catalysts

Review Enantioselective Catalytic Transformations of Barbituric Acid Derivatives

Claire Segovia, Arthur Lebrêne , Vincent Levacher , Sylvain Oudeyer and Jean-François Brière *

Normandie University, UNIROUEN, INSA Rouen, CNRS, COBRA, 76000 Rouen, France; [email protected] (C.S.); [email protected] (A.L.); [email protected] (V.L.); [email protected] (S.O.) * Correspondence: [email protected]; Tel.: +33-235-522-464



Received: 20 December 2018; Accepted: 15 January 2019; Published: 1 February 2019


Abstract: Since the beginning of the 20th century, numerous research efforts made elegant use of barbituric acid derivatives as building blocks for the elaboration of more complex and useful molecules in the field of pharmaceutical chemistry and material sciences. However, the construction of chiral scaffolds by the catalytic enantioselective transformation of barbituric acid and derivatives has only emerged recently. The specific properties of these rather planar scaffolds, which also encompass either a high Brønsted acidity concerning the native barbituric acid or the marked electrophilic character of alkylidene barbituric acids, required specific developments to achieve efficient asymmetric processes. This review covers the enantioselective catalytic reactions developed for barbituric acid platforms using an organocatalytic and metal-based enantioselective sequences. These achievements currently allow several unique addition and annulation reactions towards the construction of high valued chiral heterocycles from barbituric acid derivatives along with innovative enantioselective developments.

Keywords: organocatalysis; asymmetric synthesis; barbituric acid; alkylidene barbituric acid; metal based-catalysis; cycloaddition; annulation reaction

1. Introduction

1.1. Context Barbituric acid 1, namely 2,4,6-(lH,3H,5H)-pyrimidinetrione, and derivatives are fascinating building blocks in organic synthesis (Figure1). This story dates back to 1894 when von Baeyer reported on the preparation of barbituric acid [1]. Later, in 1903, Fisher and von Mering highlighted the pharmacological properties of 5,5-diethyl barbituric acid, the so-called barbital, as a potent hypnotic agent [2]. Ever since, barbituric acid derivatives served as starting materials for the elaboration of thousands of complex architectures useful in medicinal chemistry, a field of research covered by several exhaustive reviews [3–6]. Selected examples of bioactive compounds in this series are depicted in Figure1, which highlights scaffolds that possess, at least, one stereogenic center or a tetrasubstituted carbon as a source of chemical diversity and structural complexity. Phenobarbital, involved in the treatment of certain types of epilepsy, derived from the original barbital but displays two different substituents at C-5 position (Figure1a) [ 7]. The opportunity afforded by the double functionalization of the C-5 position of barbituric acid allowed the construction of several spiro-compounds and, thus, more rigid architectures highlighted by the development of nucleotide mimics [8], inhibitor of matrix metalloproteinases (MMP) [9] and anticancer agents [10], for example (Figure1b–d) [ 11,12]. On the other hand, the synthesis of fused-bicycle derivatives led to ingredients possessing either

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antidiabetic [13] or antituberculosis properties (Figure1e–f) [ 14]. Besides medicinal chemistry, theCatalysts photophysical 2018, 8, x FOR properties PEER REVIEW of barbituric acid derivatives were exploited in colorimetric or heat2 of 30 detection [15], and provided promising dyes or fluorogenic probes to name a few [16,17]. 45

46 47 FigureFigure 1. Barbituric 1. Barbituric acid acid scaffolds scaffolds within within bioactive bioactive architectures. architectures.

48 TheThe versatile versatile properties properties of productsof products obtained obtained from from barbituric barbituric acid acid elicited elicited the the motivation motivation of of 49 organicorganic chemists chemists to to explore explore its its chemistry chemistry [3 ,4[3,4,6],,6], and and more more recent recent evolutions evolutions have have met met the the 50 developmentdevelopment of efficientof efficient multicomponent multicomponent reactions reactions (MCR) (MCR) [16,18 [16,18].]. Despite Despite great great synthetic synthetic advances advances in 51 thisin field this of research,field of theresearch, use of diastereoselectivethe use of diastere sequencesoselective or separation sequences techniques or separation (crystallization techniques or 52 chromatography)(crystallization of or racemic chromatography) mixtures were of required racemic for mixtures the elaboration were required of enantiopure for the architectures elaboration of of 53 chiralenantiopure bioactive architectures compounds asof chiral depicted bioactive in Figure compounds1[ 19]. At as thedepicted end of in the Figure 1990s, 1 [19]. the pioneeringAt the end of 54 researchthe 1990s, of Brunner’s the pioneering group, onresearch the palladium-catalyzed of Brunner’s group, enantioselective on the palladium-catalyzed alkylation of barbituric enantioselective acid 55 derivativesalkylation have of barbituric shed light acid on thederiva potentialtives have of this shed starting light on material the potential in asymmetric of this starting synthesis material while in 56 pointingasymmetric out challenges, synthesis which while have pointing to be out overcome challenges, with thiswhich unique have architecture to be overcome [20–23 with]. This this review unique 57 intendsarchitecture to cover [20–23]. the literature This review dealing intends with the to enantioselective cover the literature catalytic dealing transformations with the enantioselective of barbituric 58 acidcatalytic derivatives, transformations an exercise of which barbituric is unprecedented acid derivatives, to the an best exercise of our which knowledge. is unprecedented The literature to the 59 concerningbest of our the knowledge. enantioselective The literature transformations concerning of barbituricthe enantioselective acid and alkylidenetransformations barbituric of barbituric acid 60 derivativesacid and willalkylidene be discussed barbituric separately, acid derivatives to focus on specificwill be typesdiscussed of reactions separately, developed to focus for on a givenspecific 61 barbituratetypes of reactions structure. developed To give a flavor for a given of the barbiturate uniqueness structure. of barbituric To acidgive compounds,a flavor of the its uniqueness properties of 62 willbarbituric first be introduced. acid compounds, its properties will first be introduced.

63 1.2.1.2. Properties Properties of Barbituricof barbituric Acid acid Derivatives derivatives 64 To gainTo gain insight insight into into the reactivitythe reactivity of barbituric of barbituric acid acid derivatives, derivatives, the unique the unique chemical chemical properties properties of 65 theseof these molecules molecules have have to be to taken be taken into account.into account. As shownAs shown in Figure in Figure2a, barbituric2a, barbituric acid acid1 displays 1 displays a a 66 ratherrather low low pK apKvaluea value (pK (pa K=a 8.4= 8.4 in in DMSO) DMSO) [24 [24]] lying lying just just above above Meldrum’s Meldrum’s acid acid2 well-known 2 well-known for for its its 67 remarkableremarkable acidity acidity (pK (pa =Ka 7.03 = 7.03 in DMSO)in DMSO) [25 [25,26].,26]. Consequently, Consequently, barbituric barbituric acid acid1 and 1 and derivatives derivatives will will 68 be much more prone to deprotonation by soft bases than dimedone 3 or non-cyclic homologues, 69 such as malonate 4, for instance. However, direct correlation between the pKa value and the 70 nucleophilic behavior is not always feasible [27]. 71

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Catalystsbe much 2018, more 8, x FOR prone PEER to REVIEW deprotonation by soft bases than dimedone 3 or non-cyclic homologues,3 suchof 30 as malonate 4, for instance. However, direct correlation between the pKa value and the nucleophilic 72 behavior is not always feasible [27].

73 74 FigureFigure 2. 2.PropertiesProperties of ofbarbituric barbituric acid acid derivatives. derivatives. (a) (Aciditya) Acidity given given in inDMSO. DMSO. (b) ( bNucleophilic) Nucleophilic 75 reactivityreactivity parameters parameters of ofanions. anions.

76 In In2017, 2017, Spange Spange and and co-workers co-workers embarked embarked on on the the insightful insightful evaluation evaluation of ofthe the kinetics kinetics of of 77 derivativesderivatives of ofbarbiturate barbiturate acid acid anions anions thanks thanks to tothe the reaction reaction with with specific specific electrophiles, electrophiles, such such as as 78 benzhydryliumbenzhydrylium cations cations and and Michael Michael acceptors acceptors [28]. [28 Then,]. Then, the the so-called so-called nucleophilicity nucleophilicity parameter parameter N N 79 andand the the corresponding corresponding nucleophile-sp nucleophile-specificecific susceptibility susceptibility parameter parameter sNs ofN ofbarbiturate barbiturate anions anions 1’ 1’couldcould 80 bebe determined determined and and compared compared to torelated related 1,3-dicarbonyl 1,3-dicarbonyl anions anions 2’-2’4’- 4(Figure’ (Figure 2b)2b) [27]. [ 27 ].Barbituric Barbituric acid acid 81 anionanion 1’ 1’featuresfeatures a nucleophilic a nucleophilic character character between between Meldrum’s Meldrum’s acid acid 2’ 2’andand dimedone dimedone 3’ 3’anionsanions but but is is 82 muchmuch less less reactive reactive than than malonate malonate anion anion 4’,4’ which, which actually actually leads leads to toa rather a rather good good correlation correlation with with the the 83 scalescale of ofpK paK values.a values. In Inaddition addition to tobeing being more more soluble, soluble, the the 1,3-dimethyl 1,3-dimethyl barbituric barbituric acid acid 5a’5a’ reactedreacted 84 fasterfaster than than the the parent parent anion 1’1’,, aa phenomenon phenomenon attributed attributed to theto the electron-donating electron-donating effect effect of the ofN -alkylthe 85 N-alkylgroups. groups. Nevertheless, Nevertheless, a ground a ground state stabilization state stabilization of the negative of the negative charge of charge1’ by hydrogenof 1’ by hydrogen bonding of 86 bondingthe NH of moieties the NH might moieties also might account also for account this outcome. for this In outcome. comparison, In thecomparison, anionic thiobarbiturate the anionic 87 thiobarbiturateanalogues 6’ andanalogues7’ proved 6’ to and be less7’ nucleophilicproved to be due less to superiornucleophilic electron due withdrawing to superior properties electron of 88 withdrawingthe thiocarbonyl properties versus of carbonyl the thiocarbonyl of 1’ for instance.versus carbonyl Interestingly, of 1’ for during instance. this study,Interestingly, the O-alkylation during 89 thisreaction study, hasthe neverO-alkylation been observed. reaction Accordingly,has never been a computational observed. Accordingly, study showed a computational that the C-alkylation study 90 showedprocess that is favoredthe C-alkylation both from process a thermodynamic is favored both and from a kinetic a thermodynamic point of view. and This a scenariokinetic point might of be 91 view.different This scenario with harder might electrophiles, be different however. with harder electrophiles, however. 92 MayrMayr and and co-workers co-workers studied studied the the electrophilicity electrophilicity of ofbenzylidene benzylidene barbituric barbituric acid acid derivatives derivatives 93 (Figure(Figure 3)3 [29],)[ 29 which], which proved proved to tobe be a potent a potent electrophile electrophile in invariou variouss conjugate conjugate addition addition reactions reactions or or 94 cycloadditioncycloaddition processes processes (vide(vide infra infra). 5-Arylidene). 5-Arylidene 1,3-dimethylbarbituric 1,3-dimethylbarbituric acid 8a hasacid an electrophilicity8a has an 95 electrophilicityparameter E parametersimilar to E 5-arylidene similar to Meldrum’s5-arylidene acidMeldrum’s10, which acid is 10 in, which line with is in the line reactivity with the of 96 reactivitybenzylidenemalononitriles, of benzylidenemalononitriles, such as 12 .such For comparisonas 12. For purposes,comparison the purposes, benzylidene the barbituricbenzylidene acid 97 barbituric acid derivative 8a is a much more potent electrophile than the malonate counterpart 11 98 and, thus, affords interesting reactivity to be exploited in catalysis. Another important feature, relies 99 on the modulation of reactivity by moving from barbiturate 8a to thiobarbiturate 9a which displays a

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derivative 8a is a much more potent electrophile than the malonate counterpart 11 and, thus, affords interesting reactivity to be exploited in catalysis. Another important feature, relies on the modulation of CatalystsreactivityCatalysts 2018 2018, 8 by,, x8 , movingFOR x FOR PEER PEER from REVIEW REVIEW barbiturate 8a to thiobarbiturate 9a which displays a superior electrophilicity.4 of4 of30 30 The authors attributed this phenomenon to the higher positive polarization of nitrogen in the 100 100 superiorthiobarbituratesuperior electrophilicity. electrophilicity.9a versus The The barbiturate authors authors attributed attributed8a [29]. this phenomenon to to the the higher higher positive positive polarization polarization 101101 of ofnitrogen nitrogen in inthe the thiobarbiturate thiobarbiturate 9a 9a versus versus barbituratebarbiturate 8a [29].[29].

102 102 103 Figure 3. Reactivity issues. 103 FigureFigure 3. Reactivity 3. Reactivity issues. issues. 104 2.2. Enantioselective Transformations Transformations of of Barbituric Barbituric Acid Acid Derivatives Derivatives 104 2. Enantioselective Transformations of Barbituric Acid Derivatives 105 As aforementioned,aforementioned, barbituricbarbituric acidacid derivativesderivatives areare easilyeasily deprotonateddeprotonated withwith regard regard to to their their rather 105106 ratherAs aforementioned,low pKa value. Simple barbituric reasoning acid basedderivatives upon resoarenance easily structures deprotonated obviously with shows regard that to thetheir low pKa value. Simple reasoning based upon resonance structures obviously shows that the conjugate 106107 ratherconjugate low p Kbasea value. of barbituric Simple reasoningacid may basedundergo upon eith resoer anance C-alkylation structures or an obviously O-alkylation shows reaction that the base of barbituric acid may undergo either a C-alkylation or an O-alkylation reaction (Figure4a), 107108 conjugate(Figure 4a),base an of issue barbituric known toacid be dependentmay undergo on the eith natureer a ofC-alkylation the electrophile or anand O-alkylation reaction conditions reaction an issue known to be dependent on the nature of the electrophile and reaction conditions [28]. Several 108109 (Figure[28]. 4a),Several an issue research known groups to be dependenttook advantage on the ofnature these of thefeatures electrophile to develop and reactionenantioselective conditions research groups took advantage of these features to develop enantioselective transformations based on 109110 [28].transformations Several research based groupson three tookdifferent advantage strategies of (Figure these 4b).features Barbituric to developacid derivatives enantioselective having three different strategies (Figure4b). Barbituric acid derivatives having different N-substituents 110111 transformationsdifferent N-substituents based on (R three1 ≠ R 2different) are pro-chiral strategies by nature (Figure (if R 4b).3 = H) Barbituric and, consequently, acid derivatives they provide having (R1 6= R2) are pro-chiral by nature (if R3 = H) and, consequently, they provide the corresponding 111112 differentthe corresponding N-substituents alkylated (R1 ≠ Rproducts2) are pro-chiral with a stereocenter by nature inside(if R3 = the H) ring and, (strategy consequently, A). This they approach provide 113 alkylatedwas mainly products applied with to the a stereocenter formation of inside tetrasubstituted the ring (strategy productsA). This(R3 ≠ approach H). On the was other mainly hand, applied 112 the corresponding alkylated products with a stereocenter3 inside the ring (strategy A). This approach to the formation of tetrasubstituted1 2 products (R 6= H). On the other hand, symmetrical architectures 113114 wassymmetrical mainly applied architectures to the (R formation = R , strategy of tetrasubstituted B) will furnish products products along (R3 with≠ H). the On construction the other ofhand, a 115 (R1 = R2, strategy B) will furnish products along with the construction of a stereocenter outside the ring 114 symmetricalstereocenter architectures outside the (Rring1 = afterR2, strategy the reaction B) will wi furnishth a pro-chiral products electrophi along withle. Finally,the construction annulation of a 116 afterprocesses the reaction may take with place, a pro-chiral through both electrophile. a C- and Finally, O-alkylation annulation sequence processes (strategy may C take), allowing place, throughthe 115 stereocenter outside the ring after the reaction with a pro-chiral electrophile. Finally, annulation 117 bothsynthesis a C- andof fused O-alkylation ring scaffolds sequence while (strategy the initialC), allowingsymmetry the of synthesis the barbituric of fused acid ring precursor scaffolds is while 116 processes may take place, through both a C- and O-alkylation sequence (strategy C), allowing the 118 thebroken. initial symmetry of the barbituric acid precursor is broken. 117 synthesis of fused ring scaffolds while the initial symmetry of the barbituric acid precursor is 119 118 broken. (a) Resonance structures 119 O O E (a) Resonance structures R2 R2 E O N O N E C-alkylationR2 R2 O-alkylation E O N N O O N NO C-alkylationR1 R1 O-alkylation O N O O N O (b) Enantioselective strategies R1 R1 E O O *R O R3 R3 R2 (b) EnantioselectiveR2 strategies E R2 E N *E N E N *O O *R O R3 R3 O N RO2 O N OR2 Symmetry OE N OR2 E N *E N N * R1 R1 R1 (A)O stereocenterN O inside (B) stereocenterO N O outsideSymmetry(C) annulationO N reactionO the ring (R1 R2) thering(R1 R2) (R1 R2) 120 R1 R1 R1 121 Figure(A) stereocenter4. ReactivityReactivity issues inside issues and and asymmetric asymmetric(B) stereocenter synthesis. synthesis. outside(a) Resonance (a) Resonance (structuresC) annulation structures towards towards reaction C or C or 1 2 1 2 1 2 120122 O-alkylationthe ring reaction. reaction. (R (bR (b) )Enantioselective) Enantioselective thering(Rstrategies. strategies. R ) (R R )

121123 FigureIn the the 4. following followingReactivity Section, Section,issues weand we will willasymmetric describe describe the synthesis. the achievement achievement (a) Resonance based based on these onstructures these three three towardsenantioselective enantioselective C or 122124 syntheticsyntheticO-alkylation strategies. strategies. reaction. (b) Enantioselective strategies.

123125 2.1.In Addition the following Reactions Section, with Ste wereocenters will describe Created the Inside achievement the Ring based on these three enantioselective 124 synthetic strategies.

125 2.1. Addition Reactions with Stereocenters Created Inside the Ring

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Catalysts 2018, 8, x FOR PEER REVIEW 5 of 30 2.1. Addition Reactions with Stereocenters Created Inside the Ring 126 CatalystsIn the 2018 1990s,, 8, x FOR the PEERBrunner REVIEW group published a series of pioneering investigations highlighting5 of 30 the In the 1990s, the Brunner group published a series of pioneering investigations highlighting 127 stereoselective alkylation reaction of non-symmetrical barbituric acid derivatives. In 1994 [21], the 126 the stereoselectiveIn the 1990s, the alkylation Brunner group reaction published of non-symmetrical a series of pioneering barbituric investigations acid derivatives. highlighting In the 1994 [21], 128 authors succeeded in the Pd-catalyzed allylation reaction of the 1,5-dimethylbarbituric acid 13 to 127 thestereoselective authors succeeded alkylation in reaction the Pd-catalyzed of non-symmetrical allylation barbituric reaction acid of derivatives. the 1,5-dimethylbarbituric In 1994 [21], the acid 129 give the corresponding product 14 in 68% yield and 12.7% ee (Scheme 1), along with the creation of 128 13 authorsto give succeeded the corresponding in the Pd-catalyzed product allylation14 in 68% reaction yield of and the 12.7%1,5-dimethylbarbituricee (Scheme1), acid along 13 withto the 130129 an giveall-carbon the corresponding tetrasubstituted product stereocenter. 14 in 68% Theyield pr andocess 12.7% needed ee (Scheme the use 1), of alonga stoichiometric with the creation amount of of creation of an all-carbon tetrasubstituted stereocenter. The process needed the use of a stoichiometric 131130 1,8-diazabicyclo[5.4.0]an all-carbon tetrasubstituted undec-7-ene stereocenter. (DBU) asThe a prbaseocess to needed deprotonate the use theof a stoichiometricstarting material amount 13. Thisof amount of 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) as a base to deprotonate the starting material 13. 132131 beautiful1,8-diazabicyclo[5.4.0] early achievement undec-7-ene was allowed (DBU) with as a thebase parallel to deprotonate development the starting of novel material chelating 13. Thischiral 133132 Thisphosphinebeautiful beautiful imine early early ligands,achievement achievement such wasas 15 wasallowed. allowed with withthe parallel the parallel development development of novel of chelating novel chelating chiral chiral 134133 phosphinephosphine imine imine ligands, ligands, suchsuch as 1515. . 134

135 135 136 Scheme 1. Pioneering investigations. 136 SchemeScheme 1. 1.PioneeringPioneering investigations. investigations. 137 137 DuringDuring subsequentsubsequent subsequent investigations,investigations, investigations, this thisthis group groupgroup of of researchers researchers took tooktook advantage advantageadvantage of of theof the readilythe readily readily available 138138 phosphineavailableavailable phosphine iminesphosphine like imines imines17, easily like like synthesized1717, , easilyeasily synthesizedsynthesized from the correspondingfromfrom thethe correspondingcorresponding aldehyde aldehyde withaldehyde suitable with with chiral 139 suitable chiral amines (Scheme 2). Then, 134 various ligands were evaluated in this enantioselective 139 aminessuitable (Scheme chiral amines2). Then, (Scheme 134 2). various Then, 134 ligands variou weres ligands evaluated were evaluated in this in enantioselective this enantioselective allylation 140 allylation process of 13 [20,23]. The novel phosphine ligand 17 allowed to improve the ee up to 34% 140 processallylation of 13 process[20,23]. of The 13 [20,23]. novel phosphineThe novel phosphine ligand 17 allowedligand 17 toallowed improve to improve the ee up the to 34%ee upfor to 34% product 14, 141141 for product 14, and another side-product, 16, which originated from the double allylation reaction andfor another product side-product, 14, and another16, side-product,which originated 16, which from originated the double from allylation the double reaction allylation was reaction observed in 142142 waswas observed observed in inthese these conditions. conditions. Based Based onon preliminarypreliminary theoretical andand NMR NMR investigations, investigations, the the these conditions. Based on preliminary theoretical and NMR investigations, the authors have proposed 143143 authorsauthors have have proposed proposed a atransition transition state state whereinwherein the (η33-allyl)-palladium-allyl)-palladium complex complex would would possess possess a transition state wherein the (η3-allyl)-palladium complex would possess two phosphine-ligands 144144 twotwo phosphine-ligands phosphine-ligands L Lfeaturing featuring ππ-π-π stackingstacking eventsevents betweenbetween theirtheir phenylphenyl rings. rings. Then, Then, the the π π 145145 Lhydroxylfeaturinghydroxyl functional functional- stacking group group events of of the betweenthe ligandligand their maymay phenyl create rings.hydrogen-bonding Then, the hydroxyl interactionsinteractions functional with with the groupthe of 146146 thebarbituricbarbituric ligand acid may acid anion createanion to to hydrogen-bondingdifferentiate differentiate the the two two interactionsenan enantiotopictiotopic withenolateenolate the faces faces barbituric (Scheme (Scheme acid 2). 2). These These anion pioneering pioneering to differentiate 147147 theachievementsachievements two enantiotopic are are noteworthy noteworthy enolate facessi sincence (Scheme thethe pro-chiralpro-chiral2). These incoming pioneering anion,anion, achievements andand the the palladium palladium are noteworthy complex complex since 148148 the(having(having pro-chiral the the chiral incomingchiral information) information) anion, andare are lying thelying palladium atat thethe opopposite complex facesfaces (having ofof allylicallylic the activated activated chiral information) species, species, which which are lying 149149 atmakes themakes oppositethe the design design faces of of a allylicasuited suited activated ligandligand for species,for thisthis whichasymmetric makes reactionreaction the design significantlysignificantly of a suited challenging challenging ligand for this 150150 asymmetriccontrariwisecontrariwise reactionto tothe the one one significantly used used for for a apro-chiral challengingpro-chiral electrophile.electrophile. contrariwise to the one used for a pro-chiral electrophile. 151 151

152 152153 Scheme 2. Ligand optimization for the Pd-catalyzed allylation reaction.

153 SchemeScheme 2. 2.LigandLigand optimization optimization for forthe thePd-c Pd-catalyzedatalyzed allylation allylation reaction. reaction.

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154 In 1999, Brunner and colleagues tackled the stereoselective synthesis of methohexital 19, a 155 potent short-timeIn 1999, Brunner anesthetic and (Scheme colleagues 3) [22]. tackled As me thentioned stereoselective in the article, synthesis the four of stereoisomers methohexital of19 , 156 barbiturica potent acid short-time derivatives anesthetic 19 displayed (Scheme distinct3)[ 22]. Asnarcotic mentioned effects in that the make article, asymmetric the four stereoisomers synthesis a of 157 usefulbarbituric constructive-tool acid derivatives in this19 case.displayed The palladiu distinctm-promoted narcotic effects allylation that make reaction asymmetric was, obviously, synthesis a a 158 suiteduseful approach constructive-tool to 19 but in this had case. to Thechallenge palladium-promoted the presence allylationof a stereogenic reaction was, center obviously, on 159 1-methyl-5-(1’-methylpent-2’-ynyl)a suited approach to 19 but barbituric had to challengeacid 18, in so the much presence as this ofstarting a stereogenic material was center used on 160 as 1-methyl-5-(1’-methylpent-2’-ynyl)a racemic mixture. The phosphine imine barbituric 17 proved acid 18 to, inbe so the much best asligand this startingfor this reaction, material wasand an used 161 advancedas a racemic investigation mixture. revealed The phosphine salient features. imine 17 Inproveddeed, the to stereoselective be the best ligand allylation for this of reaction,one of the and 162 prostereogenican advanced faces investigation of the transient revealed enolate salient features.species took Indeed, place the upon stereoselective the influence allylation of the ofchiral one of 163 ligandthe prostereogenic17, giving two diastereoisomers faces of the transient (19, ( enolateR,R) and species (R,S), for took instance) place upon for a thegiven influence enantiomer of the of chiral 18 164 (forligand instance,17, giving from twothe one diastereoisomers having the R ( 19propargylic-stereocenter).,(R,R) and (R,S), for instance) Additionally, for a given this enantiomer allylation of 165 sequence18 (for instance,also led to from a kinetic the one resolution having process the R propargylic-stereocenter). resulting in the faster transformation Additionally, rate this of allylation either 166 (R)-sequence18 or (S)- also18 at led the to apropargylic-stereocenter. kinetic resolution process Inresulting line with in these the faster two processes transformation (Scheme rate 3), of eitherthe 167 reaction(R)-18 orstopped (S)-18 atafter the 9 propargylic-stereocenter. hours and provided two In linediastereoisomers with these two 19 processes with 26% (Scheme yield3 ),and the one reaction of 168 themstopped was obtained after 9 hours in up andto 80% provided ee (the twoother diastereoisomers one in 13% ee). The19 withremaining 26% yield starting and material one of them18 was was 169 recoveredobtained in in 79% up toyield 80% andee (the a combined other one 5% in 13%ee. Afteree). The 72 hours remaining of reaction, starting the material enantiomeric18 wasrecovered excess of in 170 the79% first yield pairand of enantiomers a combined 5%decreasedee. After to 72 46% hours while of reaction, the other the one enantiomeric reached 72%. excess Nonetheless, of the first pairthe of 171 combinedenantiomers ee of decreasedthe starting to 46%material while 18 the (7%) other was one improved reached 72%. to 83% Nonetheless, in accordance the combined with a kineticee of the 172 resolutionstarting materialevent. 18 (7%) was improved to 83% in accordance with a kinetic resolution event. 173

174 175 SchemeScheme 3. Synthesis 3. Synthesis of stereoisomers of stereoisomers of methohexital. of methohexital.

176 In In2000 2000 the the Trost Trost group group envisaged envisaged the the elaboration elaboration of ofa simplified a simplified analogue analogue 21 21of ofmethohexital, methohexital, 177 lackinglacking a stereogenic a stereogenic center center at atthe the propargylic propargylic po positionsition (Scheme (Scheme 4)4 [30].)[ 30 The]. The catalyzed catalyzed asymmetric asymmetric 178 allylicallylic alkylation alkylation reaction reaction (AAA), (AAA), using using the the C2-symmetricalC2-symmetrical cyclohexyldiamine cyclohexyldiamine ligands ligands 23 23or or24 24in in 179 thethe presence presence of ofpalladium palladium chloride chloride species, species, allo allowedwed the the transformation transformation of ofthe the starting starting material material 20 20 180 intointo the the corresponding corresponding allylated allylated product product 21 albeit21 albeit in modest in modest 19% 19%yield yield and 37% and ee 37%. In eethis. In case, this the case, 181 morethe sterically more sterically hindered hindered ligand ligand24 versus24 versus23, having23, havingtwo naphthyl two naphthyl moieties, moieties, proved provedto be the to most be the 182 efficientmost efficientone. The one. authors The authorsmoved movedto a prochiral to a prochiral cyclopentenyl cyclopentenyl carbonate carbonate as electrophile as electrophile with the with 183 hopethe to hope favor to the favor stereodifferentiation the stereodifferentiation of the prochi of theral prochiral faces of faces the enolate of the enolateintermediate intermediate derived derivedfrom 184 deprotonationfrom deprotonation of nucleophile of nucleophile 20. In 20a .similar In a similar catalytic catalytic system, system, but butin dichloromethane in dichloromethane solvent solvent 185 insteadinstead of ofDMSO, DMSO, the the product product 22 22waswas obtained obtained in ina good a good 78% 78% yield, yield, modest modest 2:1 2:1 dr drbutbut with with excellent excellent 186 eesees of of93% 93% and and 86% 86% for for both both diastereoisomers, diastereoisomers, respec respectively.tively. This This constitutes constitutes the the highest highest selectivity selectivity 187 obtainedobtained at that at that time time for a for catalytic a catalytic metal-based metal-based transformation transformation of a non-symmetrical of a non-symmetrical barbituric barbituric acid. 188 Thatacid. is Thatnoteworthy is noteworthy as this asrequires this requires the chiral the chiral discrimination discrimination between between an N anMeN Meand and NHN Hamide amide 189 moietiesmoieties of ofthe the pro-nucleophilic pro-nucleophilic partner partner 20.20 . 190

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191 192 SchemeScheme 4. Catalyzed 4. Catalyzed asymmetric asymmetric allylic allylic alkylation alkylation reaction. reaction.

193 Recently,Recently, Palomo Palomo and and co-workers co-workers tackled tackled the the enantioselective enantioselective alkylation alkylation reaction reaction of of 194 non-symmetricalnon-symmetrical barbituric barbituric acid acid derivatives derivatives making making use of anan organocatalyticorganocatalytic strategy strategy (Scheme (Scheme5)[ 5)31 ]. 195 [31].After After the the observation observation of of very very moderatemoderate ees obtainedobtained using using (thio)barbituric (thio)barbituric acid acid nucleophiles, nucleophiles, 196 thisthis research research established established that that 2-alkylthio-4,6-dioxopyrimides 2-alkylthio-4,6-dioxopyrimides 25 25werewere competent competent barbituric barbituric acid acid 197 surrogatessurrogates for forthe theconjugate conjugate addition addition reaction reaction to vinyl to vinylaryl ketones aryl ketones 26. Upon26. the Upon influence the influence of a newly of a 198 designednewly designedsquaramide-derived squaramide-derived 9-epi-amino 9- epiquinine-amino 28a quinine organocatalyst,28a organocatalyst, as a chiral asBrønsted a chiral base, Brønsted an 199 arraybase, of an Michael array of adducts Michael 27 adducts were 27synthesizedwere synthesized in good in yields good yieldsand ees and rangingees ranging from from 90 to 90 to97% 97% 200 irrespectiveirrespective of ofthe the nature nature of ofsubstituents substituents (R (R1, R1,R2, and2, and Ar) Ar) on onprecursors precursors 25 25andand 26.26 To. Toexplain explain the the 201 enantioselectivityenantioselectivity of ofthis this reaction, reaction, the the authors authors prop proposedosed a transition a transition state state in inwhich which the the bifunctional bifunctional 202 organocatalystorganocatalyst 28a28a wouldwould create create two two hydrogen hydrogen bonds bonds be betweentween the the squaramide squaramide moiety moiety and and the the 203 correspondingcorresponding enolate enolate of ofbarbiturate barbiturate derivative derivative 25 25withinwithin the the ion-pair ion-pair 29 29(Scheme(Scheme 5),5 ),and and more more 204 preciselyprecisely with with the the most most accessible accessible oxy-anion. oxy-anion. Then, Then, enones enones 26 26wouldwould approach approach the the front-face front-face of ofthe the 205 barbituratebarbiturate enolate enolate escorted escorted by by a hydrogen a hydrogen bondin bondingg allowed allowed by by the the quinuclidinium quinuclidinium cation cation moiety. moiety. 206 Notwithstanding this major achievement in this field of research, the Michael reaction could not be extrapolated to less reactive acrylate derivatives, and the moderately sterically hindered acrolein led to a modest ee of 48% [31]. Nevertheless, this group showed that enone 30 (Scheme6), a precursor of acrylates or acrolein after oxidative cleavage sequences, was able to undergo the stereoselective conjugate addition of 25 under rather similar organocatalytic conditions to give barbituric acid products 31 with ees between 81% and 94%, after an acidic hydrolysis of the 2-benzylthioether moiety. As depicted in Scheme6, this reaction tolerates various linear and branched alkyl substituents at C5 (R1), and both alkyl and aryl pendants on nitrogen (R2) of products 31a-f. Curiously, as an exception, the precursors 29 with an iso-propyl (R1) did not furnish any product 31g in these conditions (Scheme6).

Catalysts 2019, 9, 131 8 of 27 Catalysts 2018, 8, x FOR PEER REVIEW 8 of 30

207 208 SchemeScheme 5. Organocatalytic 5. Organocatalytic conjugate conjugate addition addition reaction. reaction. Catalysts 2018, 8, x FOR PEER REVIEW 9 of 30 209 Notwithstanding this major achievement in this field of research, the Michael reaction could not 210 be extrapolated to less reactive acrylate derivatives, and the moderately sterically hindered acrolein 211 led to a modest ee of 48% [31]. Nevertheless, this group showed that enone 30 (Scheme 6), a 212 precursor of acrylates or acrolein after oxidative cleavage sequences, was able to undergo the 213 stereoselective conjugate addition of 25 under rather similar organocatalytic conditions to give 214 barbituric acid products 31 with ees between 81% and 94%, after an acidic hydrolysis of the 215 2-benzylthioether moiety. As depicted in Scheme 6, this reaction tolerates various linear and 216 branched alkyl substituents at C5 (R1), and both alkyl and aryl pendants on nitrogen (R2) of products 217 31a-f. Curiously, as an exception, the precursors 29 with an iso-propyl (R1) did not furnish any 218 product 31g in these conditions (Scheme 6). 219

220 221 SchemeScheme 6. Organocatalytic 6. Organocatalytic Michael Michael reac reactiontion to versatile to versatile enones. enones.

222 The scope of this transformation was further broadened during the development of an 223 asymmetric allylation reaction thanks to the potent Cinchona derived organocatalyst 28a (Scheme 7). 224 The reaction proceeded smoothly between barbiturate 32 and the Morita-Baylis-Hillman allyl 225 bromide 33 in the presence of potassium carbonate to neutralize the HBr production. As a 226 representative example, the allylated product 34 was synthesized in 65% yield and 92% ee. The 227 optimization demonstrated that the best results were obtained with electrophile 33 having a

228 tert-butyl ester and K2CO3 proved to be the more suitable base. The authors illustrated the usefulness 229 of the obtained barbiturate derivatives, such as 34, possessing an all-carbon quaternary stereocenter 230 by performing various transformations [31]. For instance, a metathesis reaction on product 34 231 furnished the cyclopentene 35 in 78% yield (Scheme 7). Eventually, the barbituric acid architecture 232 36 was formed upon an acidic hydrolysis. 233

234 235 Scheme 7. Organocatalytic allylation reaction.

236 These achievements constitute a breakthrough in the field of catalytic enantioselective 237 transformations of non-symmetrical barbituric acid derivatives along with the demonstration of 238 useful transformations of the obtained enantioenriched products. In parallel, the development of

Catalysts 2018, 8, x FOR PEER REVIEW 9 of 30

220 Catalysts 2019, 9, 131 9 of 27 221 Scheme 6. Organocatalytic Michael reaction to versatile enones.

222 TheThe scope scope of of thisthis transformationtransformation was was further furthe broadenedr broadened during during the development the development of an asymmetric of an 223 asymmetricallylation reactionallylation thanks reaction to thethanks potent to theCinchona potentderived Cinchona organocatalyst derived organocatalyst28a (Scheme 28a7). (Scheme The reaction 7). 224 Theproceeded reaction smoothlyproceeded between smoothly barbiturate between32 barbiturateand the Morita-Baylis-Hillman 32 and the Morita-Baylis-Hillman allyl bromide 33 allylin the 225 bromidepresence 33of in potassium the presence carbonate of potassium to neutralize carbonate the HBr to production.neutralize the As aHBr representative production.example, As a 226 representativethe allylated example, product 34 thewas allylated synthesized product in 65%34 was yield synthesized and 92% ee .in The 65% optimization yield and 92% demonstrated ee. The 227 optimizationthat the best demonstrated results were obtainedthat the withbest electrophileresults were33 havingobtained a tertwith-butyl electrophile ester and 33 K2 COhaving3 proved a 228 tertto-butyl be the ester more and suitable K2CO3 proved base. to The be authorsthe more illustrated suitable base the. The usefulness authors of illustrated the obtained the usefulness barbiturate 229 of derivatives,the obtained suchbarbiturate as 34, possessingderivatives, ansuch all-carbon as 34, possessing quaternary an all-carbon stereocenter quaternary by performing stereocenter various 230 bytransformations performing various [31]. Fortransfor instance,mations a metathesis [31]. For reactioninstance, on a productmetathesis34 furnishedreaction on the product cyclopentene 34 231 furnished35 in 78% the yield cyclopentene (Scheme 735). in Eventually, 78% yield the(Scheme barbituric 7). Eventually, acid architecture the barbituric36 was acid formed architecture uponan 232 36 acidicwas formed hydrolysis. upon an acidic hydrolysis. 233

234 235 SchemeScheme 7. Organocatalytic 7. Organocatalytic allylation allylation reaction. reaction.

236 TheseThese achievements achievements constitute constitute a abreakthrough breakthrough in inthe the field field of ofcatalytic catalytic enantioselective enantioselective 237 transformationstransformations of of non-symmetrical non-symmetrical barbituric acidacid derivativesderivatives along along with with the the demonstration demonstration of useful of 238 usefultransformations transformations of the of obtained the obtained enantioenriched enantioenriched products. products. In parallel, In parallel, the development the development of catalytic of asymmetric addition reactions of symmetrical barbituric acid derivatives to prochiral electrophiles has evolved (see Section below).

2.2. Addition Reactions with Stereocenters Created Outside the Ring Inspired by previous reports by Brunner et al., dealing with the Pd-catalyzed asymmetric allylic alkylation reaction (AAA) of pro-chiral barbituric acid derivatives [20–23], Trost et al. reported the AAA reaction of symmetrical barbituric acid derivatives in the course of the synthesis of cyclopentobarbital 38 and pentobarbital 42 that are known to exhibit sedative and hypnotic properties, respectively (Scheme8)[ 30]. Initial attempt to synthesize cyclopentobarbital 38 from allylic barbituric acid 1 derivatives 37a (R = allyl) and allylic carbonate in the presence of Pd2(dba)3·CHCl3 (2.5 mol%), ◦ ligand (S,S)-23 (5 mol%, see Scheme4 for structure), and Et 3N (1 equivalent) in CH2Cl2 at 25 C allowed the formation of the expected product 38 in high enantiomeric excess (84% ee). However, moderate isolated yield of 39% was obtained due to the presence of significant amounts of di- and tri-alkylated products 40 and 41, respectively (38/40/41 = 4.3:1:1). The presence of polyalkylated products was assigned to the higher solubility and hence reactivity of the first formed monoalkylated product 38 versus barbituric acid 37a. To solve this issue, the reaction was performed without base but in the presence of an ammonium salt (n-Hex4NBr) playing a dual role of (1) providing a more sterically congested nucleophile resulting in the diminution of polyalkylated products, and (2) increasing interactions between the nucleophile and the ligand, thus, improving the enantiomeric excesses. Indeed, by implementing such conditions and by switching to ligand (S,S)-24 (see Scheme4), Catalysts 2019, 9, 131 10 of 27

a selective formation of the cyclopentobarbital 38 was observed in a good isolated yield of 85% and excellent 91% ee. The (R)-absolute configuration of 38 was proposed using the predictive model previously developed by Trost et al. for such type of ligands and nucleophiles [32]. To synthesize pentobarbital 42 from barbituric acid derivative 37b and allylic carbonate, the reaction conditions were slightly modified. Indeed, by using the same palladium(0) source (Pd2(dba)3·CHCl3, 1 mol%) in the presence of ligand (R,R)-23 (2 mol%), the mono alkylated product 39 was obtained in almost quantitative yield (96%) and 78% ee in 3h providing that 10 mol% of TBAT (tetra n-butylammonium triphenyldifluorosilicate) was used as additive. After a hydrogenation step, the enantioenriched pentobarbital 38 was obtained in a quantitative yield and 81% ee after a simple recrystallization. (R)-42 is known in the literature, the absolute configuration was eventually ascertained by comparison of the

Catalystsoptical 2018 rotation., 8, x FOR PEER REVIEW 11 of 30

270 271 SchemeScheme 8. Pd-catalyzed 8. Pd-catalyzed allylation allylation of ofmono-substituted mono-substituted 5-barbituric 5-barbituric acid acid derivatives. derivatives. Later, Rawal et al. reported an enantioselective Michael addition of N,N0-disubstituted barbituric 272 Later, Rawal et al. reported an enantioselective Michael addition of N,N’-disubstituted acid derivatives 5 to β-nitro olefins 43 using chiral thiosquaramides 44 as a bifunctional organocatalyst 273 barbituric acid derivatives 5 to β-nitro olefins 43 using chiral thiosquaramides 44 as a bifunctional (Scheme9)[ 33]. To circumvent the known solubility issue of the original squaramide catalysts, 274 organocatalyst (Scheme 9) [33]. To circumvent the known solubility issue of the original squaramide the authors have developed an unprecedented and more soluble chiral thiosquaramide version 44. 275 catalysts, the authors have developed an unprecedented and more soluble chiral thiosquaramide Furthermore, the higher acidity of the N–H bonds of the thiosquaramide moiety was estimated with a 276 version 44. Furthermore, the higher acidity of the N–H bonds of the thiosquaramide moiety was lower pKa of 4 to 5 units in comparison to the squaramide counterpart allowing stronger hydrogen 277 estimated with a lower pKa of 4 to 5 units in comparison to the squaramide counterpart allowing bonding activation events. Several chiral thiosquaramides 44, having a chiral cyclohexanediamine 278 stronger hydrogen bonding activation events. Several chiral thiosquaramides 44, having a chiral scaffold, were synthesized in three steps from commercially available butyl squaramate ester in 279 cyclohexanediamine scaffold, were synthesized in three steps from commercially available butyl good yields ranging from 67 to 83%. These catalysts were evaluated in the nucleophilic 1,4-addition 280 squaramate ester in good yields ranging from 67 to 83%. These catalysts were evaluated in the reaction of N,N0-diphenyl barbituric acid 5b acid to β-nitro styrene 43a. In each case, complete 281 nucleophilic 1,4-addition reaction of N,N’-diphenyl barbituric acid 5b acid to β-nitro styrene 43a. In conversions into adduct 45 were obtained in toluene at room temperature in half an hour along with 282 each case, complete conversions into adduct 45 were obtained in toluene at room temperature in half 283 an hour along with ees ranging from 45 to 97% even at catalyst loading as low as 0.5 mol%. 284 Interestingly, a comparison of catalyst 44b to its squaramide version 46 revealed that both catalysts 285 are very similar in terms of conversion (above 98%) and enantioselectivity (97% ee vs 95% ee, 286 respectively). It is noteworthy that the reaction could be carried out using only 0.05 mol% of catalyst 287 44b in toluene without erosion of both conversion and enantioselectivity (>98%, 96% ee). As 288 mentioned by the authors, these reactions were conducted without any precautions under air 289 atmosphere. Thus, by implementing optimized conditions (i.e., 0.5 mol% of catalyst 44b in toluene at 290 room temperature for 0.5 h to 24 h), several addition products 45 have been obtained in excellent 291 isolated yields and ees regardless to the substitution of the barbituric precursors 5 or the 292 β-nitrostyrenes 43 (Scheme 9c). Only for more sterically hindered precursors 5 or 43, longer reaction 293 times (24 h instead of 0.5 h) and higher catalyst loading (5 mol% instead of 0.5 mol%) were required 294 to maintain the level of isolated yields and ees. For HPLC analysis issue (high retention times and 295 broad peaks), the addition products 45 were chlorinated to afford 47 before analysis. 296

Catalysts 2019, 9, 131 11 of 27

ees ranging from 45 to 97% even at catalyst loading as low as 0.5 mol%. Interestingly, a comparison of catalyst 44b to its squaramide version 46 revealed that both catalysts are very similar in terms of conversion (above 98%) and enantioselectivity (97% ee vs 95% ee, respectively). It is noteworthy that the reaction could be carried out using only 0.05 mol% of catalyst 44b in toluene without erosion of both conversion and enantioselectivity (>98%, 96% ee). As mentioned by the authors, these reactions were conducted without any precautions under air atmosphere. Thus, by implementing optimized conditions (i.e., 0.5 mol% of catalyst 44b in toluene at room temperature for 0.5 h to 24 h), several addition products 45 have been obtained in excellent isolated yields and ees regardless to the substitution of the barbituric precursors 5 or the β-nitrostyrenes 43 (Scheme9c). Only for more sterically hindered precursors 5 or 43, longer reaction times (24 h instead of 0.5 h) and higher catalyst loading (5 mol% instead of 0.5 mol%) were required to maintain the level of isolated yields and ees. For HPLC analysis issue (high retention times and broad peaks), the addition products 45 were

Catalystschlorinated 2018, 8, tox FOR afford PEER47 REVIEWbefore analysis. 12 of 30

297 0 298 SchemeScheme 9. 9. OrganocatalyzedOrganocatalyzed enantioselec enantioselectivetive Michael Michael addition addition of ofN,N’N,-disubstitutedN -disubstituted barbituric barbituric acid acid 299 derivativesderivatives to to ββ-nitro olefins.olefins. ( a()a General) General conditions. conditions. (b) Catalyst(b) Catalyst optimization. optimization. (c) Scope (c) andScope limitations. and 300 limitations.

301 The same year, Wang and co-workers reported on the enantioselective organocatalytic Michael 302 addition of N,N’-dialkylbarbituric acid derivatives 5 to β-substituted enones 48 making use of chiral 303 bifunctional squaramide catalyst 28b based upon a 9-epi-aminoquinine scaffold (Scheme 10) [34]. 304 The screening of reaction parameters was performed using N,N’-dimethyl barbituric acid 5a and 305 chalcone 48a as model substrates in toluene at 25 °C. Quinine (QN) provided the corresponding 306 addition product 49a in a good yield of 68%, but ee values did not exceed 15% (Scheme 10a). Drastic 307 improvement of the induction was achieved by switching to bifunctional squaramide catalyst 28b 308 (10 mol%) allowing to obtain product 49a in 78% ee. After an optimization endeavor, the best 309 conditions were set as followed: o-xylene as solvent at room temperature in the presence of 10 mol% 310 of catalyst 28b using N,N’-di-tert-butylbarbituric acid 5c as substrate. Then, a survey of the scope of 311 the reaction was undertaken using various substituted enones 48 and barbituric acid 5c (R1 = t-Bu, 312 Scheme 10c). A large panel of Michael adducts 49 flanked by mono or di-substituted 313 (electron-withdrawing or electron-donating groups) aryl, heteroaryl could be tolerated as long as R2

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The same year, Wang and co-workers reported on the enantioselective organocatalytic Michael addition of N,N0-dialkylbarbituric acid derivatives 5 to β-substituted enones 48 making use of chiral bifunctional squaramide catalyst 28b based upon a 9-epi-aminoquinine scaffold (Scheme 10)[34]. The screening of reaction parameters was performed using N,N0-dimethyl barbituric acid 5a and chalcone 48a as model substrates in toluene at 25 ◦C. Quinine (QN) provided the corresponding addition product 49a in a good yield of 68%, but ee values did not exceed 15% (Scheme 10a). Drastic improvement of the induction was achieved by switching to bifunctional squaramide catalyst 28b (10 mol%) allowing to obtain product 49a in 78% ee. After an optimization endeavor, the best conditions were set as followed: o-xylene as solvent at room temperature in the presence of 10 mol% of catalyst 28b using N,N0-di-tert-butylbarbituric acid 5c as substrate. Then, a survey of the scope of the reaction was undertaken using various substituted enones 48 and barbituric acid 5c (R1 = t-Bu, Scheme 10c). A large panel of Michael adducts 49 flanked by mono or di-substituted (electron-withdrawing or electron-donatingCatalysts 2018, 8, x FOR groups) PEER REVIEW aryl, heteroaryl could be tolerated as long as R2 and R3 substituents13 of 30 are concerned in almost perfect stereoinduction (25 examples, 95–99% ee) with, nonetheless, variable 314 and R3 substituents are concerned in almost perfect stereoinduction (25 examples, 95–99% ee) with, 2 3 315isolated nonetheless, yields (44–99%).variable isolated Aliphatic yields R (44–99%).group (Aliphaticn-Pr) in associationR2 group (n-Pr) with in association phenyl R withgroup phenyl resulted in a 3 2 316slight R3 dropgroup of resulted the ee (92%)in a slight whereas drop of enones the ee (92%) with whereas R = Me, enones and Rwith= PhR3 = or Me,n-Pr and remained R2 = Ph or unreactiven-Pr in 317the reactionremained conditions. unreactive in The the absolutereaction conditions. configuration The absolute of compounds configuration49i was of compounds attributed 49i as (wasS) thanks to 318single-crystal attributed as X-ray (S) thanks analysis. to single-crystal To account forX-ray the analysis. high level To ofaccount induction for the observed, high level the of induction authors proposed 319a transitionobserved, state the authors where proposed the squaramide a transition part stat ofe thewhere catalyst the squaramide28b binds part to theof the carbonyl catalyst of28b the enone 320 binds to the carbonyl of the enone while the barbituric acid moiety (under its enol form) is while the barbituric acid moiety (under its enol form) is well-positioned by the quinucline Brønsted 321 well-positioned by the quinucline Brønsted base part (Scheme 10b). Thus, an addition to the Re-face 322base of part the enone (Scheme is favored. 10b). Thus, an addition to the Re-face of the enone is favored. 323

324 325 SchemeScheme 10. 10.Organocatalyzed Organocatalyzed enantioselective Michael Michael addition addition of N,N’ of-disubstitutedN,N0-disubstituted barbituric barbituric acid acid 326 derivativesderivatives to toβ -substitutedβ-substituted enones. (a ( aand,b) b Importance) Importance ofof the bifunctional bifunctional nature nature of the of catalyst the catalyst in in the 327 transitionthe transition state. state. (c) Scope (c) Scope and and limitations. limitations.

328 2.3. Annulation Reactions 329 Barbituric acid derivatives may also be involved in annulation reactions. This approach was 330 first tackled by Chen and co-workers during the synthesis of tetrahydropyrano bicycles 50 (Scheme 331 11) [35]. Starting from N,N’-dimethyl barbituric acid 5a and Morita-Baylis-Hillman (MBH) acetate of 332 nitroalkene 51, a domino Michael-oxa-Michael addition reaction was achieved upon 333 organocatalysis. During the reaction investigation, it was found that the original tertiary 334 amine-thiourea bifunctional organocatalyst 52 was superior to the other organocatalysts. Thus, by 335 applying optimized conditions (i.e. 10 mol% of 52, CH2Cl2, 25 °C), the investigation of the scope of 336 the reaction was undertaken. Excellent results were obtained regardless of the substitution pattern

Catalysts 2019, 9, 131 13 of 27

2.3. Annulation Reactions Barbituric acid derivatives may also be involved in annulation reactions. This approach was first tackled by Chen and co-workers during the synthesis of tetrahydropyrano bicycles 50 (Scheme 11)[35]. Starting from N,N0-dimethyl barbituric acid 5a and Morita-Baylis-Hillman (MBH) acetate of nitroalkene 51, a domino Michael-oxa-Michael addition reaction was achieved upon organocatalysis. During the reaction investigation, it was found that the original tertiary amine-thiourea bifunctional organocatalyst 52 was superior to the other organocatalysts. Thus, by applying optimized conditions (i.e., 10 mol% of ◦ 52, CH2Cl2, 25 C), the investigation of the scope of the reaction was undertaken. Excellent results were obtained regardless of the substitution pattern on the aromatic ring to give 76–99% isolated yields, Catalysts 2018, 8, x FOR PEER REVIEW 14 of 30 dr <19:1 and 86–99% ees. Polyaromatic or heretoaromatic ring pendants of the MBH adduct 51 were 337tolerated on the but aromatic at the expensering to give of a 76-99% slight dropisolated of yields, the diastereoisomeric dr <19:1 and 86-99% ratio ees. ( drPolyaromatic>10:1) or isolatedor yield 338(51%), heretoaromatic respectively. ring To accountpendants forof the the MBH high adduct diastereo- 51 were and tolerated enantioselectivity, but at the expense the of authors a slight proposed a 339 drop of the diastereoisomeric ratio (dr >10:1) or isolated yield (51%), respectively. To account for the transition state where the amine part of the catalyst would deprotonate the barbituric acid 5a while 340 high diastereo- and enantioselectivity, the authors proposed a transition state where the amine part 341its thioureaof the catalyst part binds would to deprotonate the nitro group the barbituric of the MBHacid 5a derivative while its thiourea51. This part results binds to in the a well-definednitro TS 342allowing group an of attack the MBH of the derivative enolate 51 to. This the resultsRe-face in a of well-defined the nitroalkene TS allowing51. Then, an attack a 6-endo-trig of the enolateannulation to took 343place throughthe Re-face a 6-memberedof the nitroalkene ring 51 transition. Then, a 6-endo-trig state where annulation the nitro took group place isthrough in pseudo-equatorial a 6-membered position 344 to minimizering transition steric interactionsstate where the with nitro an aromaticgroup is in group, pseudo-equatorial thus, leading position to product to minimize50 as transsteric -isomers in 345 interactions with an aromatic group, thus, leading to product 50 as trans-isomers in high diastereo- 346high diastereo-and enantioselectivity. and enantioselectivity. 347

348 349 SchemeScheme 11. Organocatalyzed 11. Organocatalyzed enantioselective enantioselective Michael-oxa-Michael Michael-oxa-Michael addition addition sequence sequence of Nof,N 0-dimethyl 350 barbituricN,N’-dimethyl acid to Morita-Baylis-Hillmanbarbituric acid to Morita-Baylis-Hillman adduct. adduct.

351 One year later, the same group reported on a (3+3) annulation reaction consisted of a similar 352 Michael-oxa-Michael sequence starting from N,N’-dimethyl barbituric acid 5a but in the presence of 353 2-(1-alkynyl)-2-alken-1-ones 53 as electrophilic partners (Scheme 12) [36]. Thus, by implementing the

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One year later, the same group reported on a (3+3) annulation reaction consisted of a similar Michael-oxa-Michael sequence starting from N,N0-dimethyl barbituric acid 5a but in the presence of 2-(1-alkynyl)-2-alken-1-ones 53 as electrophilic partners (Scheme 12)[36]. Thus, by implementing the Takemoto’s organocatalyst, possessing an amine-thiourea bifunctional scaffold 54 (10 mol%) in mesitylene at −20 ◦C, almost 20 cyclic products 55 were obtained in fair to good isolated yields (32–87%) and moderate to high ees of 67–94%. The substitution of Ar1 by either electro-withdrawing or -donating groups proved to have a low impact on the ees being generally above 80% except for nitro-substituted compounds obtained in 67% ee values. This was attributed to possible interactions with the catalyst that hamper the optimal activation process. Contrariwise, substitution of Ar2 was found to have a positive effect on the asymmetric induction leading to ees ranging from 84 to 94%. Generally speaking, the steric effect seems to be detrimental to obtain high yields and enantioselectivties as shown by results obtained with 2,4-dichloro substituent on Ar1 whereas no reaction was observed when cyclohexyl was used instead of Ar1 group or in the presence of N,N0-diethyl barbituric acid 5d. From a mechanistic point of view, the authors proposed the activation of the barbituric acid 5a, under its enol form, by the tertiary amine part of the catalyst meanwhile the thiourea moiety chelates the carbonyl group of the enynone 53 to favor the attack of nucleophile to the Si-face of the C–C double bond of 53. Then, an oxa-Michael addition to the transient allene 56 takes place, thus, affording the (3+3) cycloadduct 55. Catalysts 2018, 8, x FOR PEER REVIEW 16 of 30

370 371 Scheme 12. Organocatalyzed enantioselective Michael-oxaMichael addition sequence of Scheme 12. Organocatalyzed enantioselective Michael-oxaMichael addition sequence of N,N0-dimethyl 372 N,N’-dimethyl barbituric acid to enynones. barbituric acid to enynones. 373 An example of annulation reaction consisted of two consecutive C–C bonds was reported in 374 2015 by Lam and co-workers during the synthesis of a series of spiro-indenes of type 59 with good to 375 excellent ees. However, in this study, a single example was reported which involved the 376 1-methyl-5-phenylbarbituric acid 57 and alkynes 58 in the presence of chiral rhodium complexes 60 377 as catalyst and Cu(OAc)2 as oxidant giving rise to the formation of 59 in good isolated yield (76%) 378 but with only 11% ee (Scheme 13) [37]. This low enantioselection was attributed to the fact that both 379 carbonyl functional groups (which act as directing groups for the formation of the rhodacycle 61 in

Catalysts 2019, 9, 131 15 of 27

An example of annulation reaction consisted of two consecutive C–C bonds was reported in 2015 by Lam and co-workers during the synthesis of a series of spiro-indenes of type 59 with good to excellent ees. However, in this study, a single example was reported which involved the 1-methyl-5-phenylbarbituric acid 57 and alkynes 58 in the presence of chiral rhodium complexes 60 Catalysts 2018, 8, x FOR PEER REVIEW 17 of 30 as catalyst and Cu(OAc)2 as oxidant giving rise to the formation of 59 in good isolated yield (76%) Catalystsbut with2018, 8 only, x FOR 11% PEERee REVIEW(Scheme 13)[37]. This low enantioselection was attributed to the fact17 that of 30 both 380 the catalytic cycle) adjacent to the phenyl substituent are electronically and sterically similar. This carbonyl functional groups (which act as directing groups for the formation of the rhodacycle 61 in the 381 results in a lack of stereodifferentiation between the two possible transition states (rhodacycles 61 380 thecatalytic catalytic cycle) cycle) adjacent adjacent to to the the phenyl phenyl substituent substituent are are electronically electronically and and sterically sterically similar. similar. This This results 382 and ent-61) obtained after the coordination and migratory insertion of the alkyne partner. 381 resultsin a lackin a oflack stereodifferentiation of stereodifferentiation between between the two the possible two possible transition transition states (rhodacycles states (rhodacycles61 and ent 61-61 ) 383 382 andobtained ent-61) obtained after the coordinationafter the coordination and migratory and mi insertiongratory insertion of the alkyne of the partner. alkyne partner. 383

384 384 385 Scheme 13. Rhodium(III)-catalyzed enantioselective CH-functionalization-spiroannulation 386 sequence. 385 SchemeScheme 13. 13. Rhodium(III)-catalyzedRhodium(III)-catalyzed enantioselective enantioselective CH-functionalization-spiroannulation CH-functionalization-spiroannulation sequence. 386 sequence. 387 3. Enantioselective3. Enantioselective Transformations Transformations from from Alkylidene Alkylidene Barbituric Barbituric Acid Acid 387 3883. EnantioselectiveAsAs discussed discussed Transformations in in the the introduction introduction from (Cf.Alkylidene (Cf. § 1.2),§ 1.2), alkylideneBarbituric alkylidene Acid barbituric barbituric acids acids are are highly highly reactive reactive 388 389 electron-poorAselectron-poor discussed alkene inalkene the derivatives introductionderivatives which which (Cf. have § have 1.2), been beenalkylidene involved involved barbituric into into either either acids cycloaddition cycloaddition are highly or or annulationreactive annulation 389 390electron-poor reactionreaction (Scheme alkene(Scheme 14derivatives ).14). On On the thewhich one one hand, have hand, been under under involved asymmetric asymmetric into either catalytic catalytic cycloaddition conditions, conditions, or (3+2) annulation(3+2) and and (4+2) (4+2) 390 391reaction cycloadditioncycloaddition (Scheme or14). or annulation annulationOn the one reactions reactions hand, tookunder took place asplacymmetric one on the the C–C catalytic C–C double double conditions, bond bond and and (3+2) have have and allowed allowed (4+2) the the 391 392cycloaddition constructionconstruction or of annulation of spiro-compounds spiro-compounds reactions (path took(path A). plac A). On eOn theon the otherthe other C–C hand, hand,double suitably suitably bond designed anddesigned have dienophiles dienophilesallowed the led led to to 392 393construction enantioselectiveenantioselective of spiro-compounds Diels–Alder Diels–Alder reactions (path reactions A). through On through the other the the concomitant hand, concomitant suitably C–C C–C designed and and C–O C–Odienophiles bond bond formation formation led to to to 393 394enantioselective provideprovide chiral chiral Diels–Alder fused-compounds fused-compounds reactions (path (paththrough B). B). the concomitant C–C and C–O bond formation to 394 395provide chiral fused-compounds (path B). 395

396 396 397 SchemeScheme 14. 14.Annulation Annulation reaction reaction onto onto alkylidene alkylidene barbituric barbituric acids. acids. 397 Scheme 14. Annulation reaction onto alkylidene barbituric acids. 398 3.1. (3+2) Cycloaddition Reactions 398 3993.1. (3+2) CycloadditionAlkylidene barbituratesReactions have been involved in (3+2) cycloaddition as found by different 399 400 Alkylideneresearch groups. barbiturates First of haveall, isothiocyanates been involved were in (3+2) used cycloadditionwith amine catalysis as found (Scheme by different 15, a). Then, 400 401research Morita-Baylis-Hillman groups. First of all, isothiocyanates(MBH) adduct wereor ynoneused with starting amine materials catalysis (Schemewere reported 15, a). Then,as dipole 401 402Morita-Baylis-Hillman precursors along with(MBH) phosphine adduct catalysis. or ynone (Scheme starting 15, bmaterials and c). were reported as dipole 402 403precursors along with phosphine catalysis. (Scheme 15, b and c). 403

Catalysts 2019, 9, 131 16 of 27

3.1. (3+2) Cycloaddition Reactions Alkylidene barbiturates have been involved in (3+2) cycloaddition as found by different research groups. First of all, isothiocyanates were used with amine catalysis (Scheme 15a). Then, Morita-Baylis-Hillman (MBH) adduct or ynone starting materials were reported as dipole precursors Catalysts 2018, 8, x FOR PEER REVIEW 18 of 30 along with phosphine catalysis (Scheme 15b,c). 404

405

406 SchemeScheme 15. Reagents 15. Reagents in in (3+2) (3+2) cycloadditioncycloaddition with with alkylidene alkylidene barbiturate. barbiturate.

407 For moreFor than more ten than years, ten isothiocyanates years, isothiocyanates have been have engaged been engaged in catalytic in catalytic reactions reactions as isothiocyanato as amides,408 isothiocyanato esters or phosphonates. amides, esters or In phosphonates. 2015, Liu’s groupIn 2015, published Liu’s groupon published a racemic on a(3+2) racemic cycloaddition (3+2) between409 cycloaddition alkylidene between barbiturates alkylidene8 and barbiturates 3-isothiocyanato 8 and 3-isothiocyanato oxindoles 62oxindolescatalyzed 62 catalyzed by triethylamine by 410 triethylamine (Scheme 16) [38]. In 2016, the same authors reported on an enantioselective version (Scheme 16)[38]. In 2016, the same authors reported on an enantioselective version catalyzed by a 411 catalyzed by a Cinchona-based thiourea 64 leading to spirobarbiturates 63 in modest to excellent ees Cinchona412 and-based 20:1 thioureadr in most64 casesleading (Scheme to spirobarbiturates 16) [39]. The best reaction63 in modest conditions to excellent involved eesthe anduse 20:1of dr in most413 cases9-epi (Scheme-quinine-thiourea 16)[39 64]. The(10 mol%), best reaction p-toluic acid conditions (10 mol%) involved and 4 Å molecular the use sieves of 9-epi in -quinine-thioureachloroform. 64414(10 mol%),Accordingp-toluic to the proposed acid (10 mechanism mol%) and (see 4TS Å in molecular Scheme 16), sievesp-toluic inacid chloroform. drives the equilibrium According of to the proposed415 62 mechanismtowards its enol (see form, TS inwhich Scheme forms 16 a), hydrogenp-toluic bond acid driveswith the the tertiary equilibrium amine of ofcatalyst62 towards 64. The its enol 416 form, whichbifunctional forms nature a hydrogen of organocatalyst bond with 64 the allows tertiary extra-hydrogen amine of bonding catalyst interactions64. The bifunctional between both nature of 417 the thiourea and barbituric acid moieties, thus, providing a well-organized transition state that organocatalyst 64 allows extra-hydrogen bonding interactions between both the thiourea and barbituric 418 favors the selective addition of the nucleophile 62 to one the two prosterogeneic faces of the acid419 moieties,alkylidene thus, derivative providing 8. The a scope well-organized with regard to transition alkylidene statebarbiturates that favors 8 was studied the selective and showed addition of the420 nucleophilethat aryl substituents62 to one (R the1) were two well-tolerated prosterogeneic irrespective faces to of the the substitution alkylidene patte derivativern on the rings8. The(R2 scope with421 regard= R3 = toMe: alkylidene 80–99% yield, barbiturates 13:1 to >20:18 wasdr, 75–99% studied ee). andNevertheless, showed it that was aryldemonstrated substituents that the (R 1) were well-tolerated422 position irrespective of substituents to thesignificantly substitution influenced pattern the on selectivity the rings (Ras 2shown= R3 = with Me: 3-chlorophenyl 80–99% yield, 13:1 to 423 >20:1 drderivative, 75–99% 63bee). obtained Nevertheless, in 96% itee waswhereas demonstrated 4-chlorophenyl that derivative the position 63d was of isolated substituents in only significantly 75% 424 ee. Moreover, cycloaddition products 63f-g with 2-naphthyl and iso-propyl pendants were influenced425 synthesized the selectivity in high 93% as shownand 75% with yields, 3-chlorophenyl respectively, albeit derivative with a dramatic63b obtained drop in ees in 96%(31% eeandwhereas 4-chlorophenyl426 18% ees, respectively), derivative 63dprobablywas due isolated to steric in onlyand el 75%ectronicee. Moreover,issues. The scope cycloaddition of 3-isothiocyanato products 63f-g with427 2-naphthyloxindoles and62 hasiso -propylalso been pendants surveyed were showing synthesized that variations in high of 93% R2 and and 75% R3 yields,groups respectively,were albeit428 withwell-tolerated. a dramatic drop in ees (31% and 18% ees, respectively), probably due to steric and electronic issues.429 The scope of 3-isothiocyanato oxindoles 62 has also been surveyed showing that variations of R2 and R3 groups were well-tolerated. In 2018, the Albrecht group tackled the first use of α-substituted α-amino acid-based isothiocyanates 65 in the annulation reaction with alkylidene barbituric acids 8 leading to the spiranic 2-pyrrolidinethiones 66 (Scheme 17)[40]. The original idea was to combine barbituric acid and quaternary α-amino acid, which are both known as bio-relevant architectures. After the screening of solvents and organocatalysts, the best reaction conditions made use of 9-epi-quinine-squaramide 28b (20 mol%) in toluene, leading to 66a in 95% conversion and 94% ee (Scheme 17b). With their optimized conditions in hand, the authors first studied the scope of the reaction from the alkylidene barbiturates point of view. First of all, the substitution pattern of the aromatic part of the benzylidene barbituric acid 8 (R1 = Ar) had almost no influence on the reaction outcome, and excellent ees were generally obtained independently of the nature or the position of the substituents on the aromatic ring. Interestingly, the alkylidene barbituric acids 8 (R1 = i-Pr) also yielded the corresponding product 66e with excellent 92% ee but at the expense of a lower isolated yield of 40%. To account for the high

Catalysts 2019, 9, 131 17 of 27 level of stereoinduction observed, the authors proposed a transition state where the catalyst binds to the alkylidene barbituric acid through hydrogen bonding thanks to the thiourea moiety while the tertiary amineCatalysts part2018, 8 deprotonates, x FOR PEER REVIEW the isothiocyanate 65 (Scheme 17c). 19 of 30

3 R R3 N O N O R1 O R1 R2 O Me 2 N SCN Me R 62 (1 equiv.) N NH O N O 64 S (10 mol%), CHCl3, rt O N O Me p-toluic acid (10 mol%) 4ÅMS Me 63 8 80-99%, 9:1 to >20:1 dr, 18-99% ee

Proposed transition state (TS)NR3 Catalyst 64 (NR3) H 3 1 O R Me O R N OMe N N O CF3 N N NH Me O S R2 N S N CF3 1 2 3 R =4-ClC6H4,R =H,R =Bn H Selected examples (>20:1 dr) 3 R 63a (R1 =Ph,R2 =Me,R3 = Me), 93%, 97% ee O 1 2 3 N 63b (R =3-ClC6H4,R =Me,R = Me), 95%, 96% ee R1 1 2 3 O 63c (R =3-ClC6H4,R =OMe,R = Me), 85%, 65% ee 2 63d (R1 =4-ClC H ,R2 =Me,R3 = Me), 88%, 75% ee Me NH R 6 4 N 1 2 3 63e (R =4-ClC6H4,R =OMe,R = Me), 95%, 97% ee S 1 2 3 O N O 63f (R = 2-Naphthyl, R =Me,R = Me), 93%, 31% ee 63g (R1 = i-Pr, R2 =Me,R3 = Me), 75%, 18% ee 430 Me 431Scheme 16.SchemeOrganocatalytic 16. Organocatalytic synthesis synthesis of of dispirobarbiturates dispirobarbiturates from from 3-isothiocyanato 3-isothiocyanato oxindoles oxindoles and and 432 alkylidenes barbituric acid. alkylidenes barbituric acid. Catalysts 2018, 8, x FOR PEER REVIEW 20 of 30 433 In 2018, the Albrecht group tackled the first use of α-substituted α-amino acid-based 434 isothiocyanates 65 in the annulation reaction with alkylidene barbituric acids 8 leading to the 435 spiranic 2-pyrrolidinethiones 66 (Scheme 17) [40]. The original idea was to combine barbituric acid 436 and quaternary α-amino acid, which are both known as bio-relevant architectures. After the 437 screening of solvents and organocatalysts, the best reaction conditions made use of 438 9-epi-quinine-squaramide 28b (20 mol%) in toluene, leading to 66a in 95% conversion and 94% ee 439 (Scheme 17b). With their optimized conditions in hand, the authors first studied the scope of the 440 reaction from the alkylidene barbiturates point of view. First of all, the substitution pattern of the 441 aromatic part of the benzylidene barbituric acid 8 (R1 = Ar) had almost no influence on the reaction 442 outcome, and excellent ees were generally obtained independently of the nature or the position of the 443 substituents on the aromatic ring. Interestingly, the alkylidene barbituric acids 8 (R1 = i-Pr) also 444 yielded the corresponding product 66e with excellent 92% ee but at the expense of a lower isolated 445 yield of 40%. To account for the high level of stereoinduction observed, the authors proposed a 446 transition state where the catalyst binds to the alkylidene barbituric acid through hydrogen bonding 447 thanks to the thiourea moiety while the tertiary amine part deprotonates the isothiocyanate 65 448 (Scheme 17c). 449

450

451Scheme 17.SchemeEnantioselective 17. Enantioselective synthesis synthesis of spiranic of 2-pyrrolidinethionesspiranic 2-pyrrolidinethiones fromamino from acidamino isothiocyanate acid 452derivatives isothiocyanate and alkylidene derivatives barbituric and alkylidene acids. barbituric (a) General acids. conditions.(a) General conditions. (b) Scope (b) Scope and limitations.and 453 limitations. (c) Proposed transition state. (c) Proposed transition state. 454 Eventually, the Albrecht group envisioned the use of isothiocyanato α-aminophosphonates 67 455 for the synthesis of spirobarbiturates 68 (Scheme 18) [40]. By switching the solvent from toluene to 456 THF, the diphenyl derivative 68a was obtained in 99% yield and 98% ee. Albrecht and co-workers 457 then modified the R1 substituent. Various aryl substituted moieties were tolerated without showing 458 a significant impact on the enantiomeric excesses of the reaction, as exemplified with 3-ClC6H4 and 459 2-ClC6H4 derivatives 68b–68c together with 4-MeOC6H4 derivative 68d providing almost the same 460 ees (92%, 96% and 98%, respectively). Finally, the same trend was observed for the R2 substituents on 461 isothiocyanate nucleophile 67 as underlined by the excellent level of enantioselection obtained either 462 for the 4-ClC6H4 derivative 68e or the 4-MeOC6H4 derivative 68f (96% ee and 94% ee, respectively).

463 464 Scheme 18. Enantioselective spirobarbiturates synthesis from phosphonate isothiocyanate 465 derivatives.

Catalysts 2018, 8, x FOR PEER REVIEW 20 of 30

450

451 CatalystsScheme2019, 9, 13117. Enantioselective synthesis of spiranic 2-pyrrolidinethiones from amino acid18 of 27 452 isothiocyanate derivatives and alkylidene barbituric acids. (a) General conditions. (b) Scope and 453 limitations. (c) Proposed transition state. Eventually, the Albrecht group envisioned the use of isothiocyanato α-aminophosphonates 67 454 for theEventually, synthesis of the spirobarbiturates Albrecht group 68envi(Schemesioned 18the)[ use40]. of By isothiocyanato switching the α solvent-aminophosphonates from toluene to 67 455 THF,for the the synthesis diphenyl of derivative spirobarbiturates68a was obtained68 (Scheme in 99%18) [40]. yield By and switchin 98% eeg. the Albrecht solvent and from co-workers toluene to 456 thenTHF, modified the diphenyl the R1 derivativesubstituent. 68a Various was obtained aryl substituted in 99% yield moieties and were98% toleratedee. Albrecht without and co-workers showing 1 457 athen significant modified impact the R on substituent. the enantiomeric Various excesses aryl substituted of the reaction, moieties as exemplified were tolerated with without 3-ClC6 Hshowing4 and 458 2-ClCa significant6H4 derivatives impact 68bon the–68c enantiomerictogether with excesse 4-MeOCs of6 Hthe4 derivativereaction, as68d exemplifiedproviding with almost 3-ClC the6H same4 and 459 ees2-ClC(92%,6H 96%4 derivatives and 98%, 68b respectively).–68c together Finally, with the 4-MeOC same trend6H4 derivative was observed 68d providing for the R2 substituentsalmost the same on 460 isothiocyanateees (92%, 96% nucleophileand 98%, respectively).67 as underlined Finall byy, the the same excellent trend level was of observed enantioselection for the R obtained2 substituents either on 461 forisothiocyanate the 4-ClC6H4 nucleophilederivative 68e 67 asor underlined the 4-MeOC by6H the4 derivative excellent 68flevel(96% of enantioselectionee and 94% ee, respectively). obtained either 462 for the 4-ClC6H4 derivative 68e or the 4-MeOC6H4 derivative 68f (96% ee and 94% ee, respectively).

463 464 SchemeScheme 18. 18.Enantioselective Enantioselective spirobarbiturates spirobarbiturates synthesis synt fromhesis phosphonate from phosphonate isothiocyanate isothiocyanate derivatives. 465 derivatives. MBH adducts have also been used in (3+2) cycloaddition reaction with alkylidenes barbituric acids 8 as dipolarophile partners. In this reaction, the phosphine catalyst reacts with the MBH adducts 69 to furnish a transient 1,3-dipole giving rise to a (3+2) cycloaddition with the alkylidene barbiturate 8 (Schemes 15b and 19)[41]. In this vein, Guo et al. described in 2016 the first enantioselective phosphine-catalyzed (3+2) annulation of alkylidene barbiturates 8 with MBH adducts 69 leading to spirobarbiturates 70 in excellent diastereoselectivities (>20:1 dr) and high to excellent enantiomeric excesses of 81 to 99% ees (Scheme 19)[41]. Optimization of the catalyst showed that bifunctional phosphine catalyst 71 afforded the best balance between yield and ee of product 70a for instance (76% yield and 93% ee in PhCF3). It was also noted that the addition of molecular sieves along with 20 mol% of K2CO3 increased the yield of 70a from 76 to 85% while ee reached 96%. It is believed that K2CO3 facilitates the formation of the reactive phosphonium zwitterion (See Scheme 15b). Thereafter, the scope of benzylidene barbituric acids 8 was studied, and it was found that aromatic substituents were, in general, well tolerated and gave rise to the formation of products 70 with 60–98% yields and 91–99% ee. However, the use of a cyclohexyl moiety (R1 = cyclohexyl) on the corresponding alkylidene barbituric acid 70d instead of an aromatic ring decreased the yield of product 70d significantly to 30%, while still affording 81% ee. Guo et al. also showed that the MBH precursors 69 including aromatic substituents (R2 = Ar) furnished a wide range of cycloaddition products 70 in excellent yields (64–99%) and enantioselectivities (85–93% ee), independently of the electronic properties of the substituent on 2 the phenyl ring. However, one should note that the yield decreases when R is 3-ClC6H4 (70g, 64%) and that the presence of an aliphatic group (either a cyclohexyl for 70h or an iso-propyl for 70i) on the MBH adduct completely inhibits the reaction. Catalysts 2018, 8, x FOR PEER REVIEW 21 of 30

466 467 MBH adducts have also been used in (3+2) cycloaddition reaction with alkylidenes barbituric 468 acids 8 as dipolarophile partners. In this reaction, the phosphine catalyst reacts with the MBH 469 adducts 69 to furnish a transient 1,3-dipole giving rise to a (3+2) cycloaddition with the alkylidene 470 barbiturate 8 (Scheme 15b and Scheme 19) [41]. In this vein, Guo et al. described in 2016 the first 471 enantioselective phosphine-catalyzed (3+2) annulation of alkylidene barbiturates 8 with MBH 472 adducts 69 leading to spirobarbiturates 70 in excellent diastereoselectivities (>20:1 dr) and high to 473 excellent enantiomeric excesses of 81 to 99% ees (Scheme 19) [41]. Optimization of the catalyst 474 showed that bifunctional phosphine catalyst 71 afforded the best balance between yield and ee of 475 product 70a for instance (76% yield and 93% ee in PhCF3). It was also noted that the addition of 476 molecular sieves along with 20 mol% of K2CO3 increased the yield of 70a from 76 to 85% while ee 477 reached 96%. It is believed that K2CO3 facilitates the formation of the reactive phosphonium 478 zwitterion (See Scheme 15b). Thereafter, the scope of benzylidene barbituric acids 8 was studied, and 479 it was found that aromatic substituents were, in general, well tolerated and gave rise to the 480 formation of products 70 with 60–98% yields and 91–99% ee. However, the use of a cyclohexyl 481 moiety (R1 = cyclohexyl) on the corresponding alkylidene barbituric acid 70d instead of an aromatic 482 ring decreased the yield of product 70d significantly to 30%, while still affording 81% ee. Guo et al. 483 also showed that the MBH precursors 69 including aromatic substituents (R2 = Ar) furnished a wide 484 range of cycloaddition products 70 in excellent yields (64–99%) and enantioselectivities (85–93% ee), 485 independently of the electronic properties of the substituent on the phenyl ring. However, one 486 should note that the yield decreases when R2 is 3-ClC6H4 (70g, 64%) and that the presence of an

487 aliphaticCatalysts 2019 group, 9, 131 (either a cyclohexyl for 70h or an iso-propyl for 70i) on the MBH adduct completely19 of 27 488 inhibits the reaction. 489

490 491 SchemeScheme 19.19.(3+2) (3+2) Cycloaddition Cycloaddition between between Morita-Baylis-Hillman Morita-Baylis-Hillman adducts andadducts alkylidene and barbiturates.alkylidene 492 barbiturates. In 2017, Guo and colleagues described a (3+2) cycloaddition with alkylidene barbituric acids 493 involvingIn 2017, an Guo ynone and as dipolecolleagues precursor described (see a Scheme (3+2) cycloaddition 15c) which upon with reaction alkylidene with barbituric the phosphine acids 494 involvingcatalyst provides an ynone the as reactive dipole precursor 1,3-dipole (see [42 ].Sche Inme their 15c) publication, which upon the reaction authors with only the provided phosphine one 495 Catalystscatalystexample 2018 provides of, 8 an, x FOR asymmetric thePEER reactive REVIEW (3+2) 1,3-dipole cycloaddition [42]. betweenIn their publication, ynone 72 and the benzylidene authors only barbituric provided22 acid of one 308b 496 exampleusing the of chiral an asymmetric phosphine catalyst(3+2) cycloaddition71 (Scheme 20between). The expected ynone 72 product and benzylidene73 was, thus, barbituric obtained acid in 49% 8b 497 usingyield andthe chiral 40% ee phosphine[42]. Remarkably, catalyst during71 (Scheme the screening 20). The ofexpected the reaction product parameters 73 was, inthus, racemic obtained fashion, in 498 49% yield and 40% ee [42]. Remarkably, during the screening of the reaction parameters in racemic the authors found that using Na2CO3 as a Brønsted base additive (20 mol%) allowed the formation of 499 fashion,the expected the authors (3+2) cycloadditionfound that using adduct Na2CO73 3along as a Brønsted with equal base amount additive of the(20 mol%) (4+2) cycloaddition allowed the 500 formationproduct 74 of. the expected (3+2) cycloaddition adduct 73 along with equal amount of the (4+2) 501 cycloaddition product 74.

502

503 SchemeScheme 20. Phosphine-catalyzedPhosphine-catalyzed (3+2)(3+2) cycloaddition cycloaddition between between ynones ynones and and alkylidene alkylidene barbituric barbituric acids. 504 acids.

505 Guo’s team is not the only research group to have studied (4+2) cycloadditions involving 506 alkylidene barbituric acids. Others have published their work on asymmetric (4+2) cycloadditions, 507 the details of which will follow in the next part of this Section.

508 3.2. (4+2) Cycloaddition reactions 509 Enantioselective Diels–Alder reaction involving alkylidene dienophile intermediates, such as 510 78a, derived from barbituric acid 6, was first tackled by Tolstikov and colleagues in 2009 (Scheme 511 21a and 21b) [43]. Indeed, several chiral Diels–Alder adducts 77 were obtained using cyclic sulfone 512 75 as diene in the presence of chiral amino-acid or amino-alcohol organocatalysts. While several 513 enantioselective examples (based upon optical rotation measurement) were reported in the 514 publication, the enantiomeric excesses were only provided for the product 77a. Accordingly, several 515 chiral catalysts were evaluated for the reaction between cyclic sulfone 75 and benzylidene 78a, 516 generated in situ from thiobarbituric acid 6 and 2-methoxybenzaldehyde 76a in dioxane-water (15:3 517 v/v) at 130 °C to afford the spiranic adduct 77a (Scheme 21c). Whereas (S)-prolinol provided the 518 cycloaddition product 77a under a racemic form as a 5:1 mixture of diastereoisomer, the use of 519 L-4-(tert-butyldimethylsiloxy)-proline (L-4-(OTBDMS)-proline) or (-)-ephedrine resulted in a 520 spectacular improvement of the enantiomeric excesses (up to 80% ee and 86% ee, respectively) while 521 affording acceptable isolated yields (68 and 60%, respectively) in 77a, which was obtained as a single 522 stereoisomer. The absolute configuration of the cycloadduct 77a was ascertained by X-ray diffraction 523 analysis. 524

Catalysts 2019, 9, 131 20 of 27

Guo’s team is not the only research group to have studied (4+2) cycloadditions involving alkylidene barbituric acids. Others have published their work on asymmetric (4+2) cycloadditions, the details of which will follow in the next part of this Section.

3.2. (4+2) Cycloaddition Reactions Enantioselective Diels–Alder reaction involving alkylidene dienophile intermediates, such as 78a, derived from barbituric acid 6, was first tackled by Tolstikov and colleagues in 2009 (Scheme 21a,b) [43]. Indeed, several chiral Diels–Alder adducts 77 were obtained using cyclic sulfone 75 as diene in the presence of chiral amino-acid or amino-alcohol organocatalysts. While several enantioselective examples (based upon optical rotation measurement) were reported in the publication, the enantiomeric excesses were only provided for the product 77a. Accordingly, several chiral catalysts were evaluated for the reaction between cyclic sulfone 75 and benzylidene 78a, generated in situ from thiobarbituric acid 6 and 2-methoxybenzaldehyde 76a in dioxane-water (15:3 v/v) at 130 ◦C to afford the spiranic adduct 77a (Scheme 21c). Whereas (S)-prolinol provided the cycloaddition product 77a under a racemic form as a 5:1 mixture of diastereoisomer, the use of L-4-(tert-butyldimethylsiloxy)-proline (L-4-(OTBDMS)-proline) or (-)-ephedrine resulted in a spectacular improvement of the enantiomeric excesses (up to 80% ee and 86% ee, respectively) while affording acceptable isolated yields (68 and 60%, respectively) in 77a, which was obtained as a single stereoisomer. The absolute configuration of the cycloadductCatalysts 201877a, 8, xwas FOR ascertainedPEER REVIEW by X-ray diffraction analysis. 23 of 30

525 Scheme 21. Enantioselective Diels–Alder reaction involving in situ-generated alkylidene barbituric 526 Scheme 21. Enantioselective Diels–Alder reaction involving in situ-generated alkylidene barbituric acid as dienophile. (a) General conditions. (b) Formation of the alkylidene barbituric acid intermediate. 527 acid as dienophile. (a) General conditions. (b) Formation of the alkylidene barbituric acid c 528 ( ) Catalystsintermediate. evaluation. (c) Catalysts evaluation.

529 In 2016,In 2016, Guo, Guo, Zhou Zhou and and co-workers co-workers havehave reportedreported on on a a (4+2) (4+2) annulation annulation reaction reaction between between 530 alkylidenealkylidene barbituric barbituric acid acid8 8,, 99 or 7979 andand allenoates allenoates 80 80in thein thepresence presence of a chiral of a chiralphosphine phosphine 81 as a 81 531 as anucleophilic nucleophilic organocatalyst. organocatalyst. Chiral Chiral spirocycloalkenes spirocycloalkenes 82 were,82 were, thus, thus, provided provided even even though though 532 architecturesarchitectures are are difficult difficult to to obtain obtain through through regularregular Diels–AlderDiels–Alder reac reactiontion (Scheme (Scheme 22) 22 [44].)[44 Among]. Among 533 all theall the conditions conditions and and chiralchiral phosphines phosphines tested, tested, the theones ones displaying displaying a spiranic a spiranic architecture architecture and more and 534 moreparticularly particularly 81, 81previously, previously reported reported by bythe thesame same author authors,s, gave gave the thebest best level level of ofdiastereo-, diastereo-, 535 enantioselectivity and yields providing that 4 Å molecular sieves (MS) were used as an additive 536 (Scheme 22b). The organocatalyst 81 (20 mol%) was elected to study the scope and limitations of this 537 methodology (4 Å MS, toluene, 60 °C). Both substitutions on allenoate 80 and alkylidene 8 partners 538 were evaluated. Generally speaking, excellent ees (above 90%) along with high isolated yields were 539 obtained for a wide range of functional groups covering simple hydrogen atom to diversely 540 substituted aromatic or heteroaromatic rings. Even other alkylidene barbituric acid derivatives 79 541 and 9 possessing an N-N’-diethyl barbituric acid (R2 = Et, X = O) or N-N’-dimethyl thiobarbituric acid 542 (R2 = Me, X = S) moiety, respectively, were successfully engaged providing also excellent 543 enantiomeric excesses (97% ee and 95% ee, respectively). To underline the synthetic utility of the 544 spirocyclohexene products 82, the authors performed two chemical transformations starting from 545 enantioenriched 82a (R1 = Ph, R2 = Me, R3 = Ph, X = O, 94% ee, Scheme 22c). These encompassed an 546 epoxidation of the double bond of the cyclohexene part to give 83a (87%, 94% ee) and a nitration 547 reaction of the aromatic ring to furnish 84a (78%, 94% ee) without racemization event. 548

Catalysts 2019, 9, 131 21 of 27

enantioselectivity and yields providing that 4 Å molecular sieves (MS) were used as an additive (Scheme 22b). The organocatalyst 81 (20 mol%) was elected to study the scope and limitations of this methodology (4 Å MS, toluene, 60 ◦C). Both substitutions on allenoate 80 and alkylidene 8 partners were evaluated. Generally speaking, excellent ees (above 90%) along with high isolated yields were obtained for a wide range of functional groups covering simple hydrogen atom to diversely substituted aromatic or heteroaromatic rings. Even other alkylidene barbituric acid derivatives 79 and 9 possessing an N-N0-diethyl barbituric acid (R2 = Et, X = O) or N-N0-dimethyl thiobarbituric acid (R2 = Me, X = S) moiety, respectively, were successfully engaged providing also excellent enantiomeric excesses (97% ee and 95% ee, respectively). To underline the synthetic utility of the spirocyclohexene products 82, the authors performed two chemical transformations starting from enantioenriched 82a (R1 = Ph, R2 = Me, R3 = Ph, X = O, 94% ee, Scheme 22c). These encompassed an epoxidation of the double bond of the cyclohexene part to give 83a (87%, 94% ee) and a nitration reaction of the aromatic ring to furnishCatalysts84a 2018(78%,, 8, x FOR 94% PEERee) withoutREVIEW racemization event. 24 of 30

549 550 SchemeScheme 22. 22.Enantioselective Enantioselective (4+2) (4+2) Cycloaddition Cycloaddition Reaction. (a (a) )General General conditions. conditions. (b) (bScope) Scope and and 551 limitations.limitations. (c) ( Syntheticc) Synthetic transformations. transformations.

552 AnotherAnother application application of of alkylidene alkylidene barbituric barbituric acids in in (4+2) (4+2) cycloaddition cycloaddition reaction reaction was was reported reported 553 recentlyrecently by Zhaoby Zhao and and colleagues colleagues during during the the synthesis synthesis of of barbiturate-fused barbiturate-fused spirotetrahydroquinolinesspirotetrahydroquinolines 87 554 from87 vinyl from benzoxazinanones vinyl benzoxazinanones86 in the86 in presence the presence of chiral of chiral palladium(0)-ligand palladium(0)-ligand complex complex (Scheme (Scheme 23)[ 45]. 555 23) [45]. Thus, a chiral ligand (20 mol%) derived from BINOL in association with Pd2(dba)3·CHCl3 (5 Thus, a chiral ligand (20 mol%) derived from BINOL in association with Pd2(dba)3·CHCl3 (5 mol%) as 556 mol%) as Pd(0) source in a 4:1 ratio in CH2Cl2 at room temperature were selected as the best Pd(0) source in a 4:1 ratio in CH2Cl2 at room temperature were selected as the best conditions to obtain 557 optimalconditions levels ofto eeobtainand yieldsoptimal (Scheme levels 23ofb,c). ee and By applyingyields (Schemes the above-mentioned 23b and 23c). conditions,By applying the the scope 558 above-mentioned conditions, the scope and limitations of the reaction were investigated. By using and limitations of the reaction were investigated. By using simple N-Ts lactam 86a (R3 = R5 = H), 559 simple N-Ts lactam 86a (R3 = R5 = H), high level of ee ranging from 89% to 96% was observed for a 560 wide range of mono- or poly-substituted phenyl rings and hetero- or poly-aromatic rings along with 561 variable isolated yields (45–89%). Of note, no reaction was detected with benzylidene barbituric acid 562 having NH moiety (85a, R1 = Ph, R2 = H) or alkylidene barbituric acid having an NR moiety (8c, R1 = 563 i-Pr, R2 = Me). The substitution of the vinyl benzoxazinanone partner 86 was also possible providing 564 that R5 substituent remains a hydrogen atom and R4 substituent a tosyl group. In this case, however, 565 somewhat lower ees were obtained (35–96% ee). Finally, the best results in terms of ee were obtained 566 by introducing substituents on both aromatic parts of the benzylidene barbituric acid 85 and vinyl 567 benzoxazinanones 86, thus, providing the corresponding spirotetrahydroquinolines 87 in up to 97% 568 ee. It should be mentioned that all the spirotetrahydroquinolines 87 were obtained as a single 569 diastereoisomer where vinyl and R1 group exhibited a cis relationship. To account for this excellent 570 diastereoselectivity, the authors proposed a plausible reaction intermediate where Ts and R1 groups 571 are pseudo-trans to each other to avoid a steric clash in the intermediate resulted from a reversible

Catalysts 2019, 9, 131 22 of 27

high level of ee ranging from 89% to 96% was observed for a wide range of mono- or poly-substituted phenyl rings and hetero- or poly-aromatic rings along with variable isolated yields (45–89%). Of note, no reaction was detected with benzylidene barbituric acid having NH moiety (85a,R1 = Ph, R2 = H) or alkylidene barbituric acid having an NR moiety (8c,R1 = i-Pr, R2 = Me). The substitution of the vinyl benzoxazinanone partner 86 was also possible providing that R5 substituent remains a hydrogen atom and R4 substituent a tosyl group. In this case, however, somewhat lower ees were obtained (35–96% ee). Finally, the best results in terms of ee were obtained by introducing substituents on both aromatic parts of the benzylidene barbituric acid 85 and vinyl benzoxazinanones 86, thus, providing the corresponding spirotetrahydroquinolines 87 in up to 97% ee. It should be mentioned that all the spirotetrahydroquinolines 87 were obtained as a single diastereoisomer where vinyl and R1 group exhibited a cis relationship. To account for this excellent diastereoselectivity, the authors proposed 1 a plausibleCatalysts 2018 reaction, 8, x FOR intermediatePEER REVIEW where Ts and R groups are pseudo-trans to each other25 toof avoid30 a steric clash in the intermediate resulted from a reversible aza-Michael addition of 88 to 85 or 8c 572 (Schemeaza-Michael 23d). Then,addition the of intramolecular 88 to 85 or 8c addition(Scheme of23d). the Then, carbanion the intramolecular of the barbiturate addition occurs of the at the 573 Si-facecarbanion of the ofπ -allyl-palladium-ligandthe barbiturate occurs at the complex Si-face toof providethe π-allyl-palladium-ligand the cis-adduct. This complex cyclisation to provide step was 574 proposedthe cis-adduct. as the rate-limiting This cyclisation and step enantio-determining was proposed as the step. rate-limiting and enantio-determining step. 575

576

577 SchemeScheme 23. 23.Enantioselective Enantioselective palladium-catalyzed palladium-catalyzed (4+2) (4+2) cycloaddition cycloaddition reaction reaction between between vinyl vinyl 0 578 benzoxazinanonesbenzoxazinanones and and benzylidene benzylideneN N,N’,N -dimethyl-dimethyl barbituric barbituric acids. acids. (a ()a General) General conditions. conditions. (b) Scope (b) Scope 579 andand limitations. limitations. (c )(c Ligand) Ligand structure. structure. ((dd)) ProposedProposed reaction reaction mechanism. mechanism.

580 In 2017, the Myrboh group studied the multi-component reaction involving aromatic aldehydes 581 76, 1,3-cyclohexanediones 89 and barbituric acid 1 catalyzed by simple L-proline catalyst (15 mol%) 582 to afford chromano[2,3-d]pyrimidine-triones 90 in high yields (70–96%) and low to excellent 583 enantiomeric excesses (8–96% ee, Scheme 24) [46]. The strength of this methodology relies on the 584 user- and the eco-friendly protocol. Indeed, water was used as a solvent at room temperature and 585 pure products 90 were obtained after a simple filtration and recrystallization in ethanol. With these 586 conditions in hand, the authors studied the scope and limitations of this reaction (Scheme 24c). 587 Regarding the 1,3-dione partners, both dimedone (3, R2 = Me) or 1,3-cyclohexanedione (89, R2 = H) 588 were tested; the latter providing slightly better results in terms of ee. Nevertheless, this gem-dimethyl 589 substituent seems to have a strong, erratic impact on the stereoinduction, but this phenomenon was 590 not explained. For example, 4-fluoro benzaldehyde gave excellent results (96% yield, 96% ee) when 591 reacting with 1,3-cyclohexanedione 89 whereas its reaction with dimedone 3 resulted in a dramatic

Catalysts 2019, 9, 131 23 of 27

In 2017, the Myrboh group studied the multi-component reaction involving aromatic aldehydes 76, 1,3-cyclohexanediones 89 and barbituric acid 1 catalyzed by simple L-proline catalyst (15 mol%) to afford chromano[2,3-d]pyrimidine-triones 90 in high yields (70–96%) and low to excellent enantiomeric excesses (8–96% ee, Scheme 24)[46]. The strength of this methodology relies on the user- and the eco-friendly protocol. Indeed, water was used as a solvent at room temperature and pure products 90 were obtained after a simple filtration and recrystallization in ethanol. With these conditions in hand, the authors studied the scope and limitations of this reaction (Scheme 24c). Regarding the 1,3-dione partners, both dimedone (3,R2 = Me) or 1,3-cyclohexanedione (89,R2 = H) were tested; the latter providing slightly better results in terms of ee. Nevertheless, this gem-dimethyl substituent seems to have a strong, erratic impact on the stereoinduction, but this phenomenon was not explained. For example, 4-fluoro benzaldehyde gave excellent results (96% yield, 96% ee) when reacting with 1,3-cyclohexanedioneCatalysts 2018, 8, x FOR PEER89 REVIEWwhereas its reaction with dimedone 3 resulted in a dramatic drop26 in of efficacy 30 (80% yield, 30% ee). The opposite trend could be observed when 4-methyl benzaldehyde was used 592 drop in efficacy (80% yield, 30% ee). The opposite trend could be observed when 4-methyl (88% yield, 72% ee with dimedone vs 75% yield, 8% ee with 1,3-cyclohexanedione). Regarding 593 benzaldehyde was used (88% yield, 72% ee with dimedone vs 75% yield, 8% ee with 594 the1,3-cyclohexanedione). aldehyde partner 76 Regarding, most successful the aldehyde examples partner involve 76, most aromatic successful aldehydes examples (substituted involve by 595 electron-withdrawingaromatic aldehydes (substituted or -donating by groups electron-withdra at differentwing positions) or -donating tested groups while onlyat different two examples positions) in the 596 aliphatictested while or heteroaromatic only two examples series in were the reportedaliphatic or with heteroaromatic high ee (propanal, series 96%wereee reportedand 1-naphthaldehyde, with high ee 597 92%(propanal,ee, respectively). 96% ee and The 1-naphthaldehyde, authors proposed 92% a mechanismee, respectively). where The the authors first step proposed is the formationa mechanism of the 598 alkylidenewhere the barbituricfirst step is acid the formatio85 catalyzedn of the by alkylidene proline (Scheme barbituric 24b). acid These 85 catalyzed Michael by acceptor proline species(Scheme then 599 react24b). with These the Michael enamine acceptor formed species in situ then between react with the the catalyst enamine and formed the 1,3-diketones in situ between3 or the89 catalystto give the 600 intermediateand the 1,3-diketones91 that cyclizes 3 or to89 provide to give the the desired intermediate chromano[2,3- 91 thatd ]pyrimidine-trionescyclizes to provide 90thethanks desired to an 601 oxa-Michaelchromano[2,3- additiond]pyrimidine-triones along with the 90 regeneration thanks to of thean catalyst.oxa-Michael addition along with the 602 regeneration of the catalyst.

603

604 SchemeScheme 24. (S)-Proline-catalyzed24. (S)-Proline-catalyzed multicomponent multicompo synthesisnent of chromanosynthesis [2,3-dof]pyrimidine-triones chromano 605 from[2,3-d aldehydes,]pyrimidine-triones 1,3-cyclohexanediones from aldehydes, and 1,3- barbituriccyclohexanediones acid. (a )and General barbituric conditions. acid. (a ()b )General Proposed 606 reactionconditions. mechanism. (b) Proposed (c) Scope reaction and mechanism. limitations. (c) Scope and limitations.

607 3.3. Other Cycloaddition Reactions 608 Guo and colleagues recently tackled the challenging higher-order cycloaddition reactions both 609 in racemic and enantioselective fashion starting from a heptafulvene barbituric acid platform 92 and 610 functionalized allenoates 80 (Scheme 25) [47]. Upon phosphine catalysis a formal (8+2) cycloaddition 611 process occurred to furnish the corresponding bicyclo [5.3.0] decanes 93 with excellent ees ranging 612 from 86% to 97%. The authors observed that a rather activated ester moiety on allenoate 80 was 613 required to secure a good reactivity with sterically hindered chiral phosphine catalyst 94. Thus, for 614 examples, the arylic esters 93a–93d were obtained with high stereoinduction (86–92% ee) and 615 isolated yields ranging from 61% to 65%, together with derivatives 93e–93f having either a 616 fluorinated (93e, 92% ee) or chlorinated (93f, 97% ee) alkyl substituents on the ester moiety. 617

Catalysts 2019, 9, 131 24 of 27

3.3. Other Cycloaddition Reactions Guo and colleagues recently tackled the challenging higher-order cycloaddition reactions both in racemic and enantioselective fashion starting from a heptafulvene barbituric acid platform 92 and functionalized allenoates 80 (Scheme 25)[47]. Upon phosphine catalysis a formal (8+2) cycloaddition process occurred to furnish the corresponding bicyclo [5.3.0] decanes 93 with excellent ees ranging from 86% to 97%. The authors observed that a rather activated ester moiety on allenoate 80 was required to secure a good reactivity with sterically hindered chiral phosphine catalyst 94. Thus, for examples, the arylic esters 93a–93d were obtained with high stereoinduction (86–92% ee) and isolated yields ranging from 61% to 65%, together with derivatives 93e–93f having either a fluorinated (93e, 92% ee)

or chlorinatedCatalysts 2018 (, 93f8, x FOR, 97% PEERee REVIEW) alkyl substituents on the ester moiety. 27 of 30 Catalysts 2018, 8, x FOR PEER REVIEW 27 of 30 O O O R1 MeN O R1 MeN NMe Me 2 O NMe Me CO R2 O N + CO2R 94 (P R,10mol%) 2 N + 2 3 O CO2R2 94 (P3R,10mol%) O CO2R O N O PhF, rt, 3 Å MS O N O PhF, rt, 3 Å MS Me Me R1 R1 92 80 (1.2 equiv.) 93, 55-67%, 86-97% ee 92 80 (1.2 equiv.) 93, 55-67%, 86-97% ee Selected examples O O Selected examples O O MeN MeN MeN NMe MeN NMe O NMe O NMe O O 2 O CO2Ph O CO2R2 O CO2Ph O CO2R

R1 Ph R1 Ph 1 2 93a (R1 = Ph), 64%, 90% ee 93e (R2 =CH2CHF2), 60%, 92% ee 93a (R = Ph), 64%, 90% ee 93e (R =CH2CHF2), 60%, 92% ee 93b (R1 =4-MeC H ), 64%, 90% ee 93f (R2 =CH CCl ), 55%, 97% ee 93b (R1 =4-MeC6H4), 64%, 90% ee 93f (R2 =CH2CCl3), 55%, 97% ee 1 6 4 2 3 93c (R1 =2-FC6H4), 61%, 92% ee 93c (R =2-FC6H4), 61%, 92% ee 93d (R1 = 1-naphthyl), 65%, 86% ee 618 93d 1 618 (R = 1-naphthyl), 65%, 86% ee 619 Scheme 25. Phosphine-catalyzed (8+2) annulation of barbituric acid heptafulvenes. 619 SchemeScheme 25. 25.Phosphine-catalyzed Phosphine-catalyzed (8+2) (8+2) annulation annulation of barbituric of barbituric acid heptafulvenes. acid heptafulvenes. 620 Actually, a screening of chiral phosphines revealed that the best results were achieved using 620 Actually,Actually, a screening a screening of of chiral chiral phosphinesphosphines reveal revealeded that that the best the results best results were achieved were achieved using using 621 Kwon’s endo phosphine 94 (Scheme 26). Regarding the mechanism, the authors proposed a formal 621Kwon’s Kwon’s endo endo phosphine phosphine94 94(Scheme (Scheme 2626).). Regarding Regarding the the mechanis mechanism,m, the authors the authors proposed proposed a formal a formal 622 (8+2) cycloaddition triggered by the addition reaction of the phosphine organocatalyst 94 to the 622(8+2) (8+2) cycloaddition cycloaddition triggered triggered byby thethe addition addition reaction reaction of the of thephosphine phosphine organocatalyst organocatalyst 94 to the 94 to the 623 allenoate 80 to form the phosphonium betaine intermediate 95. Then, an addition reaction takes 623 allenoate 80 to form the phosphonium betaine intermediate 95. Then, an addition reaction takes 624allenoate place80 to tothe form heptafulvene the phosphonium barbituric acid betaine 92 to give intermediate 96, giving rise95. to Then, a cyclization an addition process reaction that leads takes place 624 place to the heptafulvene barbituric acid 92 to give 96, giving rise to a cyclization process that leads 625to theto heptafulvene the transient cyclopentane barbituricacid 97. This92 to charged give 96 intermediate, giving rise undergoes to a cyclization the final elimination process that event leads to the 625 to the transient cyclopentane 97. This charged intermediate undergoes the final elimination event 626 allowing the formation of product 93 along with the concomitant regeneration of phosphine 626transient allowing cyclopentane the formation97. Thisof product charged 93 intermediatealong with the undergoes concomitant the regeneration final elimination of phosphine event allowing 627 organocatalyst 94. 627the formationorganocatalyst of product 94. 93 along with the concomitant regeneration of phosphine organocatalyst 94. 628 628

629 629 630 Scheme 26. Proposed mechanism of the (8+2) Annulation reaction. 630 SchemeScheme 26. 26.Proposed Proposed mechanism mechanism of the of the(8+2) (8+2) Annulation Annulation reaction. reaction. 631 4. Conclusions 631 4. Conclusions 632 Despite the long-standing interest in barbituric acid derivatives as useful building blocks for the 632 Despite the long-standing interest in barbituric acid derivatives as useful building blocks for the 633 elaboration of both bio-relevant products or architectures having interesting properties in material 633 elaboration of both bio-relevant products or architectures having interesting properties in material 634 science, the enantioselective catalytic synthesis of chiral non-racemic barbiturates-derived products 634 science, the enantioselective catalytic synthesis of chiral non-racemic barbiturates-derived products 635 slowly emerged in the 1990s. The marked Brønsted acidity of barbituric acid derivatives or 635 slowly emerged in the 1990s. The marked Brønsted acidity of barbituric acid derivatives or

Catalysts 2019, 9, 131 25 of 27

4. Conclusions Despite the long-standing interest in barbituric acid derivatives as useful building blocks for the elaboration of both bio-relevant products or architectures having interesting properties in material science, the enantioselective catalytic synthesis of chiral non-racemic barbiturates-derived products slowly emerged in the 1990s. The marked Brønsted acidity of barbituric acid derivatives or electrophilicity of alkylidene counterparts have required the development of specific catalysts or catalytic approaches to manage these unique properties. Furthermore, as far as non-symmetrical barbituric acid scaffolds are concerned, the challenging stereo-differentiation of rather similar functionality on both nitrogen atoms required ingenious methodological approaches to be carried out. Nonetheless, both metal- and organic catalysts are currently able to engage barbituric derivatives into highly enantioselective addition and cycloaddition reactions to provide original chiral linear, fused, and spiro-bicyclic architectures. The panel of enantioselective reactions carried out on barbituric acids remains, however, rather limited and many opportunities to develop new processes still exist. By giving an overview of the state-of-the-art of catalytic enantioselective transformations, we hope this review will provide a springboard to elicit new developments in this field of research.

Author Contributions: writing—original draft preparation, C.S., A.L., V.L., S.O., J.-F.B.; supervision, J.-F.B. Acknowledgments: This work has been partially supported by INSA Rouen, Rouen University, CNRS, EFRD, Labex SynOrg (ANR-11-LABX-0029) and region Normandie (CRUNCh network). This work was also supported by the French National Research Agency (ANR) as part of the ANR-16-CE07-0011-01 project. Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations The following abbreviations are used in this manuscript:

BINOL 1,10-Bi-2-naphthol DMSO dimethyl sulfoxide HPLC High Performance Liquid Chromatography THF tetrahydrofuran TS Transition state

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