhich betterbetter describesdescribes aa certaincertain reactionreaction andand thethe search is done for the transition state, which better describes a certain reaction and the originsorigins ofof stereoinduction.stereoinduction. origins of stereoinduction.

FigureFigure 3.3. PossiblePossible bindingbinding modesmodes initiallyinitially selectedselected byby PPápaiápai [[19].19]. Figure 3. Possible binding modes initially selected by Pápai [19].

Figure 4. (a) Possible binding conformations of thiourea and (b) modes of activation proposed for Figure 4. (a) Possible binding conformations of thiourea and (b) modes of activation proposed for Figurethiourea-tertiary 4. (a) Possible amine binding organocatalysis conformations [17,19,24]. of thiourea and (b) modes of activation proposed for thiourea-tertiarythiourea-tertiary amine amine organocatalysis organocatalysis [ 17[17,19,24].,19,24]. A recent study by Hirschi, Vetticatt and coworkers on the Michael addition of malo- A recent study by Hirschi, Vetticatt and coworkers on the Michael addition of malo- natesA to recent nitro olefins study byaimed Hirschi, to clarify Vetticatt the mechanism and coworkers of catalysis on the by Michael tertiary addition amine thiourea of mal- nates to nitro olefins aimed to clarify the mechanism of catalysis by tertiary amine thiourea onatesorganocatalysts to nitro oleﬁns [25]. aimedThe addition to clarify of the diethyl mechanism malonate of catalysis to trans by-β-nitrostyrene tertiary amine catalyzed thiourea organocatalysts [25]. The addition of diethyl malonate to trans-β-nitrostyrene catalyzed organocatalystsby Takemoto’s catalyst [25]. The (C1 addition) was selected of diethyl as malonatea model system to trans. Kinetic-β-nitrostyrene isotope effects catalyzed (KIEs) by by Takemoto’s catalyst (C1) was selected as a model system. Kinetic isotope effects (KIEs) Takemoto’swere determined catalyst for (C1 both) was the selected malonate as a and model the system. nitrostyrene Kinetic using isotope NMR effects at natural (KIEs) abun- were were determined for both the malonate and the nitrostyrene using NMR at natural abun- determineddance from forstarting both thematerial malonate analysis and [26]. the nitrostyrene At ~80% conversion using NMR of the at naturalnitrostyrene abundance (−65% fromdance starting from starting material material analysis analysis [26]. At [26]. ~80% At conversion ~80% conversion of the nitrostyrene of the nitrostyrene (−65% in(−65% the in the malonate), the unreacted substances were isolated, and their 13C isotopic composi- malonate),in the malonate), the unreacted the unreacted substances substances were isolated, were isolated, and their and13C their isotopic 13C compositionisotopic composi- was tion was compared to samples of both substances that had not been subjected to any re- comparedtion was compared to samples to of samples both substances of both substa that hadnces not that been had subjected not been to subjected any reaction. to any KIEs reaction. KIEs were calculated in the usual manner (Figure 5). wereaction. calculated KIEs were in thecalculated usual manner in the usual (Figure manner5). (Figure 5).

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FigureFigure 5. 5.Experimentally Experimentally measured measured KIEs KIEs for for the the enantioselective enantioselective Michael Michael addition addition of diethyl of diethyl malonate malo- tonate trans- to trans-β-nitrostyreneβ-nitrostyrene catalyzed catalyzed by C1 by [25 C1]. [25].

TheThe resultsresults revealedrevealed aa significantsignificant primaryprimary13 13CC KIEKIE onon C1C1 ofof 1a1a( ∼(∼3%)3%) andand C1C10′ ofof 2a2a,, suggestingsuggesting thatthat bothboth atomsatoms werewere involvedinvolved inin thethe rate-determiningrate-determining TS,TS, i.e.,i.e., thatthat carbon–carbon– carboncarbon bondbond formation is is the the first first irreversible irreversible step step of of the the catalytic catalytic cycle, cycle, as proposed as proposed ini- initiallytially by by Takemoto Takemoto and and Pápai. Pápai. DFT DFT calculations calculations were were also performed forfor thethe transitiontransition structuresstructures in in each each step step in in the the catalytic catalytic cycle, cycle, using using the the B3LYP B3LYP method method and and a a 6-31+G** 6-31+G** basis basis setset [[27].27]. AA polarizablepolarizable continuumcontinuum modelmodel (PCM)(PCM) forfor toluene, toluene, as as implemented implemented in in Gaussian Gaussian 09,09, waswas usedused toto considerconsider solventsolvent effects.effects. TheThe procedureprocedure tooktook into into account account the the full full system system (89(89 atoms),atoms), and and it it has has been been shown shown previously previously to accurately to accurately describe describe the energetics the energetics of other of otherbifunctional bifunctional thiourea-catalyzed thiourea-catalyzed reactions. reactions. It was It the was first the time first that time it that was it applied was applied to Take- to Takemoto’smoto’s full fullsystem system [28]. [ 28Values]. Values of 13 ofC 13KIEsC KIEs were were also also obtained obtained from from scaled scaled vibrational vibrational fre- frequenciesquencies of of the the respective respective transition transition stru structuresctures using using the program ISOEFF98.ISOEFF98. AA WignerWigner tunnelingtunneling correctioncorrection was used. The The resulting resulting theoretical theoretical predictions predictions at at the the key key carbon carbon at- atomsoms of of 1a1a andand 2a2a werewere found found to to be in good agreement withwith thethe experimentallyexperimentallyobtained obtained values,values, supportingsupporting the the above above conclusions. conclusions. TheThe relativerelative energies of of the the transition transition state state structures structures leading leading to the to two the twoisomers isomers were werecalculated. calculated. Single Single point point energies energies were were obtained obtained using using B3LYLP-D3(BJ)/6-311++G** B3LYLP-D3(BJ)/6-311++G** PCM PCM(toluene). (toluene). The energies The energies of the of lowest the lowest energy energy structures structures for C–C for bond C–C bondformation, formation, the enan- the enantioselectivitytioselectivity determining determining step, step, were were determ determinedined using using DFT DFT calculations calculations based based upon upon ex- existingisting models models in in the the literature literature and and a conformational searchsearch usingusing quantumquantum mechanicalmechanical + simulationssimulations asas implementedimplemented inin DFTBDFTB+.. TheThe lowestlowest energyenergy structurestructure found,found, TS2-BMB-S,TS2-BMB-S, −1 givinggiving riserise toto thethe major major enantiomer, enantiomer, is is 2.4 2.4 kcal kcal mol mol−1 lowerlower inin energyenergy thanthan TS2-BMB-R,TS2-BMB-R, leadingleading toto thethe minorminor isomerisomer (Figure(Figure6 )[6) 25[25]].. TheseThese valuesvalues correspondcorrespond totoa a predicted predictedee eeof of 97%97% (S), (S), consistent consistent with with the the observed observed value value (93% (93%ee (eeS)). (S The)). The origin origin of enantioselectivity of enantioselectivity for thisfor this reaction reaction may may be inferred be inferred from from an analysis an analysis of the of interactions the interactions between between the different the different com- ponentscomponents involved. involved. TS2-BMB-S TS2-BMB-S and TS2-BMB-R and TS2-BMB-R possess possess very similarvery similar H-bonding H-bonding networks. net- The geometry around the forming C–C bond explains the difference in energy between works. The geometry around the forming C–C bond explains the difference in energy be- the two transition states. To accommodate the H-bonding stabilizing interactions with the tween the two transition states. To accommodate the H-bonding stabilizing interactions catalyst, the substituents adopt a staggered conformation (dihedral angle of ∼60◦ between with the catalyst, the substituents adopt a staggered conformation (dihedral angle of ∼60° the alkene of 2a and the ester groups of 1a) in TS2-BMB-S during C–C bond formation. On between the alkene of 2a and the ester groups of 1a) in TS2-BMB-S during C–C bond for- the contrary, transition structure TS2-BMB-R has a more eclipsed configuration for these mation. On the contrary, transition structure TS2-BMB-R has a more eclipsed configura- groups (dihedral angle of ∼30◦) when the C–C bond is forming. The result is increased tion for these groups (dihedral angle of ∼30°) when the C–C bond is forming. The result steric interactions between substrates in TS2-BMB-R compared to TS2-BMB-S, and this is is increased steric interactions between substrates in TS2-BMB-R compared to TS2-BMB- very likely the origin of enantioselectivity in this reaction. S, and this is very likely the origin of enantioselectivity in this reaction.

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Figure 6. Lowest energy transition structures for the Michael addition of 1a to 2a catalyzed by C1. Reprinted and adapted from Organic and Biomolecular Chemistry with permission from Royal Society of Chemistry [25]. Figure 6. Lowest energy transition structures for the Michael additionaddition ofof 1a1a toto 2a2a catalyzedcatalyzed byby C1.. Reprinted andand adaptedadapted fromfrom Organic andand BiomolecularBiomolecular ChemistryChemistry withwith permissionpermission fromfrom RoyalRoyal SocietySociety ofof ChemistryChemistry [[25].25]. A recent study performed by Pliego Jr on the addition of acetylacetone to β-nitrostyrene catalyzed by Takemoto’s catalyst in toluene used the PBE functional for geometry A recent studystudy performedperformed by by Pliego Pliego Jr Jr on on the the addition addition of acetylacetoneof acetylacetone to β to-nitrostyrene β-nitrosty- optimization and the DLPNO–CCSD(T) benchmark method for single-point energy [29]. renecatalyzed catalyzed by Takemoto’s by Takemoto’s catalyst catalyst in toluene in toluene used used the PBE the functionalPBE functional for geometry for geometry opti- The complete free energy profile calculated for the reaction supported the theory that car- optimizationmization and and the DLPNO–CCSD(T)the DLPNO–CCSD(T) benchmark benchmar methodk method for single-point for single-point energy energy [29]. [29]. The bon–carbon bond formation is the rate-determining step. The overall barrier was calcu- Thecomplete complete free free energy energy proﬁle profile calculated calculated for the for reactionthe reaction supported supported the theorythe theory that that carbon– car- lated to be 22.8 kcal mol−1 (experimental value ~20 kcal mol−1). It was found that three bon–carboncarbon bond bond formation formation is the is rate-determining the rate-determining step. Thestep. overall The overall barrier barrier was calculated was calcu- to transition states− with1 S stereochemistry and one with−1 R stereochemistry contribute to the latedbe 22.8 to kcal be 22.8 mol kcal(experimental mol−1 (experimental value ~20 value kcal mol~20 kcal). It mol was−1 found). It was that found three that transition three enantioselectivity, and the ee was calculated as 88% (experimental value = 84–92%). Some transitionstates with states S stereochemistry with S stereochemistry and one with and R one stereochemistry with R stereochemistry contribute contribute to the enantiose- to the functionals were tested for single-point energy using the DLPNO–CCSD(T) method as a enantioselectivity,lectivity, and the ee andwas the calculated ee was ascalculated 88% (experimental as 88% (experimental value = 84–92%). value Some= 84–92%). functionals Some reference. The M06-2X functional provided the best results, even compared to double- werefunctionals tested forwere single-point tested for energysingle-point using energy the DLPNO–CCSD(T) using the DLPNO–CCSD(T) method as a reference. method as The a hybrid functionals. It was also concluded that the additivity approximation of the corre- reference.M06-2X functional The M06-2X provided functional the best provided results, eventhe best compared results, to even double-hybrid compared functionals.to double- lation energy worked well, and it can be used as an alternative method to obtain accurate hybridIt was alsofunctionals. concluded It was that also the additivityconcluded approximation that the additivity of the approximation correlation energy of the worked corre- well,electronic and it energies. can be used as an alternative method to obtain accurate electronic energies. lation energy worked well, and it can be used as an alternative method to obtain accurate InIn recentrecent years years carbohydrates carbohydrates have have been been used used more more frequently frequently as chiral as chiral modular modular units electronic energies. forunits bifunctional for bifunctional organocatalysts organocatalysts [30]. In[30]. 2016 In Khan,2016 Khan, Narula Narula and coworkersand coworkers developed devel- In recent years carbohydrates have been used more frequently as chiral modular thiourea-basedoped thiourea-based catalysts catalysts incorporating incorporatingD-glucose D-glucose as a coreas a unitcore andunit testedand tested them them on the on units for bifunctional organocatalysts [30]. In 2016 Khan, Narula and coworkers devel- additionthe addition of ketones of ketones to nitroalkenes. to nitroalkenes. One ofOne them, of them,C2, provided C2, provided high ee highs and ee excellents and excellent stere- oped thiourea-based catalysts incorporating D-glucose as a core unit and tested them on oselectivitiesstereoselectivities on the on addition the addition of cyclohexanone of cyclohexanone (6) to ( nitrooleﬁns6) to nitroolefins (7) (Figure (7) (Figure7)[ 31 ].7) DFT[31]. the addition of ketones to nitroalkenes. One of them, C2, provided high ees and excellent studies,DFT studies, with the Gaussianwith the 09 programGaussian package09 program and the B3LYP/6-311G(d,p)//B3LYP/6-package and the B3LYP/6- stereoselectivities on the addition of cyclohexanone (6) to nitroolefins (7) (Figure 7) [31]. 31G(d)311G(d,p)//B3LYP/6-31G(d) basic set, were utilized basic to explain set, were the stereochemicalutilized to explain outcome the stereochemical of the reaction outcome leading DFT studies, with the Gaussian 09 program package and the B3LYP/6- toof productsthe reaction8. The leading QM/MM to products calculations 8. The suggested QM/MM that calculations cyclohexanone suggested plays that two cyclohexa- roles, that 311G(d,p)//B3LYP/6-31G(d) basic set, were utilized to explain the stereochemical outcome−1 ofnone solvent plays as two well roles, as of that reactant, of solvent in the as rate-determining well as of reactant, step, in imparting the rate-determining31.91 kcal mol step, of the reaction leading to products 8. The QM/MM calculations suggested that cyclohexa- ofimparting energy towards 31.91 kcal product mol−1 formation.of energy towards product formation. none plays two roles, that of solvent as well as of reactant, in the rate-determining step, imparting 31.91 kcal mol−1 of energy towards product formation.

FigureFigure 7.7. MichaelMichael additionaddition reactionreaction catalyzedcatalyzed bybyC2 C2 [[31].31]. FigureA 7. Michael Michael addition reaction of isobutyraldehyde catalyzed by C2 [31]. (9) to nitroalkenes (2) was achieved in a highly enantioselective manner by Chinchilla, Nájera and coworkers with primary amine-

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A Michael addition of isobutyraldehyde (9) to nitroalkenes (2) was achieved in a highly enantioselective manner by Chinchilla, Nájera and coworkers with primary amine- guanidine C3, derived from trans-cyclohexane-1,2-diamine, as catalyst (Figure 8) [32]. Be- sides other optimizations, with DMF proving to be the best solvent, the addition of water was found to increase both the reaction rate and the ees leading to 10a (10, Ar = Ph) (at 25 °C, with DMF/imidazole, 99% yield, 48% ee, with DMF/imidazole/water, 99% yield, 70% ee). At lower temperatures, the ee improved (to 80%) with a 10% decrease in yield. DFT theoretical calculations helped to explain the origin of the stereoselectivity observed, as well as the role of water in the reaction [32]. Taking into account intramolecular H-bonding only (TSH-S vs. TSH-R), the calculations revealed a preference for the transition state leading to the wrong enantiomer, the (S)-enantiomer, found to be 1.8 kcal/mol lower in energy than TSH-R. This is the result of Catalysts 2021, 11, 569 8 of 54 having both the nitrostyrene and the guanidine subunit both in the lower face of the enamine (from our point of view), adopting a less strained disposition. In TSH-R, the structure needs to twist to form the internal H-bonds, adding strain to the transition state struc- guanidineture. In practice,C3, derived the enantiomer from trans obtained-cyclohexane-1,2-diamine, was the (R)-enantiomer, as catalyst suggesting (Figure that8)[ intra-32]. Besidesmolecular other H-bonding optimizations, was not with present. DMF proving Another to betransition the best solvent,state was the found addition (TS ofW-S), water in waswhich found the nitro to increase group bothwas theactivated reaction by ratethe andsolvent the (implicitees leading water to 10a solvent(10, Ar model), = Ph) (at1.7 ◦ 25kcal/molC, with lower DMF/imidazole, in activation energy 99% yield, than 48%TSH-S.ee, In with fact, DMF/imidazole/water, water may serve two purposes, 99% yield, to 70%loweree the). At activation lower temperatures, energy, since theit canee solvimprovedate better (to the 80%) more with polar a 10% transition decrease state in yield.(TSW- DFTS vs. theoreticalTSH-S), and calculations to form intermolecular helped to explain hydrogen the originbondsof with the the stereoselectivity nitro group, disrupting observed, asthe well intramolecular as the role of ones. water in the reaction [32].

Figure 8. Enantioselective Michael Michael addition addition of of isobut isobutyraldehydeyraldehyde to to nitroalkenes nitroalkenes catalyzed catalyzed by by C3C3 (top) and comparison of the guanidine activated transition states (TSH-S and TSH-R) with the wa- (top) and comparison of the guanidine activated transition states (TSH-S and TSH-R) with the ter-activated TS (TSW-S). Free Gibbs energies computed at B3LYP/6-311+G(d,p) (CPCM, water) water-activated TS (TSW-S). Free Gibbs energies computed at B3LYP/6-311+G(d,p) (CPCM, water) level [32]. level [32]. Although the lack of intramolecular bonding implies much more molecular freedom Taking into account intramolecular H-bonding only (TSH-S vs. TSH-R), the calculations revealedand a higher a preference number of for possible the transition conformations, state leading the two to most the wrong stable conformations enantiomer, the of (theS)- reactive enamine could eventually be found (Figure 9a,b). In theory, nitrostyrene may ap- enantiomer, found to be 1.8 kcal/mol lower in energy than TSH-R. This is the result of havingproach each both enamine the nitrostyrene following and two the different guanidine trajectories. subunit In both (a), the in face the lowerleading face to the of the(S)- enantiomer is blocked by the guanidine group and can be ruled out. The remaining three enamine (from our point of view), adopting a less strained disposition. In TSH-R, the structureapproaches needs are tofeasible, twist tobut form there the is internal not much H-bonds, difference adding in energy strain between to the transition them. Hence state structure.it appears Inthat practice, the (R)-enantiomer the enantiomer is obtained obtained preferentially was the (R)-enantiomer, due to the predominance suggesting that of intramolecular H-bonding was not present. Another transition state was found (TSW-S), in which the nitro group was activated by the solvent (implicit water solvent model), 1.7 kcal/mol lower in activation energy than TSH-S. In fact, water may serve two purposes, to lower the activation energy, since it can solvate better the more polar transition state

(TSW-S vs. TSH-S), and to form intermolecular hydrogen bonds with the nitro group, disrupting the intramolecular ones. Although the lack of intramolecular bonding implies much more molecular freedom and a higher number of possible conformations, the two most stable conformations of the reactive enamine could eventually be found (Figure9a,b). In theory, nitrostyrene may approach each enamine following two different trajectories. In (a), the face leading to the (S)-enantiomer is blocked by the guanidine group and can be ruled out. The remaining three approaches are feasible, but there is not much difference in energy between them. Hence it appears that the (R)-enantiomer is obtained preferentially due to the predominance of the sum of TSA-R and TSB-R over TSB-S, and the non-existence of TSA-S, i.e., the steric effect of the guanidine group seems to be the ﬁnal reason for the preference observed. Catalysts 2021, 11, x FOR PEER REVIEW 9 of 55

Catalysts 2021, 11, 569 9 of 54 the sum of TSA-R and TSB-R over TSB-S, and the non-existence of TSA-S, i.e., the steric effect of the guanidine group seems to be the final reason for the preference observed.

Figure 9.9. 3D-models for the reaction of nitrostyrene with the two most stable conformations of the enamine, as shown in ((aa)) andand ((bb),), leadingleading toto (R)-(R)- andand (S)- (S)-1010.. Free Free Gibbs Gibbs energies energies computed computed at at B3LYP/6-311+G(d,p) B3LYP/6-311+G(d,p) (CPCM,(CPCM, water)water) (M06-2X/6-(M06-2X/6- 311+G(d,p) (SMD, water) in parenthesis) Reprinted and adapted from Tetrahedron:Tetrahedron: Asymmetry with permissionpermission from Elsevier [[32].32].

In 2019, Zlotin and coworkerscoworkers developed a new squaramide-basedsquaramide-based organocatalyst, which promoted the conjugate addition of ββ-dicarbonyl compounds ( 11) and kojickojic acidacid Catalysts 2021, 11, x FOR PEER REVIEWderivatives (13)) toto nitrooleﬁns,nitroolefins, toto yieldyield productsproducts12 12and and14 14,, respectively, respectively, in in nearly nearly quantita- quanti-10 of 55

tativetive yields yields and and up up to to 99% 99%ee ,ee with, with a catalytica catalytic loading loading of of only only 1 mol%1 mol% (Figure (Figure 10 10))[33 [33].]. The best catalyst out of a homologous series tried was C4, a C2-symmetric tertiary amine-squaramide organocatalyst. The reactions with kojic acid derivatives worked well under “green” conditions (in 96% EtOH, or even in pure water). The catalyst could also be easily recovered since it has extremely low solubility in organic solvents, and it was reused up to seven times, making it attractive for applications in the industry. To ascertain if one or both tertiary amino groups in the catalyst participate in the reaction, the relationship between the ee values of the catalyst and those of the corresponding products were determined in protic and aprotic solvents (96% EtOH, H2O, and CH2Cl2). Irrespective of the solvent, a linear effect was observed for both compounds, suggesting that diastereomeric associates (especially meso forms) between C4 and the reaction products were absent. This can only happen if desymmetrization occurs and only one of the two tertiary amino groups in C4 acts as deprotonating agents in the corresponding transition states TS1 and TS2. These deductions were also confirmed by experiments in which acid was added to the reaction mixture. The addition of 1 mol% of TFA did not have a negative impact on the results (on the yield or ee of 12). However, if enough TFA was added to protonate both amine groups, i.e., 2 mol%, the catalyst was completely deactivated, and no reaction was observed.

Figure 10. Asymmetric MichaelMichael reactionsreactions catalyzed catalyzed by by C 2C-symmetric2-symmetric amine-squaramide amine-squaramide catalyst catalystC4 C4and and plausible plausible transition transi- statetion state TS1 forTS1 the for addition the addition of the of diesters the diesters to the to nitrooleﬁns the nitroolefins [33]. [33].

InThe 2017 best Rawal catalyst introduced out of a bifunctional homologous thio seriessquaramides tried was asC4 a, nove a C2-symmetricl type of organocat- tertiary alystamine-squaramide [34]. A range of organocatalyst. novel thiosquaramide-t The reactionsertiary with amines kojic acidwas derivativestested on the worked enantiose- well lectiveunder “green”conjugate conditions addition (in reaction 96% EtOH, of barbituric or even inacid pure (15 water).) to nitroalkenes The catalyst (Figure could also11). beIn theeasily same recovered way that since changing it has extremelyan oxygen low atom solubility in urea to in sulfur organic makes solvents, the product and it was thioureas reused moreup to catalytic seven times, active making than the it attractiveureas, the for new applications thiosquaramide in the catalysts industry. based on the squar- amidesTo also ascertain proved if one to be or highly both tertiary active. aminoThe squaramides, groups in the originally catalyst participateintroduced in by the Rawal reac- andtion, coworkers the relationship in 2008, between have found the ee valuesmany applications of the catalyst in andorganic those synthesis, of the corresponding particularly asproducts bifunctional were determinedorganocatalysts, in protic and andhave aprotic become solvents one of (96%the major EtOH, types H2O, of and organocata- CH2Cl2).

lysts available for developing novel reactions [12]. Despite their popularity, one of their inherent properties is low solubility in nonpolar solvents and a limited ability to modulate the pKa of the donor hydrogens. These characteristics limit their utility in some applications. The new thiosquaramides are more acidic and significantly more soluble in nonpolar solvents than their oxo-counterparts, showing great promise for future applications. In this work, a series of barbiturates (16) was produced in very high yields and excellent ees, with only 0.5 mol% of catalyst. However, the catalysts could be even more efficient. In a model reaction with nitrostyrene, i.e., 7a, R1 = Ph and 15a (R2 = Ph), when the catalytic loading was lowered to 0.05 mol%, the product (16a) was obtained with 96% ee and the conversion (determined by NMR spectroscopy) was >98% in a 10 h reaction. The corresponding oxosquaramide (C6) at 0.5 mol% afforded identical results to C5 in terms of yield and a similar ee (97 versus 95%, C5/C6). X-ray crystallography revealed the presence of two rotameric forms. The H–H distance of the two rotamers was shown to be slightly smaller than those of the corresponding oxosquaramide by X-ray crystallography. Har- tree−Fock calculations for C7 at the 3-21G level of theory gave an H−H distance of 2.60 Å, which suggests that the smaller distance is due to the interactions with the sulfur atoms rather than packing forces or other interactions in the crystal structure. Intermolecular hydrogen bonds to give ladder structures, analogous to those found in the oxosquaramides, were not observed.

Catalysts 2021, 11, 569 10 of 54

Irrespective of the solvent, a linear effect was observed for both compounds, suggesting that diastereomeric associates (especially meso forms) between C4 and the reaction products were absent. This can only happen if desymmetrization occurs and only one of the two tertiary amino groups in C4 acts as deprotonating agents in the corresponding transition states TS1 and TS2. These deductions were also confirmed by experiments in which acid was added to the reaction mixture. The addition of 1 mol% of TFA did not have a negative impact on the results (on the yield or ee of 12). However, if enough TFA was added to protonate both amine groups, i.e., 2 mol%, the catalyst was completely deactivated, and no reaction was observed. In 2017 Rawal introduced bifunctional thiosquaramides as a novel type of organocatalyst [34]. A range of novel thiosquaramide-tertiary amines was tested on the enantioselective conjugate addition reaction of barbituric acid (15) to nitroalkenes (Figure 11). In the same way that changing an oxygen atom in urea to sulfur makes the product thioureas more catalytic active than the ureas, the new thiosquaramide catalysts based on the squaramides also proved to be highly active. The squaramides, originally introduced by Rawal and coworkers in 2008, have found many applications in organic synthesis, particularly as bifunctional organocatalysts, and have become one of the major types of organocatalysts available for developing novel reactions [12]. Despite their popularity, one of their inherent properties is low solubility in nonpolar solvents and a limited ability to modulate the pKa of the donor hydrogens. These characteristics limit their utility in some applications. The new thiosquaramides are more acidic and significantly more soluble in nonpolar solvents than their oxo-counterparts, showing great promise for future applications. In this work, a series of barbiturates (16) was produced in very high yields and excellent ees, with only 0.5 mol% of catalyst. However, the catalysts could be even more efficient. In a model reaction with nitrostyrene, i.e., 7a,R1 = Ph and 15a (R2 = Ph), when the catalytic loading was lowered to 0.05 mol%, the product (16a) was obtained with 96% ee and the conversion (determined by NMR spectroscopy) was >98% in a 10 h reaction. The corresponding oxosquaramide (C6) at 0.5 mol% afforded identical results to C5 in terms of yield and a similar ee (97 versus 95%, C5/C6). X-ray crystallography revealed the presence of two rotameric forms. The H–H distance of the two rotamers was shown to be slightly smaller than those of the corresponding oxosquaramide by X-ray crystallography. Hartree−Fock calculations for C7 at the 3-21G level of theory gave an H−H distance of 2.60 Å, which suggests that the smaller distance is due to the interactions with the sulfur atoms rather than packing forces or other interactions in the crystal structure. Intermolecular hydrogen Catalysts 2021, 11, x FOR PEER REVIEW 11 of 55 bonds to give ladder structures, analogous to those found in the oxosquaramides, were not observed.

FigureFigure 11.11. EnantioselectiveEnantioselective Michael additions of barbituricbarbituric acids to nitroalkenesnitroalkenes catalyzed by C5,, aa novelnovel thiosquaramidethiosquaramide catalystcatalyst [[34].34].

The development of an enantio- and diastereoselective reaction provides access to the desired enantiomer of a substance whose properties may be quite distinct from those of the other enantiomer, which is of importance for several applications. For example, in pharmaceuticals, the bioactivity of one enantiomer may be different from that of its antipode, and it is not only the absolute configuration of each chiral centre that may be vital, but also the relative configuration if more than one chiral center is present. It may be desirable to access all enantiomers separately from each other, for example, to use authentic standards to test for purity in a manufacturing process, which can be a very challenging task. The development of new strategies to perform diastereodivergent asymmetric synthesis is, therefore, a subject of great interest [35,36]. The utilization of the same synthetic route for all stereoisomers wanted may be possible if a simple change in catalyst provides alternative isomers as the main product. In 2020 Wang, Zhao and coworkers reported a catalyst-controlled stereodivergent asymmetric Michael addition of α-azido ketones 17 to nitroolefins 7 (Figure 12) [37]. A squaramide-based catalyst (C9) afforded selectively anti-adducts, while a new bifunctional tertiary amine-phosphoramide catalyst (C10) provided preferentially syn-adducts. The resulting multifunctional tertiary azides (18) were converted to spiro-pyrrolidines with four continuous stereocenters in a one-pot operation. Mechanistic studies were performed to elucidate the reasons for the diastereoselectivity switch, which took place simply by changing the two H-bond donor catalysts. To elucidate the mode of interaction of the catalysts with the substrates, control experiments were performed. In a model reaction producing 18a (Figure 13), it was observed that in the case of C9, the presence of two NH groups was critical for the yield, although moderate ees could be obtained. Blocking NH(3) with a methyl group caused a reversal in diastereoselectivity. Thus, both NH groups are important for a high yielding and stereoselective anti reaction to take place. In the reaction promoted by C10, both the NH group and the tertiary N are critical for high reactivity and high ees to be obtained. The presence of the ring nitrogen ensures that there is syn selectivity.

Catalysts 2021, 11, 569 11 of 54

The development of an enantio- and diastereoselective reaction provides access to the desired enantiomer of a substance whose properties may be quite distinct from those of the other enantiomer, which is of importance for several applications. For example, in pharmaceuticals, the bioactivity of one enantiomer may be different from that of its antipode, and it is not only the absolute configuration of each chiral centre that may be vital, but also the relative configuration if more than one chiral center is present. It may be desirable to access all enantiomers separately from each other, for example, to use authentic standards to test for purity in a manufacturing process, which can be a very challenging task. The development of new strategies to perform diastereodivergent asymmetric synthesis is, therefore, a subject of great interest [35,36]. The utilization of the same synthetic route for all stereoisomers wanted may be possible if a simple change in catalyst provides alternative isomers as the main product. In 2020 Wang, Zhao and coworkers reported a catalyst-controlled stereodivergent asymmetric Michael addition of α-azido ketones 17 to nitroolefins 7 (Figure 12)[37]. A squaramide-based catalyst (C9) afforded selectively anti-adducts, while a new bifunctional tertiary amine-phosphoramide catalyst (C10) provided preferentially syn-adducts. The resulting multifunctional tertiary azides (18) were converted to spiro-pyrrolidines with four continuous stereocenters in a one-pot operation. Mechanistic studies were performed Catalysts 2021, 11, x FOR PEER REVIEW 12 of 55 to elucidate the reasons for the diastereoselectivity switch, which took place simply by changing the two H-bond donor catalysts.

FigureFigure 12.12. StereodivergentStereodivergent MichaelMichael additionaddition ofofα α-azido-azido ketones ketones 1 177to to nitrooleﬁns nitroolefins7 7[ 32[32].].

To elucidate the mode of interaction of the catalysts with the substrates, control experiments were performed. In a model reaction producing 18a (Figure 13), it was observed that in the case of C9, the presence of two NH groups was critical for the yield, although moderate ees could be obtained. Blocking NH(3) with a methyl group caused a reversal in diastereoselectivity. Thus, both NH groups are important for a high yielding and stereoselective anti reaction to take place. In the reaction promoted by C10, both the NH group and the tertiary N are critical for high reactivity and high ees to be obtained. The presence of the ring nitrogen ensures that there is syn selectivity.

Figure 13. Stereodivergent synthesis of 18a [37].

A search for nonlinear effects revealed that in the case of C10, a monomeric catalytic species was operating since there was a linear relationship between the catalyst ee value and that of the product syn-18a. No conclusions could be drawn for the reactions catalyzed by C9 due to its very low solubility in CH2Cl2. Theoretical studies were performed, and from the lowest energy TS structures, the main interactions responsible for the reactivities observed could be identified (Figure 14). It was found that, while the squaramide-catalyzed reaction proceeded with a TS (TS1-C9) in which both squaramide N–H bonds bind to an enolate intermediate, in the phosphoramide-mediated reaction, an amide N–H bond and an alkylammonium ion formed in situ interact with the nitroolefins, while the enolate is stabilized by nonclassical C–H/O hydrogen-bonding interactions (TS1-C10). This model has no precedence in the literature.

Catalysts 2021, 11, x FOR PEER REVIEW 12 of 55

Catalysts 2021, 11, 569 12 of 54

Figure 12. Stereodivergent Michael addition of α-azido ketones 17 to nitroolefins 7 [32].

Figure 13. Stereodivergent synthesis of 18a [[37].37].

A search for nonlinear effects revealed that in the case of C10, a monomeric catalytic speciesspecies was was operating since since there there was a linear relationship between the catalyst ee value and that that of of the the product product synsyn--18a.. No No conclusions conclusions could could be be drawn drawn for for the the reactions reactions catalyzed catalyzed by C9 due to its veryvery lowlow solubilitysolubility inin CHCH22ClCl22. Theoretical studies were performed, and fromfrom the the lowest lowest energy energy TS TS structures, structures, the main main interactions interactions responsible for the reactivities reactivities observed couldcould bebe identiﬁedidentified (Figure (Figure 14 14).). It wasIt was found found that, that, while while the squaramide-catalyzedthe squaramide-cata- lyzedreaction reaction proceeded proceeded with awith TS (TS1-C9) a TS (TS1-C9) in which in which both squaramideboth squaramide N–H bondsN–H bonds bind tobind an toenolate an enolate intermediate, intermediate, in the in phosphoramide-mediated the phosphoramide-mediated reaction, reaction, an amide an amide N–H N–H bond bond and andan alkylammonium an alkylammonium ion ion formed formed in situ in situ interact interact with with the the nitrooleﬁns, nitroolefins, while while the the enolate enolate is Catalysts 2021, 11, x FOR PEER REVIEW 13 of 55 isstabilized stabilized by by nonclassical nonclassical C–H/O C–H/O hydrogen-bonding hydrogen-bonding interactionsinteractions (TS1-C10).(TS1-C10). This model has no precedence in the literature.

Figure 14. The optimized structures for the transition states of the squaramide and phosphoramide catalyzed reactions Figure 14. The optimized structures for the transition states of the squaramide and phosphoramide catalyzed reactions 1 } between 18a18a (R(R1 == H) H) and and 7b7b (7,( R7, = R Ph). = Ph). Only Only the lowest the lowest energy energy structures structures (with (withΔΔGǂ =∆∆ 0.0)G are= shown. 0.0) are The shown. bondThe distances bond −1 distancesare given in are Å. given The relative in Å. The Gibbs relative free energies Gibbs free are energiesin kcal mol are−1, incalculated kcal mol at the, calculated IEFPCMM06-2X-D3/6-311++G(d,p)// at the IEFPCMM06-2X-D3/6- 311++G(d,p)//IEFPCM-M06-2X/6-31G(d,p)IEFPCM-M06-2X/6-31G(d,p) level. Reprinted level.and adapted Reprinted from and Chemical adapted Science from Chemical with permission Science withfrom permissionRoyal Society from of RoyalChemistry Society [37]. of Chemistry [37].

The thiourea-catalyzed Friedel–Crafts alky alkylationlation reaction reaction between between indoles indoles and and ni- ni- troalkenestroalkenes (e.g., (e.g., 19a19a andand 7b7b) )has has been been the the subject subject of of a few a few studies studies since since its itsfirst ﬁrst report report by Ricciby Ricci and and coworkers coworkers [38]. [ 38The]. Theutilization utilization of thiourea-aminoindanol of thiourea-aminoindanol catalyst catalyst C11aC11a to pro-to motepromote the thereaction reaction afforded afforded the the alkylated alkylated indole indole (20a (20a) in) in 78% 78% yield yield and and 85% 85% eeee (Figure(Figure 15).15). A bifunctional mode of action was envisioned, and TS1 and TS2 were postulated as being the TSs responsible for the results obtained. In 2014 Herrera and coworkers reported the results of theoretical studies performed on this reaction to clarify the origin of stereoselectivity [39]. Of interest were previous results that showed that if the configuration of the thiourea-aminoindanol was R,R, i.e., as in C11c, there was hardly any reaction; with C12, missing a hydroxyl group, the product was racemic; and with the analogous catalyst C13, lacking an aromatic ring in the aminoindanol skeleton, the yield was very low and the ee moderate only (Figure 15) [38,40]. Initially, it was envisaged that the hydroxyl group would drive the reaction to one face of the indole in preference to the other, while the configuration of product 20a was dependent on the enantiomer of the catalyst used.

Figure 15. Thiourea-catalyzed Friedel–Crafts alkylation of indole 19a and the results obtained with catalysts C11–C13 [38–40]. AH = Brønsted acid additive.

Catalysts 2021, 11, x FOR PEER REVIEW 13 of 55

Figure 14. The optimized structures for the transition states of the squaramide and phosphoramide catalyzed reactions between 18a (R1 = H) and 7b (7, R = Ph). Only the lowest energy structures (with ΔΔGǂ = 0.0) are shown. The bond distances are given in Å. The relative Gibbs free energies are in kcal mol−1, calculated at the IEFPCMM06-2X-D3/6-311++G(d,p)// IEFPCM-M06-2X/6-31G(d,p) level. Reprinted and adapted from Chemical Science with permission from Royal Society of Chemistry [37].

The thiourea-catalyzed Friedel–Crafts alkylation reaction between indoles and ni- Catalysts 2021, 11, 569 troalkenes (e.g., 19a and 7b) has been the subject of a few studies since its first report13 of 54by Ricci and coworkers [38]. The utilization of thiourea-aminoindanol catalyst C11a to promote the reaction afforded the alkylated indole (20a) in 78% yield and 85% ee (Figure 15). A bifunctional mode of action was envisioned, and TS1 and TS2 were postulated as being thethe TSs TSs responsible responsible for for the the results results obtained. obtained. In In 2014 2014 Herrera Herrera and and coworkers coworkers reported reported the the resultsresults of of theoretical theoretical studies studies performed performed on on this this reaction reaction to to clarify clarify thethe originorigin ofof stereoselec-stereoselec- tivitytivity [39[39].]. OfOf interestinterest werewere previousprevious resultsresults that that showed showed that that if if the the conﬁguration configuration of of the the thiourea-aminoindanolthiourea-aminoindanol waswasR,R R,R,, i.e., i.e., as as in inC11c C11c,, there there was was hardly hardly any any reaction; reaction; with withC12 C12,, missingmissing a a hydroxyl hydroxyl group, group, the the product product was was racemic; racemic; and and with withthe theanalogous analogous catalystcatalystC13 C13,, lackinglacking anan aromaticaromatic ringring inin the aminoindanol skeleton, skeleton, the the yield yield was was very very low low and and the the ee eemoderatemoderate only only (Figure (Figure 15) 15 )[[38,40].38,40]. Initially, Initially, it it was envisagedenvisaged thatthat thethe hydroxylhydroxyl groupgroup wouldwould drivedrive thethe reactionreaction toto oneone faceface ofof thethe indoleindole inin preferencepreference toto thethe other,other, while while the the conﬁgurationconfiguration of of product product20a 20awas was dependent dependent on on the the enantiomer enantiomer of of the the catalyst catalyst used. used.

FigureFigure 15. 15.Thiourea-catalyzed Thiourea-catalyzed Friedel–Crafts Friedel–Crafts alkylation alkylation of of indole indole19a 19aand and the the results results obtained obtained with with catalystscatalystsC11–C13 C11–C13 [ 38[38–40].–40]. AH AH = = BrønstedBrønsted acidacid additive.additive.

may play yet another role in the reaction. In C11c and C11d, the hydroxyl group occupies a trans orientation, and hence the results obtained suggest the importance of a cis relationship in order for the hydroxyl group to play its role in directing the attack of the indole in a stereoselective manner. Theoretical calculations were performed to clarify the origin of the enantioselectivity. The calculations were carried out at the PCM(CH2Cl2)/M06-2X/6- 311G(d,p) level. A simpliﬁed system was studied initially, but the complete system was also studied with catalyst (1R,2S)-C11a, indole (19a) and nitrostyrene (7b). In all the transition states obtained for the Friedel–Crafts alkylation reaction using a catalyst (1R,2S)-C20a, the hydroxyl group of the catalyst interacts with the NH group of the indole through H-bonding, i.e., in an H–O··· H–N interaction, leading the nucleophilic attack as predicted (Figure 16). The small difference in activation energy for indole attack (TS1, 0.0 kcal mol−1) for the Si face and (TS2, 2.1 kcal mol−1) for the Re face explains the differences in ee obtained (85% ee). A product with (R)-conﬁguration is expected, as observed. In all structures except in TS2, there is bidentate coordination of the nitroalkene, as observed previously by Etter and coworkers [41], which helps to create a more rigid transition state involving all three molecules. The higher stability of TS1 may be the result of a less hindered packaging, minimizing repulsive forces, with the relative orientation of the indole-nitroalkene playing a crucial role in the selectivity. An interesting interaction was found between the hydroxyl group and one of the oxygen atoms of the nitroalkene (O–H··· O–N=O) (TS1, TS2, TS5 and Catalysts 2021, 11, x FOR PEER REVIEW 14 of 55

The very low reactivity and selectivity of catalysts C12 and C13 are quite noticeable. The lack of a hydroxyl group to direct the attack of an incoming nucleophile can explain the lack of selectivity, but not the low reactivity, which suggests that the hydroxyl group may play yet another role in the reaction. In C11c and C11d, the hydroxyl group occupies a trans orientation, and hence the results obtained suggest the importance of a cis relationship in order for the hydroxyl group to play its role in directing the attack of the indole in a stereoselective manner. Theoretical calculations were performed to clarify the origin of the enantioselectivity. The calculations were carried out at the PCM(CH2Cl2)/M06-2X/6- 311G(d,p) level. A simplified system was studied initially, but the complete system was also studied with catalyst (1R,2S)-C11a, indole (19a) and nitrostyrene (7b). In all the transition states obtained for the Friedel–Crafts alkylation reaction using a catalyst (1R,2S)- C20a, the hydroxyl group of the catalyst interacts with the NH group of the indole through H-bonding, i.e., in an H–O⋯H–N interaction, leading the nucleophilic attack as predicted (Figure 16). The small difference in activation energy for indole attack (TS1, 0.0 kcal mol−1) for the Si face and (TS2, 2.1 kcal mol−1) for the Re face explains the differences in ee obtained (85% ee). A product with (R)-configuration is expected, as observed. In all structures except in TS2, there is bidentate coordination of the nitroalkene, as observed previously by Etter and coworkers [41], which helps to create a more rigid transition state involving all Catalysts 2021, 11, 569 three molecules. The higher stability of TS1 may be the result of a less hindered packaging,14 of 54 minimizing repulsive forces, with the relative orientation of the indole-nitroalkene playing a crucial role in the selectivity. An interesting interaction was found between the hydroxyl group and one of the oxygen atoms of the nitroalkene (O–H⋯O–N=O) (TS1, TS2, TS5TS6), and which TS6), supports which supports the lack ofthe reactivity lack of re observedactivity whenobserved an OHwhen group an OH is not group present is not in presentthe catalyst, in the or catalyst, it is not or placed it is not in the placed correct in the position correct (Figure position 16). (Figure 16).

Figure 16. Transition states for the Friedel–Crafts alkylation with catalyst (1R,2S)-C11a.. The relative relative free energies are given in kcal mol−11 andand the the distances distances in in Å. Å. Reprinted Reprinted and and adapted adapted from from OrganicOrganic and and Biomolecular Biomolecular Chemistry Chemistry with permission from the Royal Society of Chemistry [[39].39].

In 2017 Fan and Kass achieved high yielding and highly stereoselective Friedel–Crafts alkylations of indoles (19) with nitroalkenes using as catalysts a series of methylated and octylated pyridinium- and quinolinium-containing thiourea salts with a chiral 2-indanol

substituent, e.g., C14 (Figure 17)[42]. The new organocatalysts are positively charged analogs of the privileged bis(3,5-triﬂuoromethyl)phenyl-substituted thioureas. They were shown to be much more active catalysts in many cases, despite the absence of an additional hydrogen bond donor or acceptor site (i.e., the presence of a heteroatom−hydrogen bond or a heteroatom with free lone pairs). Yields in the order of 30% were observed with indoles bearing an electron-withdrawing group, i.e., 5-Cl. Otherwise, they were higher than 75% ◦ in reactions conducted at–35 C. The temperature was kept low since the ee was largely inﬂuenced by temperature. Catalysts 2021, 11, x FOR PEER REVIEW 15 of 55

In 2017 Fan and Kass achieved high yielding and highly stereoselective Friedel– Crafts alkylations of indoles (19) with nitroalkenes using as catalysts a series of methylated and octylated pyridinium- and quinolinium-containing thiourea salts with a chiral 2-indanol substituent, e.g., C14 (Figure 17) [42]. The new organocatalysts are positively charged analogs of the privileged bis(3,5-trifluoromethyl)phenyl-substituted thioureas. They were shown to be much more active catalysts in many cases, despite the absence of an additional hydrogen bond donor or acceptor site (i.e., the presence of a heteroatom−hydrogen bond or a heteroatom with free lone pairs). Yields in the order of 30% were observed with indoles bearing an electron-withdrawing group, i.e., 5-Cl. Otherwise, they were higher than 75% in reactions conducted at–35 °C. The temperature was kept low since the ee was largely influenced by temperature. Kinetic studies showed that the reaction is first-order in both indole and trans-β-nitrostyrene. A plot of the second-order rate constants versus the square of the catalyst mol% is linear, which suggests that the active catalytic species of the thiourea is dimeric. It was postulated as having structure C14a. In the 1H NMR spectra of the catalyst recorded from 5.0 to 20.0 mM, it was observed that both NH signals moved downfield linearly with Catalysts 2021, 11, 569 increasing concentration, consistent with the occurrence of a rapidly occurring 15mono- of 54 mer/dimer equilibrium. These results suggest that the association constant is small and that the resting state for the catalyst is largely monomeric.

FigureFigure 17. 17. EnantioselectiveEnantioselective Friedel− FriedelCrafts −alkylationCrafts alkylationbetween nitroalkenes between and nitroalkenes indoles catalyzed and in- by charge activated thiourea organocatalyst C14; BArF4− = tetrakis(3,5-bis(trifluoromethyl)phe-− doles catalyzed by charge activated thiourea organocatalyst C14; BArF4 = tetrakis(3,5- bis(triﬂuoromethyl)phenyl)boratenyl)borate anion [42]. anion [42].

2.2. AdditionsKinetic studies to Enones showed and Unsaturated that the reaction Esters is first-order in both indole and trans-β- nitrostyrene.The first cinchona-thiourea A plot of the second-order catalyzed the rate Mich constantsael addition versus of the nitroalkanes square of to the enones cata- lystwas mol%reported is linear, independently which suggests by four that different the active groups catalytic in 2005 species [43–46]. of theGiven thiourea the im- is dimeric.portance It of was this postulated C–C bond-forming as having reaction, structure itC14a has been. In the the1 Hsubject NMR of spectra a few computational of the catalyst recordedstudies, but from the 5.0 mechanism to 20.0 mM, still it wasremains observed unclear, that and both it NHcontinues signals to moved attract downfield attention. linearlyThree activation with increasing modes concentration, are possible, mode consistent A, mode with B the and occurrence mode C, as of ashown rapidly in occurringFigure 4b monomer/dimer[17,19,24]. equilibrium. These results suggest that the association constant is small and thatSince the none resting of these state forstudies the catalystexplained is largely the origin monomeric. of selectivity, Grayson undertook a new work in 2017 (Figure 18) [47]. Quantum mechanical calculations were performed us- 2.2. Additions to Enones and Unsaturated Esters ing Gaussian 09 (Revision D.01). Mode A, B and C complexes are expected to exist in rapid equilibrium,The first and cinchona-thiourea therefore, their catalyzed relative thermodynamic the Michael addition stabilities of nitroalkanes do not determine to enones the wascourse reported of the independently reaction (Curtin by− fourHammett different conditions). groups in In 2005 this [43 work,–46]. Giventhe relative the importance stabilities ofof thisthe C–CC−C bond-formingbond-forming reaction, TSs (the it rate-determining has been the subject step) of awere few computationaldetermined to studies,find the but fa- thevored mechanism activation still mode remains and explain unclear, the and origin it continues of stereoselectivity. to attract attention. Catalyst Three C16 activationwas used. modes are possible, mode A, mode B and mode C, as shown in Figure4b [17,19,24]. Since none of these studies explained the origin of selectivity, Grayson undertook a new work in 2017 (Figure 18)[47]. Quantum mechanical calculations were performed using Gaussian 09 (Revision D.01). Mode A, B and C complexes are expected to exist in rapid equilibrium, and therefore, their relative thermodynamic stabilities do not determine the course of the reaction (Curtin−Hammett conditions). In this work, the relative stabilities of the C−C bond-forming TSs (the rate-determining step) were determined to find the favored activation mode and explain the origin of stereoselectivity. Catalyst C16 was used. DFT calculations showed that the preferred mode of activation is B, in which the electrophile is activated by the catalyst protonated amine and the nucleophile through hydrogen bonds with the thiourea moiety. The TSs that lead to the major and minor products following mode B of activation have s-cis and s-trans enone conformations, respectively, which differ ◦ from each other only by rotation of the quinoline ring by ∼180 (TSthio-Bcis-(major) and TSthio-Btrans-(minor), Figure 19). Previous works have shown that these conformations are strongly preferred over all other possibilities [48]. The other two possible TSs may be obtained if the quinoline ring methoxy group is rotated by ∼180◦ so that the methyl group is oriented away from the thiourea moiety, but the new conformations were found to be disfavored by at least 2.2 kcal mol−1 for the syn and anti-open conformations of TSthio-Bcis-(major) and were disregarded. Catalysts 2021, 11, x FOR PEER REVIEW 16 of 55 Catalysts 2021, 11, x FOR PEER REVIEW 16 of 55

DFT calculations showed that the preferred mode of activation is B, in which the electro- DFT calculations showed that the preferred mode of activation is B, in which the electrophile is activated by the catalyst protonated amine and the nucleophile through hydrogen phile is activated by the catalyst protonated amine and the nucleophile through hydrogen bonds with the thiourea moiety. The TSs that lead to the major and minor products fol- bonds with the thiourea moiety. The TSs that lead to the major and minor products following mode B of activation have s-cis and s-trans enone conformations, respectively, lowing mode B of activation have s-cis and s-trans enone conformations, respectively, which differ from each other only by rotation of the quinoline ring by ∼180° (TSthio-Bcis- which differ from each other only by rotation of the quinoline ring by ∼180° (TSthio-Bcis- (major) and TSthio-Btrans-(minor), Figure 19). Previous works have shown that these confor- (major) and TSthio-Btrans-(minor), Figure 19). Previous works have shown that these conformations are strongly preferred over all other possibilities [48]. The other two possible TSs mations are strongly preferred over all other possibilities [48]. The other two possible TSs may be obtained if the quinoline ring methoxy group is rotated by ∼180° so that the me- may be obtained if the quinoline ring methoxy group is rotated by ∼180° so that the methyl group is oriented away from the thiourea moiety, but the new conformations were Catalysts 2021, 11, 569 thyl group is oriented away from the thiourea moiety, but the new conformations16 were of 54 found to be disfavored by at least 2.2 kcal mol−1 for the syn and anti-open conformations found to be disfavored by at least 2.2 kcal mol−1 for the syn and anti-open conformations of TSthio-Bcis-(major) and were disregarded. of TSthio-Bcis-(major) and were disregarded.

FigureFigure 18.18.Cinchona-thiourea-catalyzed Cinchona-thiourea-catalyzed asymmetric asymmetric Michael Michael addition addition of of chalcone chalcone to to enones enones and and the Figure 18. Cinchona-thiourea-catalyzed asymmetric Michael addition of chalcone to enones and the possible activation modes [47]. possiblethe possible activation activation modes modes [47]. [47].

Figure 19. C−C bond-forming TSs in the cinchona thiourea-catalyzed asymmetric Michael addition of nitroalkanes to enones shown in Figure 18, according to mode B. M06-2X/def2-TZVPP- IEFPCM(toluene)//M06-2X/6-31G(d)-IEFPCM(toluene). The noncritical hydrogen atoms were

omitted for clarity. All energies are in kcal mol−1. Reprinted and adapted from Grayson, M.N. J. Org. Chem. 2017, 82, 4396–4401, the Journal of Organic Chemistry with permission from the American Chemical Society, Copyright 2017. Note: further permissions related to the material excerpted should be directed to the ACS [47].

The lowest energy TS, TSthio-Bcis-(major), leads to the major product observed experimentally (Figure 19). Unfavorable interactions between the enone’s phenyl substituent and the catalyst’s quinuclidine ring raise the energy of TSthio-Bcis-(minor) relative to TSthio-Bcis- (major). TSthio-Bcis-(major) is also stabilized by π-stacking interactions between the enone’s Catalysts 2021, 11, x FOR PEER REVIEW 17 of 55

Figure 19. C−C bond-forming TSs in the cinchona thiourea-catalyzed asymmetric Michael addition of nitroalkanes to enones shown in Figure 18, according to mode B. M06-2X/def2-TZVPP- IEFPCM(toluene)//M06-2X/6-31G(d)-IEFPCM(toluene). The noncritical hydrogen atoms were omitted for clarity. All energies are in kcal mol−1. Reprinted and adapted from Grayson, M.N. J. Org. Chem. 2017, 82, 4396–4401, the Journal of Organic Chemistry with permission from the American Chemical Society, Copyright 2017. Note: further permissions related to the material excerpted should be directed to the ACS [47].

The lowest energy TS, TSthio-Bcis-(major), leads to the major product observed experi- Catalysts 2021, 11, 569 mentally (Figure 19). Unfavorable interactions between the enone’s phenyl substituent17 of 54 and the catalyst’s quinuclidine ring raise the energy of TSthio-Bcis-(minor) relative to TSthio- Bcis-(major). TSthio-Bcis-(major) is also stabilized by π-stacking interactions between the enone’s phenyl group and the catalyst’s aromatic ring, which does not happen in TSthio- phenyl group and the catalyst’s aromatic ring, which does not happen in TSthio-Bcis-(minor). Bcis-(minor). In the other two conformations examined, TSthio-Btrans-(major) and TSthio-Btrans- In the other two conformations examined, TSthio-Btrans-(major) and TSthio-Btrans-(minor), the(minor), enone the has enone the less has favorable the less favorable s-trans conformation s-trans conformation and are, and therefore. are, therefore. They are They higher are inhigher energy. in energy. They also They have also no favorablehave no favorableπ-stacking π-stacking interactions. interactions. The s-cis conformationThe s-cis confor- of themation enone of onthe its enone own on was its calculated own was tocalculated be favored to overbe favored the s-trans overby the 1.0 s-trans kcal molby 1.0−1. kcal All −1 thio cis modemol . AAll TSs mode are disfavoredA TSs are disfavored relative to TSrelativethio-B cisto-(major) TS -B because-(major) in because mode Bin TSs mode stabilize B TSs thestabilize enone’s the developing enone’s developing alkoxide to alkoxide a greater to extent a greater than extent mode than A TSs. mode In the A firstTSs. case,In the there first iscase, proton there transfer is proton from transfer the quinuclidinium from the quinucli ion.dinium In the ion. second, In the there second, is hydrogen there is hydrogen bonding frombonding the thiourea.from the Attemptsthiourea. Attempts to find TSs to corresponding find TSs corresponding to mode C, to optimized mode C, insteadoptimized to modeinstead A. to mode A. TheThe reactionreaction waswas alsoalso studiedstudied withwith catalysiscatalysis byby cinchonacinchona squaramidesquaramide C17C17.. ModeMode BB waswas againagain favored over mode mode A. A. For For generality, generality, the the Michael Michael addition addition of of nitromethane nitromethane to tocyclohexenone cyclohexenone was was also also studied. studied. The The calculations calculations showed showed that thatin the in case the casewhen when the reac- the reactiontion is catalyzed is catalyzed by squaramide by squaramide C17C17 modemode B is B also is also favored, favored, by by2.0 2.0 kcal kcal mol mol−1, −when1, when the thetwo two lowest lowest energy energy transition transition states states found found for each for each mode mode of activation of activation are compared, are compared, con- confirmingfirming the thegenerality generality of the ofthe reaction. reaction. Furthermore,Furthermore, inin 20172017 SongSong andand coworkerscoworkers reportedreported thethe additionaddition ofof nitromethanenitromethane toto αα,,ββ-unsaturated-unsaturated ketonesketones 2424 containingcontaining pyridinepyridine [[49].49]. AA seriesseries ofof cinchona-thiourea-basedcinchona-thiourea-based catalystscatalysts werewere evaluatedevaluated forfor thethe reaction,reaction, andand finally,finally, high high yields yields and andee eess couldcould bebe obtainedobtained withwithC19 C19 oror entent--C19C19.. TheThe originsorigins ofof enantioselectivity werewere probedprobed throughthrough computationalcomputational studies.studies. DFT DFT calculations calculations showed showed that that in in the the most most stable stable Cat–Nu Cat–Nu complex, complex, there there were were hy- hydrogendrogen bonding bonding interactions interactions between between the the oxygen oxygen on on the the nucleophile nucleophile and an N–HN–H groupgroup onon thethe thioureathiourea as as well well as as with with the the protonated protonated quinine quinine amine, amine, in in line line with with Wang Wang´s´s mode mode C ofC activationof activation (Figure (Figure4b) 4b) [ 19 ].[19]. The The reaction reaction was was postulated postulated to proceed to proceed via TS1via TS1 (Figure (Figure 20). It20). was It was also also shown shown that that the the products products were were highly highly active active against against rice rice bacterial bacterial leaf leaf blight,blight, withwith thethe S-enantiomer displaying displaying higher higher activity activity than than the the R-enantiomerR-enantiomer (for (for (S)- (S25a,)-25a, b, (a: b, µ (a:R = R 2-FC = 2-FC6H46,H b:4 ,R b: = R4-ClC = 4-ClC6H4)6 atH 4100) at μ 100M/mL,M/mL, 100% 100% inhibition). inhibition).

Figure 20. Solvent-free enantioselective conjugate addition of nitromethane to chalcone-containing pyridine [49].

In 2011 Rodriguez and coworkers reported the ﬁrst organocatalyzed enantioselective Michael addition of β-ketoamides (26) to enals and enones (e.g., 27) (Figure 21)[50]. Products 28, containing one all-carbon quaternary stereogenic center, are useful synthetic intermediates. The reaction was subsequently the subject of further experimental, spectroscopic and theoretical studies [51]. Tertiary β-ketoamides did not react, showing that the presence of amide hydrogen is crucial for the reaction to occur. Neither did an enone containing an internal double bond, i.e., chalcone. NMR studies with 26a (R = Ts) showed the absence of an enol form of the substrate in a reagent/catalyst mixture. The presence of hydrogen bonding was suggested by a strong downﬁeld shift of the signals caused by Catalysts 2021, 11, x FOR PEER REVIEW 18 of 55

Figure 20. Solvent-free enantioselective conjugate addition of nitromethane to chalcone-containing pyridine [49].

In 2011 Rodriguez and coworkers reported the first organocatalyzed enantioselective Michael addition of β-ketoamides (26) to enals and enones (e.g., 27) (Figure 21) [50]. Prod- ucts 28, containing one all-carbon quaternary stereogenic center, are useful synthetic intermediates. The reaction was subsequently the subject of further experimental, spectroscopic and theoretical studies [51]. Tertiary β-ketoamides did not react, showing that the Catalysts 2021, 11, 569 presence of amide hydrogen is crucial for the reaction to occur. Neither did an enone18 ofcon- 54 taining an internal double bond, i.e., chalcone. NMR studies with 26a (R = Ts) showed the absence of an enol form of the substrate in a reagent/catalyst mixture. The presence of hydrogen bonding was suggested by a strong downfield shift of the signals caused by H1 H1(δ = (δ 0.5= 0.5 ppm) ppm and) and by by H7 H7 (δ ( δ== 0.7 0.7 ppm) ppm) of of the the catalyst. The signals duedue toto thethearomatic aromatic protonsprotons ofof bothboth thethe catalystcatalyst andand thethe enone enone were were also also signiﬁcantly significantly shifted, shifted, indicating indicatinga a possiblepossible interactioninteraction betweenbetween the the corresponding corresponding functional functional groups. groups. When When the the ketoamide ketoamide waswas mixed mixed with with the the catalyst catalyst only, only, fast fast deprotonation deprotonation was was observed. observed. From From a kinetic a kinetic analysis, analy- amongsis, among other other results, results, it was it was found found that th theat the reaction reaction was was zero-order zero-order for for the theβ β-ketoamide.-ketoamide. AA signiﬁcantsignificant primaryprimary KIE (KH/D (KH/D = =1.15) 1.15) was was also also observed observed in a in reaction a reaction with with >80% >80% deu- β deuteratedterated β–ketoamide,–ketoamide, consistent consistent with with rapid rapid deprotonation deprotonation leading leading to the to the active active form. form.

FigureFigure 21. 21.Michael Michael additions additions of ofβ β-ketoamides-ketoamides to toα α,β,β-unsaturated-unsaturated carbonyl carbonyl compounds, compounds, catalyzed catalyzed by C1by [C151] .[51].

ComputationalComputational studiesstudies werewere performedperformed withwith the the hybrid hybrid meta-GGA meta-GGA DFT DFT functional functional M06-2X,34M06-2X,34 withwith thethe 6-31G(d)6-31G(d) basisbasis set. set. RelativeRelativeGibbs Gibbsfree free energies energies were were determined determined for for thethe TSs TSs along along the the reaction reaction coordinate. coordinate. Based Based on on the the results, results, as as well well as as on on the the experimental experimental observations,observations, aa detaileddetailed catalyticcatalytic cyclecycle waswas postulated postulated (Figure (Figure 22 22).). ItIt seemsseems that that amide amide hydrogenhydrogen abstractionabstraction byby thethe organocatalystorganocatalyst takestakes placeplace initially,initially, leading leading reversibly reversibly to to an an off-cycleoff-cycle unreactiveunreactive form.form. AnAn equilibriumequilibrium backback toto thethe startingstartingβ β-ketoamide-ketoamide andand subse-subse- quentquent enolateenolate methinemethine hydrogen abstraction abstraction wo woulduld be be the the preferred preferred path. path. Subsequent Subsequent co- coordinationordination of of the the enone enone to to the the amide amide hydrogen hydrogen leads to the directdirect formationformation ofof thethe most most stablestable enolate enolate intermediate. intermediate. Nucleophilic Nucleophilic addition addition takes takes place place next, next, a a thermodynamically thermodynamically unfavoredunfavored process process because because the the resulting resulting intermediate intermediate lies lies higher higher in energy in energy than than the ternarythe ter- −1 complexnary complex deprotonated deprotonatedβ-ketoamide-protonated β-ketoamide-protonated catalyst-enone catalyst-enone (∆∆G = ( 3.9ΔΔG kcal = mol3.9 kcal). Enantiodifferentiationmol−1). Enantiodifferentiation takes place takes in place this step. in this step. In the most favored transition states, the β-ketoamide takes up a perpendicular orientation concerning the thiourea. The TS leading to the R adducts was found to be lower in energy by 2.9 kcal mol−1 over the TS leading to the S adducts (e.g., 28a), in agreement with the experimentally observed 99% ee value. The ease of proton transfer from the amide to the enolate, and the high stability of the resulting intermediate, are probably responsible for the equilibrium shift in this thermodynamically unfavorable C–C bond-forming step. This probably explains why the acidity of the amide proton is crucial for success. Furthermore, of interest is the fact that the deprotonated amide–ammonium complex was found to be thermodynamically more stable than the separated products (∆∆G = 4.6 kcal mol−1), in complete agreement with the experimentally observed inhibition of the catalyst by the product. An enantioselective organocatalytic conjugate addition of α,β-unsaturated ketones 29, promoted by a bifunctional organocatalyst, cinchona-squaramide C17, was described Catalysts 2021, 11, x FOR PEER REVIEW 19 of 55

In the most favored transition states, the β-ketoamide takes up a perpendicular orientation concerning the thiourea. The TS leading to the R adducts was found to be lower in energy by 2.9 kcal mol−1 over the TS leading to the S adducts (e.g., 28a), in agreement with the experimentally observed 99% ee value. The ease of proton transfer from the amide to the enolate, and the high stability of the resulting intermediate, are probably responsible for the equilibrium shift in this thermodynamically unfavorable C–C bond-forming step. This probably explains why the acidity of the amide proton is crucial for success. Furthermore, of interest is the fact that the deprotonated amide–ammonium complex was found to be thermodynamically more stable than the separated products (ΔΔG = 4.6 kcal −1 Catalysts 2021, 11, 569 mol ), in complete agreement with the experimentally observed inhibition of the catalyst19 of 54 by the product. An enantioselective organocatalytic conjugate addition of α,β-unsaturated ketones 29, promoted by a bifunctional organocatalyst, cinchona-squaramide C17, was described byby Fern Fernández-Salas,ández-Salas, AlemAlemánán andand coworkers in 2019 2019 (Figure (Figure 23)23)[ [52].52]. The The attractiveness attractiveness of ofthis this method method lies lies in in its its environmentally environmentally friendly friendly nature nature since since employing employing TMSN TMSN33 (30(30) )as as a anucleophile nucleophile avoids avoids the the use use or preformation of hydrazoichydrazoic acid,acid, aa dangerousdangerous andand highly highly explosiveexplosive substance.substance. NoNo acidicacidic additivesadditives werewere requiredrequired either. either. The The formation formation of of a a chiral chiral carboncarbon at at the the carbon carbon C–N C–N bond bond occurs occurs in in a highlya highly enantioselective enantioselective manner, manner, and and the the product prod- βuct-azido β-azido ketones ketones31 were 31 were obtained obtained with goodwith yields.good yields. It was It found was found that the that presence the presence of water of waswater important, was important, causing causing a signiﬁcant a significant enantioselectivity enantioselectivity enhancement enhancement (from 53 to(from 93% 53 ee), to and93% an ee), initial and controlled an initial controlled amount was amount used to was ensure used reproducibility to ensure reproducibility issues. The best issues. results The werebest obtainedresults were in the obtained presence in the of 0.5 pr equivalentesence of 0.5 of equivalent water. of water.

FigureFigure 22. 22. Mechanism postulated postulated for for the the Michael Michael addition addition of ofβ-ketoamidesβ-ketoamides to α to,βα-unsaturated,β-unsaturated carbonylcarbonyl compounds, compounds, catalyzed catalyzed by byC1 C1 [ 51[51].].

TheThe reactionreaction mechanismmechanism was studied by by 1H1H and and 29Si29 SiNMR NMR spectroscopy spectroscopy and and DFT DFT cal- calculations.culations. The The role role of ofwater water was was studied studied throug throughh analysis analysis of of the the reaction reaction side-products. side-products. It It was found that after a catalytic run, even if water was not added to the system, two new silylated species had been produced, trimethyl silanol (δ 15.82 ppm (29Si-NMR)) and its corresponding siloxane (δ 6.57 ppm), as observed using 2D-HMBC{1H,29Si}. The addition of excess water accelerated the reaction but deteriorated the ee. These results appear to suggest that activation of TMSN3 proceeds via hydrolysis, although, in the absence of catalyst, water could not activate TMSN3. DFT calculations showed that proton transfer is involved in the rate-determining step (in good agreement with experimental kinetic data). In control experiments, it was observed that TMSN3 hydrolyzes in hexaﬂuorobenzene in the presence of an acid additive but not in the presence of water alone. Therefore, no NH3 is formed in situ during the reaction, but it appears that there is proton transfer from the water molecule to the nitrogen atom of the quinuclidine unit followed by a nucleophilic attack of the resulting hydroxide to the silicon atom and N–Si bond cleavage. The theoretical results suggested that these processes take place in an asynchronous concerted manner. Catalysts 2021, 11, x FOR PEER REVIEW 20 of 55

was found that after a catalytic run, even if water was not added to the system, two new silylated species had been produced, trimethyl silanol (δ 15.82 ppm (29Si-NMR)) and its corresponding siloxane (δ 6.57 ppm), as observed using 2D-HMBC{1H,29Si}. The addition of excess water accelerated the reaction but deteriorated the ee. These results appear to suggest that activation of TMSN3 proceeds via hydrolysis, although, in the absence of catalyst, water could not activate TMSN3. DFT calculations showed that proton transfer is involved in the rate-determining step (in good agreement with experimental kinetic data). In control experiments, it was observed that TMSN3 hydrolyzes in hexafluorobenzene in the presence of an acid additive but not in the presence of water alone. Therefore, no NH3 is formed in situ during the reaction, but it appears that there is proton transfer from the water molecule to the nitrogen atom of the quinuclidine unit followed by a nucleophilic Catalysts 2021, 11, 569 attack of the resulting hydroxide to the silicon atom and N–Si bond cleavage. The theoret-20 of 54 ical results suggested that these processes take place in an asynchronous concerted manner.

FigureFigure 23.23. Enantioselective organocatalytic conjugate conjugate azidation azidation of of αα,β,β-unsaturated-unsaturated ketones ketones with with

TMSNTMSN33;; HFBHFB == hexaﬂuorobenzenehexafluorobenzene [[52].52].

OrganocatalyzedOrganocatalyzed sulfa-Michael sulfa-Michael reactions reactions have have been been known known since since 1977, 1977, when when Winberg Win- andberg coworkers and coworkers showed showed that aromaticthat aromatic thiols thio couldls could add toadd cycloalkenones to cycloalkenones in an in enantios- an enan- electivetioselective manner manner in the in the presence presence of cinchonaof cinchona alkaloids alkaloids [53 [53].]. These These findings findings represent represent a a milestonemilestone in in organocatalysis, organocatalysis, and and since since then, then many, many cinchona cinchona alkaloid alkaloid derivatives derivatives have beenhave developedbeen developed to promote to promote a wide a rangewide range of asymmetric of asymmetric reactions reactions [54,55 ].[54,55]. Wynberg Wynberg proposed pro- aposed dual-mode a dual-mode of activation of activation in which in thewhich thiol, the after thiol, deprotonation after deprotonation by the by quinuclidine the quinu- nitrogenclidine nitrogen of the organocatalyst, of the organocatalyst, would remainwould coordinatedremain coordinated to the tertiary to the tertiary amine center,amine whilecenter, the while enone the hydrogen, enone hydrogen, bonded bonded to the hydroxyl to the hydroxyl group, wasgroup, placed was inplaced a good in a orien- good tationorientation for the for reaction the reaction to proceed to proceed in an enantioselectivein an enantioselective manner. mann Catalysiser. Catalysis by cinchona by cin- alkaloid-squaramidechona alkaloid-squaramide catalysts catalysts was introduced was introduced by Chen by Chen and coworkersand coworkers in 2010 in 2010 [56]. [56]. A theoreticalA theoretical study study on thison this reaction reaction was was performed performed by Guoby Guo and and Wong Wong recently recently to investigate to investi- thegate mode the mode of bifunctional of bifunctional activation activation and the and origin the origin of stereoselectivity of stereoselectivity [57]. The[57]. authors The au- aimedthors aimed to disclose to disclose guidelines guidelines that that could could beused be used for for the the rational rational development development of of more more efficientefficient bifunctionalbifunctional catalyticcatalytic systems systems based based on on hydrogen-bonding hydrogen-bonding activation. activation. GeometryGeometry optimizationsoptimizations of of equilibrium equilibrium and and transition transition state state structures structures were were performed performed using using the M06- the 2XM06-2X density density functional functional with the with standard the standard 6-31G(d) 6-31G(d) basis set. basis In a similarset. In a manner similar to manner catalysis to by bifunctional thiourea-based organocatalysts (Figure4b), it is also possible to distinguish catalysis by bifunctional thiourea-based organocatalysts (Figure 4b), it is also possible to a few modes of activation with squaramide-based organocatalysts. For the formation of the distinguish a few modes of activation with squaramide-based organocatalysts. For the C–S bond in the sulfa-Michael reaction between 21 and 22, four distinct modes of activation formation of the C–S bond in the sulfa-Michael reaction between 21 and 22, four distinct (A–D) are possible (Figure 24). Mode A is Takemoto’s mode of bifunctional activation modes of activation (A–D) are possible (Figure 24). Mode A is Takemoto’s mode of bi- also observed for bifunctional thiourea-based catalysts; in a similar manner, mode B is functional activation also observed for bifunctional thiourea-based catalysts; in a similar Pápai’s; mode C was postulated in a joint experimental/theoretical study on a bifunctional cinchona alkaloid-thiourea catalyst by Wang and coworkers, although they also considered it for squaramide-catalyzed reactions [24]; and finally, in mode D, the electrophile interacts with the alkylammonium and one of the N−H groups of the Brønsted acid, while the nucleophile does so with the distal N−H of the acid. All these modes of activation were investigated by Guo and Wong as possibilities for activation of the sulfa-Michael addition reaction between benzyl thiol 32 and trans-chalcone 21, leading to 33. It has been shown that, since the initial protonation of the catalyst, as well as its final deprotonation in the catalytic cycle, is facile, the C–S bond-forming step is the rate-determining step. The conformations of the protonated catalyst were investigated first. The two N−H groups of the squaramide have a syn alignment in the active catalytic conformation. The vinyl group on the quinuclidine moiety has been shown to be anti concerning C2−C3 bond in a different study, and it was adopted as such in this study [58]. Since there is free rotation around the C8−C9 and C40-C9 bonds, six main conformations are possible, anti-open, syn-open, anti-closed, syn-closed, plus two hindered conformations, which were ignored since coop- Catalysts 2021, 11, x FOR PEER REVIEW 21 of 55

manner, mode B is Pápai’s; mode C was postulated in a joint experimental/theoretical study on a bifunctional cinchona alkaloid-thiourea catalyst by Wang and coworkers, although they also considered it for squaramide-catalyzed reactions [24]; and finally, in mode D, the electrophile interacts with the alkylammonium and one of the N−H groups of the Brønsted acid, while the nucleophile does so with the distal N−H of the acid. All these modes of activation were investigated by Guo and Wong as possibilities for activation of the sulfa-Michael addition reaction between benzyl thiol 32 and trans-chalcone 21, leading to 33. It has been shown that, since the initial protonation of the catalyst, as well as its final deprotonation in the catalytic cycle, is facile, the C–S bond-forming step is the rate-determining step. The conformations of the protonated catalyst were investigated first. The two N−H groups of the squaramide have a syn alignment in the active catalytic conformation. The vinyl group on the quinuclidine moiety has been shown to be anti con- Catalysts 2021, 11, 569 21 of 54 cerning C2−C3 bond in a different study, and it was adopted as such in this study [58]. Since there is free rotation around the C8−C9 and C4′-C9 bonds, six main conformations are possible, anti-open, syn-open, anti-closed, syn-closed, plus two hindered conformations,erativity betweenwhich were the ignored three N− sinceH functionalities cooperativity of between the protonated the three catalyst N−H functionalities is not possible ofin the those protonated cases, and catalyst therefore, is theynot possible are not catalyticallyin those cases, active. and Previous therefore, studies they are also not showed cata- lyticallythat the protonatedactive. Previous catalyst studies CatH also+ favors showed the openthat the conformations protonated catalyst by at least CatH 16+ kJ/mol favors theover open the closedconformations ones, and by therefore, at least 16 closed kJ/mol conformations over the closed were ones, also and not examinedtherefore, closed in this conformationsstudy. The energies were of also these not conformations examined in this were study. calculated, The energies and the of lowest theseenergy conformations one was werefound calculated, to have the andanti -openthe lowest form. energy The next one lowest was conformationfound to have is the the antisyn-open conformer,form. The − nextwhich lowest is less conformation stable by 7.0 is kJ the mol syn1-open. These conformer, results agree which with is less a report stable byby Sharpless7.0 kJ mol of−1. Theseepiquinine results in agree solution, with for a report which by the Sharpleanti-openss of formepiquinine was the in onlysolution, conformer for which found the toanti be- openpresent form [59 was]. the only conformer found to be present [59].

Figure 24. The sulfa-Michael addition reac reactiontion between benzyl thiol and trans-chalcone catalyzed catalyzed by by cinchona cinchona alkaloid- alkaloid- squaramide catalyst C17 and the four modes of bifunctional activationactivation possiblepossible inin thethe C–SC–S bond-formingbond-forming stepstep [[57].57].

InIn thisthis conformation, conformation, the the squaramide squaramide ring isring coplanar is coplanar to the 3,5-bis(trifluoromethyl)phenyl to the 3,5-bis(trifluoromethyl)phenylgroup, and thisgroup, orientation and this is orientation stabilized byis anstabilized attractive by Can− Hattractive···O interaction C−H···O between interaction one betweencarbonyl one oxygen carbonyl of the oxygen squaramide of the moietysquarami andde the moiety acidic and ortho-proton the acidic ortho-proton of the aromatic of thering. aromatic The 60-methoxy ring. The group 6′-methoxy of the quinolinegroup of moietythe quinoline is also moiety coplanar is toalso the coplanar quinoline to ring. the quinolineTransition ring. states for the C–S bond-forming step were calculated for each activation mode, with the anti-conformation of the protonated catalysts (Figure 25). The lowest energy TS was found to be in mode B, TS-B-R, which gave rise to the major (R)-configured product, in agreement with the experimental findings. Both TS’s of mode A (TS-A-R and TS-A-S) are less stable by more than 13 kJ mol−1. The TSs with syn-open arrangements were much − higher in energy (by at least 26 kJ mol 1), and those related to mode C were even higher in energy. Hence, they were all disregarded. TS’s for mode D could not be located. To determine the origin of stereo-induction, a distortion−interaction analysis was carried out. The factors that make mode B the preferred conformation are a greater stabilization of the developing alkoxide by the quinuclidinium ion rather than hydrogen-bonding interactions. The excellent stereo-selectivity observed with mode B stems from the more favorable cooperative noncovalent interactions: hydrogen bond, π-stacking, C−H···π interaction, and C−H···F interactions, between the catalyst and the substrates in the major transition state. NCI plots show that the 3,5-bis(trifluoromethyl)phenyl moiety is capable of forming multiple attractive interactions with the substrates to help in differentiating the stereo- controlling transition states. These results are in agreement with Houk’s Brønsted acid- hydrogen bonding model for the sulfa-Michael addition reaction with enones, catalyzed by Catalysts 2021, 11, 569 22 of 54

Catalysts 2021, 11, x FOR PEER REVIEWcinchona alkaloids, in which the enone is activated by the alkylammonium ion, while23 theof 55

thiolate electrophile coordinates with the catalyst’s hydroxyl group [60].

FigureFigure 25.25.C–S C–S bond-formingbond-forming transitiontransition states for the su sulfa-Michaellfa-Michael reaction reaction between between benzyl benzyl thiol thiol andand chalconechalcone in in modes modes A A and and B. B. Relative Relative Gibbs Gibbs energies energies (in (in kJ/mol) kJ/mol) areare givengiven inin parentheses.parentheses. Inter-In- moleculartermolecular distances distances are are given given in Å. inNonessential Å. Nonessential hydrogen hydrogen atoms atoms are omittedare omitted for clarity.for clarity. Reprinted Re- andprinted adapted and adapted from Guo, from J.; Wong,Guo, J.; M.W.Wong,J. M.W. Org. ChemJ. Org.. 2017Chem, 82. 2017, 4362–4368,, 82, 4362–4368, the Journal the Journal of Organic of Organic Chemistry with permission from the American Chemical Society (Copyright 2017) [57]. Chemistry with permission from the American Chemical Society (Copyright 2017) [57].

GraysonIn these studies, and Houk the recentlyrate-determining published C− DFTS bond-forming studies on step the asymmetricwas investigated conjugate to de- additiontermine ofthe aromatic preferred thiols, mode e.g., of catalyst35 to cycloalkenones activation and (34 to) explain catalyzed the by observed cinchona selectivity. alkaloid- derivedThe activation ureas C20/C21 modes ,considered a reaction ﬁrstwere reported the same by as Singh those and described coworkers above and reportedfor thiourea in 2010catalyzed [48,61 reaction,]. This was modes the ﬁrstA, B detailed and C (Figure mechanistic 4b) [17,19,24]. study of The a cinchona TSs were urea-catalyzed located at the reactionM06-2X/def2-TZVPP-IEFPCM(toluene)//M06-2X/6-31G(d)-IEFPCM(toluene) [61]. In recent reports on other reactions catalyzed by cinchona-ureas, level itof was the- generallyory using found Gaussian that when09, and comparison a methyl datagroup were was available, used instead cinchona of the urea vinyl catalysts group yielded on the similarquinuclidine or better ring levels to simplify of enantioselectivity the calculations. than Of their all the thiourea major counterparts conformations [48 ,possible62], which for promptedthe protonated this study. catalyst, Since the urea anti- isopen a much conformation weaker acid was than found thiourea to have (pK thea = lowest 26.9 and energy, 21.1, respectively,and it was considered in DMSO), for it mayfurther happen study that(Figure cinchona 26). A ureatotal andof 78 thiourea unique pre-reaction catalysts operate com- byplexes different were reaction located mechanisms.[48]. In complex 113, found to have the lowest energy, the thiolate is closelyIn theseassociated studies, with the the rate-determining alkylammonium C ions,−S bond-forming and there are stephydrogen-bonding was investigated inter- to determineactions from the the preferred urea group mode ofto catalystthe thiolate activation. The alkylammonium and to explain the ion observed interacts selectivity. with the Theenone activation too. It was modes found considered in this study were that the the same transition as those states described of lowest above energy, for giving thiourea rise catalyzedto the major reaction, and minor modes products A, B andobserved C (Figure expe4rimentally,b) [ 17,19, 24were]. The obtained TSs were via mode located B, i.e., at TS1 for the major product, Figure 26.

Catalysts 2021, 11, 569 23 of 54

the M06-2X/def2-TZVPP-IEFPCM(toluene)//M06-2X/6-31G(d)-IEFPCM(toluene) level of theory using Gaussian 09, and a methyl group was used instead of the vinyl group on the quinuclidine ring to simplify the calculations. Of all the major conformations possible for the protonated catalyst, the anti-open conformation was found to have the lowest energy, and it was considered for further study (Figure 26). A total of 78 unique pre-reaction complexes were located [48]. In complex 113, found to have the lowest energy, the thiolate is closely associated with the alkylammonium ions, and there are hydrogen- bonding interactions from the urea group to the thiolate. The alkylammonium ion interacts with the enone too. It was found in this study that the transition states of lowest energy, Catalysts 2021, 11, x FOR PEER REVIEWgiving rise to the major and minor products observed experimentally, were obtained24 viaof 55

mode B, i.e., TS1 for the major product, Figure 26.

FigureFigure 26. 26.Asymmetric Asymmetric conjugate conjugate addition addition of of thiophenol thiophenolto tocyclopentenone cyclopentenone catalyzedcatalyzed byby cinchonacinchona alkaloid-ureaalkaloid-ureaC20 C20[ 61[61]] and and possible possible conformations conformations of of the the protonated protonated catalyst catalystC21 C21[ 48[48].]. All All energies energies −1 areare in in kcal kcal mol mol−1..

FromFrom37 37, the, the free free energy energy barrier barrier to to TS-B(major) TS-B(major) is is 10.9 10.9 kcal kcal mol mol−1−.1 The. The nucleophilic nucleophilic attackattack takes takes place place axially axially on on the the half-chair half-chair cyclohexenone, cyclohexenone, in preferencein preference to equatorial to equatorial attack at- bytack 3.3 by kcal 3.3 mol kcal−1 mol. TS-B(minor),−1. TS-B(minor), which which leads leads to the to minor the minor product product via mode via mode B, is destabi- B, is de- lizedstabilized relative relative to TS-B(major) to TS-B(major) by 3.9 kcalby 3.9 mol kcal−1. Nomol obvious−1. No obvious steric interactions steric interactions were found were tofound contribute to contribute to this differenceto this difference in energy. in en However,ergy. However, the geometry the geometry adopted adopted by enone by 34enonein TS-B(minor)34 in TS-B(minor) results inresults a longer in a and longer less and directional less directional interaction interaction from the quinuclidiniumfrom the quinuclidinium ion to the enone oxygen relative to TS-B(major) (N−H···O distance = 1.59 and 1.65 Å and N−H···O angle = 151° and 143° in TS-B(major) and TSB(minor), respectively). It was also found that in TS-B(major), there is a staggered conformation about the developing C−S bond, whereas, in TS-B(minor), there is an eclipsed conformation (CSCH dihedral = 69° and 6°, respectively). In TS-B(major) there is only one NH···S interaction is present, but the other urea NH hydrogen interacts with the π system of the thiolate instead. It was also found in this study that the quinoline ring methoxy group has a strong effect on the TS energy, an effect, which has not been considered in previous mechanistic studies of reactions catalyzed by cinchona alkaloids. In 2020 Vetticatt, Hirschi, Seidel and coworkers described a new type of bifunctional catalyst, a selenourea-thiourea Brønsted acid catalyst (C22), which catalyzed the conjugate addition of cyclic amines 39 to inactivated α,β-unsaturated esters 38 [63] (Figures 27 and

Catalysts 2021, 11, 569 24 of 54

ion to the enone oxygen relative to TS-B(major) (N−H···O distance = 1.59 and 1.65 Å and N−H···O angle = 151◦ and 143◦ in TS-B(major) and TSB(minor), respectively). It was also found that in TS-B(major), there is a staggered conformation about the developing C−S bond, whereas, in TS-B(minor), there is an eclipsed conformation (CSCH dihedral = 69◦ and 6◦, respectively). In TS-B(major) there is only one NH···S interaction is present, but the other urea NH hydrogen interacts with the π system of the thiolate instead. It was also found in this study that the quinoline ring methoxy group has a strong effect on the TS energy, an effect, which has not been considered in previous mechanistic studies of reactions catalyzed by cinchona alkaloids. Catalysts 2021, 11, x FOR PEER REVIEW 25 of 55 Catalysts 2021, 11, x FOR PEER REVIEW In 2020 Vetticatt, Hirschi, Seidel and coworkers described a new type of bifunctional25 of 55 catalyst, a selenourea-thiourea Brønsted acid catalyst (C22), which catalyzed the conjugate addition of cyclic amines 39 to inactivated α,β-unsaturated esters 38 [63](Figures 27 and 28). 13 β28).-amino β-amino esters esters40 were 40 were obtained obtained with with high highees. DFTees. DFT calculations calculations and andC kinetic13C kinetic isotope iso- 28). β-amino esters 40 were obtained with high ees. DFT calculations and 13C kinetic iso- effecttope effect studies studies helped helped to throw to throw some lightsome onlight the on reaction the reaction mechanism. mechanism. The catalyst The catalyst could tope effect studies helped to throw some light on the reaction mechanism. The catalyst alsocould be also successfully be successfully used for used the for kinetic the kinetic resolution resolution of cyclic of amines.cyclic amines. could also be successfully used for the kinetic resolution of cyclic amines.

Figure 27. Synthesis of ββ-amino esters 40 with C22 as catalyst [58]. FigureFigure 27.27. Synthesis ofof β-amino estersesters 40 with C22 as catalyst [[58].58].

Figure 28. Synthesis of amino esters 40 from compounds 38. (a) Observed KIEs (in black) and calculated KIEs for the C−N FigureFigure 28. SynthesisSynthesis of of amino amino esters esters 4040 fromfrom compounds compounds 3838. (a.() Observeda) Observed KIEs KIEs (in black) (in black) and andcalculated calculated KIEs KIEs for the for C the−N bond-forming transition structure R-TSC−N (in red) and for the direct C-protonation transition structure R-TSC--prot (in blue) Cbond-forming−N bond-forming transition transition structure structure R-TSC R-TS−N (in red)(in and red) for andthe direct for the C-protonation direct C-protonation transition transition structure structure R-TSC--prot R-TS (in blue) and the possible transition states according toC the−N experimental KIEs; (b) catalyst-mediated C-protonation and (c) catalyst-C–prot and the possible transition states according to the experimental KIEs; (b) catalyst-mediated C-protonation and (c) catalyst- (inmediated blue) and tautomerization the possible transition[63]. states according to the experimental KIEs; (b) catalyst-mediated C-protonation and (mediatedc) catalyst-mediated tautomerization tautomerization [63]. [63]. 13C kinetic isotope effects (KIEs) were determined for benzyl crotonate using Single- 13C kinetic isotope effects (KIEs) were determined for benzyl crotonate using Single- ton’s 13C NMR methodology for starting materials at natural abundance. Benzyl crotonate ton’s 13C NMR methodology for starting materials at natural abundance. Benzyl crotonate and piperidine were reacted and taken as 75 ± 2% and 79 ± 2% conversion concerning the and piperidine were reacted and taken as 75 ± 2% and 79 ± 2% conversion concerning the ester. Unreacted benzyl crotonate was reisolated, and the 13C isotopic composition was ester. Unreacted benzyl crotonate was reisolated, and the 13C isotopic composition was compared that in samples of crotonate not subjected to the reaction conditions. From the compared that in samples of crotonate not subjected to the reaction conditions. From the changes in relative isotopic composition and the fractional conversion, 13C KIEs were de- changes in relative isotopic composition and the fractional conversion, 13C KIEs were determined (in duplicate) in the standard way. The values obtained are shown in Figure 28. termined (in duplicate) in the standard way. The values obtained are shown in Figure 28. For confirmation, 13C values of KIEs were also predicted from the scaled vibrational fre- For confirmation, 13C values of KIEs were also predicted from the scaled vibrational fre- quencies using the program ISOEFF98 for both R-TSC−N and R-TSC--prot, then applying quencies using the program ISOEFF98 for both R-TSC−N and R-TSC--prot, then applying a Wigner tunneling correction to all values. The most interesting results are the unity KIE a Wigner tunneling correction to all values. The most interesting results are the unity KIE observed at the β-carbon and the normal KIE of ∼1.5% on the α-carbon. If C−N bond for- observed at the β-carbon and the normal KIE of ∼1.5% on the α-carbon. If C−N bond formation was the first irreversible step in the catalytic cycle, a normal KIE was expected on mation was the first irreversible step in the catalytic cycle, a normal KIE was expected on the β-carbon, not unity, which implies reversible C−N bond formation. A normal KIE on the β-carbon, not unity, which implies reversible C−N bond formation. A normal KIE on the α-carbon (∼1.5%) suggests that α-protonation is likely to be the first irreversible step the α-carbon (∼1.5%) suggests that α-protonation is likely to be the first irreversible step

Catalysts 2021, 11, 569 25 of 54

13C kinetic isotope effects (KIEs) were determined for benzyl crotonate using Single- ton’s 13C NMR methodology for starting materials at natural abundance. Benzyl crotonate and piperidine were reacted and taken as 75 ± 2% and 79 ± 2% conversion concerning the ester. Unreacted benzyl crotonate was reisolated, and the 13C isotopic composition was compared that in samples of crotonate not subjected to the reaction conditions. From the changes in relative isotopic composition and the fractional conversion, 13C KIEs were determined (in duplicate) in the standard way. The values obtained are shown in Figure 28. For confirmation, 13C values of KIEs were also predicted from the scaled vibrational fre- quencies using the program ISOEFF98 for both R-TSC−N and R-TSC–prot, then applying a Wigner tunneling correction to all values. The most interesting results are the unity KIE observed at the β-carbon and the normal KIE of ∼1.5% on the α-carbon. If C−N bond Catalysts 2021, 11, x FOR PEER REVIEW 26 of 55 formation was the first irreversible step in the catalytic cycle, a normal KIE was expected on the β-carbon, not unity, which implies reversible C−N bond formation. A normal KIE on the α-carbon (∼1.5%) suggests that α-protonation is likely to be the first irreversible stepin the in catalytic the catalytic cycle. cycle. The calculated The calculated values values are in agreement are in agreement with these with postulates. these postulates. There- Therefore,fore, C–N bond C–N bondformation formation is a reversible is a reversible event, event, and the and rate- the rate-and enantio-determining and enantio-determining step stepoccurs occurs after. after. These These results results suggested suggested that the that origin the origin of enan oftioselectivity enantioselectivity would would be better be betterunderstood understood if the transition if the transition state analysis state analysis were weremade madefor the for α the-carbonα-carbon protonation protonation step. step.Since Sincethere thereis no isexternal no external Brønsted Brønsted acid, acid,the most the mostacidic acidic proton proton would would be one be of one the of thio- the thioureaurea NHs, NHs, which which would would then then be beinvolved involved in in α-protonation.α-protonation. Two Two situations situations are are possible: an αα-carbon-carbon−−catalyst-mediated tautomerizationtautomerization or or catalyst-mediated catalyst-mediated direct direct C-protonation. C-protona- Antion. investigation An investigation using DFTusing calculations DFT calculations showed showed that catalyst-mediated that catalyst-mediated tautomerization tautomeri- of −1 thezation enol of is the prohibitively enol is prohibitively high in energy high (in∆ Genergy} = 48.6 (Δ kcalG⧧ = mol 48.6 kcal), whereas mol−1), catalyst-mediatedwhereas catalyst- −1 C-protonationmediated C-protonation is energetically is energetically accessible ( ∆accessibleG} = 18.2 (Δ kcalG⧧ mol= 18.2) kcal (Figure mol 29−1)). (Figure In the lowest29). In energythe lowest TS energy leading TS to leading the R-enantiomer, to the R-enantiom it waser, found it was that found there that is there strong is intramolecu-strong intra- larmolecular H-bonding H-bonding between between the protonated the protonated piperidine piperidine and the and enolate the enolate oxygen oxygen (1.81 Å).(1.81 One Å). thioureaOne thiourea NH isNH loosely is loosely bound bound (2.35 (2.35 Å), while Å), while the otherthe other (more (more acidic) acidic) is transferred is transferred to the to esterthe esterα-carbon. α-carbon. Selenium Selenium forms forms a weak a weak nonconventional nonconventional CH··· CH···SeSe interaction interaction (2.76 Å)(2.76 with Å) onewith of one the ofα the-CHs α-CHs of the of piperidine the piperidine moiety. moiety. There There have have been been a few a scantyfew scanty reports reports on the on involvementthe involvement of aof thiourea a thiourea catalyst catalyst as as a Brønsteda Brønsted acid acid in in mechanisms, mechanisms, and and thisthis relatedrelated behavior of Se represents a newnew modemode ofof catalysis,catalysis, which could be usedused asas aa guideguide inin future developments.developments.

FigureFigure 29.29. LowestLowest energyenergy transitiontransition structuresstructures forfor CC−−N bond formation catalyzed by selenourea-thiourea catalyst C22. ReprintedReprinted andand adaptedadapted fromfrom TheThe JournalJournal ofof thethe AmericanAmerican ChemicalChemical SocietySociety withwith permissionpermission fromfrom thethe AmericanAmerican ChemicalChemical SocietySociety [[63].63].

2.3. Cascade Reactions Involving Conjugate Addition In 2014 Carrillo, Vicario and coworkers reported a stereoselective and diastereo-divergent procedure to synthesize functionalized cyclohexanes containing four stereocenters through an asymmetric Michael-initiated ring closure (MIRC) cascade reaction [64]. Two different (R,R)-configured bifunctional squaramide-based organocatalysts (C23 and C24) made possible the conversion of the same starting materials into products with different absolute configurations. This was possible by the introduction of subtle structural differences in the two catalysts. A wide range of nitroalkenes 7 and α-nitro-δ-oxo esters 41 reacted in a highly diastereo- and enantioselective Michael/Henry cascade giving high yields of products 42 (Figure 30). A gram-scale synthesis was also possible without loss of stereoselectivity. Kinetic experiments were performed to find the rate-determining step, and DFT calculations were performed at the B3LYP/6-31G(d) level of theory using the PCM model to explain the reaction process and the origin of stereo-divergence. The initial Michael reaction, in which the initial two stereocenters are formed, was considered as the stereo-defining step. It is in this step that the diastereo-divergency of the reaction occurs when the

Catalysts 2021, 11, x FOR PEER REVIEW 27 of 55

Catalysts 2021, 11, 569 26 of 54

two different C-1 epimers are formed with each catalyst. It was observed that the reaction was first-order for all reagents: both catalysts, nitronate 41a (117, R1 = Et, R2 = Me), and 2.3.nitrostyrene. Cascade Reactions The fact Involving that the rate Conjugate of the reac Additiontion was strongly dependent on the electronic natureIn 2014of the Carrillo, aryl substituent Vicario and of the coworkers nitroalkene reported also suggested a stereoselective that the andinitial diastereo- Michael divergentreaction is procedure the rate-limiting to synthesize step. Among functionalized others, an cyclohexanes experiment containingwas performed four stereocen-with a pre- tersprepared through Michael an asymmetric intermediate, Michael-initiated which, when ring stirred closure with (MIRC) either catalyst, cascade reactionprovided [64 the]. Twosame different product ( R,Rin comparable)-conﬁgured yields. bifunctional This is squaramide-baseda strong indication organocatalyststhat although the (C23 configu-and C24ration) made of the possible two stereocenters the conversion generated of the same during starting the initial materials Michael into reaction products step with is dif-con- ferenttrolled absolute by the conﬁgurations.catalyst, the diastereoselectivi This was possiblety of by the the intramolecular introduction of Henry subtle structuralreaction is differencesstrictly governed in the twoby the catalysts. substrate. A wide Hence range the DFT of nitroalkenes analysis was7 and performedα-nitro- forδ-oxo each esters cata- 41lystreacted on a simplified in a highly Michael diastereo- reaction and enantioselective between 44 and Michael/Henry 7b. The optimized cascade transition giving high state yieldsstructures of products (TS1 and42 TS2)(Figure found 30). by A gram-scaleFDT analys synthesisis leading wasto the also major possible isomer without formed loss by ofeach stereoselectivity. catalyst are shown in Figure 31.

FigureFigure 30. 30.Diastereo-divergent Diastereo-divergent synthesis synthesis of of functionalized functionalized cyclohexanes cyclohexanes [ 64[64].].

Kinetic experiments were performed to find the rate-determining step, and DFT calculations were performed at the B3LYP/6-31G(d) level of theory using the PCM model to explain the reaction process and the origin of stereo-divergence. The initial Michael reaction, in which the initial two stereocenters are formed, was considered as the stereo- defining step. It is in this step that the diastereo-divergency of the reaction occurs when the two different C-1 epimers are formed with each catalyst. It was observed that the reaction was first-order for all reagents: both catalysts, nitronate 41a (117,R1 = Et, R2 = Me), and nitrostyrene. The fact that the rate of the reaction was strongly dependent on the electronic nature of the aryl substituent of the nitroalkene also suggested that the initial Michael reaction is the rate-limiting step. Among others, an experiment was performed with a preprepared Michael intermediate, which, when stirred with either catalyst, provided the same product in comparable yields. This is a strong indication that although the configuration of the two stereocenters generated during the initial Michael reaction step is controlled by the catalyst, the diastereoselectivity of the intramolecular Henry reaction is strictly governed by the substrate. Hence the DFT analysis was performed for each catalyst on a simplified Michael reaction between 44 and 7b. The optimized transition state structures (TS1 and TS2) found by FDT analysis leading to the major isomer formed by each catalyst are shown in Figure 31.

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FigureFigure 31. 31.Model Model of of the the initial initial diastereo-divergent diastereo-divergent Michael Michae additionl addition in thein the cascade cascade reaction reaction leading leading to functionalizedto functionalized cyclohexanes cyclohexanes42 and 42 and43 and 43 and TSs TSs leading leading to the to majorthe major products products45 and 45 and46 determined 46 deter- bymined DFT calculationsby DFT calculations [64]. [64].

FromFrom the the DFT DFT experiments, experiments, it it could could be be concluded concluded that that the the mode mode of of activation activation of of the the catalystscatalysts involves involves activation activation of of the the nucleophile nucleophile by by the the squaramide squaramide unit unit through through multiple multiple H-bondingH-bonding interactions, interactions, while while the the nitroalkene nitroalkene stays stays bound bound to to the the ammonium ammonium salt salt (formed (formed afterafter the the initial initial deprotonation deprotonation of of the the pronucleophile) pronucleophile) via via a a single single H-bond. H-bond. The The different different simplesimple diastereo-selections diastereo-selections provided provided by by each each catalyst catalyst depend depend on on their their ability ability to to form form two two differentdifferent H-bondedH-bonded complexescomplexes withwith thethe nitroacetatenitroacetate enolate,enolate, withwiththe the nitronate nitronate moiety moiety exposingexposing a a different different reactive reactive prochiral prochiral face face depending depending on on the the catalyst catalyst used. used. Meninno,Meninno, Lattanzi Lattanzi and and coworkers coworkers reported reported the firstthe enantioselectivefirst enantioselective catalytic catalytic approach ap- toproachcis- and to trans-cis- and2,3-diaryl-substituted trans-2,3-diaryl-substituted 1,5-benzothiazepines 1,5-benzothiazepines in 2018 [65 in]. 2018 The [65]. one-pot The two- one- steppot sulfa-Michael/lactamizationtwo-step sulfa-Michael/lactamization sequence sequence between compoundsbetween compounds47 and 48 47, promoted and 48, pro- by thiourea-basedmoted by thiourea-based bifunctional bifunctional catalyst C25 catalystand p-toluenesulfonic C25 and p-toluenesulfonic acid, afforded acid, products afforded49 inproducts good to 49 high in good yields to and high very yields high andees very (Figure high 32 ee).s Mechanistic(Figure 32). Mechanistic studies were studies performed were 1 onperformed the reaction. on the An reaction. uncatalyzed An uncatalyzed reaction monitored reaction by monitoredH NMR by in 1 toluene-dH NMR in8 overtoluene-d time 8 revealedover time that revealed small that amounts small ofamountscis-Michael of cis- adductMichael50 adduct, as well 50, as as cyclizedwell as cyclized product prod-49a (Ruct1 = 49a R2 (R= Ph,1=R2 R=Ph,3 = H)R3,=H), are formedare formed during during the reaction, the reacti whichon, which contributes contributes to lower to lower the ee theof theee ofcis the-benzothiazepine. cis-benzothiazepine. A similar A similar experiment experiment in the in presence the presence of the of catalyst the catalyst showed showed the formationthe formation of an of increasing an increasing amount amount of Michael of Mich adductael adduct over over time, time, but but not not a cyclic a cyclic product. prod- Ituct. was It foundwas found that that the the organocatalyst organocatalyst promoted promoted a competitive a competitive 1,2-addition/elimination 1,2-addition/elimination reaction,reaction, confirmed confirmed by by detecting detecting 30% 30% of of free free pyrazole pyrazole at theat the end end of the of reaction.the reaction. The The mixture mix- ofturecis/trans of cis/trans-49a was-49a recoveredwas recovered with with the same the same level level of diastereo- of diastereo- and and enantioselectivity enantioselectivity of theof the starting starting adduct adduct50, 50 which, which suggests suggests that that a retro-sulfa a retro-sulfa Michael/sulfa-Michael Michael/sulfa-Michael process process doesdoes not not happen happen since since that that would would lead lead to to epimerization/racemization. epimerization/racemization. A A racemic racemic mixture mixture ofof adduct adduct treated treated with with the the catalyst catalyst afforded afforded <10% <10% of of the thetrans- trans-benzothiazepinebenzothiazepine after after two two days,days, showingshowing thatthat thethe lactamizationlactamization reactionreaction isisnegligible negligiblewithin withinthe the overall overall reaction reaction timestimes forfor thethe method developed. developed. Overall, Overall, although although the the uncatalyzed uncatalyzed Michael Michael reaction, reaction, lac- lactamization,tamization, as as well well as as catalyst catalyst promoted promoted lactamization, lactamization, may influenceinfluence thethe diastereo-diastereo- and and

Catalysts 2021, 11, 569 28 of 54 CatalystsCatalysts 2021 2021, ,11 11, ,x x FOR FOR PEER PEER REVIEW REVIEW 2929 of of 55 55

enantioselectivitiesenantioselectivities observed observedobserved at atat the thethe end, end, they they were were neverthelessnevertheless predicted predicted to to bebe poorlypoorly effective during the overall reaction times taken by both sequential steps. effectiveeffective during during the the overall overall reaction reaction ti timesmes taken taken by by both both sequential sequential steps. steps.

FigureFigure 32. 32. One-pot One-potOne-pot synthesis synthesis of of chiral chiral 1,5-benzothiazepines 1,5-benzothiazepines 49 49 [65].[ [65].65].

Recently,Recently, Liu, Liu,Liu, Li, Li,Li, Song, Song,Song, Ban BanBan and andand coworkers coworkerscoworkers described describeddescribed a thiosquaramide aa thiosquaramidethiosquaramide (C26 ()-catalyzed(C26C26)-cata-)-cata- lyzedcascadelyzed cascade cascade Michael Michael Michael−Henry−−HenryHenry elimination elimination elimination reaction reaction reaction for synthesizing for for synt synthesizinghesizing cyclopentenes cyclopentenes cyclopentenes [66]. [66]. In[66]. this In In thisreaction,this reaction,reaction, phenacylmalononitriles phenacylmalononitrilesphenacylmalononitriles51 and 5151 and nitrooleﬁns,and nitroolefins,nitroolefins,7 reacted 77 reactedreacted with withwith very veryvery high highhigh diastere- dia-diastereoselectivity,oselectivity,stereoselectivity, giving giving giving high high high yields yields yields of productsof of products products52 52 with52 with with moderate moderate moderate to to to high high highee ee ees,s,s, whichwhich which could could neverthelessnevertheless be bebe as as highhigh asas 98%98% (Figure(Figure 33 33).33).). PreviousPrevious approachesapproaches toto cyclopentenescyclopentenescyclopentenes fromfrom thethethe same samesame substrates substrates were were were reported reported reported previously, previously, previously, but but but in in inthe the the racemic racemic racemic series, series, series, the the thelatest latest latest one one oneus- us- ingusinging TBAFTBAF TBAF asas as catalystcatalyst catalyst [67].[67]. [67 The].The The productsproducts products containcontain contain aa chiralchiral a chiral quaternaryquaternary quaternary centercenter center asas well aswell well asas an asan internalaninternal internal doubledouble double bond,bond, bond, withwith with manymany many possibilitiespossibilities possibilities forfor for derivatization.derivatization. derivatization. BasedBased Based onon on experimentalexperimental experimen- datataldata data andand and preliminarypreliminary preliminary theoreticaltheoretical theoretical analysisanalysis analysis (Hartree(Hartree (Hartree−−FockFock−Fock calculations),calculations), calculations), aa mechanismmechanism a mechanism waswas proposedwasproposed proposed involving involving involving an an organocatalyzed organocatalyzed an organocatalyzed asymmetric asymmetric asymmetric Michael Michael Michael addition addition addition (with (with (with TS1) TS1) TS1) and and andcat- cat- alyst-assistedcatalyst-assistedalyst-assisted E2E2 E2 eliminationelimination elimination (with(with (with TS3)TS3) TS3) (Figure(Figure (Figure 34).34). 34). AlthoughAlthough Although an an alternative alternative path pathpath existsexists viavia non-catalyzednon-catalyzed EE11 eliminationeliminationelimination (path (path(path A), A),A), this thisthis route routeroute wowouldwoulduld givegive riserise toto twotwo isomers,isomers, thethe productproduct observed, observed, 52a 52a and and E E. .However, However, E E was was not not observed. observed. Therefore,Therefore, it it was was concluded concluded that the reaction proceeds via the catalyzed E elimination path. thatthat the the reaction reaction proceeds proceeds via via the the catalyzed catalyzed E E22 elimination elimination path. path.

FigureFigure 33.33. Enantioselective Enantioselective synthesis synthesis ofof cyclopentenescyclopentenes 127 127 [[66]. 66[66].].

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Figure 34. Mechanism proposed for the Michael–Henry–eliminationMichael–Henry–elimination cascade leading toto cyclopentenescyclopentenes [[66].66].

3. Cycloaddition Reactions Another classclass ofof reactionsreactions that that have have been been shown shown to to beneﬁt benefit from from developing developing hydrogen- hydro- gen-bondingbonding catalysis catalysis with with bifunctional bifunctional catalysts catalysts is cycloaddition is cycloaddition reactions. reactions. [4 + 2] [4 Cycloaddi- + 2] Cy- cloadditionstions as well as as well [3 + as 2], [3 i.e.,+ 2], formal i.e., formal [3 + [3 2], + formal2], formal [3 +[3 3],+ 3], [5 [5 + + 2], 2], 1,3-dipolar1,3-dipolar cycloadditions and and Tamura Tamura cycloadditions cycloadditions have have been been successfully successfully achieved. achieved. This This topic topic was was re- viewedreviewed by by Held Held and and Tsogoeva Tsogoeva in 2016 in 2016 [68]. [ 68Some]. Some interesting interesting kinetic kinetic and theoretical and theoretical studiesstudies have have been been reported reported recently. recently. Wang, Wang, Wang Wang and andcoworkers coworkers described described a formal a formal thio thio[3 + 3]-cyclization[3 + 3]-cyclization catalyzed catalyzed by a thiourea-based by a thiourea-based bifunctional bifunctional catalyst catalyst (C27) (inC27 2014) in [69]. 2014 Start- [69]. ingStarting from from 2-benzylidenemalononitrile 2-benzylidenemalononitrile (54) and (54) andindoline-2-thiones indoline-2-thiones 55, optically55, optically active active thiopyrano-indolethiopyrano-indole annulated annulated heterocyclic heterocyclic compounds compounds 5656 werewere obtained obtained in in high high yields and excellent eeees.s. The The authors authors also also attempted attempted to to react react the the less less acidic acidic indolin-2-ones indolin-2-ones 5757 withwith 2- benzylidenemalononitrile2-benzylidenemalononitrile in in a asimilar similar way, way, bu butt these these attempts attempts were were unsuccessful, and no reaction was observed. To explain the differencesdifferences in reactivityreactivity betweenbetween the twotwo indolineindoline substrates, DFT calculationscalculations werewere performedperformed atat thethe B3LYP/6-311++G(d,p)B3LYP/6-311++G(d,p) level using thethe CPCM solvent model. Based on previous transition-state models for thiourea-catalyzed CPCM solvent model. Based on previous transition-state models for thiourea-catalyzed reactions, it was assumed that both reactants are activated simultaneously by the catalyst, reactions, it was assumed that both reactants are activated simultaneously by the catalyst, as shown in Figure 35. According to the theoretical results obtained, enolization of the as shown in Figure 35. According to the theoretical results obtained, enolization of the indolin-2-one (57) is much more difﬁcult than that of indoline-2-thione (55a). Catalyst indolin-2-one (57) is much more difficult than that of indoline-2-thione (55a). Catalyst pro- protonation by the enol forms is facile according to the Pápai and Wong models. The enan- tonation by the enol forms is facile according to the Pápai and Wong models. The enanti- tioselectivity obtained is dependent on the way the substrates coordinate to the catalyst. oselectivity obtained is dependent on the way the substrates coordinate to the catalyst. Complex S-M1 (3.75 kcal mol−1) is more stable than O-M1 (8.80 kcal mol−1), in agreement Complex S-M1 (3.75 kcal mol−1) is more stable than O-M1 (8.80 kcal mol−1), in agreement with the experimental observations that 55 is much more reactive than 57. The energy with the experimental observations that 55 is much more reactive than 57. The energy barrier for C–C bond formation is 1.34 kcal mol−1 lower for the indoline-2-thione, which also explains why the thiopyrano-indoles are easier to obtain.

Catalysts 2021, 11, 569 30 of 54

− Catalysts 2021, 11, x FOR PEER REVIEWbarrier for C–C bond formation is 1.34 kcal mol 1 lower for the indoline-2-thione,31 of which 55

also explains why the thiopyrano-indoles are easier to obtain.

FigureFigure 35. 35.Enantioselective Enantioselective synthesis synthesis of of thiopyrano-indole-annulated thiopyrano-indole-annulated heterocyclesheterocycles via a a formal formal thio thio [3+3]-cyclization [3 + 3]-cyclization [69]. [69 ].

InIn 2017 2017 JacobsenJacobsen and and coworkers coworkers introduced introduced a new a new concept concept in H-bond in H-bond donor donor catalysis catalysis[70]. [70 To]. Toovercome overcome the fact the that fact small-molecule that small-molecule dual hydrogen-bond dual hydrogen-bond donors, such donors, as ureas, such as ureas,thioureas, thioureas, squaramides, squaramides, and guanidinium and guanidinium ions are ions only are weakly only weakly acidic acidicand, therefore, and, therefore, fa- favorvor reactions reactions with with highly highly reactive reactive electrophilic electrophilic substrates, substrates, they developed they developed a way to a wayacti- to activatevate them them through through by byassociating associating them them with with Lewis Lewis acids. acids. Silyl Silyltriflates triﬂates (58) were (58) werefound found to tobe be ideal ideal for for this this purpose purpose since since they they are arereadily readily available, available, have havebroad broad applicability applicability in or- in organicganic synthesis, synthesis, and and when when they they coordinate coordinate with withweakly weakly coordi coordinatingnating anionic anionic ligands, ligands, e.g., e.g.,disulfonimides, disulfonimides, their their reactivity reactivity is increased is increased [71,72]. [71 Association,72]. Association with a withchiral a H-bond chiral H-bond do- donornor catalyst, catalyst, as as in in 5959, can, can give give rise rise to to a acharge-separated charge-separated complex, complex, by byanion anion abstraction, abstraction, withwith higher higher Lewis Lewis acidityacidity than that of the the silyl silyl triflate triﬂate alone alone (Figure (Figure 36a). 36a).

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FigureFigure 36.36.( (aa)) ActivationActivation of of a a silyl silyl triﬂate triflate (58 (58) via) via anion anion abstraction abstraction by by a squaramidea squaramide catalyst; catalyst; (b )(b Application) Application of theof the type type of activationof activation shown shown in (a):in (a): Cooperative Cooperative reactivity reactivity of squaramide-basedof squaramide-based catalyst catalystC28a C28aand and TESOTf TESOTf in in enantioselective enantioselective [4 [4+3] + 3] cycloadditionscycloadditions viavia oxyallyloxyallyl cationcation intermediates;intermediates; r.r. r.r. is is the the regioisomeric regioisomeric ratio ratio [ 70[70].].

OneOne ofof thethe systemssystems utilized utilized to to investigate investigate the the H-bond H-bond donor–silyl donor–silyl triflate triflate cooperativity cooperativ- wasity was a [4 a + [4+3] 3] cycloaddition cycloaddition reaction, reaction, which which gives gives rise rise to to functionalized functionalized seven-membered seven-membered carbocycliccarbocyclic frameworks, a a reaction reaction which which had had proved proved previously previously to be to challenging be challenging to per- to performform in inan anenantioselective enantioselective manner. manner. Silyl Silyl enol enol ethers ethers capable capable of of acting acting as oxyallyl cationcation precursorsprecursors ((6060)) werewere reactedreacted withwith furansfurans ((6161)) toto generategenerate bicyclicbicyclic [4[4 ++ 3]3] cycloadductscycloadducts ((6262)) inin goodgood yieldyield andand highhigh eeees,s, asas singlesingle diastereomersdiastereomers inin somesome casescases inin thethe presencepresence ofof C28aC28a (Figure(Figure 3636b).b). KineticsKinetics andand theoreticaltheoretical studiesstudies werewere performedperformed onon thisthis reaction.reaction. ForFor thethe kineticskinetics studies,studies, BurBurés’és’ methodmethod waswas utilizedutilized [[73].73]. AA first-orderfirst-order kinetickinetic dependencedependence onon thethe acetal,acetal, zero-orderzero-order dependencedependence onon thethe furanfuran andand aa first-orderfirst-order dependencedependence onon thethe catalystcatalyst werewere observed,observed, asas wellwell asas saturation kinetics concerningconcerning triethylsilyl trifluoromethanesulfonatetrifluoromethanesulfonate (TESOTf).(TESOTf). The The data data are are consistent consistent with with a pre- a pre-equilibriumequilibrium formation formation of a ofresting-state a resting-state com- complexplex between between the catalyst the catalyst and andTESOTf, TESOTf, and anda rate-limiting a rate-limiting reaction reaction of this of complex this complex with withthe acetal. the acetal. It was It found was found that there that therewas a was1:1 binding a 1:1 binding interaction interaction between between the simpler the simpler squar- squaramideamide C28bC28b and anddifferent different triflate triflate sources, sources, and and the the bonding bonding constants constants were determineddetermined 1 fromfrom titrationtitration experiments experiments by byH 1H NMR NMR spectroscopy. spectroscopy. TESOTf TESOTf was foundwas found to bind to4000 bind times 4000 astimes tightly as tightly as NBu as4 OTf,NBu4 whichOTf, which suggests suggests that therethat there is the is simultaneous the simultaneous binding binding of both of both the triflatethe triflate and and the trialkylthe trialkyl silyl silyl component component in the in complexthe complex formed. formed. Taking Taking into into account account the combinedthe combined results, results, it appears it appears that there that isthere a formation is a formation of an unexpectedly of an unexpectedly strong 1:1 strong complex 1:1 betweencomplex TESOTfbetween and TESOTf 5 as the and resting 5 as the state resting of the catalyststate of inthe the catalyst reactions in the described. reactions described.The kinetics and DFT studies suggest that in this resting state, the complex acts as a potent Lewis acid that promotes acetal ionization. Post-rate-determining reaction of the

Catalysts 2021, 11, 569 32 of 54

oxyallyl cation intermediate with the furan gives rise to the [4 + 3] cycloadduct. Since similar ees were obtained with different trialkyl silyl triflate promoters tried, it appears that the enantioselectivity-determining step occurs after the formation of the oxyallyl cation and involves the reaction with furan. Single-point calculations at the M062X/6-31+G(d,p) ‡ −1 level of theory could reproduce both the sense and magnitude (∆∆E calc = 1.28 kcal mol ) of enantioinduction determined experimentally. The structure corresponding to the lowest- energy TS (TS1) for the first, enantioselectivity-determining C–C bond-forming step, towards the major enantiomer of product, is shown in Figure 36. Besides a network of hydrogen-bonding interactions between the different reacting components, there seems to be a stabilizing interaction between the furan and the catalyst in the TS leading to the major enantiomer, absent in the TS leading to the minor enantiomer, which can be deduced from the position of the furan ring close to the aromatic substituent of the catalyst. This may be a key factor responsible for enantioselectivity. When homophthalic anhydrides 63 are reacted with imines 64, chiral lactams 65 can be obtained in a highly enantioselective manner in the presence of bifunctional squaramide– based catalysts (Figure 37). This was discovered by Vetticatt and Seidel, who proposed a novel ion-pairing mechanism to achieve a formal [4 + 2] cycloaddition [74]. Although this reaction had been previously used in synthesis and even been applied to alkaloid synthesis, no asymmetric versions had yet been developed [75,76]. The new mode of activation, an anion-binding/ion-pairing approach, was based on the concept that the hydrogen-bonding catalyst, which itself remains neutral throughout the reaction, can convey enantioselectivity by interacting with an anionic nucleophile and a cationic electrophile at the same time. The interaction of the hydrogen-bonding thiourea with the anhydride increases the acidity of the substrate, facilitating ion-pair formation. The result is an increased equilibrium concentration of the ion pair intermediate. The iminium ion generated can then interact with another binding site on the catalyst, which results in creating a well-defined ion pair, which then undergo the enantioselective Mannich reaction. Catalyst C29 was found to be the best out of a range tried. The reaction mechanism was investigated, and it was observed that there were no nonlinear effects, which suggested that the rate-limiting step involves only one catalyst unit. The nature of the transition state of the rate- and stereo-determining step, the Mannich addition for the reaction between 63 and N-phenyl benzimine catalyzed by C29 was investigated using B3LYP-GD3[22]/6-311+G** PCM [23] (diethyl ether)//B3LYP/6-31G* calculations as implemented by Gaussian 09. The lowest- energy transition structures found leading to the major and minor enantiomers of the product are shown in Figure 37. The results show an early C–C bond formation step. In the TS structure leading to the major enantiomer (SS-TS), the enolate is bound to the catalyst through two strong H-bonds via the thiourea NH groups (Figure 37). The protonated imine is directed to the Re face of the enolate through a strong H-bond with the carbonyl oxygen of the amide moiety of the catalyst. Similar H-bonding interactions exist in TS leading to the minor enantiomer (RR-TS), but this TS is higher in energy by 2.0 kcal mol−1, which agrees with the experimentally observed value of ee. Thiourea-based bifunctional catalysis was also responsible for an enantioselective 1,3- dipolar cycloaddition of salicylaldehyde (66)-derived azomethine ylides with nitroalkenes 67 that proceeded with excellent exo/endo selectivity [77]. An intramolecular hydrogen bond involving an o-hydroxy group allowed the reaction with azomethine ylides bearing only one activating group. In methods previously developed, two activating groups (two EWGs or one EWG and one aryl group) were required at the dipole to increase the acidity of α-protons. As a result, the substitution pattern of the final products was restricted. Catalysts 2021, 11, 569 33 of 54 Catalysts 2021, 11, x FOR PEER REVIEW 34 of 55

Figure 37. Enantioselective synthesis of lactams by [4 + 2] cycloadditions catalyzed by C29, including the lowest-energy transitionFigure 37. structuresEnantioselective leading synthesis to the major of lactams and minor by [4 enantiomers + 2] cycloadditions of product catalyzed65a (65 ,Rby1 C29,=R2=Ph). including Distances the lowest-energy are in Å, and transition structures leading to the major and minor enantiomers of product 65a (65, R1=R2=Ph). Distances are in Å, and some hydrogen atoms are omitted for clarity [74]. Reprinted and adapted from Angewandte Chemie International Edition some hydrogen atoms are omitted for clarity [74]. Reprinted and adapted from Angewandte Chemie International Edition with permission from Wiley. with permission from Wiley. In this work, the activation of the azomethine ylide by intramolecular bonding, as In this work, the activation of the azomethine ylide by intramolecular bonding, as well as the intermolecular hydrogen bonding with the catalyst, was demonstrated by DFT well as the intermolecular hydrogen bonding with the catalyst, was demonstrated by DFT calculations to be crucial for the reaction. For these studies, β-nitrostyrene, Takemoto’s calculations to be crucial for the reaction. For these studies, β-nitrostyrene, Takemoto’s catalyst C1 and azomethine ylide 69, formed by deprotonation of 66 by the catalyst, were catalystconsidered C1 and as the azomethine reacting species.ylide 69,Three formed different by deprotonation coordination of 66 points by the of catalyst, the reactants were withconsidered the catalyst as the with reacting both species. endo and Three exo approachesdifferent coordination were considered, points accordingof the reactants to the withTakemoto, the catalyst Pápai andwith Zhong’s both endo models and exo discussed approaches above. were The considered, pre-association according complex, to the Takemoto,intermediates, Pápai and and the Zhong’s catalyst-bound models productsdiscussed were above. computed, The pre-association as well as the complex, correspond- the intermediates,ing TSs. The ﬁrst and TS, the TS1, catalyst-bound gives rise to the produc formationts were of the computed, C–C bond, as whereas well as thethe second, corre- spondingTS2, to the TSs. intramolecular The first TS, attack TS1, gives of the rise imine to the leading formation to ring of closure. the C–C Calculations bond, whereas for the second,Zhong´ sTS2, model to the (Figure intramolecular 38) showed attack that of the the energy imine ﬁrstleading barrier to ring (TS1 closure. = 3.35 Calculations kcal mol−1) wasfor the higher Zhong´s than model in the case(Figure of P á38)pai’s showed model that (TS1 the = 1.84energy kcal/mol), first barrier but the (TS1 second = 3.35 lower kcal mol(TS2−1 =) was 14.48 higher and 16.47 than kcal in the mol case−1, respectively).of Pápai’s model The (TS1 intermediate = 1.84 kcal/mol), and the catalyst-boundbut the second lowerproduct, (TS2 according = 14.48 and to Zhong 16.47 ´kcals model, mol−1 were, respectively). thermodynamically The intermediate more stable. and the Altogether catalyst- boundthe results product, suggest according that Zhong’s to Zhong´s mechanism model, is were in operation. thermodynamically An intermolecular more stable. hydrogen Alto- getherbond between the results the suggest thiourea that and Zhong’s the OH mechan group ofism ylide is in is operation. observed onlyAn intermolecular in Zhong’s model. hy- Whiledrogen it bond provides between additional the thiourea stabilization and the to OH the group PAC, itof alsoylide increases is observed the reactivityonly in Zhong’s of the model.azomethine While ylide, it provides and it isadditional one of the stabilization factors that to favor the PAC, Zhong’s it also approach increases to the the reactivity others. of the azomethine ylide, and it is one of the factors that favor Zhong’s approach to the others.

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FigureFigure 38. 38.Synthesis Synthesis ofof pyrrolidinespyrrolidines byby 1,3-dipolar1,3-dipolar cycloadditioncycloaddition of 66 with nitroalkenes 67 under bifunctionalbifunctional catalysis catalysis [ 77[77].].

CinchonaCinchona thiourea thiourea catalysts catalysts have have also also been been used used to to induce induce axial axial chirality. chirality. In In a a recent recent workwork described described by by Yan Yan and and coworkers, coworkers, an an atroposelective atroposelective intramolecular intramolecular [4 [4 + + 2]2] cycload-cycload- ditiondition was was used used to to convert convert in in situ situ generated generated vinylidene vinylidene ortho-quinone ortho-quinone methides methides (VQM), (VQM), formedformed by by the the intramolecular intramolecular reaction reaction of of 2-ethynylphenol 2-ethynylphenol derivatives derivatives with with alkynes, alkynes, into into axiallyaxially chiralchiral heterobiaryls,heterobiaryls, i.e., naphthalenylpyran naphthalenylpyran 7171 [78].[78]. Several Several products products could could be beob- obtainedtained in in very very high high yields yields and and eeeess (96–>99% (96–>99% eeee)) at rt. Subsequently, Yan,Yan, Bai,Bai, LanLan and and coworkerscoworkers performedperformed theoreticaltheoretical studies, i.e., DFT DFT calculations, calculations, on on the the reaction reaction shown shown in inFigure Figure 39 39 to to investigate investigate the the mechanism mechanism and and origin origin of ofenantioselectivity enantioselectivity [79]. [79 All]. AllDFT DFT cal- calculationsculations were were performed performed with with thethe Gaussian Gaussian 09 series 09 series of programs, of programs, and andthe B3-LYP the B3-LYP func- functionaltional with with the thestandard standard 6-31G(d) 6-31G(d) basis basis set setwas was used used for for geometry geometry optimization. optimization. The The re- resultssults obtained obtained led led to tothe the proposal proposal of the of the mech mechanismanism shown shown in Figure in Figure 39. The 39. reaction The reaction starts startswith withdeprotonation deprotonation of the of naphthol the naphthol moiety moiety by the by thequinuclidine, quinuclidine, facilitated facilitated by the by thefor- formationmation of oftwo two hydrogen hydrogen bonds bonds with with the the thiourea thiourea moiety, moiety, which which enhances enhances the the acidity acidity of ofthe the alkynyl alkynyl naphthol. naphthol. Conjugation Conjugation with with the thenaphthalenoate naphthalenoate enhances enhances the basicity the basicity of posi- of positiontion C2 C2in inthe the alkyne alkyne moiety, moiety, facilitating facilitating prot protonation.onation. Intramolecular Intramolecular protonproton transfertransfer of of ammoniumammonium naphthalenolate naphthalenolate salt saltB Bgives gives rise rise to to the the VQM VQM intermediate intermediateC- C-RRwith with dearomati- dearoma- −1 zation.tization. This This process process is endergonicis endergonic by by 15.3 15.3 kcal kcal mol mol−.1. The The conjugative conjugative allene allene and and carbonyl carbonyl moietiesmoieties actact as as an an enophile enophile in in the the ensuing ensuing [4 [4 + + 2] 2] hetero-Diels–Alder hetero-Diels–Alder cycloaddition. cycloaddition. The The axialaxial chirality chirality of of the the VQM VQM intermediate intermediate is is created created in in the the protonation protonation step step and and the the enantios- enanti- electivityoselectivity of theof the reaction. reaction. The The enantioselectivity enantioselectivity is controlled is controlled by steric by steric repulsions repulsions with with the cinchoninethe cinchonine framework, framework, leading leading to an toR -axialan R-axial chiral chiral VQM VQM as the as major the major intermediate. intermediate. The enantioselectivityThe enantioselectivity for the for axial the axial chirality chirality of the of product the product is controlled is controlled in the in cycloadditionthe cycloaddi- step. An additional hydrogen bond between the naphthalenol and quinuclidine moieties tion step. An additional hydrogen bond between the naphthalenol and quinuclidine moi- makes the generation of an S-axial chiral naphthopyran the most favorable (Figure 40). The eties makes the generation of an S-axial chiral naphthopyran the most favorable (Figure calculated energy barrier for this step is only 6.8 kcal mol−1, whereas the energy barrier 40). The calculated energy barrier for this step is only 6.8 kcal mol−1, whereas the energy for the formation of its enantiomer was calculated to be 13.1 kcal mol−1. The difference barrier for the formation of its enantiomer was calculated to be 13.1 kcal mol−1. The differ- in energy (6.3 kcal mol−1) predicts >99% ee for the S-axial enantiomer, which corresponds ence in energy (6.3 kcal mol−1) predicts >99% ee for the S-axial enantiomer, which corre- with the experimental observations. sponds with the experimental observations.

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FigureFigure 39. 39.Intramolecular Intramolecular [4[4+2] + 2] cycloaddition cycloaddition of of 2-ethynylphenol 2-ethynylphenol and and the the proposed proposed cata catalyticlytic cycle; cycle; the the relative relative energies energies are givenareFigure given concerning 39. concerning Intramolecular catalyst catalystent [4+2] -entC19- C19cycloadditionwith with substrate substrate of 702-ethynylphenol 70 [79 [79].]. The The free free energies andenergies the wereproposedwere obtained cata lyticby by adding adding cycle; DGcorrthe DGcorr relative (the (the ther-energies thermo- mochemicalare given concerning correction catalyst for the Gibbsent-C19 free with energy substrate calculated 70 [79]. at theThe B3-LYP/6-31G(d) free energies were level obtained in the gas by phase)adding to DGcorr DEM11/sol- (the ther- chemical correction for the Gibbs free energy calculated at the B3-LYP/6-31G(d) level in the gas phase) to DEM11/solvent ventmochemical (the single-point correction energy for the calculated Gibbs free at the energy M11/6-311+G(d,p calculated at) levelthe B3-LYP/6-31G(d) in toluene-based levelon the in gas-phase the gas phase) stationary to DEM11/sol- point). (thevent single-point (the single-point energy energy calculated calculated at the at M11/6-311+G(d,p) the M11/6-311+G(d,p level) level in toluene-based in toluene-based on theon the gas-phase gas-phase stationary stationary point). point).

Figure 40. TSs for the cycloaddition step of the ent-C19-catalyzed intramolecular [4 + 2] cycloaddition reaction. Bond lengths are in Å. Reprinted and adapted from Chemistry—An Asian Journal with permission from Wiley [79]. Figure 40. TSs for the cycloadditionFigure 40. TSsstep for of thethe cycloadditionent-C19-catalyzed step of intramolecular the ent-C19-catalyzed [4 + 2] cycloaddition intramolecular reaction. [4 + 2] cycloaddition Bond lengths are in Å. Reprinted and adapted from Chemistry—An Asian Journal with permission from Wiley [79]. reaction. Bond lengths are in Å. Reprinted and adapted from Chemistry—An Asian Journal with permission from Wiley [79].

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The Tamura reaction, the cycloaddition between activated alkynes or alkenes and The Tamura reaction, the cycloaddition between activated alkynes or alkenes and enolizable anhydrides, such as homophthalic anhydride, was studied by Connon and enolizable anhydrides, such as homophthalic anhydride, was studied by Connon and coworkers. They reported the first examples of asymmetric Tamura cycloaddition reac- coworkers. They reported the first examples of asymmetric Tamura cycloaddition reactions involving singly activated alkenes in 2016 [80]. Homophthalic anhydride (63) was tions involving singly activated alkenes in 2016 [80]. Homophthalic anhydride (63) was reacted with α-methyl nitrostyrenes (72) in the presence of squaramide-based catalyst C30 reacted with α-methyl nitrostyrenes (72) in the presence of squaramide-based catalyst to produce bicyclic aromatic ketones 73/74 with three new stereocenters in 12–99% ee. It C30 to produce bicyclic aromatic ketones 73/74 with three new stereocenters in 12–99% was found that the products were susceptible to equilibration, 74 equilibrated to 73, which ee. It was found that the products were susceptible to equilibration, 74 equilibrated to 73, was observed even during evaporation of the solvent during purification. To obtain prod- which was observed even during evaporation of the solvent during purification. To obtain ucts under reproducible conditions, the reaction conditions described in the equation in products under reproducible conditions, the reaction conditions described in the equation Figurein Figure 41 41hadhad to tobe be followed followed carefully, carefully, and and also also the the purification, purification, with with a a concentration concentration of the solvent performed at low temperatures (not higher than 30 ◦°C).C). It was also observed with 73a (73, RR == Ph) that when the pure diastereoisomerdiastereoisomer was subjected to epimerization conditions in the presence of CD3OD, i.e., heating to 55 °C◦ for 55 h in MTBE (0.1 M), that conditions in the presence of CD3OD, i.e., heating to 55 C for 55 h in MTBE (0.1 M), that there was 60% incorporation of deuteriumdeuterium atat thethe ester’sester’s α position. It was also found that 73a epimerizes faster than 74a and that 74a is the moremore stablestable isomerisomer in thethe presencepresence ofof MeOH. This experiment showed that even the moremore stablestable diastereoisomerdiastereoisomer undergoesundergoes proton transfer. This unusual equilibration, whichwhich occurs in a methanolic solution in the absence of a recognizable base via proton transfer at the the αα-carbon-carbon of of the the ester, ester, was was subse- subse- quently investigated computationally. These calculations, as well as XRD data, indicated that the nitro group and the proton involved in the epimerization areare ca.ca. 2.74 Å apart, and hence it was proposed that proton transfer is mediated by the proximal nitronitro functionalfunctional group. However, such mechanism is thermody thermodynamicallynamically unfavorable (relative energyenergy >50>50 kcal mol mol−−1 with1 with respect respect 74a74a), and), and another another mechanism mechanism was was considered considered solvent-assisted solvent-assisted protonproton transfer. transfer. The Theinvolvement involvement of two of MeOH two MeOH molecules molecules was found was found to be tokinetically be kinetically more favorablemore favorable than one than only. one It only. was, Ittherefore, was, therefore, proposed proposed that two that molecules two molecules of MeOH of interact MeOH withinteract the with product; the product; subsequently, subsequently, a shuttle a shuttle (concerted) (concerted) deprotonation/protonation deprotonation/protonation takes placetakes placewith the with participation the participation of both of bothMeOH MeOH molecules molecules bound bound to both to both each each other other and andto the to substrate,the substrate, leading leading to intermediate to intermediate 75. 75The. The energy energy barrier barrier for forthis this process process was was calculated calculated to beto be18.7 18.7 kcal kcal mol mol−1. The−1. Thecorresponding corresponding reaction reaction involving involving the other the other diastereoisomer diastereoisomer (74) has(74) a has slightly a slightly higher higher energy energy barrier barrier (21.5 kcal (21.5 mol kcal−1). mol 74·2MeOH−1). 74·2MeOH was foundwas to found be 1.6 to kcal be 1.6mol kcal−1 more mol stable−1 more than stable 73a·2MeOH than 73a, consistent·2MeOH, consistentwith the findings with the from findings deuteration from deuter- exper- iments,ation experiments, that 73a epimerizes that 73a fasterepimerizes than 74a faster, and than that74a 74a, andis the that more74a stableis the diastereoiso- more stable mer.diastereoisomer.

Figure 41. Asymmetric Tamura cycloaddition reaction catalyzed byby C30C30 [[80].80].

The Connon group also showed that a wide range of aldehydes undergoes cycloaddition with homophthalic anhydride ( (6363)) in the presence of organocatalyst C31 to yieldyield substituted lactoneslactones77 77in in excellent excellent yield yield and andee see (Figures (Figure 42)[ 42)81 ].[81]. In 2016In 2016 Rozas, Rozas, Connon Connon and

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andcoworkers coworkers reported reported the ﬁrst the DFTfirst mechanisticDFT mechanis studytic study on the on cycloaddition the cycloaddition of benzaldehyde of benzal- (dehyde76a) with (76a homophthalic) with homophthalic anhydride anhydride [82]. The [82]. reaction The reaction was found was found to follow to follow a mechanism a mech- anismin which in which the catalyst the catalyst binds tobinds the anhydride,to the anhydride, a highly a highly energetically energetically favorable favorable process pro- (ca. cess40 kJ (ca. mol 40− 1kJ), mol which−1), thenwhich deprotonates then deprotonates it, leading it, leading to a squaramide-bound to a squaramide-bound enolate. enolate. This Thisreaction reaction is thermodynamically is thermodynamically favorable, favorable, with with the catalyst-boundthe catalyst-bound enolate enolate found found to beto be21.1 21.1 kJ molkJ mol−1 −more1 more stable stable than than the the substrate–catalyst substrate–catalyst complex. complex. ThisThis reactionreaction isis followedfollowed by C–C bond formation. An atoms in molecu moleculesles (QTAIM) analysis revealed the existence of a web of HBHB interactionsinteractions betweenbetween enolateenolate oxygenoxygen atomsatoms notnot involvedinvolved inin squaramidesquaramide binding and both the catalyst’s quinoline ring and the C-2C-2 phenylphenyl substituent,substituent, shown in previous studies to be beneﬁcialbeneficial for product dr andand ee.ee. Therefore it seems that thisthis unitunit facilitates face-selective binding of the enolate,enolate, which then adds to the aldehyde, which is at the same timetime beingbeing activatedactivated by by the the catalyst’s catalyst’s ammonium ammonium ion. ion. In In the the C–C C–C bond-forming bond-form- ingstep, step, in which in which the the stereocenter stereocenter is is established, established, the the binding binding interaction interaction between between C31C31 andand the anhydride is mostly unaffected by the aldehyde.aldehyde. This implies that as a result ofof thethe location of the ammonium ion, only one enolateenolate face is available to attack the aldehyde, which leads leads to to the the high high enantioselectivity enantioselectivity obse observed.rved. It also It also appeared appeared from from the results the results that thethat face-selective the face-selective addition addition to the to aldehyde the aldehyde was wasprimarily primarily directed directed by the by HB the to HB the to am- the moniumammonium ion. ion. A computational A computational analysis analysis of all of available all available pathways pathways revealed revealed that the that path- the pathwayway leading leading to trans to -(R,R)trans-(R,R) was clearly was clearly favored. favored. C–C bond C–C formation bond formation is followed is followed by acyla- by tionacylation to give to the give lactone the lactone in a concerted in a concerted and general-base/hydrogen and general-base/hydrogen bonding bonding catalyzed catalyzed step. Thestep. web The of web attractive of attractive interactions interactions between between the catalyst’s the catalyst’s quinoline/quinuclidine quinoline/quinuclidine ring ringand theand anhydride the anhydride O-atoms O-atoms was found was found to be toabsent be absent in the in TSs/intermediates the TSs/intermediates leading leading to minor to stereoisomers.minor stereoisomers. The calculated The calculated ee valueee agreedvalueagreed well with well the with experimental the experimental results. results.

Figure 42. The organocatalytic asymmetric reaction of benzaldehydebenzaldehyde andand homophthalichomophthalic anhydrideanhydride [[82].82].

4. Aldol and Henry Reactions In 2017 2017 an an organocatalytic organocatalytic decarboxylative decarboxylative aldol aldol reaction reaction of β of-ketoacidsβ-ketoacids with withα-keto-α- phosphonatesketophosphonates allowed allowed the theenantios enantioselectiveelective synthesis synthesis of oftertiary tertiary α-hydroxyphosphonatesα-hydroxyphosphonates was described described by by Chowdhury Chowdhury and andcoworker coworkerss for the for first the time ﬁrst (Figure time 43) (Figure [83]. α -Hydrox-43)[83]. yphosphonatesα-Hydroxyphosphonates have been haveshown been to exhibit shown many to exhibit kinds manyof useful kinds biol ofogical useful activities, biological in- cludingactivities, in including reports by in one reports of us, by and one ofthey us, are and the they object are the of objectmuch ofresearch much research [84–86].[ 84Recent–86]. accountsRecent accounts on the synthesis on the synthesis of tertiary of α tertiary-hydroxyphosphonatesα-hydroxyphosphonates include cross include aldol cross reactions aldol atreactions low temperatures, at low temperatures, but long but reaction long reaction times are times required. are required. Up to Up this to report this report from from the Chowdhurythe Chowdhury group, group, cross cross aldol aldol reactions reactions of α of-ketophosphonatesα-ketophosphonates (79) ( 79with) with acetone acetone or ac- or etaldehydeacetaldehyde were were reported, reported, but but reactions reactions with with aromatic aromatic ketones, ketones, e.g., e.g., acetophenones, acetophenones, not. not. In this report,report, β-aryl β-ketoacids 78 were employed as surrogates of thethe acetophenoneacetophenone enolate toto ﬁllfill thisthis gap. gap. In In this this quinidine-derived quinidine-derived urea urea (C32 (C32)-catalyzed)-catalyzed process, process, the the products prod- ucts80 were 80 were obtained obtained in high in high yields yields and eeands. ees.

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Figure 43. Organocatalytic synthesis of tertiary α-hydroxyphosphonates [[83].83].

Control experiments were performed to investigate the mechanism. The reaction was thought to to proceed proceed via via the the formation formation of of an an intermediate intermediate of of type type 8181, which, which can can lose lose CO CO2 to2 yieldto yield the the desired desired product. product. 31P 31NMRP NMR studies studies of a ofreaction a reaction between between α-ketophosphonateα-ketophosphonate 79a, benzoylacetic79a, benzoylacetic acid acid78a and78a andthe catalyst the catalyst showed showed that, that, soon soon after after 78a 78aandand the thecatalyst catalyst are addedare added to a tosolution a solution with with 79a,79a a few, a few signals signals appear appear in the in thespectrum, spectrum, due due to the to the product, product, to twoto two diastereoisomers diastereoisomers of intermediate of intermediate 81 and81 and also also to dimethylphosphite to dimethylphosphite (82), ( 82due), dueto the to decompositionthe decomposition of 79a of 79a. An. Anadditional additional signal signal at at22.54 22.54 ppm, ppm, possibly possibly due due to to a a complexcomplex formed betweenbetween 79a79a andandthe the catalyst catalystC32 C32, was, was also also observed. observed. After After some some time, time, the the intensity inten- sityof the of signalthe signal due due to product to product80a increased,80a increased, while while all those all those of the of signals the signals at δ 25.46at δ 25.46 ppm ppm and and25.1 25.1 ppm ppm decreased, decreased, which which is consistent is consistent with with the mechanism the mechanism proposed. proposed. The Henry Henry or or nitroaldol nitroaldol reaction, reaction, mechanisti mechanisticallycally similar similar to tothe the aldol aldol reaction, reaction, is an- is otheranother important important tool tool for forcarbon–carbon carbon–carbon bond bond formation. formation. Several Several studies studies have have shown shown that 0 cinchonathat cinchona alkaloids alkaloids bearing bearing a hydr a hydrogenogen bonding bonding group group at at the the C-6 C-6′ positionposition can can catalyze the Henry reaction in high yields and ees [87]. [87]. The The first ﬁrst theoretical theoretical studies aiming to clarify the mode of action ofof thiourea-cinchonathiourea-cinchona alkaloid bifunctional catalysts (e.g., C33) werewere reported by by Himo Himo and and coworkers coworkers in in 2007 2007 [88]. [88 In]. the In thereaction reaction between between nitromethane nitromethane and 76a C34 benzaldehydeand benzaldehyde (76a), ( with), with simplified simpliﬁed catalyst catalyst C34, the, theresults results supported supported a mechanism a mechanism in- involving initial nitromethane deprotonation and aldehyde complexation (Figure 44a). Two volving initial nitromethane deprotonation and aldehyde complexation (Figure 44a). Two pathways with comparable energy barriers are then possible for C–C bond formation. They pathways with comparable energy barriers are then possible for C–C bond formation. differ in the way the reactants bind to the catalyst. Either nitromethide binds both to the They differ in the way the reactants bind to the catalyst. Either nitromethide binds both to quinuclidinium and one thiourea NH, while the aldehyde binds to one thiourea NH only the quinuclidinium and one thiourea NH, while the aldehyde binds to one thiourea NH (path A), or nitromethide binds to both thiourea NH hydrogens and benzaldehyde to the only (path A), or nitromethide binds to both thiourea NH hydrogens and benzaldehyde quinuclidinium unit (path B). A small preference for path A was found to exist. Experiments to the quinuclidinium unit (path B). A small preference for path A was found to exist. have shown that the results are strongly dependent on the nature of the solvent and not Experiments have shown that the results are strongly dependent on the nature of the sol- simply a polar, nonpolar distinction, often observed in some organocatalyzed reactions. vent and not simply a polar, nonpolar distinction, often observed in some organocata- This type of correlation is not possible with the Henry reaction. Ees correlate roughly with lyzed reactions. This type of correlation is not possible with the Henry reaction. Ees cor- the Lewis basicity of the solvent, so that the higher the Lewis basicity, the higher the ee. relateThis suggests roughly thatwith thethe energiesLewis basicity leading of tothe both solvent, TSs areso that similar. the higher In this the study, Lewis TSs basicity, states theleading higher to boththe ee enantiomers. This suggests were that located the energies for the twoleading pathways to both (Figure TSs are 44 similar.b); forpath In this A, study,three TS TSs rotamers states leading were found to both for eachenantiomers enantiomer, were corresponding located for the to two the differentpathways Newman (Figure 44b);projections for path for A, C–C three bond TS rotamers formation, were as found shown for in each Figure enantiomer, 44b. For pathcorresponding B, since there to the is differentbidentate Newman coordination projections between for both C–C NH bond groups formation, of the thiourea as shown and in theFigure nitro 44b. group, For path only B,one since TS isthere possible is bidentate for the formationcoordination of eachbetween enantiomer both NH ( Rgroupsand S ).of It the was thiourea found thatand the nitrolowest group, energy only TS one (TS-S) TS correspondsis possible fo tor the the formationS-product of as each observed enantiomer experimentally, (R and S). and It was the foundcalculated that energythe lowest difference energy between TS (TS-S) TS-S corresponds and TS-R to was the quite S-product small, onlyas observed 1.1 kcal experi- mol−1, mentally, and the calculated energy difference between TS-S and TS-R was quite small,

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only 1.1 kcal mol−1, which is also in agreement with the experimental observations from solventwhich is effects. also in The agreement energies with calculated the experimental for the six lowest-lying observations transition from solvent states effects. are shown The inenergies Figure calculated 44b. Slight for differences the six lowest-lying in the inte transitionraction of states the solvent are shown with in the Figure TSs 44leadingb. Slight to thedifferences S and R-enantiomers in the interaction cause of thesmall solvent differences with the in TSsenergy, leading which to the resultS and in Rthe-enantiomers changes in eecause observed. small differences in energy, which result in the changes in ee observed.

Figure 44. ((aa)) Cinchona Cinchona thiourea-catalyzed thiourea-catalyzed en enantioselectiveantioselective Henry reaction; ( b) Calculated Calculated relative relative transition transition state state energies energies for C–C bond formation. Values includeinclude solvationsolvation effectseffects [[87,88].87,88].

MoreMore recently, Otevrel and Bobal developeddeveloped a novelnovel multifunctionalmultifunctional C2-symmetric biphenyl-basedbiphenyl-based diamine-tethered bis(thiourea) organocatalyst ( C35), which was tested in thethe Henry Henry reaction reaction and and also also applied applied with with success success to to the the catalytic catalytic enantioselective enantioselective synthe- synthe- sesses of the enantiopure drug (S)-econazole and (R)-mirabegron, a late-stagelate-stage intermediateintermediate (Figure(Figure 45)45)[ [89].89]. Under optimized conditions, the catalyst provided excellent yields and eeees,s, particularly with electron-deficient electron-deficient aromatic and heterocyclic substrates, although moderatemoderate drs. Preliminary Preliminary kinetic kinetic and and spectr spectroscopicoscopic experiments were also performed to studystudy the the reaction. reaction. Among Among other other parameters, parameters, th thee effect of temperature was probed. A plot ofof temperature vs. stereoselectivity stereoselectivity of of nitroaldol 86a exhibited a linear trend intersecting ◦ atat a value ofof thethe reciprocalreciprocal inversioninversion temperaturetemperature (T(Tinvinv == −−55 °C).C). The syn diastereomers prevailed only at reaction temperatures lowerlower thanthan TTinvinv.. This This unusual unusual temperature temperature effect onon the the eeee and dr values was attributed to catalyst-mediated reversibility of the reaction at T > T Tinvinv. .On On the the contrary, contrary, temperature temperature variations variations were were less less pronounced on the formation ofof 86b,, which displayed a simple temperature effect. No No nonlinear nonlinear effects effects were were found, found, suggestingsuggesting that that the the active active form form of ofthe the catalyst catalyst is monomeric. is monomeric. Kinetic Kinetic studies studies revealed revealed first- orderfirst-order kinetics kinetics concerning concerning the themodel model aldehy aldehyde,de, 2-nitrobenzaldehyde, 2-nitrobenzaldehyde, and and the the catalyst. catalyst. SimilarSimilar experiments experiments to to determine determine the the reaction reaction order of the nitroalkane were not possible due to solubility problems and volatility. Instead, the role of nitromethane was investigated by isotopic substitution with MeNO2-d3. Proton abstraction of the nitroalkane was identified as the rate-limiting (or a partially rate-limiting) step in the overall reaction.

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Catalysts 2021, 11, 569 due to solubility problems and volatility. Instead, the role of nitromethane was investi-40 of 54 gated by isotopic substitution with MeNO2-d3. Proton abstraction of the nitroalkane was identified as the rate-limiting (or a partially rate-limiting) step in the overall reaction.

Figure 45. Asymmetric Henry reaction catalyzed by C35C35 [[89].89].

In 2017 Herrera and coworkers performed a study to test thethe accuracyaccuracy ofof differentdifferent combinations of of DFT DFT methods methods and and basis basis sets sets in in squaramide squaramide catalysis catalysis [90]. [90 The]. The Henry Henry reactionreaction between between 4-cyanobenzaldehyde 4-cyanobenzaldehyde and and nitrom nitromethaneethane was was selected selected as as a a model model reaction. reaction. This waswas aa complexcomplex reaction reaction of of about about 100 100 atoms atoms and and many many diverse diverse non-covalent non-covalent interactions. interactions.Eighteen Eighteen different different computational computational approaches approaches were compared were compared to find anto accuratefind an accurate one that onerequired that required the least the possible least amountpossible ofamount calculation of calculation time. Functional time. Functional wB97X-D wB97X-D provided pro- the videdbest results the best when results used when with used different with versionsdifferent ofversions the 6-311 of basisthe 6-311 sets. basis Highly sets. accurate Highly accuratecalculations calculations of the outcomes of the outcomes were obtained were whenobtained the methodwhen the was method tried onwas nine tried aldehydes on nine withaldehydes different with structural different characteristics. structural characterist It was alsoics. found It was that also for found relatively that largefor relatively systems, largesuch assystems, this, using such aas split-valence this, using a triple-zeta split-valence basis triple-zeta saves much basis time saves compared much time to usingcom- paredlarger basisto using sets larger sometimes basis employedsets sometimes in organocatalytic employed in studies, organocataly as, fortic example, studies, the as, TZV for example,and Def2TZV the TZV basis and set Def2TZV families. basis set families. 5. Miscellaneous Reactions Involving Anion-Binding Catalysis 5. Miscellaneous Reactions Involving Anion-Binding Catalysis Besides the synthesis of chiral lactams described by Vetticat and Seidel (Figure 37, Besides the synthesis of chiral lactams described by Vetticat and Seidel (Figure 37, Section3), other examples of anion-binding catalysis have been described [ 74]. Those whichSection do 3), not other fit in examples the categories of anion-binding covered in the catalysis previous have sections been havedescribed been grouped[74]. Those in whichthis section. do not Anion-binding fit in the categories catalysis covered by dual in the H-bond previous donors sections may take have place been via grouped different in thisactivation section. modes Anion-binding (Figure 46 catalysis): there by may dual be H-bond an association donors may of the take H-bond place via donor different to a preformedactivation modes ion pair, (Figure as in 46): A; therethere maymay bebe Brønstedan association acid co-catalysis,of the H-bond with donor the to H-bond a pre- formeddonor enhancing ion pair, as the in acidityA; there of may a weak be Brønst acided by acid stabilizing co-catalysis, its conjugate with the base, H-bond as in donor B or enhancingthey may be the anion acidity abstraction of a weak from acid a by neutral stabilizing substrate its conjugate as in C [91 base,]. Mode as in C hasB or been they usedmay beto explainanion abstraction many enantioselective from a neutral reactions, substrate butas in until C [91]. 2016 Mode it remained C has been still used a mechanism to explain poorlymany enantioselective understood. In reactions, 2016 Jacobsen but until and 2016 coworkers it remained published still a amechanism study on thepoorly amido- un- derstood.thiourea ( InC36 2016)-catalyzed Jacobsen alkylation and coworkers of racemic publishedα-chloroisochroman a study on the amido-thiourea87 with silyl ketene (C36)- catalyzedacetal 88, whichalkylation sheds of some racemic light α on-chloroisochroman this topic [92]. This 87 study with followedsilyl ketene mechanistic acetal 88, studies which performedsheds some onlight this on reaction this topic by [92]. the This group, study which followed suggested mechanistic that an studies unusual performed cooperative on thismechanism reaction was by the in operation, group, which with suggested the catalyst that resting an unusual as a dimeric cooperative aggregate mechanism under typical was inreaction operation, conditions with the (0.1 catalyst M in the resting substrate, as a dimeric 10 mol% aggregate of catalyst). under For typical the catalyst reaction to reactcon- withditions the (0.1 substrate M in the and substrate, drive the 10 rate-determining mol% of catalyst). C− CFor bond the formationcatalyst tostep, react deaggregation with the sub- wasstrate necessary. and drive This the canrate-determining limit efficiency. C Catalytic−C bond loadingsformation of step, 5–20 deaggregation mol% and long was reaction necessary.times (>24 This h) can are limit often efficiency. required byCatalytic H-bond loadings donor-catalyzed of 5–20 mol% reactions, and long and inreaction many cases,times (>24they h) have are the often limitation required of by working H-bond better donor-ca undertalyzed dilute reactions, reaction conditions and in many (≤0.1 cases, M in they the substrate). These studies aimed to help the design of more efficient catalysts.

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Catalysts 2021, 11, 569 41 of 54 have the limitation of working better under dilute reaction conditions (≤0.1 M in the substrate). These studies aimed to help the design of more efficient catalysts.

FigureFigure 46.46. ActivationActivation modesmodes inin anion-bindinganion-binding catalysiscatalysis byby dualdual H-bondH-bond donordonor catalysts:catalysts: ((AA)) BindingBind- involvinging involving pre-formed pre-formed ion pairs;ion pairs; (B) Br(Bφ) nstedBrϕnsted acid acid co-catalysis; co-catalysis; (C) ( AnionC) Anion abstraction abstraction catalysis catalysis [91 ]. [91].

Epimerization rate data alone did not allow a distinction to be made between an SN2 Epimerization rate data alone did not allow a distinction to be made between an SN2 and an SN1 mechanism. However, whereas racemization of 89 through an SN1 mechanism and an SN1 mechanism. However, whereas racemization of 89 through an SN1 mechanism should be inhibited by exogenous chloride sources, racemization via an SN2 mechanism shouldshould bebe promotedinhibited by anexogenous increased chloride concentration sources, of racemization an exogenous via chloride an SN2 mechanism nucleophile. SIRshould experiments be promoted with by the an additionincreased ofconcentration tetraoctylammonium of an exogenous chloride chloride or hydrogen nucleophile. chlo- rideSIR experiments (such that [Cl with−] =the [C36 addition]T) were of tetraoct performed.ylammonium It was foundchloride that or epimerizationhydrogen chloride was (such that [Cl−] = [C36]T) were performed. It was found that epimerization was com- completely suppressed in both cases, consistent with an SN1 mechanism for substrate racemization.pletely suppressed Ionization in both promoted cases, consistent by the catalystwith an S affordsN1 mechanism the oxocarbenium for substrate− chlorideracemi- ionzation. pair. Ionization Substrate promoted epimerization by the and catalyst alkylation affords share the oxocarbenium the same kinetic−chloride dependence ion pair. on catalystSubstrate and epimerizationα-chloroether, and which alkylation means share that thethe same two processes kinetic dependence have a common on catalyst transition- and stateα-chloroether, stoichiometry. which Comparingmeans that the two rate proc lawsesses reveals have that a common epimerization transition-state catalyzed stoi- by C36chiometry.or C37 Comparingis 101–103 timesthe rate faster laws than reveals alkylation, that epimerization which would catalyzed be needed by C36 for or alkyla- C37 is 101–103 times faster than alkylation, which would be needed for alkylation via either tion via either dynamic kinetic resolution or a stereoablative SN1 mechanism. Since the oxocarbeniumdynamic kinetic−chloride resolution ion pairor isa generatedstereoablative in the SN epimerization,1 mechanism. it Since must alsothe beoxocarbe- an inter- mediatenium−chloride in the alkylation. ion pair is Alkylationgenerated in proceeds the epimer viaization, an anion-abstraction it must also be ion-pairing an intermediate mechanism,in the asalkylation. shown in Alkylation Figure 47 ,proceeds involving via the an cooperative anion-abstraction action ion-pairing of two catalyst mechanism, molecules. as Theshown racemization in Figure 47, iscatalyst-mediated involving the cooperative and Cl− actioninhibited. of two catalyst molecules. The race- mizationCatalyst is catalyst-mediated aggregation is counterproductive. and Cl- inhibited. In further studies by the Jacobsen group, a linkageCatalyst was introduced aggregation between is counterproductive. two catalyst monomers, In further aimingstudies toby improve the Jacobsen stabilization group, ofa thelinkage dominant was introduced TS complex between and hence two to catalyst improve monomers, catalytic activityaiming [to93 ].improve Although stabiliza- prelim- inarytion of DFT the analysisdominant did TS not complex distinguish and hence whether to improve catalyst catalytic activation activity proceeds [93]. by Although a 4H- or apreliminary 2H-Cl−-binding DFT analysis geometry, did i.e., not via distinguish I or II (Figure whether 48), catalyst in the solid-state, activation aproceeds 4H-geometry by a was4H- observed,or a 2H-Cl a--binding fact, which geometry, guided i.e., the via choices I or II of (Figure structural 48), in changes the solid-state, [90,91]. Aa 4H-ge- methyl substituent,ometry was shownobserved, previously a fact, which to minimize guided competingthe choices reactionof structural pathways changes and [90,91]. improve A reactivitymethyl substituent, and the ees, shown was introduced previously [ 94to ].mi Thenimize bisthioureas competing were reaction also linked pathways in a wayand im- that disfavoredprove reactivity aggregation and the while ees, was still introduced resembling [94]. the structuresThe bisthioureas of theuntethered were also linked monomers. in a Ofway all that the catalystsdisfavored prepared, aggregation the bestwhile results still resembling were obtained the structures with ent- C38,of thewhich, untethered when applied to the enantioselective alkylation of racemic isochroman 87 (Figure 47a), afforded the product in 96% yield, 92% ee, in 3 h at −78 ◦C with a catalytic load of 0.1 mol% only,

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Catalysts 2021, 11, 569 42 of 54 monomers. Of all the catalysts prepared, the best results were obtained with ent-C38, monomers. which,Of all whenthe catalysts applied prepared, to the enantioselective the best results alkylation were obtained of racemic with isochroman ent-C38, 87 (Figure which, when47a), applied afforded to the the enantioselective product in 96% alkylationyield, 92% of ee ,racemic in 3 h at isochroman –78 °C with 87 a catalytic(Figure load of 0.1 47a), affordedi.e.,mol% the with only,product 100 i.e., times in with 96% lower 100 yield, catalysttimes 92% lower loading,ee, in catalyst 3 h 8at times –78 loading, °C shorter with 8 timesa reaction catalytic shorter time load reaction and of a0.1 5 timestime and more a times mol% only,concentrated5 i.e., times with more 100 solution.concentratedtimes lower catalyst solution. loading, 8 shorter reaction time and a 5 times more concentrated solution.

Figure 47. Enantioselective α-chloroisochroman alkylationalkylation viavia anion-abstractionanion-abstraction catalysiscatalysis ((aa)) andand itsits mechanismmechanism ((bb)[) [91].91]. Figure 47. Enantioselective α-chloroisochroman alkylation via anion-abstraction catalysis (a) and its mechanism (b) [91].

Figure 48. Anion-abstraction catalysis via the cooperative action of two amido-thioureas and catalyst C38 [93]. Figure 48. Anion-abstractionFigure 48. Anion-abstraction catalysis via catalysisthe cooperative via the action cooperative of two action amido-thioureas of two amido-thioureas and catalyst andC38 catalyst[93]. C38 [93]. The kinetic resolution of racemic amines via acylation and other methods is an im- The kinetic resolution of racemic amines via acylation and other methods is an im- The kineticportant resolution means to of obtain racemic chiral amines amines via acylationfor various and applications. other methods The isutilization an im- of small- portant meansportant to obtain means chiral to obtain amines chiral for aminesvarious forapplications. various applications. The utilization The of utilization small- of small- molecule catalysts for resolution is still challenging, in contrast to enzymatic methods, and only recently have solutions started to appear, which nevertheless, are not as advanced as

Catalysts 2021, 11, 569 43 of 54

the corresponding methods for kinetic resolution of alcohols [95,96]. The kinetic resolution of various classes of amines has been achieved by the Seidel group, with asymmetric nucleophilic catalysis, using an in situ generated chiral acylating reagent [97]. Three components are involved: 4-dimethylaminopyridine (DMAP, a nucleophilic catalyst), an achiral acylating reagent (91), and a chiral anion receptor/hydrogen bonding (HB) catalyst (Figure 49). DMAP, which exists in equilibrium with the corresponding acylpyridinium salt (e.g., ion- pair I), is converted into a chiral species through the interaction of the counteranion with a chiral anion receptor, e.g., a thiourea catalyst, forming ion-pair II. This has an impact on the DMAP/acylpyridinium salt equilibrium. Since ion-pair II is more electrophilic and/or soluble than ion-pair I, reactions with amines should occur more readily with ion-pair II than with ion-pair I, a fact that has been applied in the kinetic resolution of amines. In a recent study, the Seidel group investigated the role of ion-pair II and other reaction components in the enantioselectivity of the kinetic resolution shown in Figure 49a as a model reaction [90]. Computational studies at the M06/6-31G(d,p) level of theory, including solvent modeling utilizing a polarized continuum model, provided new information on the nature of the ion pair and revealed a range of important secondary interactions responsible for enantiodis- crimination. Catalyst C39 was found to be the most efficient. Toluene was the best solvent, and it has been generally observed to be a privileged solvent for enantioselective reactions preceding via catalyst−substrate ion pairing, which agrees with the fact that the nature of the ion pair is influenced by the reaction medium, with nonpolar solvents favoring tight (contact) ion pairs and the more polar ones leading to solvent-shared or solvent-separated ion pairs. NMR studies at different concentrations suggested that the catalyst is present in a nonaggregated form at the concentrations used for catalysis. A 1:1 binding stoichiometry of benzoate by the catalyst was inferred by titration studies with tetrabutylammonium benzoate (TBAB) monitored by NMR and UV-vis titration. This information confirms the idea that the key ion pair involved in catalysis consists of a catalyst with a thiourea subunit binding to the benzoate counteranion of the DMAP-derived N-benzoylpyridinium salt. Deprotonation of the catalyst and involvement of a neutral acylating agent in the reaction could be ruled out by comparison of NMR data with spectra obtained when the catalyst was treated with different bases. Evaluation of two diastereomeric quaternary complexes helped to rationalize the experimental observation that the R-enantiomer of 92 is benzoylated preferentially over the corresponding S-enantiomer. In the case of both the bis-thiourea C39 and the amide-thiourea catalyst C40, dual intramolecular hydrogen bonding to the sulfur atom of a thiourea subunit was found to occur, and the result was activation of this moiety for anion binding since the two N−H bonds become more acidic. A recent example of anion binding catalysis involves the nucleophilic addition of N-tert-butylhydrazones to isoquinolinium ions (from 95) (Figure 50). This reaction, which leads to the dearomatization of the isoquinoline, proceeded in a highly enantioselective manner in the presence of bifunctional thiourea-based catalyst C41. Two chiral centers were formed in the reaction, and the diastereoselectivity was >20:1 in all cases studied [98]. If the reaction proceeds by anion-binding catalysis, it is expected that the geometry, size and coordination ability of the counteranion should have a marked effect on the results. As a test, anion exchanges (Cl!TFA, BF4, BARF) were performed before the addition of hydrazone 97a. Poorer reactivities and ees were observed in all cases, as expected when the spherical, small chloride anion was replaced by the new anions. In addition, an experiment with pyrrolidine-derived hydrazone 97b yielded low amounts of product, but racemic, which confirms that the chloride-binding ability of the hydrazone is essential. Further, the evidence available pointed to the formation of a 1:1 complex: the absence of a significant nonlinear effect suggests that a 2:1 complex may not be operating, information, which was also confirmed by the method of continuous variation, for which the data obtained fits with a 1:1 complex. Catalysts 2021, 11, 569 44 of 54 Catalysts 2021, 11, x FOR PEER REVIEW 45 of 55 Catalysts 2021, 11, x FOR PEER REVIEW 45 of 55

Figure 49. (a) The concept of anion binding and the formation of a chiral ion pair in an asymmetric acyl transfer reaction; Figure 49. (a) The concept of anion binding and the formation of a chiral ion pair in an asymmetric acyl transfer reaction; (b) Kinetic resolution of amines by a dual-catalysis anion-binding approach [95]. ((bb)) KineticKinetic resolutionresolution ofof aminesamines byby aa dual-catalysisdual-catalysis anion-bindinganion-binding approachapproach [ [95].95].

Figure 50. Asymmetric addition of N-tert-butylhydrazones to isoquinolinium ions [98]. Figure 50. Asymmetric addition of N--terttert-butylhydrazones-butylhydrazones toto isoquinoliniumisoquinolinium ionsions [[98].98]. Computational studies revealed that in the most favored TS, the azomethine carbon Computational studies revealed that in thethe most favored TS,TS, thethe azomethineazomethine carboncarbon approaches the Si face of the isoquinolinium C(1)=N bond (Figure 51A). A difference of approaches the SiSi faceface of of the the isoquinolinium isoquinolinium C(1)=N C(1)=N bond bond (Figure (Figure 51A). 51A). A Adifference difference of 10.5 kcal mol−1 was−1 found concerning the most stable transition structure leading to the R of10.5 10.5 kcal kcal mol mol−1 was wasfound found concerning concerning the most the most stable stable transition transition structure structure leading leading to theto R enantiomer of 97c. NCI analysis of the lowest energy transition structure showed the pres- theenantiomerR enantiomer of 97c. ofNCI97c analysis. NCI analysis of the lowest of the energy lowest tr energyansition transition structure structure showed the showed presence of stabilizing Cl–π, CH–π and π–π interactions [99]. A new tool for NCI quantitative theence presence of stabilizing of stabilizing Cl–π, CH– Cl–π andπ, CH– π–ππ interactionsand π–π interactions [99]. A new [99 tool]. Afor new NCI tool quantitative for NCI analysis showed that noncovalent interactions of the chloride ion with the NH’s of the quantitativeanalysis showed analysis that showednoncovalent that noncovalentinteractions of interactions the chloride of theion chloridewith the ionNH’s with of thethe thiourea moiety and hydrazone, as well as with the azomethine hydrogen atom, are NH’sthiourea of themoiety thiourea and moietyhydrazone, and hydrazone,as well as with as well the as azomethine with the azomethine hydrogen hydrogenatom, are stronger in the preferred TS (Figure 51B, bottom square). These interactions fix the orien- atom,stronger are in stronger the preferred in the preferredTS (Figure TS 51B, (Figure bottom 51 B,square). bottom These square). interactions These interactions fix the orien- ﬁx tation of the reagents in a highly ordered [120]-Cl-hydrazone complex as the key interme- thetation orientation of the reagents of the reagentsin a highly in ordered a highly [ ordered120]-Cl-hydrazone [120]-Cl-hydrazone complex complexas the key as interme- the key diate, from which there is the preferential approach of the azomethine carbon to the Si intermediate,diate, from which from there which is therethe preferential is the preferential approach approach of the azomethi of the azomethinene carbon carbon to the toSi face of the isoquinolinium C(1)=N bond. This mode of reaction is responsible for the high theface Si of face the ofisoquinolinium the isoquinolinium C(1)=N C(1)=N bond. bond.This mode This modeof reaction of reaction is responsible is responsible for the for high the stereoselectivity observed, as well as the S,S absolute configuration of the product. highstereoselectivity stereoselectivity observed, observed, as well as as well the as S,S the absoluteS,S absolute configuration conﬁguration of the of product. the product.

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FigureFigure 51.51. (A(A) )TS TS structure structure and and (B) NCI (B) NCITS analysis TS analysis of the ofasymmetric the asymmetric addition addition of N-tert-butylhy- of N-tert- butylhydrazonesdrazones to isoquinolinium to isoquinolinium ions. Reprinted ions. Reprinted and adapted and from adapted Angewandte from Angewandte Chemie International Chemie Inter- Edition with permission from Wiley [98]. national Edition with permission from Wiley [98].

6.6. Miscellaneous Miscellaneous EnantioselectiveEnantioselective transfertransfer hydrogenationhydrogenation isis anotheranother reactionreaction that that has has benefited benefited from from developingdeveloping bifunctional bifunctional dual dual hydrogen hydrogen donor dono catalystsr catalysts [100 ].[100]. The reductionThe reduction of nitroalkenes of nitroal- iskenes an example. is an example. In 2015 In Benaglia 2015 Benaglia and coworkers and coworkers developed developed a procedure a procedure for the reductionfor the re- ofductionβ-trifluoromethyl-substituted of β-trifluoromethyl-substituted nitroalkenes nitroalkenes99 with Hantzsch99 with Hantzsch esters 100 estersas hydrogen 100 as hy- sourcesdrogen (Figuresources 52 (Figure)[101]. 52) A multifunctional[101]. A multifunctional thiourea-based thiourea-based (S)-valine (S)-valine derivative derivative (C42a) was(C42a found) was to found be a to good be a catalyst, good catalyst, affording affording very good very yieldsgood yields and ee ands of ee aminess of amines in the in casethe case of trisubstituted of trisubstituted olefins. olefins. Tetrasubstituted Tetrasubstituted olefins olefins reacted reacted with lowerwith lower stereoselectivity. stereoselec- Computationaltivity. Computational studies studies were performed were performed to investigate to investigate the reaction the reaction further. further. The transition The tran- statessition leadingstates leading to the to formation the formation of both of both (R)- ( andR)- and (S)- 101a(S)-101a(101 (,R1011, R=1 Ph),= Ph), TS- TS-RRand and TS- TS- SS,, for for the the reaction reaction with with catalyst catalystC42b C42b,, located located at at a a B3LYP/6-31G(d) B3LYP/6-31G(d) level level of of theory theory are are shownshown in in Figure Figure 52 52;; finer finer electronic electronic energies energies were were obtained obtained increasing increasing the the basic basic setup setup to to 6/311+(2df,2pd)6/311+(2df,2pd) with twotwo differentdifferent functionals:functionals: B3LYPB3LYP andand M062X. M062X. A A methyl-substituted methyl-substituted HantzschHantzsch ester ester was was used used instead instead of of100 100for for simplification. simplification. A A preliminary preliminary conformational conformational analysisanalysis revealedrevealed aa very rigid rigid structure, structure, and and only only three three conformations conformations were were found. found. It was It wasassumed assumed that thatthere there was wasthe coordination the coordination of the of nitro the nitrogroup group to the to thiourea the thiourea moiety moiety and of

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theand Hantzsch of the Hantzsch ester NH ester group NH to the group catalyst to the carboxyamide catalyst carboxyamide group. At a group.first inspection, At a ﬁrst it mayinspection, be seen it that may the be seenpyrrole that moiety the pyrrole plays moiety an important plays an role. important In TS-S, role. there In is TS- a S,repulsivethere is interactiona repulsive interactionbetween the between pyrrole the ring pyrrole and phenyl ring and group phenyl of the group nitroalkene, of the nitroalkene, which disfavors which thedisfavors formation the formationof the S enantiomer. of the S enantiomer. In addition, In with addition, the substrate with the coordinated substrate coordinated to the thiourea,to the the thiourea, nitroolefin the nitrooleﬁn C2 electrophilic C2 electrophilic carbon atom carbon in TS- atomS is incloser TS-S tois the closer bulky to thediamino- bulky cyclohexanediaminocyclohexane moiety than moiety in TS- thanR. This in TS- forcesR. This the forces Hantszch the Hantszch ester, in releasing ester, in releasing the hydride, the tohydride, a hindered to ahindered area with area the withester thegroup ester repu grouplsively repulsively interacts interacts with the with 2,5-methyl the 2,5-methyl pyrrole pyrrolesubstituents, substituents, thus further thus favoring further favoring TS-R. TS-R.

Figure 52. Enantioselective organocatalytic reduction ofof ββ-triﬂuoromethyl-trifluoromethyl nitroalkenesnitroalkenes 9999 [[101].101].

Qiu, Zhao Zhao and and coworkers coworkers described described a Morita–Baylis–Hillman a Morita–Baylis–Hillman reaction reaction of N of-alkylN-alkyl isa- tinsisatins 102102 withwith acrylates acrylates 103103 catalyzedcatalyzed by by aa bifunction bifunctionalal phosphine–squaramide phosphine–squaramide ( C43) inin 2015 (Figure 5353))[ [102].102]. The catalyst was part of a series synthesized from inexpensive and commercially available available ββ-amino-amino alcohols. alcohols. The The products, products, ch chiraliral 3-substituted 3-substituted 3-hydroxy-2- 3-hydroxy- oxindoles2-oxindoles (104 (104) bearing) bearing an anexocyclic exocyclic double double bond, bond, were were obtained obtained in very in very high high yields yields and eeands andees the and reaction the reaction mechanism mechanism was probed was probed by means by means by 31P by NMR,31P NMR, ESI-MS ESI-MS and KIE and stud- KIE ies.studies. KIE studies KIE studies with with N-methylisatinN-methylisatin and andbutyl butyl acrylate acrylate revealed revealed a carbon a carbon isotope isotope effect effect on 13 theon the3-carbon 3-carbon when when the the13C ratioC ratio of recovered of recovered N-methylN-methyl isatin isatin was was compared compared to that to that of the of originalthe original sample sample (C3 (C3 = 1.021). = 1.021). This This suggests suggests that that C–C C–C bond-formation bond-formation is is the the rate-limiting step of the MBH reaction. A mechanism was proposed,proposed, as shown in Figure 5353,, with thethe support of MS since some of the intermediates could be detected.detected. The Pictet–Spengler reaction reaction allows allows the the effi efﬁcientcient construction construction of ofimportant important heterocy- hetero- clescycles of ofinterest interest for forthe thepharmaceutical pharmaceutical industry industry.. In nature, In nature, this reaction this reaction gives givesrise to rise mon- to oterpenemonoterpene indole indole alkaloids, alkaloids, as well as well as many as many secondary secondary metabolites. metabolites. The The reaction reaction mecha- mech- nismanism was was investigated investigated by by Jacobsen Jacobsen and and coworkers coworkers recently recently [103]. [103 Initially,]. Initially, there there is a con- is a β densationcondensation of a ofβ-arylethylamine a -arylethylamine with withan aldehyde, an aldehyde, C–C bond C–C bondformation formation by addition by addition of the pendantof the pendant arene to arene the resultant to the resultant iminium iminium ion and ion subsequent and subsequent rearomatization rearomatization (via depro- (via − tonation).deprotonation). In tryptamine In tryptamine derivatives, derivatives, the C− theC bond-formation C C bond-formation may take may place take by place direct by electrophilicdirect electrophilic aromatic aromatic substitution substitution at C2 or at by C2 alkylation or by alkylation at the more at the nucleophilic more nucleophilic C3 po- C3 position, followed by C−C migration. Although both pathways had been shown to be sition, followed by C−C migration. Although both pathways had been shown to be viable, viable, some questions remained unknown, such as how rearomatization occurred in the some questions remained unknown, such as how rearomatization occurred in the nonpo- nonpolar media commonly used in asymmetric synthesis, and the studies by the Jacobsen lar media commonly used in asymmetric synthesis, and the studies by the Jacobsen group group aimed to clarify those issues. Based on a system previously shown by the group aimed to clarify those issues. Based on a system previously shown by the group to have to have broad applicability, with 105 and 76, and to afford chiral tetrahydro-β-carboline broad applicability, with 105 and 76, and to afford chiral tetrahydro-β-carboline products products 106 with high ees thanks to the cooperative action between a bifunctional chiral 106 with high ees thanks to the cooperative action between a bifunctional chiral thioureathiourea-based catalyst (C44) and weak achiral Brønsted acids, such as benzoic acids, based catalyst (C44) and weak achiral Brønsted acids, such as benzoic acids, new studies

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new studies were undertaken (Figure 54)[104]. It was found by applying kinetic studies, were undertakenisotope (Figure effects, 54) structure [104]. It− wasenantioselectivity found by applying relationships, kinetic studies, and computational isotope ef- analyses fects, structurethat− rearomatizationenantioselectivity (the relationships, deprotonation) and is computational the rate- and enantioselectivity-determining analyses that re- aromatizationstep. (the The deprotonation) indole N-H was is foundthe rate- to beand important enantioselectivity-determining for enantioinduction since step. the reaction The indole ofN-H a methylated was found substrateto be important yielded for a nearlyenantioinduction racemic product. since the In addition,reaction of it a was also ob- methylated servedsubstrate that yielded the co-catalysts a nearly racemic play key product. roles in In several addition, steps it was leading also upobserved to and, including that the co-catalyststhe deprotonation play key roles step. in Coordination several steps to leading the thiourea up to and, increases including the acidity the depro- of benzoic acid tonation step.leading Coordination to substrate to the protonation. thiourea increases Anion-binding the acidity to of the benzoic conjugate acid base leading helps to to stabilize β substrate protonation.the pentahydro- Anion-bi-carboliniumnding to the ionconjugate intermediate. base helps These to stabilize interactions the pentahy- contribute to rate π···π − ···π dro-β-carboliniumacceleration. ion intermediate. Enantiodifferentiation These interactio is duens tocontribute differential to rate acceleration.and C H En-interactions in the TSs leading to the two enantiomers, which are organized by hydrogen-bonding antiodifferentiation is due to differential π···π and C−H···π interactions in the TSs leading interactions. On the whole, catalyst C44 displays many of the features of enzymatic to the two enantiomers, which are organized by hydrogen-bonding interactions. On the Pictet−Spengler catalysts. whole, catalyst C44 displays many of the features of enzymatic Pictet−Spengler catalysts.

Figure 53. EnantioselectiveFigure 53. Enantioselective Morita–Baylis–Hillman Morita–Baylis–Hillman reaction of N reaction-alkyl isatins of N-alkyl with isatins acrylates with and acrylates the mechanism and proposed [102]. the mechanism proposed [102].

In 2018 Zhong and coworkers did a related study on a cinchona alkaloid squaramide- catalyzed asymmetric Pictet–Spengler reaction [105]. DFT calculations were also performed to clarify the reaction mechanism. The products were obtained with very high yields and moderate to very high ees when quinidine-derived squaramide catalyst C44 was employed to promote the reaction. In this process, there was no need for the addition

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Catalysts 2021, 11, 569 of a co-acid catalyst. The ees were found to be highly dependent on the nature of the alde- 48 of 54 hyde used. They were as high as 99%, but generally, when a 2- or 4-electron-withdrawing substituent was present in an aryl aldehyde, the ees were low.

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of a co-acid catalyst. The ees were found to be highly dependent on the nature of the aldehyde used. They were as high as 99%, but generally, when a 2- or 4-electron-withdrawing substituent was present in an aryl aldehyde, the ees were low.

FigureFigure 54. EnantioselectiveEnantioselective Pictet–Spengler Pictet–Spengler reaction reaction catalyzed catalyzed by C44 by [103,104].C44 [103 ,104].

BifunctionalIn 2018 Zhong dialkyl and sulfide coworkers catalysts did are a related still rare. study However, on a cinchonain 2018 Yamanaka, alkaloid squaramide-Shi- catalyzedrakawa and asymmetric coworkers described Pictet–Spengler the synthesis reaction of some [105 ].novel DFT catalysts calculations with these were features also performed tothat clarify could the promote reaction regio-, mechanism. diastereo-, Theand productsenantioselective were obtainedbromolactonization with very of high 107 yieldsto and moderateyield compounds to very 109 high [106].ees whenC45 was quinidine-derived the best. The presence squaramide of the urea catalyst functionalityC44 was was employed found to be critical since an analogous catalyst bearing a methyl group instead of SBu to promote the reaction. In this process, there was no need for the addition of a co-acid afforded racemic product only. Hence, was the nature of the brominating agent 108. The catalyst.results for The a fewees regents were found 108 tried to be are highly shown dependent in Figure 55. on DFT the calculations nature of the were aldehyde per- used. Theyformed were to provide as high some as 99%, insight but generally,into the orig whenin of a stereoselectivity. 2- or 4-electron-withdrawing An associative substituentTS

wasmodel present involving in an monocoordinated aryl aldehyde, thesuccinimideees were anion low. fitted best. The structures of the Figure 54. Enantioselective Pictet–Spengler reaction catalyzed by C44 [103,104]. mostBifunctional promising TS dialkylmodels are sulfide shown catalysts in Figure are 56. stillA 4.3 rare. kcal mol However,−1 difference in 2018between Yamanaka, ShirakawaTSmajor and TS andminor coworkersagrees with the described experimental the synthesisresults. The of succinimide some novel anion catalysts is found with to these Bifunctional dialkyl sulfide catalysts are still rare. However, in 2018 Yamanaka, Shi- featuresbe coordinated that could with promoteboth the urea regio-, and diastereo-, the sulfide and moieties enantioselective in TSmajor, but bromolactonization only with the of rakawa and coworkers described the synthesis of some novel catalysts with these features urea moiety in TSminor, and additional NH/π interaction between a portion of the NH res- 107thatto could yield promote compounds regio-,109 diastereo-,[106]. C45 andwas enantioselective the best. The bromolactonization presence of the urea of 107 functionality to idue of the urea moiety and the naphthyl moiety in TSmajor account for the higher stability wasyield found compounds to be 109 critical [106]. since C45 was an analogousthe best. The catalyst presence bearing of the urea a methyl functionality group was instead of obtained. SBufound afforded to be critical racemic since product an analogous only. Hence,catalyst wasbearing the a nature methyl of group the brominating instead of SBu agent 108. Theafforded results racemic for aproduct few regents only. Hence,108 tried was arethe nature shown of in the Figure brominating 55. DFT agent calculations 108. The were performedresults for a to few provide regents some 108 tried insight are intoshown the in origin Figure of 55. stereoselectivity. DFT calculations Anwere associative per- TS modelformed involvingto provide monocoordinatedsome insight into the succinimide origin of stereoselectivity. anion fitted best. An Theassociative structures TS of the mostmodel promising involving monocoordinated TS models are shown succinimide in Figure anion 56 fitted. A 4.3 best. kcal The mol structures−1 difference of the between most promising TS models are shown in Figure 56. A 4.3 kcal mol−1 difference between TSmajor and TSminor agrees with the experimental results. The succinimide anion is found TSmajor and TSminor agrees with the experimental results. The succinimide anion is found to to be coordinated with both the urea and the sulfide moieties in TSmajor, but only with be coordinated with both the urea and the sulfide moieties in TSmajor, but only with the the urea moiety in TSminor, and additional NH/π interaction between a portion of the urea moiety in TSminor, and additional NH/π interaction between a portion of the NH res- NH residue of the urea moiety and the naphthyl moiety in TSmajor account for the higher idue of the urea moiety and the naphthyl moiety in TSmajor account for the higher stability stabilityobtained. obtained.

Figure 55. Synthesis of 3,4-dihydroisocoumarin 109 via an asymmetric bromolactonization reaction [106].

FigureFigure 55. SynthesisSynthesis of 3,4-dihydroisocoumarin of 3,4-dihydroisocoumarin 109 via109 an asymmetricvia an asymmetric bromolactonization bromolactonization reac- reac- tion [106]. tion [106].

Catalysts 2021, 11, 569 49 of 54 Catalysts 2021, 11, x FOR PEER REVIEW 50 of 55

Figure 56. Asymmetric bromolactonization of alkenes 107 catalyzed by a urea-sulfide urea-sulﬁde bifunctional catalyst. 3D structures −1 −1 and the the relative relative Gibbs Gibbs free free energies energies (kcal (kcal mol mol) of) TS ofmajor TSmajor (a) and(a) TS andminor TS (bminor). Bond(b). lengths Bond lengthsare in Å. are Reprinted in Å. Reprinted and adapted and fromadapted Chemistry—A from Chemistry—A European European Journal with Journal permission with permission from Wiley from [106]. Wiley [106].

AA recent development in this field ﬁeld is using multivariate linear regression analysis to helphelp the the design design of of new new catalysts. catalysts. One One of th ofese these works works was was recently recently published published by Werth by Werth and Sigmanand Sigman [107]. [ 107By ].connecting By connecting catalyst catalyst and substrate and substrate structural structural features, features, the proposed the proposed transitiontransition states states and the and noncovalent the noncovalent interactions interactions responsible responsible for asymmetric for asymmetric induction, induction, using anusing iterative an iterative statistical statistical modeling modeling process, process, this research this research aimed to aimed provide to provide a basis for a basis extrap- for olationextrapolation to new to reactions new reactions and/or and/or catalysts catalysts so that somore that accurate more accurate predictions predictions could be could made be inmade future in futuredevelopments developments rather ratherthan utilizing than utilizing a totally a totally empirical empirical approach. approach.

7.7. Conclusions Conclusions DualDual H-bond donor bifunctionalbifunctional catalystscatalysts havehave become become in in recent recent years years a a very very popular popu- and efﬁcient means to perform both new and old reactions in a highly stereoselective lar and efficient means to perform both new and old reactions in a highly stereoselective manner. Understanding the mechanisms of these reactions and the origin of stereoinduc- manner. Understanding the mechanisms of these reactions and the origin of stereoinduction can help the rational development of new powerful catalysts for future applications. tion can help the rational development of new powerful catalysts for future applications. Computational tools and DFT calculations have helped to elucidate mechanisms and reveal Computational tools and DFT calculations have helped to elucidate mechanisms and re- nonbonding interactions, which are responsible for the stabilization of transition states veal nonbonding interactions, which are responsible for the stabilization of transition and selectivity. Additional studies, such as the determination of acidity scales and kinetic states and selectivity. Additional studies, such as the determination of acidity scales and isotopic effects, have had important contributions too. Catalytic loadings are becoming kinetic isotopic effects, have had important contributions too. Catalytic loadings are be- lower, with successful transformations being achieved with even less than 1 mol% of cata- coming lower, with successful transformations being achieved with even less than 1 mol% lysts of interest for large-scale applications. Given the easy-to-assemble modular nature of catalysts of interest for large-scale applications. Given the easy-to-assemble modular of these catalysts, the large number of reactions that they have made possible with high naturestereoselectivities, of these catalysts, and the the mild large reaction number conditions of reactions under that they which have they made operate, possible a bright with highfuture stereoselectivities, is expected for further and the developments mild reaction in this conditions area. under which they operate, a bright future is expected for further developments in this area. Author Contributions: All authors contributed to this work. All authors have read and agreed to Authorthe published Contributions: version of All the authors manuscript. contributed to this work. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Funding: This research received no external funding. Acknowledgments: This work was supported by Fundação para a Ciência e a Tecnologia (FCT), Acknowledgments:Portugal, in the form This of project work UIDB/00100/2020 was supported by of Fundação Centro de para Química a Ciência Estrutural e a Tecnologia and by the RUDN(FCT), Portugal, in the form of project UIDB/00100/2020 of Centro de Química Estrutural and by the RUDN

Catalysts 2021, 11, 569 50 of 54

University Strategic Academic Leadership Program. Furthermore, the Deutsche Forschungsgemein- schaft (DFG) is acknowledged. Conﬂicts of Interest: The authors declare that there are no conﬂicts of interest.

References 1. Zhao, B.-L.; Li, J.-H.; Du, D.-M. Squaramide-catalyzed asymmetric reactions. Chem. Rec. 2017, 17, 994–1018. [CrossRef] 2. Parvin, T.; Yadava, R.; Choudhurym, L.H. Recent applications of thiourea-based organocatalysts in asymmetric multicomponent reactions (AMCRs). Org. Biomol. Chem. 2020, 18, 5513–5532. [CrossRef][PubMed] 3. Limnios, D.; Kokotos, C.G. Ureas and thioureas as asymmetric organocatalysts. In Sustainable Catalysis: Without Metals or Other Endangered Elements, Part 2; North, M., Ed.; The Royal Society of Chemistry: London, UK, 2016; pp. 196–255. 4. Xiang, S.H.; Tan, B. Advances in asymmetric organocatalysis over the last 10 years. Nat. Commun. 2020, 11, 3786. [CrossRef] 5. Ni, X.; Li, X.; Wang, Z.; Cheng, J.-P. Squaramide equilibrium acidities in DMSO. Org. Lett. 2014, 16, 1786–1789. [CrossRef] [PubMed] 6. Storer, R.I.; Aciro, C.; Jones, L.H. Squaramides: Physical properties, synthesis and applications. Chem. Soc. Rev. 2011, 40, 2330–2346. [CrossRef][PubMed] 7. Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K.A. Squaramides: Bridging from molecular recognition to bifunctional organocatalysis. Chem. Eur. J. 2011, 17, 6890–6899. [CrossRef] 8. Li, Z.; Li, X.; Cheng, J.-P. Recent progress in equilibrium acidity studies of organocatalysts. Synlett 2019, 30, 1940–1949. [CrossRef] 9. Li, X.; Deng, H.; Zhang, B.; Li, J.; Zhang, L.; Luo, S.; Cheng, J.-P. Physical organic study of structure–activity–enantioselectivity relationships in asymmetric bifunctional thiourea catalysis: Hints for the design of new organocatalysts. Chem. Eur. J. 2010, 16, 450–455. [CrossRef] 10. Jakab, G.; Tancon, C.; Zhang, Z.; Lippert, K.M.; Schreiner, P.R. (Thio)urea organocatalyst equilibrium acidities in DMSO. Org. Lett. 2012, 14, 1724–1727. [CrossRef][PubMed] 11. Lu, T.; Wheeler, S.E. Origin of the superior performance of (thio)squaramides over (thio)ureas in organocatalysis. Chem. Eur. J. 2013, 19, 15141–15147. [CrossRef] 12. Malerich, J.P.; Hagihara, K.; Rawal, V.H. Chiral squaramide derivatives are excellent hydrogen bond donor catalysts. J. Am. Chem. Soc. 2008, 130, 14416–14417. [CrossRef] 13. Žabka, M.; Šebesta, R. Experimental and theoretical studies in hydrogen-bonding organocatalysis. Molecules 2015, 20, 15500–15524. [CrossRef] 14. Faisca Phillips, A.M. Organocatalytic asymmetric nitro-Michael reactions. Curr. Org. Synth. 2016, 13, 687–725. [CrossRef] 15. Alonso, D.A.; Baeza, A.; Chinchilla, R.; Gómez, C.; Guillena, G.; Pastor, I.M.; Ramón, D.J. Recent advances in asymmetric organocatalyzed conjugate additions to nitroalkenes. Molecules 2017, 22, 895. [CrossRef][PubMed] 16. Okino, T.; Hoashi, Y.; Takemoto, Y. Enantioselective Michael reaction of malonates to nitroolefins catalyzed by bifunctional organocatalysts. J. Am. Chem. Soc. 2003, 125, 12672–12673. [CrossRef][PubMed] 17. Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. Enantio- and diastereoselective Michael reaction of 1,3-dicarbonyl compounds to nitroolefins catalyzed by a bifunctional thiourea. J. Am. Chem. Soc. 2005, 127, 119–125. [CrossRef] 18. Zhu, R.; Zhang, D.; Wu, J.; Liu, C. Theoretical study of the bifunctional-urea catalyzed Michael reaction of 1,3-dicarbonyl compounds and nitroolefins: Reaction mechanism and enantioselectivity. Tetrahedron Asymmetry 2006, 17, 1611–1616. [CrossRef] 19. Hamza, A.; Schubert, G.; Soós, T.; Pápai, I. Theoretical studies on the bifunctionality of chiral thiourea-based organocatalysts: competing routes to C−C bond formation. J. Am. Chem. Soc. 2006, 128, 13151–13160. [CrossRef][PubMed] 20. Kreienborgm, N.M.; Pollok, C.H.; Merten, C. Towards an observation of active conformations in asymmetric catalysis: Interaction- induced conformational preferences of a chiral thiourea model compound. Chem. Eur. J. 2016, 22, 12455–12463. [CrossRef] [PubMed] 21. Supady, A.; Hecht, S.; Baldauf, C. About underappreciated yet active conformations of thiourea organocatalysts. Org. Lett. 2017, 19, 4199–4202. [CrossRef] 22. Luchini, G.; Ascough, D.M.H.; Alegre-Requena, J.V.; Gouverneur, V.; Paton, R.S. Data-mining the diaryl(thio)urea conformational landscape: Understanding the contrasting behavior of ureas and thioureas with quantum chemistry. Tetrahedron 2019, 75, 697–702. [CrossRef] 23. Neuvonen, A.J.; Noutsias, D.; Topić,F.; Rissanen, K.; Földes, T.; Pápai, I.; Pihko, P.M. Dynamic refolding of ion-pair catalysts in response to different anions. J. Org. Chem. 2019, 84, 15009–15019. [CrossRef][PubMed] 24. Zhu, J.-L.; Zhang, Y.; Liu, C.; Zheng, A.-M.; Wang, W. Mechanistic insights on organocatalytic enantioselective decarboxylative protonation by epicinchona-thiourea hybrid derivatives. J. Org. Chem. 2012, 77, 9813–9825. [CrossRef] 25. Izzo, J.A.; Myshchuk, Y.; Hirschi, J.S.; Vetticatt, M.J. Transition state analysis of an enantioselective Michael addition by a bifunctional thiourea organocatalyst. Org. Biomol. Chem. 2019, 17, 3934–3939. [CrossRef][PubMed] 26. Singleton, D.A.; Thomas, A.A. High-precision simultaneous determination of multiple small kinetic isotope effects at natural abundance. J. Am. Chem. Soc. 1995, 117, 9357–9358. [CrossRef] 27. Becke, A.D. Density-functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 1993, 98, 5648–5652. [CrossRef] 28. Grimme, S.; Ehrlich, S.; Goerigk, L.J. Effect of the damping function in dispersion corrected density functional theory. Comput. Chem. 2011, 32, 1456–1465. [CrossRef] Catalysts 2021, 11, 569 51 of 54

29. Pliego, J.R., Jr. Theoretical free energy profile and benchmarking of functionals for amino-thiourea organocatalyzed nitro-Michael addition reaction. Phys. Chem. Chem. Phys. 2020, 22, 11529–11536. [CrossRef][PubMed] 30. Faisca Phillips, A.M. Applications of carbohydrate-based organocatalysts in enantioselective synthesis. Eur. J. Org. Chem. 2014, 7291–7303. [CrossRef] 31. Azad, C.S.; Khan, I.A.; Narula, A.K. Organocatalyzed asymmetric Michael addition by an efficient bifunctional carbohydrate– thiourea hybrid with mechanistic DFT analysis. Org. Biomol. Chem. 2016, 14, 11454–11461. [CrossRef][PubMed] 32. Avila, A.; Chinchilla, R.; Fiser, B.; Gómez-Bengoa, E.; Nájera, C. Enantioselective Michael addition of isobutyraldehyde to nitroalkenes organocatalyzed by chiral primary amine-guanidines. Tetrahedron Asymmetry 2014, 25, 462–467. [CrossRef] 33. Kucherenko, A.S.; Kostenko, A.A.; Komogortsev, A.N.; Lichitsky, B.V.; Fedotov, M.Y.; Zlotin, S.G. C2-Symmetric chiral squaramide, recyclable organocatalyst for asymmetric Michael reactions. J. Org. Chem. 2019, 84, 4304–4311. [CrossRef] 34. Rombola, M.; Sumaria, C.S.; Montgomery, T.D.; Rawal, V.H. Development of chiral, bifunctional thiosquaramides: Enantioselec- tive Michael additions of barbituric acids to nitroalkenes. J. Am. Chem. Soc. 2017, 139, 5297–5300. [CrossRef][PubMed] 35. Krautwald, S.; Carreira, E.M. Stereodivergence in asymmetric catalysis. J. Am. Chem. Soc. 2017, 139, 5627–5639. [CrossRef] [PubMed] 36. Beletskaya, I.P.; Nájera, C.; Yus, M. Stereodivergent catalysis. Chem. Rev. 2018, 118, 5080–5200. [CrossRef] 37. Ding, P.-G.; Zhou, F.; Wang, X.; Zhao, Q.-H.; Yu, J.-S.; Zhou, J. H-bond donor-directed switching of diastereoselectivity in the Michael addition of azido ketones to nitroolefins. Chem. Sci. 2020, 11, 3852–3861. [CrossRef] 38. Herrera, R.P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Catalytic enantioselective Friedel–Crafts alkylation of indoles by using a simple thiourea organocatalyst. Angew. Chem. Int. Ed. 2005, 44, 6576–6579. [CrossRef] 39. Roca-López, D.; Marqués-López, E.; Alcaine, A.; Merino, P.; Herrera, R.P. A Friedel–Crafts alkylation mechanism using an aminoindanol-derived thiourea catalyst. Org. Biomol. Chem. 2014, 12, 4503–4510. [CrossRef] 40. Pettersen, D.; Herrera, R.P.; Bernardi, L.; Fini, F.; Sgarzani, V.; Fernández, R.; Lassaletta, J.M.; Ricci, A. A broadened scope for the use of hydrazones as neutral nucleophiles in the presence of H-bonding organocatalysts. Synlett 2006, 239–242. [CrossRef] 41. Etter, M.C.; Panunto, T.W. 1,3-Bis(m-nitrophenyl)urea: An exceptionally good complexing agent for proton acceptors. J. Am. Chem. Soc. 1988, 110, 5896–5897. [CrossRef] 42. Fan, Y.; Kass, S.R. Enantioselective Friedel–Crafts alkylation between nitroalkenes and indoles catalyzed by charge activated thiourea organocatalysts. J. Org. Chem. 2017, 82, 13288–13296. [CrossRef] 43. Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.; Ding, L.-S.; Wu, Y. Asymmetric Michael addition of arylthiols to α,β-unsaturated carbonyl compounds catalyzed by bifunctional organocatalysts. Synlett 2005, 603–606. [CrossRef] 44. Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Highly enantioselective conjugate addition of nitromethane to chalcones using bifunctional cinchona organocatalysts. Org. Lett. 2005, 7, 1967–1969. [CrossRef][PubMed] 45. McCooey, S.H.; Connon, S.J. Urea- and thiourea-substituted cinchona alkaloid derivatives as highly efficient bifunctional organocatalysts for the asymmetric addition of malonate to nitroalkenes: Inversion of configuration at C9 dramatically improves catalyst performance. Angew. Chem. Int. Ed. 2005, 44, 6367–6370. [CrossRef][PubMed] 46. Ye, J.; Dixon, D.J.; Hynes, P.S. Enantioselective organocatalytic Michael addition of malonate esters to nitroolefins using bifunctional cinchonine derivatives. Chem. Commun. 2005, 4481–4483. [CrossRef] 47. Grayson, M.N. Mechanism and origins of stereoselectivity in the cinchona thiourea- and squaramide-catalyzed asymmetric Michael addition of nitroalkanes to enones. J. Org. Chem. 2017, 82, 4396–4401. [CrossRef] 48. Grayson, M.N.; Houk, K.N. Cinchona urea-catalyzed asymmetric sulfa-Michael reactions: The Brønsted acid−hydrogen bonding model. J. Am. Chem. Soc. 2016, 138, 9041–9044. [CrossRef] 49. Zhang, G.; Zhu, C.; Liu, D.; Pan, J.; Zhang, J.; Hu, D.; Song, B. Solvent-free enantioselective conjugate addition and bioactivities of nitromethane to Chalcone containing pyridine. Tetrahedron 2017, 73, 129–136. [CrossRef] 50. Duque, M.M.S.; Baslé, O.; Isambert, N.; Gaudel-Siri, A.; Genisson, Y.; Plaquevent, J.-C.; Rodriguez, J.; Constantieux, T. A cooperative participation of the amido group in the organocatalytic construction of all-carbon quaternary stereocenters by Michael addition with β-ketoamides. Org. Lett. 2011, 13, 3296–3299. [CrossRef][PubMed] 51. Quintard, A.; Cheshmedzhieva, D.; Duque, M.M.S.; Gaudel-Siri, A.; Naubron, J.-V.; Génisson, Y.; Plaquevent, J.-C.; Bugaut, X.; Rodriguez, J.; Constantieux, T. Origin of the enantioselectivity in organocatalytic Michael additions of β-ketoamides to α,β-unsaturated carbonyls: A combined experimental, spectroscopic and theoretical study. Chem. Eur. J. 2015, 21, 778–790. [CrossRef] 52. Humbrías-Martín, J.; Pérez-Aguilar, M.C.; Mas-Ballesté, R.; Litta, A.D.; Lattanzi, A.; Sala, G.D.; Fernández-Salas, J.A.; Alemán, J. Enantioselective conjugate azidation of α,β-unsaturated ketones under bifunctional organocatalysis by direct activation of TMSN3. Adv. Synth. Catal. 2019, 361, 4790–4796. [CrossRef] 53. Helder, R.; Arends, R.; Bolt, W.; Hiemstra, H.; Wynberg, H. Alkaloid catalyzed asymmetric synthesis III the addition of mercaptans to 2-cyclohexene-1-one; determination of enantiomeric excess using 13C NMR. Tetrahedron Lett. 1977, 18, 2181–2182. [CrossRef] 54. Connon, S.J. Asymmetric catalysis with bifunctional cinchona alkaloid-based urea and thiourea organocatalysts. Chem. Commun. 2008, 2499–2510. [CrossRef][PubMed] 55. Melchiorre, P. Cinchona-based primary amine catalysis in the asymmetric functionalization of carbonyl compounds. Angew. Chem. Int. Ed. 2012, 51, 9748–9770. [CrossRef] Catalysts 2021, 11, 569 52 of 54

56. Dai, L.; Wang, S.-X.; Chen, F.-E. A bifunctional cinchona alkaloid-squaramide catalyst for the highly enantioselective conjugate addition of thiols to trans-chalcones. Adv. Synth. Catal. 2010, 352, 2137–2141. [CrossRef] 57. Guo, J.; Wong, M.W. Cinchona alkaloid-squaramide catalyzed sulfa-Michael addition reaction: Mode of bifunctional activation and origin of stereoinduction. J. Org. Chem. 2017, 82, 4362–4368. [CrossRef] 58. Caner, H.; Biedermann, P.U.; Agranat, I. Conformational spaces of Cinchona alkaloids. Chirality 2003, 15, 637–645. [CrossRef] 59. Dijkstra, G.D.H.; Kellogg, R.M.; Wynberg, H.; Svendsen, J.S.; Marko, I.; Sharpless, K.B. Conformational study of cinchona alkaloids. A combined NMR, molecular mechanics and x-ray approach. J. Am. Chem. Soc. 1989, 111, 8069–8076. [CrossRef] 60. Grayson, M.N.; Houk, K.N. Cinchona alkaloid-catalyzed asymmetric conjugate additions: The bifunctional brønsted acid– hydrogen bonding model. J. Am. Chem. Soc. 2016, 138, 1170–1173. [CrossRef] 61. Rana, N.K.; Selvakumar, S.; Singh, V.K. Highly enantioselective organocatalytic sulfa-Michael addition to α,β-unsaturated ketones. J. Org. Chem. 2010, 75, 2089–2091. [CrossRef] 62. Bahlinger, A.; Fritz, S.P.; Wennemers, H. Stereoselective metal-free synthesis of β-amino thioesters with tertiary and quaternary stereogenic centers. Angew. Chem. Int. Ed. 2014, 53, 8779–8783. [CrossRef][PubMed] 63. Lin, Y.; Hirschi, W.J.; Kunadia, A.; Paul, A.; Ghiviriga, I.; Abboud, K.A.; Karugu, R.W.; Vetticatt, M.J.; Hirschi, J.S.; Seidel, D. A selenourea-thiourea Brønsted acid catalyst facilitates asymmetric conjugate additions of amines to α,β-unsaturated esters. J. Am. Chem. Soc. 2020, 142, 5627–5635. [CrossRef][PubMed] 64. Martínez, J.I.; Villar, L.; Uria, U.; Carrillo, L.; Reyes, E.; Vicario, J.L. Bifunctional squaramide catalysts with the same absolute chirality for the diastereodivergent access to densely functionalised cyclohexanes through enantioselective domino reactions. Synthesis and mechanistic studies. Adv. Synth. Catal. 2014, 356, 3627–3648. [CrossRef] 65. Meninno, S.; Quaratesi, I.; Volpe, C.; Mazzanti, A.; Lattanzi, A. Catalytic enantioselective one-pot approach to cis- and trans-2,3- diaryl substituted 1,5-benzothiazepines. Org. Biomol. Chem. 2018, 16, 6923–6934. [CrossRef][PubMed] 66. Chen, C.; Wei, R.; Yi, X.; Gao, L.; Zhang, M.; Liu, H.; Li, Q.; Song, H.; Ban, S.J. Diastereo- and enantioselective synthesis of functionalized cyclopentenes containing a quaternary chiral center via a thiosquaramide-catalyzed cascade Michael−Henry reaction. Org. Chem. 2019, 84, 15655–15661. [CrossRef] 67. Alishetty, S.; Shih, H.P.; Han, C.C. One-step, effective, and cascade syntheses of highly functionalized cyclopentenes with high diastereoselectivity. Org. Lett. 2018, 20, 2513–2516. [CrossRef] 68. Held, F.E.; Tsogoeva, S.B. Asymmetric cycloaddition reactions catalyzed by bifunctional thiourea and squaramide organocatalysts: Recent advances. Catal. Sci. Technol. 2016, 6, 645–667. [CrossRef] 69. Chen, X.; Qi, Z.-H.; Zhang, S.-Y.; Kong, L.-P.; Wang, Y.; Wang, X.-W. Enantioselective construction of functionalized thiopyrano- indole annulated heterocycles via a formal thio [3 + 3]-cyclization. Org. Lett. 2015, 17, 42–45. [CrossRef] 70. Banik, S.M.; Levina, A.; Hyde, A.M.; Jacobsen, E.N. Lewis acid enhancement by hydrogen-bond donors for asymmetric catalysis. Science 2017, 358, 761–764. [CrossRef][PubMed] 71. Mathieu, B.; Ghosez, L. Trimethylsilyl bis(triﬂuoromethanesulfonyl)imide as a tolerant and environmentally benign Lewis acid catalyst of the Diels–Alder reaction. Tetrahedron 2002, 58, 8219–8226. [CrossRef] 72. James, T.; van Gemmeren, M.; List, B. Development and applications of disulfonimides in enantioselective organocatalysis. Chem. Rev. 2015, 115, 9388–9409. [CrossRef] 73. Burés, J. A simple graphical method to determine the order in catalyst. Angew. Chem. Int. Ed. 2016, 55, 2028–2031. [CrossRef] 74. Jarvis, C.L.; Hirschi, J.S.; Vetticatt, M.J.; Seidel, D. Catalytic enantioselective synthesis of lactams through formal [4 + 2] cycloaddition of imines with homophthalic anhydride. Angew. Chem. Int. Ed. 2017, 56, 2670–2674. [CrossRef][PubMed] 75. Castagnoli, N. The condensation of succinic anhydride with benzylidinemethylamine. A stereoselective synthesis of trans- and cis-1-methyl-4-carbosy-5-phenyl-2-pyrrolidinone. J. Org. Chem. 1969, 34, 3187–3189. [CrossRef] 76. Castagnoli, N., Jr.; Cushman, M. Condensation of succinic anhydrides with Schiff bases. Scope and mechanism. J. Org. Chem. 1971, 36, 3404–3406. [CrossRef][PubMed] 77. Esteban, F.; Cie´slik,W.; Arpa, E.M.; Guerrero-Corella, A.; Díaz-Tendero, S.; Perles, J.; Fernández-Salas, J.A.; Fraile, A.; Alemán, J. In- tramolecular hydrogen bond activation: Thiourea-organocatalyzed enantioselective 1,3-dipolar cycloaddition of salicylaldehyde- derived azomethine ylides with nitroalkenes. ACS Catal. 2018, 8, 1884–1890. [CrossRef][PubMed] 78. Liu, Y.; Wu, X.; Li, S.; Xue, L.; Shan, C.; Zhao, Z.; Yan, H. Organocatalytic atroposelective intramolecular [4 + 2] cycloaddition: Synthesis of axially chiral heterobiaryls. Angew. Chem. Int. Ed. 2018, 57, 6491–6495. [CrossRef] 79. Shan, C.; Zhang, T.; Xiong, Q.; Yan, H.; Bai, R.; Lan, Y. Hydrogen-bond-induced chiral axis construction: Theoretical study of cinchonine–thiourea-catalyzed enantioselective intramolecular cycloaddition. Chem. Asian J. 2019, 14, 2731–2736. [CrossRef] 80. Manoni, F.; Farid, U.; Trujillo, C.; Connon, S.J. Catalytic asymmetric Tamura cycloadditions involving nitroalkenes. Org. Biomol. Chem. 2017, 15, 1463–1474. [CrossRef] 81. Cornaggia, C.; Manoni, F.; Torrente, E.; Tallon, S.; Connon, S.J. A catalytic asymmetric reaction involving enolizable anhydrides. Org. Lett. 2012, 14, 1850–1853. [CrossRef] 82. Trujillo, C.; Rozas, I.; Botte, A.; Connon, S.J. A DFT mechanistic study of the organocatalytic asymmetric reaction of aldehydes and homophthalic anhydride. Chem. Commun. 2017, 53, 8874–8877. [CrossRef] 83. Vamisetti, G.B.; Chowdhury, R.; Ghosha, S.K. Organocatalytic decarboxylative aldol reaction of β-ketoacids with α- ketophosphonates en route to the enantioselective synthesis of tertiary α-hydroxyphosphonates. Org. Biomol. Chem. 2017, 15, 3869–3873. [CrossRef] Catalysts 2021, 11, 569 53 of 54

84. Barros, M.T.; Faísca Phillips, A.M. Organocatalyzed synthesis of tertiary α-hydroxyphosphonates by a highly regioselective modified Pudovik reaction. Eur. J. Org. Chem. 2011, 4028–4036. [CrossRef] 85. Faísca Phillips, A.M.; Barros, M.T.; Pacheco, M.; Dias, R. Synthesis and biological evaluation of α-hydroxyalkylphosphonates as new antimicrobial agents. Bioorg. Med. Chem. Lett. 2014, 24, 49–53. [CrossRef][PubMed] 86. Faisca Phillips, A.M.M.M. Synthesis and applications of pharmacologically relevant phosphonates and phosphinates. In Organic and Medicinal Chemistry; Banik, B.K., Ed.; Nova Science Publishers: New York, NY, USA, 2018; Volume 2, pp. 249–319. 87. Ni, X.; Li, X.; Cheng, J.-P. Equilibrium acidities of cinchona alkaloid organocatalysts bearing 60-hydrogen bonding donors in DMSO. Org. Chem. Front. 2016, 3, 170–176. [CrossRef] 88. Hammar, P.; Marcelli, T.; Hiemstra, H.; Himoa, F. Density functional theory study of the Cinchona thiourea- catalyzed Henry reaction: Mechanism and enantioselectivity. Adv. Synth. Catal. 2007, 349, 2537–2548. [CrossRef] 89. Otevrel, J.; Bobal, P. Diamine-tethered bis(thiourea) organocatalyst for asymmetric Henry reaction. J. Org. Chem. 2017, 82, 8342–8358. [CrossRef] 90. Alegre-Requena, J.V.; Marqués-López, E.; Herrera, R.P. Optimizing the accuracy and computational cost in theoretical squaramide catalysis: The Henry reaction. Chem. Eur. J. 2017, 23, 15336–15347. [CrossRef] 91. Ford, D.D.; Lehnherr, D.; Kennedy, C.R.; Jacobsen, E.N. Anion-abstraction catalysis: The cooperative mechanism of α-chloroether activation by dual hydrogen-bond donors. ACS Catal. 2016, 6, 4616–4620. [CrossRef] 92. Ford, D.D.; Lehnherr, D.; Kennedy, C.R.; Jacobsen, E.N. On- and off-cycle catalyst cooperativity in anion-binding catalysis. J. Am. Chem. Soc. 2016, 138, 7860–7863. [CrossRef][PubMed] 93. Kennedy, C.R.; Lehnherr, D.; Rajapaksa, N.S.; Ford, D.D.; Park, Y.; Jacobsen, E.N. Mechanism-guided development of a highly active bis-thiourea catalyst for anion-abstraction catalysis. J. Am. Chem. Soc. 2016, 138, 13525–13528. [CrossRef][PubMed] 94. Lehnherr, D.; Ford, D.D.; Bendelsmith, A.J.; Kennedy, C.R.; Jacobsen, E.N. Conformational control of chiral amido-thiourea catalysts enables improved activity and enantioselectivity. Org. Lett. 2016, 18, 3214–3217. [CrossRef][PubMed] 95. Mittal, N.; Lippert, K.M.; De, C.K.; Klauber, E.G.; Emge, T.J.; Schreiner, P.R.; Seidel, D.J. A dual-catalysis anion-binding approach to the kinetic resolution of amines: Insights into the mechanism via a combined experimental and computational study. Am. Chem. Soc. 2015, 137, 5748–5758. [CrossRef] 96. Taylor, J.E.; Bull, S.D.; Williams, J.M.J. Amidines, isothioureas, and guanidines as nucleophilic catalysts. Chem. Soc. Rev. 2012, 41, 2109–2121. [CrossRef] 97. Seidel, D. The anion-binding approach to catalytic enantioselective acyl transfer. Synlett 2014, 25, 783–794. [CrossRef] 98. Matador, E.; Iglesias-Sigüenza, J.; Monge, D.; Merino, P.; Fernández, R.; Lassaletta, J.M. Enantio- and diastereoselective nucleophilic addition of N-tert-butylhydrazones to isoquinolinium ions through anion-binding catalysis. Angew. Chem. Int. Ed. 2021, 60, 5096–5101. [CrossRef] 99. Boto, R.A.; Peccati, F.; Laplaza, R.; Quan, C.; Carbone, A.; Piquemal, J.-P.; Maday, Y.; Contreras-García, J.J. NCIPLOT4: Fast, robust, and quantitative analysis of noncovalent interactions. Chem. Theory Comput. 2020, 16, 4150–4158. [CrossRef] 100. Faisca Phillips, A.M.; Pombeiro, A.J.L. Recent advances in organocatalytic enantioselective transfer hydrogenation. Org. Biomol. Chem. 2017, 15, 2307–2340. [CrossRef] 101. Massolo, E.; Benaglia, M.; Orlandi, M.; Rossi, S.; Celentano, G. Enantioselective Organocatalytic Reduction of b-Trifluoromethyl Nitroalkenes: An Efficient Strategy for the Synthesis of Chiral β-Trifluoromethyl Amines. Chem. Eur. J. 2015, 21, 3589–3595. [CrossRef] 102. Dong, Z.; Yan, C.; Gao, Y.; Dong, C.; Qiu, G.; Zhou, H.-B. Tunable bifunctional phosphine–squaramide promoted Morita–Baylis– Hillman reaction of N-alkyl isatins with acrylates. Adv. Synth. Catal. 2015, 357, 2132–2142. [CrossRef] 103. Klausen, R.S.; Kennedy, C.R.; Hyde, A.M.; Jacobsen, E.N. Chiral thioureas promote enantioselective Pictet−Spengler cyclization by stabilizing every intermediate and transition state in the carboxylic acid-catalyzed reaction. J. Am. Chem. Soc. 2017, 139, 12299–12309. [CrossRef] 104. Klausen, R.S.; Jacobsen, E.N. Weak Brønsted acid−thiourea co-catalysis: Enantioselective, catalytic protio-Pictet−Spengler reactions. Org. Lett. 2009, 11, 887–890. [CrossRef][PubMed] 105. Qi, L.; Hou, H.; Ling, F.; Zhong, W. The cinchona alkaloid squaramide catalyzed asymmetric Pictet–Spengler reaction and related theoretical studies. Org. Biomol. Chem. 2018, 16, 566–574. [CrossRef][PubMed] 106. Nishiyori, R.; Tsuchihashi, A.; Mochizuki, A.; Kaneko, K.; Yamanaka, M.; Shirakawa, S. Design of chiral bifunctional dialkyl sulfide catalysts for regio-, diastereo-, and enantioselective bromolactonization. Chem. Eur. J. 2018, 24, 16747–16752. [CrossRef] 107. Werth, J.; Sigman, M.S. Connecting and analyzing enantioselective bifunctional hydrogen bond donor catalysis using data science tools. J. Am. Chem. Soc. 2020, 142, 16382–16391. [CrossRef][PubMed]