Recent Advances in Asymmetric Organocatalyzed Conjugate Additions to Nitroalkenes

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Review Recent Advances in Asymmetric Organocatalyzed Conjugate Additions to Nitroalkenes

Diego A. Alonso *, Alejandro Baeza *, Rafael Chinchilla *, Cecilia Gómez *, Gabriela Guillena *, Isidro M. Pastor * and Diego J. Ramón *

Department of Organic Chemistry and Institute of Organic Synthesis (ISO), Faculty of Sciences, University of Alicante, PO Box 99, 03080 Alicante, Spain * Correspondence: [email protected] (D.A.A.); [email protected] (A.B.); [email protected] (R.C.); [email protected] (C.G.); [email protected] (G.G.); [email protected] (I.M.P); [email protected] (D.J.R.); Tel.: +34-96-590-3822 (R.C.)

Academic Editor: Derek J. McPhee Received: 11 May 2017; Accepted: 26 May 2017; Published: 29 May 2017

Abstract: The asymmetric conjugate addition of carbon and heteroatom nucleophiles to nitroalkenes is a very interesting tool for the construction of highly functionalized synthetic building blocks. Thanks to the rapid development of asymmetric organocatalysis, signiﬁcant progress has been made during the last years in achieving efﬁciently this process, concerning chiral organocatalysts, substrates and reaction conditions. This review surveys the advances in asymmetric organocatalytic conjugate addition reactions to α,β-unsaturated nitroalkenes developed between 2013 and early 2017.

Keywords: nitroalkenes; Michael addition; organocatalysis; asymmetric synthesis

1. Introduction Asymmetric organocatalysis is still a relatively young field for the chemical research community. Thus, not too many years ago, the term ‘catalysis’ was normally associated to transition metal-mediated reactions or to enzyme-aided biocatalysis. However, small organic molecules can achieve remarkably stereoselective and efficient transformations. In addition, the employed organocatalysts are usually of low molecular weight, easy to synthesize, chemically robust, and affordable. Additionally, the organocatalytic reactions are often carried out under virtually ‘open-flask’ conditions. All these reasons have made asymmetric organocatalysis a nowadays fast-forwarding topic, which shows continuous and rapid developments [1–3]. Among all the array of asymmetric organocatalyzed reactions, the conjugate addition reaction of carbon nucleophiles to electron-deficient alkenes is one of the most important ways of creating C-C bonds [4–12]. Particularly, the asymmetric organocatalyzed conjugate addition of carbon nucleophiles to α,β-unsaturated nitroalkenes has attracted considerable attention, as the final enantioenriched γ-nitrocarbonyl compounds can be transformed into compounds of interest [13–17]. The present review covers asymmetric organocatalytic conjugate addition reactions to α,β-unsaturated nitroalkenes published from 2013 till the first quarter of 2017, concerning substrates, organocatalysts and reactions conditions. The review has been classified depending on the nucleophile employed in the conjugate addition. Thus, Michael reactions of carbon nucleophiles such as aldehydes, ketones, 1,3-dicarbonyl compounds, nitroalkanes and heterocycles will be presented, although these systems should be considered as ‘pro-nucleophiles’, the real nucleophiles being enamines, enolates or nitronates. Finally, recent developments in asymmetric organocatalytic enantioselective hetero-Michael reactions will also be considered.

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Molecules 2017, 22, 895 2 of 51 2. Carbon Nucleophiles 2. Carbon Nucleophiles Aldehydes and ketones have been the most frequently employed carbon nucleophiles (in fact, pro-nucleophiles)Aldehydes and in theketones asymmetric have been organocatalyzed the most freq Michaeluently employed addition reaction carbon tonucleophiles nitroalkenes. (in Chiral fact, primarypro-nucleophiles) and secondary in the aminesasymmetric have organocatalyzed been used as organocatalysts, Michael addition the presencereaction to of nitroalkenes. additives as co-catalysts,Chiral primary mainly and carboxylicsecondary acids,amines being have frequently been used necessary as organocatalysts, to achieve goodthe presence optical and of additives chemical yields.as co-catalysts, Concerning mainly the mechanismcarboxylic acids, of this being process, frequently although necessary there have to been achieve suggestions good optical that enols and arechemical the involved yields. nucleophilicConcerning species,the mechanism the nowadays of this acceptedprocess, catalyticalthough cycle there for have this been reaction suggestions involves enaminesthat enols asare nucleophiles the involved (Scheme nucleophilic1). Thus, species, the chiral the amine nowadays organocatalyst accepted Acatalyticwould reactcycle withfor this the carbonylreaction compoundinvolves enamines forming anas enaminenucleophilesB (for (Sch primaryeme amines,1). Thus, R 1the= H, chiral initially amine an imine organocatalyst in tautomeric A 1 equilibriumwould react with with the the carbonyl enamine) compound which would forming add an stereoselectively enamine B (for toprimary the nitrooleﬁn, amines, R leading = H, initially to the nitronatean imine adductin tautomericC. This intermediateequilibrium iswith then the hydrolyzed enamine) driving which to would the ﬁnal addγ-nitrocarbonyl stereoselectively compound to the andnitroolefin, the initial leading amine to organocatalyst. the nitronate Recentadduct mass C. This spectrometry intermediate studies is then support hydrolyzed this mechanism driving [18to ,19the]. Itfinal is interesting γ-nitrocarbonyl to remark compound that formation and the of initial cyclobutane amineD organocatalyst.and 1,2-oxazine RecentN-oxide massE derivatives spectrometry has beenstudies observed support in this this mechanism process, these [18,19]. compounds It is interesting being resting to remark states that of the formation organocatalyst of cyclobutane [20–24]. ItsD formationand 1,2-oxazine would N ‘remove’-oxide E thederivatives amine catalyst has been from observed the cycle, in this which process, would these explain compounds the mentioned being frequentresting states necessity of the oforganocatalyst adding acid [20–24] co-catalysts . Its fo forrmation achieving would good ‘remove’ results. the The amine presence catalyst of from an acid the notcycle, only which would would promote explain a faster the imine-enamine mentioned frequent equilibrium, necessity but also of wouldadding protonate acid co-catalysts the nitronate for Cachieving, blocking good the formationresults. The of presence the D and ofE anas acid byproducts. not only Thiswould could promote also be a achievedfaster imine-enamine internally if theequilibrium, amine catalyst but also bears would an acidic protonate functionality the nitronate [25]. InC, addition, blocking therethe formation are evidences of the that, D atand least E inas somebyproducts. cases, supportThis could the also re-formation be achieved of internally an enamine if the from amine intermediates catalyst bearsC/D an/ Eacidic, with functionality stereoselectivity [25]. nowIn addition, being controlled there are byevidences the diastereoselectivity that, at least in some of enamine cases, protonationsupport the [re-formation26]. Moreover, of thean presenceenamine offrom organic intermediates bases has C/ sometimesD/E, with stereoselectivity shown a positive now effect being as controlled co-catalyst, by as the they diastereoselectivity also can accelerate of theenamine reaction protonation after favoring [26]. Moreover, the creation the of presence the enamine of organic intermediate bases has [27 sometimes]. Furthermore, shown ifa suitablepositive H-formingeffect as co-catalyst, groups are as also they present also can in accelerate the chiral th aminee reaction catalyst after (bifunctional favoring the organocatalysts), creation of the enamine the nitro groupintermediate of thenitroalkene [27]. Furthermore, will be coordinated. if suitable H-form Therefore,ing thegroups enamine are also and thepresent electrophile in the chiral will be amine close enoughcatalyst to(bifunctional get a high enantioinduction. organocatalysts), the nitro group of the nitroalkene will be coordinated. Therefore, the enamine and the electrophile will be close enough to get a high enantioinduction.

Scheme 1.1.Catalytic Catalytic cycle cycle of theof the conjugate conjugate addition addition of aldehydes of aldehydes and ketones and toketones nitroalkenes to nitroalkenes promoted bypromoted primary by or primary secondary or secondary chiral amines. chiral amines.

In the case of pro-nucleophiles bearing much more acidic α-hydrogens than those on aldehydes In the case of pro-nucleophiles bearing much more acidic α-hydrogens than those on aldehydes and ketones (i.e., in the methylene group of 1,3-dicarbonyl compounds), chiral tertiary amines are and ketones (i.e., in the methylene group of 1,3-dicarbonyl compounds), chiral tertiary amines are usually employed as organocatalysts. Their basic character allows to deprotonate the pro- usually employed as organocatalysts. Their basic character allows to deprotonate the pro-nucleophile, nucleophile, leading to an enolate which coordinates with the protonated base. Similarly to aldehydes leading to an enolate which coordinates with the protonated base. Similarly to aldehydes and ketones, and ketones, if amine-containing bifunctional organocatalysts are employed, the nitro group of the if amine-containing bifunctional organocatalysts are employed, the nitro group of the nitroalkene can nitroalkene can be also coordinated by means of hydrogen bonds with the acidic moiety of the catalyst, affording a tight transition state which lead to suitable enantioinductions. The present section has been classified according to the carbon pro-nucleophiles employed in the asymmetric addition to nitroalkenes. Firstly, recent reactions with enamine-forming compounds,

Molecules 2017, 22, 895 3 of 51 be also coordinated by means of hydrogen bonds with the acidic moiety of the catalyst, affording a tight transition state which lead to suitable enantioinductions. The present section has been classified according to the carbon pro-nucleophiles employed in the asymmetric addition to nitroalkenes. Firstly, recent reactions with enamine-forming compounds, such as aldehydes and ketones, will be presented. Secondly, more acidic systems where enolates and nitronatesMolecules are 2017 involved,, 22, 895 such as 1,3-dicarbonyl compounds and nitroalkanes, respectively,3 of will51 be shown. Finally, a section dealing to the use of carbon pro-nucleophiles contained into heterocyclic systemssuch will as aldehydes be considered. and ketones, will be presented. Secondly, more acidic systems where enolates and nitronates are involved, such as 1,3-dicarbonyl compounds and nitroalkanes, respectively, will be 2.1. Aldehydesshown. Finally, a section dealing to the use of carbon pro-nucleophiles contained into heterocyclic systems will be considered. L-Proline was the first organocatalyst employed in the asymmetric conjugate addition reaction of carbonyl2.1. Aldehydes compounds to nitroalkenes [28,29]. Its bifunctional character, suitable to form an enamine and coordinate the nitro group of the electrophile at the same time via hydrogen bond, made it a simple and L-Proline was the first organocatalyst employed in the asymmetric conjugate addition reaction easilyof available carbonyl compounds organocatalyst, to nitroalkenes although [28,29]. poorly Its effective. bifunctional Still character, nowadays, suitable most to of form the organocatalystsan enamine designedand coordinate for the asymmetric the nitro group Michael of the addition electrophile of aldehydes at the same and time ketones via hydrogen to nitroalkenes bond, made are basedit a in the presencesimple and of theeasily pyrrolidine available ringorganocatalyst, for the formation although of poorly the transient effective. enamine. Still nowadays, Their differencesmost of the relay mainlyorganocatalysts in the functional designed group for at the C-2 asymmetric intended to Michael coordinate addition the nitro of aldehydes group of theand nitroalkene ketones to with the highestnitroalkenes efficiency. are based in the presence of the pyrrolidine ring for the formation of the transient Closelyenamine. relatedTheir differences to the use relay of mainlyL-proline in the as func organocatalysttional group isat theC-2 intended recent development to coordinate ofthe rigid nitro group of the nitroalkene with the highest efficiency. chiral bicyclic prolines, such as 4,5-methano-L-proline (1), which showed high efficiency in the Closely related to the use of L-proline as organocatalyst is the recent development of rigid chiral Michael addition of aldehydes to β-arylated trans-nitroalkenes giving mainly the corresponding bicyclic prolines, such as 4,5-methano-L-proline (1), which showed high efficiency in the Michael syn-nitroaldehydesaddition of aldehydes2, the presenceto β-arylated of N ,Ntrans-4-dimethylaminopyridine-nitroalkenes giving mainly (DMAP) the corresponding as co-catalyst syn being- requirednitroaldehydes (Scheme2 a)2, [the30 ].presence Another of example N,N-4-dimethylaminopyridine of proline-like organocatalyst (DMAP) as is co-catalyst shown in thebeing use of perhydroindolicrequired (Scheme acid 3 2(a))promoting [30]. Another the reaction example between of proline-like aldehydes organocatalyst containing is an shownα,β-unsaturated in the use of ester and nitroolefinsperhydroindolic in theacid presence 3 promoting of sodiumthe reaction bicarbonate, between aldehydes which allows containing the asymmetrican α,β-unsaturated formation of polysubstitutedester and nitroolefins aliphatic in the cyclopentanespresence of sodium4 afterbicarbonate, a domino which double allows the Michael asymmetric addition formation reaction (Schemeof polysubstituted2b) [31]. aliphatic cyclopentanes 4 after a domino double Michael addition reaction (Scheme 2(b)) [31].

SchemeScheme 2. Asymmetric 2. Asymmetric addition addition of aldehydes of aldehydes to nitroalkenes to nitroalkenes catalyzed bycatalyzedL-proline-related by L-proline-related organocatalysts. organocatalysts. Chiral organocatalysts suitable for the asymmetric Michael addition reaction of aldehydes Chiral organocatalysts suitable for the asymmetric Michael addition reaction of aldehydes to L to nitrooleﬁnsnitroolefins havehave been been obtained obtained by amidation by amidation of L-proline of -proline with different with amines. different The amines. acidic hydrogen The acidic hydrogeninto the into amide the amide functionality functionality allows allows coordi coordinationnation with withthe nitro the nitrogroup group favoring favoring the the enantiodifferentiation in the enamine attack. Examples of these type of organocatalysts are the triphenylmethylamine-derived prolinamide 5 [32], the adamantyl L-prolinamide 6 [33] and the epiandrosterone-derived prolinamide 7 [34] (Figure 1). All of them have been used as organocatalysts in the conjugate addition of aldehydes to trans-nitroalkenes (using 5: R1 = alkyl, R2 = aryl; using 6: R1

Molecules 2017, 22, 895 4 of 51 enantiodifferentiation in the enamine attack. Examples of these type of organocatalysts are the triphenylmethylamine-derived prolinamide 5 [32], the adamantyl L-prolinamide 6 [33] and the epiandrosterone-derivedMolecules 2017, 22, 895 prolinamide 7 [34] (Figure1). All of them have been used as organocatalysts4 of 51 1 2 inMolecules the conjugate 2017, 22, 895 addition of aldehydes to trans-nitroalkenes (using 5:R = alkyl, R = aryl; using4 of 516: R= 1alkyl,= alkyl, R2 = R 2alkyl,= alkyl, aryl; aryl; using using 7: R71:R = 1alkyl,= alkyl, R2 = R 2aryl)= aryl) which which leads leads to the to the synsyn-adducts-adducts 2 (Scheme2 (Scheme 2(a)),2a), the= alkyl, addition R2 = alkyl, of benzoic aryl; acidusing as 7 additive: R1 = alkyl, resultingresulting R2 = aryl) crucialcrucial which inin allallleads cases.cases. to the syn-adducts 2 (Scheme 2(a)), the addition of benzoic acid as additive resulting crucial in all cases.

Figure 1. Results obtained using some L-prolinamide organocatalysts in the asymmetric addition of aldehydesFigure 1. Results to nitroalkenes obtained leading using some to nitroaldehydes L-prolinamide 22. .organocatalysts in the asymmetric addition of aldehydes to nitroalkenes leading to nitroaldehydes 2. Peptides containing the proline moiety have also been used as organocatalysts for the Peptides containing the proline moiety have also been used as organocatalysts for the asymmetric asymmetricPeptides conjugate containing addition the ofproline aldehydes moiety to trans have-β -nitrostyrenesalso been used affording as organocatalysts γ-nitroaldehydes for 2 the(R1 conjugate addition of aldehydes to trans-β-nitrostyrenes affording γ-nitroaldehydes 2 (R1 = alkyl, =asymmetric alkyl, R2 = conjugatearyl) (Scheme addition 2(a)). of Examples aldehydes are to transthe peptide-peptoid-β-nitrostyrenes hybridaffording 8 [35] γ-nitroaldehydes or the phosphonic 2 (R1 R2 = aryl) (Scheme2a). Examples are the peptide-peptoid hybrid 8 [35] or the phosphonic acid-containing= alkyl, R2 = aryl) tripeptide (Scheme 2(a)).9 [36] Examples (Figure 2). are Although the peptide-peptoid not too enantioselective, hybrid 8 [35] orit isthe interesting phosphonic to acid-containing tripeptide 9 [36] (Figure2). Although not too enantioselective, it is interesting to remarkacid-containing the low catalysttripeptide loading 9 [36] employed (Figure 2). when Although using thenot tripeptidetoo enantioselective, 9 and that itit can is interestingbe recovered to remark the low catalyst loading employed when using the tripeptide 9 and that it can be recovered by byremark extraction the low due catalyst to their loading high solubility employed in whenwater, using allowing the tripeptideits reuse in 9 ten and reaction that it cancycles be recovered extraction due to their high solubility in water, allowing its reuse in ten reaction cycles. by extraction due to their high solubility in water, allowing its reuse in ten reaction cycles

Figure 2. Results obtained using some peptide-derived organocatalysts in the asymmetric addition of Figure 2. Results obtained using some peptide-derived organocatalysts in the asymmetric addition of aldehydesFigure 2. Results to nitroalkenes obtained leadingusing some to nitroaldehydes peptide-derived 2. organocatalysts in the asymmetric addition of aldehydes to nitroalkenes leading to nitroaldehydes 2. aldehydes to nitroalkenes leading to nitroaldehydes 2. Another example related to proline-containing tripeptides as organocatalysts is the use of H- Pro-Pro-D-Gln-OH·TFAAnother example example related relatedor H-Pro- to to proline-containing proline-containingPro-Asn-OH·TFA tripeptides(TFA tripeptides = trifluor as asorganocatalystsoacetic organocatalysts acid), combinedis the is the use use toof H-N of- H-Pro-Pro-D-Gln-OHmethylmorpholinePro-Pro-D-Gln-OH·TFA (NMM),·TFA or orH-Pro-in H-Pro-Pro-Asn-OHthe Pro-Asn-OH·TFAasymmetric Michael·TFA (TFA addition (TFA = trifluor = trifluoroaceticof aldehydesoacetic acid), to acid), αcombined,β-disubstituted combined to N to- Nnitroolefins,methylmorpholine-methylmorpholine affording (NMM), (NMM),γ-nitroaldehydes in inthe the asymmetr asymmetric 10 bearingic Michael Michael three additionconsecutive addition of of aldehydes aldehydesstereogenic to centers α,,β-disubstituted (Scheme 3) nitroolefins,[37].nitroolefins, The synthetic affording affording usefulness γ-nitroaldehydesγ-nitroaldehydes of these nitroaldehydes 10 bearing10 bearing three is shown consecutive three inconsecutive the stereogenic formation stereogenic of centers fully substituted(Scheme centers 3) (Schemeβ[37].-lactam The3 12synthetic)[, obtained37]. The usefulness from synthetic 10 ofafter these usefulness oxidation nitroaldehydes of of these the aldehydenitroaldehydes is shown and in esterificationthe isformation shown into of give thefully formationnitroester substituted 11 of fullyfollowedβ-lactam substituted 12by, reductionobtainedβ-lactam from of the12 10 nitro, obtainedafter group oxidation from to the10 of am aftertheine aldehyde oxidation and subsequent and of theesterificationaldehyde cyclization. andto Thegive esterification authorsnitroester have 11 to givealsofollowed used nitroester byan reductionimmobilized11 followed of the tripeptide by nitro reduction group as organocata ofto thethe nitroaminelyst group and for subsequentthe to the asymmetric amine cyclization. and addition subsequent The of authorsaldehydes cyclization. have to Theβalso-substituted authorsused an haveimmobilized nitroolefins, also used whichtripeptide an immobilized results as organocatasuitable tripeptide to belyst reused as for organocatalyst the 30 asymmetric times and for employed addition the asymmetric ofin aldehydesa continuous addition to offlowβ-substituted aldehydes system [37]. tonitroolefins,β -substituted which nitroolefins, results suitable which to results be reused suitable 30 times to be reusedand employed 30 times in and a continuous employed inflow a continuous system [37]. flow system [37].

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SchemeScheme 3. 3.Asymmetric Asymmetric addition addition of aldehydes of aldehydes to α,β to-disubstitutedα,β-disubstituted nitroalkenes nitroalkenes catalyzed by catalyzed proline- by proline-containingcontainingScheme 3. Asymmetrictripeptides tripeptides and addition furthe and ofr further transformation aldehydes transformation to α ,toβ-disubstituted lactams. to lactams. nitroalkenes catalyzed by proline- containing tripeptides and further transformation to lactams. The diarylated prolinol silyl ether Hayashi-Jørgensen organocatalyst 13 has been successfully The diarylated prolinol silyl ether Hayashi-Jørgensen organocatalyst 13 has been successfully employedThe diarylated in the asymmetric prolinol silyl conjugate ether Hayashi-Jørgensen addition of carbonyl organocatalyst compounds 13 to has nitroolefins been successfully [38,39]. employed in the asymmetric conjugate addition of carbonyl compounds to nitrooleﬁns [38,39]. Recently,employed this in organocatalystthe asymmetric 13 conjugate has also been addition used inof the carbonyl conjugate compounds addition of to p -methoxybenzylatednitroolefins [38,39]. Recently,(PMB)Recently, this aldehyde this organocatalyst organocatalyst 14 to ketalyzed13 13has has also alsonitroalkene been been usedused 15 in, giving the conjugate conjugate nitroaldehyde addition addition 16of ofpas-methoxybenzylatedp -methoxybenzylateda 3/1 mixture of (PMB)diastereomers(PMB) aldehyde aldehyde employed14 14to to ketalyzed ketalyzedin the total nitroalkenenitroalkene synthesis of 15the15, ,isoprostanegiving giving nitroaldehyde nitroaldehyde isoketal 5-D 162-IsoK, as16 a aas 3/1prostaglandin- a mixture 3/1 mixture of of diastereomerslikediastereomers product (Scheme employed employed 4) [40]. in the in total the synt totalhesis synthesis of the isoprostane of the isoketal isoprostane 5-D2-IsoK, isoketal a prostaglandin- 5-D2-IsoK, a prostaglandin-likelike product (Scheme product 4) [40]. (Scheme 4)[40].

Scheme 4. Synthesis of precursor of isoprostanes using organocatalyst 13. SchemeScheme 4. 4.Synthesis Synthesis of of precursor precursor ofof isoprostanes using using organocatalyst organocatalyst 13.13 .

In addition, this organocatalyst 13 has been applied to the preparation of the core structure of Cephalotaxus norditerpenes, with interesting antineoplastic and antiviral properties. Thus, phenol moiety-containing aldehydes 17 were asymmetrically added to β-arylated trans-nitroalkenes in the presence of the organocatalyst 13 and 4-nitrophenol as acid additive to give the corresponding nitroaldehydes, which were reduced in situ affording nitroalcohols 18. Subsequent oxidative dearomatization gave cis-disubstituted dihydroazulenones 19 (Scheme5)[ 41]. This organocatalyst 13 has also been used in an asymmetric cascade reaction leading to polyfunctionalized cyclohexene aldehyde derivatives in the presence of an oxidant such as o-iodoxybenzoic acid (IBX) [42]. Thus, Michael addition reaction of dihydrocinnamaldehyde (2 equiv.) with nitroalkenes led to intermediate nitroaldehydes 20 (Scheme6). Simultaneously, the initial imine is oxidized in the presence of IBX to a conjugated iminium ion 21 which reacts as a Michael acceptor with the former adduct 20 to yield a cyclized product 22 through aldol condensation and hydrolysis. In addition, the same organocatalysts,Scheme in5. Asymmetric the presence synthesis of p-nitrophenol of cis-disubstituted as co-catalyst, dehydroazulenones has been using employed organocatalyst in the 13 asymmetric. reaction of succinaldehyde with 3-bromo-2-ﬂuoronitrostyrene, to give a key intermediate in the total Scheme 5. Asymmetric synthesis of cis-disubstituted dehydroazulenones using organocatalyst 13. synthesis of the prostaglandin-analog beraprost [43]. Moreover, γ-nitroaldehydes type 2 have been

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Scheme 3. Asymmetric addition of aldehydes to α,β-disubstituted nitroalkenes catalyzed by proline- containing tripeptides and further transformation to lactams.

The diarylated prolinol silyl ether Hayashi-Jørgensen organocatalyst 13 has been successfully employed in the asymmetric conjugate addition of carbonyl compounds to nitroolefins [38,39]. Recently, this organocatalyst 13 has also been used in the conjugate addition of p-methoxybenzylated (PMB) aldehyde 14 to ketalyzed nitroalkene 15, giving nitroaldehyde 16 as a 3/1 mixture of diastereomers employed in the total synthesis of the isoprostane isoketal 5-D2-IsoK, a prostaglandin- like product (Scheme 4) [40].

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Molecules 2017, 22, 895 6 of 51 prepared organocatalytically by means of 13, and have been used for the synthesis of enantioenriched In addition, this organocatalyst 13 has been applied to the preparation of the core structure of ﬁve-membered cyclicScheme nitrones 4. Synthesis after reductive of precursor cyclization of isoprostanes [44 ].using organocatalyst 13. Cephalotaxus norditerpenes, with interesting antineoplastic and antiviral properties. Thus, phenol moiety-containing aldehydes 17 were asymmetrically added to β-arylated trans-nitroalkenes in the presence of the organocatalyst 13 and 4-nitrophenol as acid additive to give the corresponding nitroaldehydes, which were reduced in situ affording nitroalcohols 18. Subsequent oxidative dearomatization gave cis-disubstituted dihydroazulenones 19 (Scheme 5) [41]. This organocatalyst 13 has also been used in an asymmetric cascade reaction leading to polyfunctionalized cyclohexene aldehyde derivatives in the presence of an oxidant such as o-iodoxybenzoic acid (IBX) [42]. Thus, Michael addition reaction of dihydrocinnamaldehyde (2 equiv.) with nitroalkenes led to intermediate nitroaldehydes 20 (Scheme 6). Simultaneously, the initial imine is oxidized in the presence of IBX to a conjugated iminium ion 21 which reacts as a Michael acceptor with the former adduct 20 to yield a cyclized product 22 through aldol condensation and hydrolysis. In addition, the same organocatalysts, in the presence of p-nitrophenol as co-catalyst, has been employed in the asymmetric reaction of succinaldehyde with 3-bromo-2-fluoronitrostyrene, to give a key intermediate in the total synthesis of the prostaglandin-analog beraprost [43]. Moreover, γ-nitroaldehydes type 2 have been prepared organocatalytically by means of 13, and have been used for the synthesis of enantioenriched five-memberedSchemeScheme 5. cyclicAsymmetric 5. Asymmetric nitrones synthesis synthesis after reductive of ofcis cis-disubstituted-disubstituted cyclization dehydroazulenones dehydroazulenones [44]. using using organocatalyst organocatalyst 13. 13.

Scheme 6. Asymmetric cascade reaction leading to cyclohexenes organocatalyzed by 13.

Some recovery-intended supported versions of this organocatalyst have been developed Some recovery-intended supported versions of this organocatalyst have been developed recently recently for the asymmetric addition of aldehydes to nitroalkenes. Thus, the organocatalyst has been for the asymmetric addition of aldehydes to nitroalkenes. Thus, the organocatalyst has been grafted grafted onto the surface of magnetic, polymer-coated cobalt/carbon nanobeads giving species 23, onto the surface of magnetic, polymer-coated cobalt/carbon nanobeads giving species 23, which which organocatalyzed the Michael addition of aldehydes to β-nitrostyrenes leading to γ- organocatalyzed the Michael addition of aldehydes to β-nitrostyrenes leading to γ-nitroaldehydes 2 nitroaldehydes 2 (R1 = alkyl; R2 = alkyl, aryl) (Figure 3) [45]. The catalyst was magnetically separated, (R1 = alkyl; R2 = alkyl, aryl) (Figure3)[ 45]. The catalyst was magnetically separated, but its activity but its activity significantly decreased from the third run. However, the catalyst with a similar significantly decreased from the third run. However, the catalyst with a similar appendage has been appendage has been grafted onto phosphorous dendrimers, the third generation displaying excellent grafted onto phosphorous dendrimers, the third generation displaying excellent recycling abilities recycling abilities since it could be recovered and reused in seven consecutive runs without loss of since it could be recovered and reused in seven consecutive runs without loss of activity [45]. Moreover, activity [45]. Moreover, a related fluorinated organocatalyst immobilized on a polystyrene resin 24 a related fluorinated organocatalyst immobilized on a polystyrene resin 24 (Figure3) has also been (Figure 3) has also been employed for the preparation of 2 (R1 = alkyl, R2 = aryl) [46]. The catalyst employed for the preparation of 2 (R1 = alkyl, R2 = aryl) [46]. The catalyst could be reused eight could be reused eight times, a decrease in its activity being observed after the seventh run. This times, a decrease in its activity being observed after the seventh run. This supported catalyst has also supported catalyst has also been implemented in continuous flow processes. Furthermore, an been implemented in continuous flow processes. Furthermore, an ionically-tagged diphenylprolinol ionically-tagged diphenylprolinol silyl ether has been employed in three different Michael additions silyl ether has been employed in three different Michael additions of aldehydes to nitroolefins in of aldehydes to nitroolefins in ionic liquids, although its recyclability was very limited [47], similar ionic liquids, although its recyclability was very limited [47], similar to when a prolinol methyl ether to when a prolinol methyl ether carrying two perfluorohexylethyl groups was used as catalyst to give carrying two perfluorohexylethyl groups was used as catalyst to give 2 (R1 = alkyl, R2 = alkyl, aryl), 2 (R1 = alkyl, R2 = alkyl, aryl), being recovered in only 40% by fluorous reverse-phase silica gel [48]. being recovered in only 40% by fluorous reverse-phase silica gel [48].

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Molecules 2017, 22, 895 7 of 51

FigureFigure 3. Supported 3. Supported organocatalysts organocatalysts for the for asymmetric the asymmetric Michael Michael addition addition of aldehydes of aldehydes to nitroalkenes to nitroalkenes leading to nitroaldehydes 2. leadingFigure to nitroaldehydes 3. Supported 2organocatalysts. for the asymmetric Michael addition of aldehydes to nitroalkenes leading to nitroaldehydes 2. L-Proline has also been the chiral starting material for the preparation of other chiral Lorganocatalysts-ProlineFigure has3. Supported employed also been organocatalysts in the asymmetric chiral for starting theMichae asymmetric materiall additions Michael for of aldehydes the addition preparation toof nitroolefins.aldehydes of other to Thus, chiral nitroalkenesL-Proline has leading also to beennitroaldehydes the chiral 2. starting material for the preparation of other chiral organocatalyststhe pyrrolidine-pyrazole employed incompound the asymmetric 25, combined Michael with benzoic additions acid of asaldehydes additive, organocatalyzed to nitrooleﬁns. the Thus, organocatalysts employed in the asymmetric Michael additions of aldehydes to nitroolefins. Thus, the pyrrolidine-pyrazoleconjugate addition of compoundaldehydes to25 β,-aromatic combined trans with-nitroalkenes, benzoic acid in absence as additive, of any organocatalyzed solvent, giving the the pyrrolidine-pyrazoleL-Proline has also compoundbeen the chiral25, combined starting with material benzoic for acid the as additive,preparation organocatalyzed of other chiral the rise to syn-γ-nitroaldehydes 2 (R1 β= alkyl, R2 = transaryl) (Figure 4) [49]. In addition, the pyrrolidine 26, conjugateorganocatalystsconjugate addition addition ofemployed aldehydesof aldehydes in the to toasymmetric -aromaticβ-aromatic Michae trans-nitroalkenes,-nitroalkenes,l additions of in aldehydes inabsence absence of to any ofnitroolefins. any solvent, solvent, givingThus, giving containing a hydroxybenzotriazole1 (HOBt)2 moiety, has shown to organocatalyze this reaction in rise totherisesyn pyrrolidine-pyrazole to- γsyn-nitroaldehydes-γ-nitroaldehydes compound2 (R2 (R=1 = alkyl, 25alkyl,, combined RR2 = aryl) with (Figure (Figure benzoic 4)4 )[acid[49].49 asIn]. additive, Inaddition, addition, organocatalyzed the thepyrrolidine pyrrolidine the26, 26, water as solvent, the presence of benzoic acid being also necessary (Figure 4) [50]. Other proline- containingconjugatecontaining a hydroxybenzotriazole addition a hydroxybenzotriazole of aldehydes (HOBt)to β(HOBt)-aromatic moiety, moiety, trans has-nitroalkenes, has shown shown to organocatalyzeto in or absenceganocatalyze of any this thissolvent, reaction reaction giving in in water related catalyst is perhydroindolinol 27, which produces the same asymmetric reaction driving to 2 as solvent,risewater to assyn the solvent,-γ presence-nitroaldehydes the ofpresence benzoic 2 (R of1 acidbenzoic= alkyl, being Racid2 = also aryl)being necessary(Figure also necessary 4) [49]. (Figure In (Figure addition,4)[ 50 4)]. [50]. the Other pyrrolidineOther proline-related proline- 26, (R1 = alkyl, R2 = aryl, alkyl), but using brine as solvent (Figure 4) [51]. catalystcontainingrelated is perhydroindolinol catalyst a hydroxybenzotriazole is perhydroindolinol27, which (HOBt) produces27, which moiety, produces the same has theshown asymmetric same to asy organocatalyzemmetric reaction reaction driving this drivingreaction to 2 (R 1to =in 2alkyl, R2 = aryl,water(R1 = alkyl, alkyl),as solvent, R2 but = aryl, usingthe alkyl), presence brine but as ofusing solventbenzoic brine (Figureacid as solvent being4)[ 51(Figurealso]. necessary 4) [51]. (Figure 4) [50]. Other proline- related catalyst is perhydroindolinol 27, which produces the same asymmetric reaction driving to 2 (R1 = alkyl, R2 = aryl, alkyl), but using brine as solvent (Figure 4) [51].

Figure 4. Results obtained using chiral pyrrolidine-containing organocatalysts in the asymmetric

addition of aldehydes to nitroalkenes leading to nitroaldehydes 2. Figure 4. Results obtained using chiral pyrrolidine-containing organocatalysts in the asymmetric Figure 4. Results obtained using chiral pyrrolidine-containing organocatalysts in the asymmetric addition of aldehydes to nitroalkenes leading to nitroaldehydes 2. additionAs previously of aldehydes shown, to nitroalkenes syn-nitroaldehydes leading to of nitroaldehydes the type 2 are2. the main adducts obtained in the conjugateFigure addition 4. Results of obtainedaldehydes using to trans chiral-β -nitroalkenes.pyrrolidine-containing However, organocatalysts a less common in the anti asymmetric-selectivity can additionAs previously of aldehydes shown, to nitroalksyn-nitroaldehydesenes leading to ofnitroaldehydes the type 2 are 2. the main adducts obtained in the be prevalent if some specific chiral amines are used as organocatalysts. Thus, the biphenyl-based Asconjugate previously addition shown, of aldehydessyn-nitroaldehydes to trans-β-nitroalkenes. of the typeHowever,2 are a theless maincommon adducts anti-selectivity obtained can in the chiral secondary amine 28 organocatalyze the Michael addition of aldehydes to nitrostyrenes, leading be prevalentAs previously if some shown, specific syn chiral-nitroaldehydes aminesβ are ofused the astype organocatalysts. 2 are the main Thus, adducts the obtainedbiphenyl-based in the conjugatemainly addition to the less of accessible aldehydes anti to-adductstrans- -nitroalkenes.29 (Scheme 7) [52]. However, a less common anti-selectivity can be prevalentconjugatechiral secondary if addition some speciﬁcamine of aldehydes 28 chiral organocatalyze aminesto trans-β are -nitroalkenes.the used Michael as organocatalysts. addition However, of aldehydes a less Thus, common to thenitrostyrenes, anti biphenyl-based-selectivity leading can chiral secondarybemainly prevalent amine to the 28ifless someorganocatalyze accessible specific anti chiral-adducts the amines Michael 29 (Schemeare addition used 7) as [52]. oforganocatalysts. aldehydes to nitrostyrenes,Thus, the biphenyl-based leading mainly chiral secondary amine 28 organocatalyze the Michael addition of aldehydes to nitrostyrenes, leading to the less accessible anti-adducts 29 (Scheme7)[52]. mainly to the less accessible anti-adducts 29 (Scheme 7) [52].

Scheme 7. Asymmetric anti-selective Michael addition of aldehydes to nitroalkenes. Scheme 7. Asymmetric anti-selective Michael addition of aldehydes to nitroalkenes.

Molecules 2017, 22, 895 8 of 51 Molecules 2017, 22, 895 8 of 51

Molecules 2017, 22, 895 8 of 51 The asymmetric synthesis of thethe A-ring fragment of C19-diterpenoid atropurpuran has been achieved after a key step consisting of an intramolecular Michael addition reaction using achievedMoleculesThe after 2017 asymmetric a, 22 key, 895 step synthesis consisting of of th ane A-ring intramolecular fragment Michaelof C19-diterpenoid addition reaction atropurpuran using 5-pyrrolidinyl has 8been of 51 5-pyrrolidinyltetrazoleachieved30 asafter tetrazole organocatalyst a key 30 step as organocatalyst (Schemeconsisting8). of In thisan(Scheme intramolecular way, 8). nitroalkene In this Michael way,31 affordednitroalkene addition four reaction 31 diastereomeric afforded using four diastereomericcyclohexanes5-pyrrolidinylThe asymmetric32 cyclohexanes tetrazolewhich synthesis were 30 32asconverted organocatalystwhich of the were A-ring into converted (Schemefragment two substituted 8).into of In C19-diterpenoid tw thiso substitutedway, cyclohexanones nitroalkene atropurpuran cyclohexanones 3133 afforded, with has differentbeen33four, with differentenantioselectivitiesachieveddiastereomeric enantioselectiviti after cyclohexanesa according key esstep according to 32consisting the which starting towere theof diastereomerconverted anstarting intramolecular diastereomer into[ tw53].o substitutedMichael [53]. addition cyclohexanones reaction 33 ,using with 5-pyrrolidinyldifferent enantioselectiviti tetrazole 30es as according organocatalyst to the starting(Scheme diastereomer 8). In this way, [53]. nitroalkene 31 afforded four diastereomeric cyclohexanes 32 which were converted into two substituted cyclohexanones 33, with different enantioselectivities according to the starting diastereomer [53].

Scheme 8. Asymmetric synthesis leading to the atropurpuran A-ring. Scheme 8. Asymmetric synthesis leading to the atropurpuran A-ring. Scheme 8. Asymmetric synthesis leading to the atropurpuran A-ring. TheThe Michael Michael addition Schemeaddition 8.of Asymmetricof αα,α,α-disubstituted-disubstituted synthesis leading aldehydesaldehydes to the atropurpuran toto ninitroalkenestroalkenes A-ring. provides provides adducts adducts possessingpossessingThe Michael all-carbon all-carbon addition quaternary quaternary of α,α-disubstituted centers.centers. IsobutyraldehydeIsobutyraldehyde aldehydes to nitroalkenes isis anan adequate adequate provides aldehyde adductsaldehyde for possessing forthis this organocatalyticall-carbonorganocatalyticThe quaternary Michael asymmetric asymmetric addition centers. reaction reactionof Isobutyraldehyde α,α (Scheme -disubstituted(Scheme 9),9), whichis aldehydes an justifies adequatejustifies toits its aldehydefrequentni frequenttroalkenes use foruse asprovides this asa model a organocatalytic model adductswhen when a a possessing all-carbon quaternary centers. Isobutyraldehyde is an adequate aldehyde for this newasymmetricnew organocatalyst organocatalyst reaction (Schemeis isdeveloped. developed.9), which Some Some justiﬁes examplesexamples its frequent ofof chiralchiral use as pyrrolidine-containingpyrrolidine-containing a model when a new catalysts organocatalyst catalysts are are organocatalytic asymmetric reaction (Scheme 9), which justifies its frequent use as a model when a diamineis developed.diamine 35 [54]35 [54] Some and and pyrrolidine-oxyimide examples pyrrolidine-oxyimide of chiral pyrrolidine-containing 3636 [55],[55], whichwhich ledled to to enantiomer catalystsenantiomer are 34b 34b diamine (R (R= aryl) = aryl)35 under[54 under] and new organocatalyst is developed. Some examples of chiral pyrrolidine-containing catalysts are pyrrolidine-oxyimidesolvent-freesolvent-free conditions conditions36 and [and55 ],in in whichthe the presence presence led to enantiomer ofof aa carboxylic34b acid (Racid = as aryl)as co-catalyst co-catalyst under solvent-free(Figure (Figure 5). The5). conditions The same same diamineenantiomer 35 [54]was andmainly pyrrolidine-oxyimide obtained using the 36 pyrrolidine-HOBt [55], which led to26 enantiomeras organocatalyst 34b (R (20 = aryl) mol under%), in enantiomerand in the presence was mainly of a carboxylicobtained using acid asthe co-catalyst pyrrolidine-HOBt (Figure5 ).26 The as sameorganocatalyst enantiomer (20 was mol mainly %), in solvent-freewater as solvent conditions at 0 °C and in thethe presencepresence of of benzoic a carboxylic acid as acid additive as co-catalyst (10 mol %)(Figure (73–91% 5). Theyield, same 77– waterobtained as solvent using theat 0 pyrrolidine-HOBt °C and in the presence26 as of organocatalyst benzoic acid as (20 additive mol %), (10 in mol water %) (73 as– solvent91% yield, at 0 77◦C– enantiomer93% ee) [50]. wasThis mainlythree organocatalysts obtained using have the alsopyrrolidine-HOBt been employed 26 using as organocatalyst cyclopentanecarbaldehyde (20 mol %), asin 93%and ee in) the[50]. presence This three of organocatalysts benzoic acid as have additive also b (10een molemployed %) (73–91% using cyclopentanecarbaldehyde yield, 77–93% ee)[50]. This as watera pro-nucleophile as solvent at affording 0 °C and inthe the compound presence ofsimilar benzoic to 34bacid [(CH as additive2)4 instead (10 ofmol 2Me] %) (73(using–91% 35 yield,: 76–93% 77– a pro-nucleophile affording the compound similar to 34b [(CH2)4 instead of 2Me] (using 35: 76–93% three93%yield, organocatalysts ee 92) [50].–96% This ee; usingthree have organocatalysts36 also: 80– been91% yield, employed have 78– also92% using beeeen; using cyclopentanecarbaldehyde employed 26: 69– using91% yield, cyclopentanecarbaldehyde 74–92% as ee a). pro-nucleophile as yield, 92–96% ee; using 36: 80–91% yield, 78–92% ee; using 26: 69–91% yield, 74–92% ee). affordinga pro-nucleophile the compound affording similar the tocompound34b [(CH similar2)4 instead to 34b of [(CH 2Me]2)4 instead (using 35of :2Me] 76–93% (using yield, 35: 76 92–96%–93% ee; usingyield,36: 80–91%92–96% ee yield,; using 78–92% 36: 80–91%ee; using yield,26 78:– 69–91%92% ee; using yield, 26 74–92%: 69–91%ee yield,). 74–92% ee).

Scheme 9. Asymmetric organocatalytic Michael addition of isobutyraldehyde to nitroalkenes. Scheme 9. Asymmetric organocatalytic Michael addition of isobutyraldehyde to nitroalkenes. SchemeScheme 9. Asymmetric 9. Asymmetric organocatalytic organocatalytic MichaelMichael additi additionon of of isobutyraldehyde isobutyraldehyde to nitroalkenes. to nitroalkenes.

Figure 5. Results obtained using chiral pyrrolidine-containing organocatalysts in the asymmetric addition of isobutyraldehyde to nitroalkenes leading to nitroaldehyde 34b. Figure 5. Results obtained using chiral pyrrolidine-containing organocatalysts in the asymmetric Figure 5. Results obtained using chiral pyrrolidine-containing organocatalysts in the asymmetric additionC2-Symmetric of isobutyraldehyde diamines have to nitroalkenes been employed leading prof to nitroaldehydeusely as chiral 34b34b .blocks in the preparation of addition of isobutyraldehyde to nitroalkenes leading toto nitroaldehydenitroaldehyde 34b.. organocatalysts for asymmetric reactions [56]. An example is the use of wedge shaped 1,3- benzenedisulfonamideC2-Symmetric diamines 37 (Figure have 6), been obtained employed from prof (1Rusely,2R)-1,2-diphenylethane-1,2-diamine, as chiral blocks in the preparation in the of C2-Symmetric diamines diamines have have been been employed employed prof profuselyusely as as chiral chiral blocks blocks in inthe the preparation preparation of organocatalystsMichael addition for of isobutyraldehydeasymmetric reactions to β-nitrostyrene [56]. An example leading tois 34bthe (Ruse = Ph)of [57].wedge This shaped compound 1,3- organocatalystsof organocatalysts for forasymmetric asymmetric reactions reactions [56]. [56 An]. example An example is the is use the of use wedge of wedge shaped shaped 1,3- benzenedisulfonamide37 mimics the chiral pocket 37 (Figure of an enzyme, 6), obtained embedding from (1 theR,2 nitroR)-1,2-diphenylethane-1,2-diamine, group in the groove of the catalyst in the by 1,3-benzenedisulfonamide 37 (Figure6), obtained from (1 R,2R)-1,2-diphenylethane-1,2-diamine, in benzenedisulfonamideMichaelmeans of addition double hydrogenof isobutyraldehyde 37 (Figure bonding, 6), obtainedwhereas to β-nitrostyrene the from enamine (1R leading,2 Rfrom)-1,2-diphenylethane-1,2-diamine, to the 34b aldehyde (R = Ph) is [57]. formed This withcompound one inof the Michaelthe37 Michael mimics addition additionthe chiralof isobutyraldehyde pocket of isobutyraldehyde of an enzyme, to β -nitrostyreneembedding to β-nitrostyrene the leading nitro group leading to 34b in the(R to =groove 34bPh) [57].(R of =the This Ph) catalyst compound [57]. by This 37compound mimicsmeans ofthe37 double chiralmimics hydrogenpocket the chiralof bonding, an enzyme, pocket whereas ofembedding an the enzyme, enamine the embeddingnitro from groupthe aldehyde thein the nitro grooveis formed group of withthe in thecatalyst one groove of by means of double hydrogen bonding, whereas the enamine from the aldehyde is formed with one of

Molecules 2017, 22, 895 9 of 51 of the catalyst by means of double hydrogen bonding, whereas the enamine from the aldehyde is Molecules 2017, 22, 895 9 of 51 formedMolecules with 2017 one, 22 of, 895 the primary amino groups. However, chiral trans-cyclohexa-1,2-diamines9 of 51 have beenthe the C2-symmetricprimary amino diaminesgroups. However, which have chiral been trans more-cyclohexa-1,2-diamine frequently used whens have designing been the new C2- chiral organocatalysts.symmetricthe primary diamines Anamino example groups.which is theHowever,have primary been chiral more amine-containing transfrequently-cyclohexa-1,2-diamine used benzimidazole when designings have38 been(Figure new the 6chiral ),C2- which acts bifunctionallyorganocatalysts.symmetric diamines by An hydrogen-bond example which ishave the primary coordinationbeen more amine-containing frequently with one used ofbenzimidazole the when hydrogens designing 38 (Figure of the new nitro6), whichchiral group of the nitroalkene,actsorganocatalysts. bifunctionally while An theby example hydrogen-b last reacts is theond with primary coordination the primaryamine-containing with amine-formed one of benzimidazolethe hydrogens enamine of38 [ 58 the(Figure]. nitro Another 6), group which example of is thetheacts guanidine-containing nitroalkene, bifunctionally while by thehydrogen-b last primary reactsond aminewith coordination the39 primary(Figure with amine-formed6), one which of the has hydrogens enamine been used[58]. of the Another for nitro the groupexample asymmetric of isthe the nitroalkene, guanidine-containing while the last primary reacts with amine the 39 primary (Figure amine-formed 6), which has enamine been used [58]. for Another the asymmetric example conjugate addition of isobutyraldehyde to nitrostyrenes to give preferentially 34b (R = aryl), working conjugateis the guanidine-containing addition of isobutyraldehyde primary amine to nitrostyrenes 39 (Figure 6),to givewhich preferentially has been used 34b for (R =the aryl), asymmetric working in aninconjugate aqueous an aqueous addition medium medium of [isobutyraldehyde59 [59].]. In In this this case case to the the nitrostyrenes catalystcatalyst cannot cannot to give be be preferentiallyconsidered considered as 34b bifunctional, as (R bifunctional, = aryl), workingas it ashas it has beenbeenin determined an aqueousdetermined by medium theoretical by theoretical [59]. calculationsIn this calculations case the that, cataly that probablyst, probablycannot due be todueconsidered the to presence the aspresence bifunctional, of water, of water, the as guanidineit hasthe functionguanidinebeen is determined not function coordinated by is nottheoretical tocoordinated the nitro calculations groupto the nitro in that the group, transitionprobably in the transition state.due to the state. presence of water, the guanidine function is not coordinated to the nitro group in the transition state.

FigureFigure 6. Results 6. Results obtained obtained using using C2-diamine-derived C2-diamine-derived organocatalysts organocatalysts in inthe the asymmetric asymmetric addition addition of of isobutyraldehydeisobutyraldehydeFigure 6. Results to nitroalkenesobtained to nitroalkenes using leading C2-diamine-derivedleading to to nitroaldehydes nitroaldehydes organocatalysts 3434. . in the asymmetric addition of isobutyraldehyde to nitroalkenes leading to nitroaldehydes 34. Chiral organocatalysts bearing a primary or a secondary amine and a thiourea have proven quite ChiraleffectiveChiral organocatalysts in organocatalystsmany asymmetric bearing bearing transformations a primarya primary oror involving aa secondary aldehydes amine amine and or and ketonesa thiourea a thiourea [60 have–63]. have proven Concerning proven quite quite effectiveacidityeffective in manyand in manygeometric asymmetric asymmetric distances, transformations transformations the hydrogens involvinginvolving on the thiourea aldehydes aldehydes group or or ketonescan ketones hydrogen [60– [6063]. –bond63 Concerning]. Concerningto both acidityoxygensacidity and and geometric of thegeometric nitrodistances, group distances, in the the thenitroolefin. hydrogens hydrogens Exampl on the thees ofthiourea thiourea organocatalysts group group can canre hydrogencently hydrogen employed bond bond to in both the to both oxygensasymmetricoxygens of the of nitrothe Michael nitro group groupaddition in in the ofthe nitrooleﬁn.isobutyraldehyde nitroolefin. ExamplesExampl to nitrostyreneses of of organocatalysts organocatalysts are shown recently recentlyin Figure employed employed7. in the in the asymmetricasymmetric Michael Michael addition addition of of isobutyraldehyde isobutyraldehyde to nitrostyrenes are are shown shown in Figure in Figure 7. 7.

Figure 7. Results obtained using primary-amine thioureas and squaramides as organocatalysts in the FigureasymmetricFigure 7. Results 7. Results addition obtained obtained of isobutyraldehyde using using primary-amine primary-amine to nitroalkenes thioureasthioureas leading and and squaramides squaramides to nitroaldehydes as organocatalysts as organocatalysts 34. in the in the asymmetric asymmetric addition addition of isobutyraldehydeof isobutyraldehyde to to nitroalkenes nitroalkenes leading leading to to nitroaldehydes nitroaldehydes 34. 34.

Molecules 2017, 22, 895 10 of 51 Molecules 2017, 22, 895 10 of 51

Thus, the useuse ofof calyx[4]arene-basedcalyx [4] arene-based chiral chir bifunctionalal bifunctional primary-amine primary-amine thiourea thiourea40 has40 has led led to the to adductthe adduct34a 34a(R =(R aryl) = aryl) [64 [64],], whereas whereas the the use use of of rosin-based rosin-based primary-amine primary-amine thiourea thiourea41 41 drovedrove to 34b (R == aryl) in high yields and enantioselectivitiesenantioselectivities [65]. [65]. This last organocatalyst 41 has also been used in thethe additionaddition ofof otherother differentlydifferently αα,,αα-disubstituted-disubstituted aldehydesaldehydes toto ββ-nitro-4-nitrostyrene,-nitro-4-nitrostyrene, achievingachieving highs eeee’s’s (up (up to to 99%) 99%) of of the the final final nitroaldehyde, nitroaldehyde, alth althoughough with with moderate moderate diastereo diastereo selectivities selectivities (up (upto 83/17). to 83/17). Kinetic Kinetic and andspectroscopic spectroscopic studies studies of ofthe the conjugate conjugate addition addition of of 2-phenylpropanal 2-phenylpropanal to nitroolefinsnitroolefins catalyzed by by two two different different primary primary amine amine thiourea thiourea catalysts catalysts have have shown shown that, that, at atleast least in inthese these cases, cases, the theresting resting state state is a product is a product imine iminespecies species that undergoes that undergoes reversible reversible hydrolysis hydrolysis to form tothe form reaction the product, reaction and product, that reversibility and that reversibility of the reaction of the is implicated reaction is in implicated cases of low in casesenantio- of and low enantio-diastereoselectivity and diastereoselectivity [66]. Amine-containing [66]. Amine-containing squaramides have squaramides shown as have efficient shown bifunctional as efficient bifunctionalorganocatalysts organocatalysts in many asymmetric in many asymmetricprocesses as processes amine-containing as amine-containing thioureas [67,68]. thioureas A [recent67,68]. Aexample recent exampleis the use is of the isosteviol-containing use of isosteviol-containing primary primary amine-squaramide amine-squaramide 42 as organocatalyst42 as organocatalyst in the inasymmetric the asymmetric conjugate conjugate addition addition of isobutyral of isobutyraldehydedehyde to nitroalkenes, to nitroalkenes, achieving achieving adduct 34a adduct (R = aryl,34a (Ralkenyl) = aryl, (Figure alkenyl) 7) [69]. (Figure It is7 )[interesting69]. It is to interesting note that similar to note values that similar of the valuesopposite of final the oppositeconfiguration final configuration34b has been34b achievedhas been exchanging achieved exchanging the cyclohexa- the cyclohexa-1,2-diamine1,2-diamine moiety moiety of the of thecatalyst catalyst by by its corresponding enantiomer,enantiomer, showing showing that thethat isosteviol the is moietyosteviol is notmoiety involved is innot the involved enantioselectivity. in the Moreover,enantioselectivity. the regioselective Moreover, functionalization the regioselective of functionalization aldehyde-derived of silyl aldehyde-derived−diene enol ethers silyl under−diene a bifunctionalenol ethers under tertiary a bifunctional amine-containing tertiary squaramide amine-containing organocatalyst squara43midehas shownorganocatalyst to produce 43 ahas change shown in theto produce regioselectivity, a change from in the the 1,5- regioselectivity, to the 1,3-functionalization, from the 1,5- affording to the 1,3-functionalization, Rauhut-Currier-type conjugated affording aldehydesRauhut-Currier-type44 after double conjugated bond isomerization, aldehydes 44 as after exemplified double inbond Scheme isomerization, 10. This procedure as exemplified has made in possibleScheme 10. the This 1,3-addition procedure of has silyl made−dienol possible ethers the to 1,3-addition nitroalkenes of [silyl70].−dienol ethers to nitroalkenes [70].

Scheme 10.10.Asymmetric Asymmetric organocatalytic organocatalytic addition addition of aldehyde-derived of aldehyde-derived silyl-enol etherssilyl-enol to nitroalkenes. ethers to nitroalkenes. 2.2. Ketones 2.2. KetonesAmong ketones, cyclohexanone have been profusely used as a model pro-nucleophile to test the catalyticAmong efficiency ketones, of organocatalystscyclohexanone have in the been Michael profusel additiony used to as nitroalkenes. a model pro-nucleophile Although high to levels test the of diastereo-catalytic efficiency and enantioselectivities of organocatalysts have in beenthe Michae obtainedl addition with several to nitroalkenes organocatalysts. Although in the high addition levels of diastereo- six-membered and enantioselectivities ring ketones to β-nitroolefins, have been ob othertained cyclic with or several acyclic organocatalysts ketones gave poorer in the results addition [8]. Inof six-membered this context, the ring conjugate ketones additionto β-nitroolefins, of ketones other to βcyclic-nitrostyrenes or acyclic catalyzedketones gave by Lpoorer-proline results showed [8]. aIn strong this context, solvent the effect, conjugate giving addition the best of results ketones in MeOHto β-nitrostyrenes [28,29,71]. Thiscatalyzed was the by solventL-proline of showed choice to a performstrong solvent the addition effect, giving of cyclohexanone the best results to several in Me arylOH [28,29,71]. nitroolefins This catalyzed was the by solvent chiral of ionic choice liquid to containingperform the proline addition moiety of cyclohexanone45 in the presence to several of triethylamine aryl nitroolefins (TEA) as catalyzed co-catalyst by (Scheme chiral ionic11), leading liquid tocontaining adducts 46proline[72]. Themoiety re-usability 45 in the of thepresence catalyst of wastriethylamine proven, as (TEA) similar as results co-catalyst wereachieved (Scheme over11), fiveleading reaction to adducts runs after 46 catalyst[72]. The recovering re-usability from of the the reaction catalyst media was by proven, precipitation as similar with diethylresults ether.were achieved over five reaction runs after catalyst recovering from the reaction media by precipitation with diethyl ether.

Molecules 2017, 22, 895 11 of 51 Molecules 2017, 22, 895 11 of 51

Scheme 11.11. AsymmetricAsymmetric organocatalytic organocatalytic Michael Michael addition addition of of cyclohexanone to nitroalkenes organocatalyzed by ionic-liquid 45..

Some proline derivatives that have shown their efficiencyefficiency as organocatalysts in the reaction between aldehydes and β-aromatic trans-nitroalkenes, were were also te testedsted under similar reactions conditions in the related process with ketones. Thus, pyrrolidine 26 (10 mol %) containing a HOBt moiety (Figure 44)) promotedpromoted the Michael addition addition of of cyclohexanone cyclohexanone to to aryl aryl nitroolefins nitroolefins in in water water as assolvent, solvent, providing providing the thecorresponding corresponding γ-nitrocarbonylγ-nitrocarbonyl derivatives derivatives 46 in46 goodin good yields yields (84–95%), (84–95%), with withhigh highdiastereo- diastereo- (91/9– (91/9–96/4)96/4) and enantioselectivities and enantioselectivities (81–95%) (81–95%) irrespective irrespective of the substitution of the substitution pattern patternon the nitroolefins. on the nitroolefins. However, lower However, results lower were results achieved were with achieved other ketones, with other such as ketones, tetrahydro- such4H as- tetrahydro-pyran-2-one,4H cyclopentenone-pyran-2-one, cyclopentenone or acetone [73]. orSimilar acetone results [73]. were Similar encountered results were when encountered organocatalyst when organocatalyst36 (10 mol %) containing36 (10 mol a %)oxyimide containing appendage a oxyimide (Figure appendage 5) was used (Figure in water5) was for used the Michael in water addition for the Michaelof cyclic additionketones ofas cyclicpro-nucleophiles ketones as pro-nucleophiles and aromatic trans and-nitrostyrenes aromatic trans (86-nitrostyrenes–95% yield, (86–95% 91/9–97/3 yield, dr, 91/9–97/385–96% ee).dr ,However, 85–96% ee ).the However, reaction the with reaction acetone with was acetone very was sluggish very sluggish and proceeded and proceeded with withlow lowstereoselectivity stereoselectivity [74]. [74For]. Forboth both catalysts, catalysts, the theuse use of ofadditives additives was was ruled ruled out out since since the the effective hydrogen bondingbonding interactioninteraction provided provided by by the the water water molecules molecules brings brings closer closer both both substrates substrates with with the appropriatethe appropriate orientation, orientation, which which would would be less be less effective effective in the in presencethe presence of an of additive. an additive. Several pyrrolidine-based catalysts containing a functional group in the side chain that provided an additional hydrogen-bond interaction have been developed and tested in this transformation. Thus, pyrrolidine derivative 47 (Figure 88)) bearingbearing aa sulfoxidesulfoxide moietymoiety waswas veryvery effectiveeffective inin thethe addition of cyclohexanone, cyclopentanonecyclopentanone and acetone to aromatic β-nitroolefins-nitroolefins [[75].75]. However, However, lower enantioselectivities (31 (31–51%–51% eeee)) were achieved when when 2-butanone 2-butanone and and 3-pentanone 3-pentanone were were used. used. Remarkably, the the formation formation of of the the Michael Michael adduct adduct took took place place at the at more the more substituted substituted site when site whenusing using2-butanone. 2-butanone. The addition addition of of a asulfonamide sulfonamide moiety moiety to the to thepyrrolidine pyrrolidine side sidechain chain led to led the to catalyst the catalyst 48 which48 whichorganocatalyzed organocatalyzed the addition the addition of cyclohexanone of cyclohexanone and acetone and acetone to trans to -transβ-nitrostyrene-β-nitrostyrene under under neat neatconditions. conditions. The Thepresence presence of water of water or acetic or acetic acid acid as asadditives additives improved improved the the achieved achieved results results with cyclohexanone (concerning yield and enantioselectivity), whereas the opposite effect was observed with acetone [[76].76]. Pyrrolidine-pyridone catalyst 49 was designed to achieve high results in diastereo- and enantioselectivities due to the effective shield of one side of thethe enamineenamine intermediate,intermediate, with the pyridine moiety. Also, the carbonyl group of the ring could stabilize the transition state through hydrogen bonding interactions. This catalyst was tested in the addition of cyclohexanone to aryl and heteroaryl nitroolefinsnitroolefins under neat conditions affording products 46 with good results, in terms of yields and stereoselectivities. Similar result was obtained when tetrahydro-4 H-pyran-2-one was used as reagent, while acyclic ketones, suchsuch asas acetoneacetone oror 2-butanone,2-butanone, gavegave poorerpoorer resultsresults [[77].77].

Molecules 2017, 22, 895 12 of 51 Molecules 2017, 22, 895 12 of 51

Figure 8. Results obtained using some pyrrolidine-based organocatalysts in the Michael reaction of Figure 8. Results obtained using some pyrrolidine-based organocatalysts in the Michael reaction of ketones to β-nitrostyrenes. ketones to β-nitrostyrenes.

A doubledouble hydrogen hydrogen bonding bonding group group was was introduced introduced in the in pyrrolidine the pyrrolidine catalyst catalyst by using by a diaminousing a methylenediamino methylene malononitrile malononitrile skeleton atskeleton the side at chain the side (Figure chain8, 50(Figure). Thus, 8, catalyst50). Thus,50 incatalyst the presence 50 in the of aceticpresence acid of as acetic additive acid underas additive neat conditions,under neat gaveconditions, the corresponding gave the corresponding Michael adducts Michael in the adducts reaction in ofthe cyclohexanone reaction of cyclohexanone with aromatic with andheteroaromatic aromatic and nitroalkenesheteroaromatic with nitroalkenes good results. with However, good results. the use ofHowever, other ketones the use such of as other acetone ketones led to disappointingsuch as acetone results led into terms disappointing of enantioselectivity results in (33%)terms [78 of]. enantioselectiviIn order toty study (33%) the [78]. effect of the conformation of the pyrrolidine ring on the outcome of the reaction,In order a fluorine to study atom the was effect added of the at theconformation 4-position ofof thethe pyrrolidinepyrrolidine ring ring in on catalyst the outcome51 (Figure of the9). Thereaction, gauche a fluorine effect cause atom by was the added fluorine at atomthe 4-position led to a drastic of the improvement pyrrolidine ring in the in formationcatalyst 51 of (Figure products 9). ofThe type gauche46, under effect solvent cause free by conditions.the fluorine It wasatom observed led to a that drastic the addition improvement of 10 mol% in the of trifluoroaceticformation of acidproducts provided of type better 46,stereoselectivities under solvent free when conditions. electron It deficient was observed substituted thatβ the-nitrostyrenes addition of were 10 mol% used asof electrophiles,trifluoroacetic while acid the provided contrary occurredbetter stereoselectivities for their electron-rich when substituted electron counterparts.deficient substituted Furthermore, β- thenitrostyrenes catalyst was were quite used efficient as electrophiles, in promoting while the reaction the contrary of other occurred cyclic ketones for their and acetoneelectron-rich with nitrostyrenessubstituted counterparts. [79]. As shown Furthermor in the proposede, the catalyst stereochemical was quite model efficienFt(Figure in promoting9) created the by reaction reaction of withother cyclohexanone, cyclic ketones whenand acetone a fluorine with atom nitrostyrene was introduceds [79]. As at the shown 4-position in the of proposed the pyrrolidine stereochemical ring, the (modelE)-trans F -C(Figureγ-endo 9)is created the favored by reaction conformation with cyclohexan due to theone, gauche when effect. a fluorine atom was introduced at the 4-positionThis gauche of the effect pyrrolidine was also observedring, the in(E)- catalysttrans-Cγ52-endo, the iscis the-diastereoisomer favored conformation providing due the to best the results.gauche effect. The introduction of the fluorine atom at the 4-position of the pyrimidinone substituted pyrrolidineThis gauche ring improvedeffect was notalso only observed the yield in catalyst but also 52, the the stereoselectivity, cis-diastereoisomer an allowedproviding to the reduce best theresults. catalyst The loadingintroduction to 5 molof the %. fluorine Not only atom aromatic at the nitroalkenes 4-position of with the electron-withdrawingpyrimidinone substituted and electron-donatingpyrrolidine ring improved substituents not only were the suitable yield electrophiles,but also the stereoselectivity, but also some aliphatic an allowed nitroalkenes to reduceand the aromaticcatalyst loading nitrodienes to 5 mol were %. successfully Not only aromatic used as Michaelnitroalkenes acceptors. with electron-withdrawing The use of brine andthe and possibility electron- ofdonating reducing substituents the reagent were ratio suitable to almost electrophiles, stoichiometric but valuesalso some by usingaliphatic catalyst nitroalkenes52 made and this aromatic protocol greennitrodienes and effective were successfully [80]. used as Michael acceptors. The use of brine and the possibility of reducing the reagent ratio to almost stoichiometric values by using catalyst 52 made this protocol green and effective [80].

Molecules 2017,, 22,, 895895 13 of 51 Molecules 2017, 22, 895 13 of 51

Figure 9. Pyrrolidine-based organocatalysts containing a ﬂuorine atom at the ring in the Michael FigureFigure 9. 9.Pyrrolidine-based Pyrrolidine-based organocatalysts organocatalysts containingcontaining aa fluorinefluorine atom atom at at the the ring ring in in the the Michael Michael addition of ketones to nitroalkenes. additionaddition of ofketones ketones to to nitroalkenes. nitroalkenes.

AnotherAnother way way of of trying trying to to improve improve thethe resultsresults ofof thethe pyrrolidine-based pyrrolidine-based catalyst catalyst in inthe the Michael MichaelMichael reactionreaction of of ofketones ketones ketones to toto nitroolefins nitroolefins nitrooleﬁns was was was to to introduce tointroduce introduce an additionaladditional an additional stereogenic stereogenic stereogenic center center in center in the the side inside thechain, chain, side chain,as aswell well as as well as a a asnew new a newhydrogen-bonding hydrogen-bonding hydrogen-bonding functionalitfunctionalit functionality.y. Thus,Thus, Thus, chiralchiral chiral 1,2-amino1,2-amino 1,2-amino alcohols alcohols alcohols have have have been been incorporatedincorporated to to the the pyrrolidine pyrrolidine moiety moiety producingproducing bifunctional organocatalysts organocatalysts such suchsuch as asas compound compound 53 53 (Figure(Figure(Figure 1010). 10).). This This This catalyst, catalyst, in inin the the presencepresence of of triﬂuoroacetictrifluoroacetic acid,acid, gave gave good good results results in inthe the reaction reactionreaction betweenbetween cyclohexanone cyclohexanone and and β β-nitrostyrene-nitrostyrene derivatives.derivatives. DFTDFT calcul calculationscalculationsations showed showed that that both both NH NH and and OHOH groups groups activated activated the the nitro nitro moietymoiety byby thethe formationformation of of hydrogen hydrogenhydrogen bonds, bonds, as as illustrated illustrated in inthe the coordinationcoordination modelmodel model GG G,, favoringfavoring, favoring itsits its approachapproach approach fromfromfrom thethe ReRe-face-face of ofof the thethe anti antianti-enamine-enamine-enamine [81]. [[81].81 ].

FigureFigure 10. 10.Pyrrolidine-based Pyrrolidine-based organocatalystsorganocatalysts containing containing an an additional additional stereogenic stereogenic center center in inthe the conjugateconjugate addition addition of of ketones ketones to to nitrooleﬁns. nitroolefins. Figure 10. Pyrrolidine-based organocatalysts containing an additional stereogenic center in the conjugate addition of ketones to nitroolefins. NaturalNatural pinane-derived pinane-derived bifunctional bifunctional catalystcatalyst 54 promoted also also effectively effectively the the reaction reaction between between cyclohexanonecyclohexanone and and heterocyclohexanone heterocyclohexanone derivatives derivatives to to aromatic aromatic and and heteroaromatic heteroaromatic nitrooleﬁns. nitroolefins. But Natural pinane-derived bifunctional catalyst 54 promoted also effectively the reaction between

cyclohexanone and heterocyclohexanone derivatives to aromatic and heteroaromatic nitroolefins.

Molecules 2017, 22, 895 14 of 51

Molecules 2017, 22, 895 14 of 51 But the reaction gave either poor enantioselectivity (40%) with acetone and failed with cyclopentanone or 1,4-cyclohexanedione monoethylene-ketal [82]. In addition, better results and substratethe reaction scope gave were either achieved poor enantioselectivity by using sugar (40%)amide-derived with acetone catalyst and failed55 (Figure with 10) cyclopentanone under solvent- or 1,4-cyclohexanedionefree conditions. Several monoethylene-ketal β-nitrostyrenes [82were]. In addition,used as betterelectrophiles results and in substratethe reaction scope werewith cyclohexanone,achieved by using providing sugar amide-derived good results irrespective catalyst 55 (Figure of the nature 10) under of substitution solvent-free at conditions. the aromatic Several ring. Alsoβ-nitrostyrenes cyclopentanone were usedand acetone as electrophiles were suitable in the reactionpro-nucleophiles, with cyclohexanone, although the providing achieved good results, results in termsirrespective of yields of the natureand selectivities, of substitution were at thelower aromatic compared ring. Also to cyclopentanonethose obtained and with acetone standard were cyclohexanonesuitable pro-nucleophiles, [83]. although the achieved results, in terms of yields and selectivities, were lowerThe compared introduction to those of a obtained heterocyclic with linkage standard between cyclohexanone the pyrrolidine [83]. ring and the unit bearing an additionalThe introduction stereogenic ofcenter a heterocyclic has been linkagetested to between study theif the pyrrolidine new rigid ring backbone and the conformation unit bearing providedan additional by the stereogenic heterocycle center would has enhance been tested the stereoselectivity to study if the new(Figure rigid 11). backbone Thus, catalyst conformation 56 [84], provided57a,b [85] byhave the been heterocycle used in would the reaction enhance between the stereoselectivity ketones and (Figurearyl nitroolefins 11). Thus, under catalyst different56 [84], reaction57a,b [85 ]conditions, have been used providing in the reaction adducts between of ketonestype 46 and in aryl good nitrooleﬁns results. under Lower different yields reaction and enantioselectivitiesconditions, providing were adducts found ofwhen type acetone46 in good was results.used as Lowerpro-nucleophile. yields and Remarkably, enantioselectivities only 0.5 were mol %found of catalyst when acetoneloading was for usedcompounds as pro-nucleophile. 57 was enough Remarkably, to promote only the 0.5 reaction, mol % ofindependently catalyst loading of the for relativecompounds position57 was of enough amide toin promote the heterocycle. the reaction, DFT independently calculations offor the catalyst relative 56 position showed of amidethat the in intramolecularthe heterocycle. hydrogen DFT calculations bonds and for the catalyst steric56 hindranceshowed thatof the the N-benzyl intramolecular oxazolecarboxamide hydrogen bonds moiety and controlthe steric the hindrance Si-face approach of the N-benzyl and the oxazolecarboxamide catalytic activity, as moiety illustrated control in the theSi coordination-face approach model and the H (Figurecatalytic 11). activity, as illustrated in the coordination model H (Figure 11).

Figure 11. Pyrrolidine-based organocatalysts containing an additional stereogenic center linked by a heterocyclic ring.

DDiaminesiamines have have also also been been employed employed as backbone as backbone to anchor to anchor pyrrolidine pyrrolidine units unitsto synthetize to synthetize useful organocatalystsuseful organocatalysts (Figure (Figure12). Examples 12). Examples of this type of this of derivatives type of derivatives are catalysts are catalysts58 (a: X = 58CH;(a :b X: X = = CH; N) [86]b: X and = N) 59 [86 [87].] and Both59 [systems87]. Both have systems been haveusedbeen in combination used in combination with benzoic with acid benzoic in the acid standard in the Michaelstandard addition Michael of addition cyclohexanone of cyclohexanone to several to aryl several and heteroaryl aryl and heteroaryl nitrostyrenes. nitrostyrenes.

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Figure 12. Results obtained using pyrrolidine-based organocatalystsorganocatalysts with a diamine backbone in the preparation ofof nitroketonenitroketone 4646..

Some efforts destined to recycle pyrrolidine-based catalyst active in the Michael addition of Some efforts destined to recycle pyrrolidine-basedpyrrolidine-based catalyst active in the Michael addition of cyclohexanone to trans-β-nitrostyrene have been carried out. Thus, resin-immobilized pyrrolidine cyclohexanone to transtrans--β-nitrostyrene have beenbeen carriedcarried out.out. Thus,Thus, resin-immobilizedresin-immobilized pyrrolidinepyrrolidine catalyst 60 [88] has been used, under solvent free conditions, in this transformation for 16 successive catalyst 60 [[88]88] has been used, under solvent free conditions,conditions, in this transformation for 16 successive runs without significant loss of enantioselectivity (Scheme 12). The catalytic efficiency was also runs withoutwithout significantsignificant lossloss ofof enantioselectivityenantioselectivity (Scheme(Scheme 1212).). The cataly catalytictic efficiency efficiency was alsoalso demonstrated by using other nitroolefins as electrophiles, leading to similar results in terms of yields demonstrated by using other nitroolefinsnitroolefins as electrophiles, leading to similar results in terms of yields and stereoselectivities. However, cyclopentanone, cycloheptanone or propanal gave the and stereoselectivities.stereoselectivities. However, However, cyclopentanone, cyclopenta cycloheptanonenone, cycloheptanone or propanal or gavepropanal the corresponding gave the corresponding Michael adducts with moderate enantioselectivities (15–50%). Michaelcorresponding adducts Michael with moderate adducts enantioselectivitieswith moderate enantioselectivities (15–50%). (15–50%).

Scheme 12. Michael addition of cyclohexanone to β-nitrostyrene organocatalyzed by resin- Scheme 12. Michael addition of cyclohexanone to β-nitrostyrene organocatalyzed by resin- immobilizedScheme 12. 58Michael. addition of cyclohexanone to β-nitrostyrene organocatalyzed by resin- immobilized 58.

Privileged type of organocatalystsorganocatalysts used in this Michael addition are those containing a thiourea moiety. ExamplesExamples of of the the combination combination of theof the pyrrolidine pyrrolidine ring ring together together with thewith thiourea the thiourea group aregroup shown are 61 inshown Figure in 13 Figure. Thus, 13. the Thus, surfactant-type the surfactant-type thiourea thioureaworked smoothly61 worked in watersmoothly as solvent, in water giving as adductssolvent, 46 ofgiving type adductsin good of results.type 46 Whenin good the results. same reaction When the conditions same reaction were applied conditions to cyclopentanone were applied orto 62 acetone,cyclopentanone the achieved or acetone, enantioselections the achieved were enanti loweroselections [89]. A similar were trend lower was [8 observed9]. A similar when trend catalyst was wasobserved used inwhen the presencecatalyst 62 of 2,4-dichlorobenzoicwas used in the presence acid (2,4-DCBA) of 2,4-dichlorobenzoic for the Michael acid addition (2,4-DCBA) of ketones for the to β Michael-nitrooleﬁns addition under neatof conditions.ketones to Although β-nitroolefins high enantioselectivities under neat conditions. were achieved Although in the reaction high ofenantioselectivities cyclohexanone with were aromatic achieved and, in the even, reaction aliphatic of cyclohexanone nitrooleﬁns, results with aromatic were not and, satisfactory even, aliphatic when thosenitroolefins, conditions results were were applied not satisfactory to cyclopentanone when those or acetone conditions [90]. The were same applied catalyst to cyclopentanone62 was also able or to β promoteacetone [90]. the addition The same of cyclohexanone catalyst 62 was to also-nitrostyrenes able to promote in water, the but addition in the presence of cyclohexanone of 2-nitrobenzoic to β- nitrostyrenes in water, but in the presence of 2-nitrobenzoic acid (10 mol %), which enhanced the

Molecules 2017, 22, 895 16 of 51 Molecules 2017, 22, 895 16 of 51 acidobtained (10 mol yields %), which[91]. Poor enhanced results the were obtained also obtained yields [91 when]. Poor acet resultsone was were used also as obtained pro-nucleophile when acetone with wastrans used-nitrostyrene as pro-nucleophile using thiazoline-thiourea-pyrrolidine with trans-nitrostyrene using catalyst thiazoline-thiourea-pyrrolidine 63 under neat conditions. However, catalyst 63theseunder reaction neat conditions conditions. allowed However, the preparation these reaction of adducts conditions 46 in allowed good results the preparation [92]. The ionic of adducts liquid- 46solublein good pyrrolidine-urea results [92]. The 64 ionicpromoted liquid-soluble the Michael pyrrolidine-urea addition of cyclohexanone64 promoted theor acetone Michael to addition several ofaryl cyclohexanone and heteroaryl or β acetone-nitroolefins. to several Although aryl and the heteroaryl yields wereβ-nitrooleﬁns. constantly high Although for both the ketones, yields were the constantlyenantioselectivities high for bothwere ketones, lower fo ther adducts enantioselectivities arising from were acetone. lower forThis adducts catalytic arising system from could acetone. be Thisreused catalytic four times system with could comparable be reused results four times[93]. with comparable results [93].

Figure 13. Results obtained using pyrrolidine-based thioureathiourea organocatalysts in the Michael addition of ketones to nitroalkenes.

The combinationcombination ofof the the thiourea thiourea motif motif with withtrans trans-1,2-diaminocyclohexane-1,2-diaminocyclohexane as theas the chiral chiral unit, unit, has has led toled organocatalysts to organocatalysts able to able catalyze to catalyze the Michael the additionMichael ofaddition acetophenone of acetophenone derivatives toderivativesβ-nitrostyrenes to β- (Schemenitrostyrenes 13). Similarly(Scheme to13). the Similarly case of aldehydes,to the casein of this aldehydes, type of catalystsin this type the primaryof catalysts amine the activatesprimary theamine carbonyl activates compound the carbonyl via iminium compound or/and via enamineiminium formation,or/and enamine whereas formation, the thiourea whereas activates the thethiourea electrophile activates via the hydrogen electrophile bonding. via Inhydrogen catalyst 66bonding., the sterical In catalyst hindrance 66, the provided sterical by hindrance ﬂuorenyl backboneprovided allowedby fluorenyl the formation backbone of allowed adducts the65 with formation moderate of toadducts good enantioselectivities65 with moderate [94to ].good The introductionenantioselectivities of a perﬂuorated [94]. The introduction alkyl chain in of this a perfluorated type of catalyst alkyl led chain to compound in this type67, whichof catalyst was testedled to incompound the Michael 67, which addition was of tested acetophenone in the Michael to trans- additionβ-nitrostyrene of acetophenone with low to trans- yieldsβ-nitrostyrene albeit in excellent with enantioselectivitylow yields albeit in [95 excell]. ent enantioselectivity [95].

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Molecules 2017, 22, 895 17 of 51

SchemeScheme 13. 13.Michael Michael addition addition of of aryl aryl methylmethyl ketones to to nitrostyrenes nitrostyrenes organo organocatalyzedcatalyzed by chiral by chiral Scheme 13. Michael addition of aryl methyl ketones to nitrostyrenes organocatalyzed by chiral cyclohexane-1,2-diamine-thioureacyclohexane-1,2-diamine-thiourea derivatives. derivatives. cyclohexane-1,2-diamine-Scheme 13. Michael additionthiourea of derivatives. aryl methyl ketones to nitrostyrenes organocatalyzed by chiral cyclohexane-1,2-diamine-thiourea derivatives. The thiourea-amino acid catalyst 69 has been used to perform the desymmetrization of prochiral The thiourea-amino acid catalyst 69 has been used to perform the desymmetrization of prochiral The3-substituted thiourea-aminoThe thiourea-amino cyclobutanones acid acid catalyst catalystafter Michael 69 69 has has been beenaddition usedused to toto trans- perform performβ-nitrostyrene the the desymmetrization desymmetrization derivatives, of leading prochiral of prochiral to trans-β 3-substituted3-substitutedproducts 68cyclobutanones with cyclobutanones moderate after enantioselectivities, after Michael Michael additionaddition and wito to th trans-trans- oneβ β-nitrostyrenepredominant-nitrostyrene derivatives,isomer derivatives, of the leading possible leading to to productsproductsdiastereoisomers 68 with 68 with moderate (Schememoderate enantioselectivities,14) enantioselectivities, [96]. and and wiwi withthth one one predominant predominant isomer isomer of the of possible the possible diastereoisomersdiastereoisomers (Scheme (Scheme 1414) )[14) [96].96 [96].].

Scheme 14. Desymmetrization of prochiral 3-substituted cyclobutanones organocatalyzed by 67. Scheme 14. Desymmetrization of prochiral 3-substituted cyclobutanones organocatalyzed by 67. SchemeA thiourea 14. Desymmetrization derived from cyclohexane-1,2-diamine of prochiral 3-substituted 71 cyclobutanoneshas shown to be organocatalyzed an efficient catalyst by 67 .to Scheme 14. Desymmetrization of prochiral 3-substituted cyclobutanones organocatalyzed by 67. carryA out thiourea the Michael derived reaction from of cyclohexane-1,2-diamine unusual β-aryl-α-ketophosphonates 71 has shown to nitroalkenesto be an efficient giving catalyst products to 70 with excellent diastereoselectivities and good enantioselectivities (Scheme 15). In this case, the Acarry thioureathiourea out the derived derivedMichael from reactionfrom cyclohexane-1,2-diamine cyclohexane-1,2-diamine of unusual β-aryl-α-ketophosphonates71 71has has shown shown to to nitroalkenes beto anbe efﬁcient an efficientgiving catalyst products catalyst to carry to 70tertiary with amineexcellent moiety diastereoselectivities of catalyst 71 deprotonates and good the en antioselectivitiesβ-aryl-α-ketophosphonate (Scheme leading15). In thisto an case, enolate the carryout the out Michael the Michael reaction reaction of unusual of unusualβ-aryl- β-aryl-α-ketophosphonatesα-ketophosphonates to nitroalkenes to nitroalkenes giving giving products products70 tertiarywhich is amine closely moiety associated of catalyst with the 71 protonated deprotonates catalyst the βby-aryl- ionicα -ketophosphonateand hydrogen bonding leading interactions to an enolate [97]. with excellent diastereoselectivities and good enantioselectivities (Scheme 15). In this case, the tertiary 70 withwhich excellent is closely diastereoselectivities associated with the protonated and good catalyst en antioselectivitiesby ionic and hydrogen (Scheme bonding 15). interactions In this case,[97]. the tertiaryamine moiety amine ofmoiety catalyst of 71catalystdeprotonates 71 deprotonates the β-aryl- theα -ketophosphonateβ-aryl-α-ketophosphonate leading toleading an enolate to an which enolate is whichclosely is associated closely associated with the with protonated the protonated catalyst catalyst by ionic by and ionic hydrogen and hydrogen bonding bonding interactions interactions [97]. [97].

Scheme 15. Michael addition of β-aryl-α-ketophosphonates to nitroalkenes organocatalyzed by Schemethiourea 6915.. Michael addition of β-aryl-α-ketophosphonates to nitroalkenes organocatalyzed by thiourea 69.

Scheme 15. Michael addition of β-aryl-α-ketophosphonates to nitroalkenes organocatalyzed by β α Schemethiourea 15.69. Michael addition of -aryl- -ketophosphonates to nitroalkenes organocatalyzed by thiourea 69.

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The Takemoto’s thiourea catalyst 73 hashas allowedallowed thethe synthesissynthesis ofof γγ-nitro--nitro-αα-ﬂuorocarbonyl-fluorocarbonyl compounds 7272 withwith good good results results (Scheme (Scheme 16). 16 In). this In thistransformation, transformation, after afterthe initial the initial formation formation of the ofprimary the primary asymmetric asymmetric Michael Michael adduct, adduct, the amino the amino group group of the of catalyst the catalyst abstracts abstracts a proton a proton from from the theaddition addition intermediate, intermediate, releasing releasing a trifluoroacetate a triﬂuoroacetate unit. unit. Then, Then, the theenolate enolate is asymmetrically is asymmetrically rere-protonatedprotonated by bythe the ammonium ammonium catalyst catalyst to togive give compounds compounds 72 72[98].[98 ].

Scheme 16.16.Michael Michael addition addition of trifluoromethyl of trifluoromethylα-fluorinated α-fluorinatedgem-diols to nitroolefinsgem-diols organocatalyzedto nitroolefins byorganocatalyzed Takemoto’s thiourea by Takemoto’s organocatalyst. thiourea organocatalyst.

The samesame catalyst catalyst73 was73 usedwas inused the additionin the ofaddition 1,3-bis(phenylthiol)propa-2-one of 1,3-bis(phenylthiol)propa-2-one to nitrostyrenes, to affordingnitrostyrenes, the expectedaffording products the expected (six examples) productswith (six moderateexamples) yields with (74–91%),moderate diastereoisomericyields (74–91%), ratiosdiastereoisomeric from 43/57 toratios 67/33 from and 43/57 enantioselectivities to 67/33 and enantioselectivities in the range 69–81% in the [99 range]. 69–81% [99]. The combination of amines derived from Cinchona alkaloids with the thiourea moiety has led to several organocatalysts useful for different transformations. For example, catalyst 74 has been used in the Michael addition of trifluoromethyl ketones to nitroolefins (Scheme 17a). After diastereoselective amino reductive cyclization of compounds 75, the corresponding pyrrolidines 76 were isolated with good yields and stereoselectivities [100]. In addition, the use of the same catalyst 74 in combination of L-phenylalanine organocatalyzed the reaction of acetone with different substituted azido nitrostyrenes to give the expected compounds 77 with moderated yields and good enantioselectivities (Scheme 17b). The diastereoselective amino reductive cyclization using indium salts and silanes allowed the preparation of tetrahydroquinolines 78 with moderate yields and high stereoselectivities [101]. The versatility of this catalyst 74 has been also showed in the simple Michael addition of cyclopentane-1,2-dione to different nitrostyrenes (11 examples), affording the expected adducts with yields ranging from 60 to 90% and moderate enantioselectivities (56–76%) [102]. A related squaramide-Cinchona Brønsted-base organocatalyst 79 has been developed and tested in the Michael addition of α-monosubstituted β-tetralones to nitroalkenes (Scheme 18). The reaction also took place using non-substituted tetralones and other aromatic ring-fused cycloalkanones as pro-nucleophiles, providing the corresponding products in good results (80–88% yield, 50/50-95/5 dr, 99% ee). The obtained adducts of type 80 were converted into diverse polycyclic compounds bearing up to six stereogenic centers, including spirocyclic structures [103]. The possibility of using continuous flow chemistry using organocatalysts has also been exemplified by using a polystyrene-supported squaramide derived from chiral trans-cyclohexa-1,2- diamine 81 as organocatalyst in the Michael addition of 2-hydroxy-1,4-naphthoquinone to nitroalkenes (Scheme 19). Thus, the β-dicarbonyl naphthoquinone derivative reacted with β-nitrostyrenes bearing electron-withdrawing or -donating groups, as well as 2-nitro-1-heteroarylethylene derivatives, lead to the corresponding products 82 in good yields and enantioselectivities. Catalyst 81 was recovered and reused for 10 consecutive runs without detrimental effects, and adapted to a continuous flow operation (24 h), achieving a high accumulated TON of 200 and a productivity of 4.07 mmol/g resin h [104]. Scheme 17. Sequential Michael addition-diastereoselective amino reductive cyclization processes.

Molecules 2017, 22, 895 18 of 51

The Takemoto’s thiourea catalyst 73 has allowed the synthesis of γ-nitro-α-fluorocarbonyl compounds 72 with good results (Scheme 16). In this transformation, after the initial formation of the primary asymmetric Michael adduct, the amino group of the catalyst abstracts a proton from the addition intermediate, releasing a trifluoroacetate unit. Then, the enolate is asymmetrically re- protonated by the ammonium catalyst to give compounds 72 [98].

Scheme 16. Michael addition of trifluoromethyl α-fluorinated gem-diols to nitroolefins organocatalyzed by Takemoto’s thiourea organocatalyst.

The same catalyst 73 was used in the addition of 1,3-bis(phenylthiol)propa-2-one to Molecules 2017, 22, 895 19 of 51 nitrostyrenes, affording the expected products (six examples) with moderate yields (74–91%), diastereoisomeric ratios from 43/57 to 67/33 and enantioselectivities in the range 69–81% [99].

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The combination of amines derived from Cinchona alkaloids with the thiourea moiety has led to several organocatalysts useful for different transformations. For example, catalyst 74 has been used in the Michael addition of trifluoromethyl ketones to nitroolefins (Scheme 17(a)). After diastereoselective amino reductive cyclization of compounds 75, the corresponding pyrrolidines 76 were isolated with good yields and stereoselectivities [100]. In addition, the use of the same catalyst 74 in combination of L-phenylalanine organocatalyzed the reaction of acetone with different substituted azido nitrostyrenes to give the expected compounds 77 with moderated yields and good enantioselectivities (Scheme 17b). The diastereoselective amino reductive cyclization using indium salts and silanes allowed the preparation of tetrahydroquinolines 78 with moderate yields and high stereoselectivities [101]. The versatility of this catalyst 74 has been also showed in the simple Michael addition of cyclopentane-1,2-dione to different nitrostyrenes (11 examples), affording the expected adducts with yields ranging from 60 to 90% and moderate enantioselectivities (56–76%) [102]. A related squaramide-Cinchona Brønsted-base organocatalyst 79 has been developed and tested in the Michael addition of α-monosubstituted β-tetralones to nitroalkenes (Scheme 18). The reaction also took place using non-substituted tetralones and other aromatic ring-fused cycloalkanones as pro- nucleophiles, providing the corresponding products in good results (80–88% yield, 50/50-95/5 dr, 99% ee). The obtained adducts of type 80 were converted into diverse polycyclic compounds bearing up Scheme 17. SequentialSequential Michael Michael addition-diastereoselect addition-diastereoselectiveive amino reductive cyclization processes. to six stereogenic centers, including spirocyclic structures [103].

Scheme 18. Asymmetric organocatalyzed Michael addition of β-tetralones-tetralones to to nitroolefins. nitrooleﬁns.

The possibility of using continuous flow chemistry using organocatalysts has also been exemplified by using a polystyrene-supported squaramide derived from chiral trans-cyclohexa-1,2- diamine 81 as organocatalyst in the Michael addition of 2-hydroxy-1,4-naphthoquinone to nitroalkenes (Scheme 19). Thus, the β-dicarbonyl naphthoquinone derivative reacted with β-nitrostyrenes bearing electron-withdrawing or -donating groups, as well as 2-nitro-1-heteroarylethylene derivatives, lead to the corresponding products 82 in good yields and enantioselectivities. Catalyst 81 was recovered and reused for 10 consecutive runs without detrimental effects, and adapted to a continuous flow operation (24 h), achieving a high accumulated TON of 200 and a productivity of 4.07 mmol/g resin h [104].

Molecules 2017, 22, 895 20 of 51 Molecules 2017, 22, 895 20 of 51 Molecules 2017, 22, 895 20 of 51

Scheme 19.19.Organocatalyzed Organocatalyzed Michael Michael addition addition of 2-hydroxy-1,4-naphthoquinoneof 2-hydroxy-1,4-naphthoquinone to nitroolefins to nitroolefins under continuousSchemeunder continuous 19. flow Organocatalyzed chemistry. flow chemistry. Michael addition of 2-hydroxy-1,4-naphthoquinone to nitroolefins under continuous flow chemistry. A single flow experiment involving six different nitroalkenes in a sequential manner showed the applicabilityA single single offlow flow the experiment system experiment for thinvolving involvinge preparation six six different differentof small nitroalkenes libraries nitroalkenes of enantiopurein ina sequential a sequential compounds. manner manner showed A showed related the applicabilitythepolystyrene-supported applicability of the of system the squaramide system for the for preparation theorganocatalyst preparation of small has of libraries small been librariesofused enantiopure in ofa enantiopurecontinuous compounds. flow compounds. A processrelated Apolystyrene-supportedinvolving related polystyrene-supporteda sequential squaramidetwo-step squaramidetransformation organocatalyst organocatalyst consisting has been of hasused a been squaramide-catalyzedin a used continuous in a continuous flow Michaelprocess flow processinvolvingaddition involving reaction a sequential of a sequential2-hydroxy-1,4-naphthoquinone two-step two-step transformation transformation consisting and consisting acetoxylated of ofa asquaramide-catalyzed nitroalkanes, squaramide-catalyzed and a subsequent Michael additionoxa-Michael reaction cyclization of 2-hydroxy-1,4-naphthoquinone to give pyranonaphthoquinones and acetoxylated [105]. nitroalkanes, and a subsequent oxa-MichaelThis transformation cyclization to givehas pyranonaphthoquinones also been performed [[105]. 105using]. phosphoramide derivatives as organocatalystThis transformationtransformation (Figure 14). has Thus,has also beenwhilealso performed beenthe open-chain perf usingormed triamide phosphoramide using 83 phosphoramgave derivatives productide 82 as (Rderivatives organocatalyst1 = H, R2 = Ph)as (Figureorganocatalystin almost 14 quantitative). Thus, (Figure while yield14). the Thus, and open-chain moderate while the triamide enantioselectivity, open-chain83 gave triamide product the 83 cis gave-cyclodiphosphane82 (R product1 = H, R822 (R=1 Ph) derivative= H, in R almost2 = Ph) 84 quantitativeinled almost to the quantitativesame yield product and yield moderate 82 withand moderate enantioselectivity,improved enantioselectivity, enantioselectivity the cis-cyclodiphosphane thebut cis as-cyclodiphosphane the opposite derivative enantiomer. derivative84 led These to the 84 ledsameresults to productthe have same been82 productwith confirmed improved 82 with byimproved enantioselectivity means enantioselectivityof theoretical but as calculations, the bu oppositet as the opposite enantiomer.showing enantiomer. that These open-chainresults These resultshavephosphorous been have confirmed triamidebeen confirmed bycomplexes means by of present theoreticalmeans a weakerof calculations,theoretical ability tocalculations, showing perform thathydrogen showing open-chain bonds that phosphorous comparedopen-chain to phosphoroustriamidecyclophosphane complexes triamide derivatives present complexes a [106]. weaker present ability a toweaker perform ability hydrogen to perform bonds hydrogen compared bonds to cyclophosphane compared to cyclophosphanederivatives [106]. derivatives [106].

Figure 14. Phosphoroamide-type organocatalysts used in the Michael addition of 2-hydroxy-1,4- Figurenaphthoquinone 14. Phosphoroamide-typePhosphoroamide-type to trans-β-nitrostyrene organocatalysts organocatalysts leading to 80used used. in in the the Michael Michael addition addition of of 2-hydroxy-1,4- naphthoquinone to trans-β-nitrostyrene leading to 80. A weak halogen bond donor is involved in the transition state proposed for catalyst 85. For this system,A weak DFT halogencalculations bond predicted donor is ainvolved Cl-O interact in theion transition involving state an proposed oxygen atom for catalyst of the nitro85. For group this system,and the chlorineDFT calculations of catalyst predicted in the reaction a Cl-O between interact acetoneion involving and trans- an oxygenβ-nitrostyrene atom of (Figure the nitro 15) group [107]. and the chlorine of catalyst in the reaction between acetone and trans-β-nitrostyrene (Figure 15) [107].

Molecules 2017, 22, 895 21 of 51

A weak halogen bond donor is involved in the transition state proposed for catalyst 85. For this system, DFT calculations predicted a Cl-O interaction involving an oxygen atom of the nitro group andMolecules the 2017 chlorine, 22, 895 of catalyst in the reaction between acetone and trans-β-nitrostyrene (Figure 15)[21107 of 51].

Figure 15.15. 1,2-Diaminocyclohexane-based1,2-Diaminocyclohexane-based organocatalysts organocatalysts used used in in the the Michael Michael addition addition of acetoneof acetone (85, 86(85), and86) and aryl aryl methyl methyl ketones ketones (86) ( to86trans-) to trans-β-nitrooleﬁns.β-nitroolefins.

A hydrogen bond interaction explained the stereochemicalstereochemical outcome achieved when catalyst 86 was used in the reaction of arylaryl methylmethyl ketonesketones withwith aryl and heteroaryl nitrooleﬁns.nitroolefins. In In this case, computational studies showed that, in apolar solvents,solvents, the existence of the hydrogen bond explained the formation of the ((R)-Michael product in highhigh enantioselectivitiesenantioselectivities whereas in polar solvents the partial rupture of the H-bond activationactivation induces the formation of the ( S)-product, explaining the loss of enantioselectivity [[108].108]. The cooperationcooperation betweenbetween BrønstedBrønsted base base catalysis catalysis with with the the hydrogen hydrogen bonding bonding ability ability provided provided by theby the guanidine-sulfonamide guanidine-sulfonamide catalyst catalyst87, promoted 87, promoted the deprotonation the deprotonation of α-keto of α esters,-keto whichesters, reactedwhich withreacted two withβ-nitrostyrene two β-nitrostyrene derivatives derivatives in a triple in cascade a triple Michael/Michael/Henry cascade Michael/Michael/Henry process, allowingprocess, theallowing formation the offormation hexa-substituted of hexa-sub cyclohexanestituted derivatives cyclohexane88, withderivatives a quaternary 88, stereocenter,with a quaternary in good yieldsstereocenter, and excellent in good stereocontrol yields and excelle (Schement stereocontrol 20)[109]. (Scheme 20) [109].

Scheme 20.20. ConstructionConstruction of of cyclohexanes cyclohexanes with with six vicinalsix vicinal stereogenic stereogenic centers throughcenters through a Michael/ a Michael/HenryMichael/Michael/Henry process. process.

Molecules 2017, 22, 895 22 of 51

The combination of simple chiral amines with different structures bearing a Brønsted acid has served as promoters for the Michael addition of ketones to nitroalkenes (Figure 16). One example of this type of cooperative catalyst was observed in the reaction between cyclohexanone and nitroolefins catalyzed by the combination of chiral secondary amine 89 and (R)-mandelic acid, providingMolecules 2017 products, 22, 895 46 under neat conditions [110]. ortho-Substituted aryl nitroolefins led to22 good of 51 enantioselectivities, whereas lower results were observed when the substitution was located at the para-position. In addition, D-isomannide 90 combined with achiral acetic acid has been used to catalyze para-position. In In addition, addition, DD-isomannide-isomannide 9090 combinedcombined with achiral acetic ac acidid has been used to catalyze the addition of acetone and acetophenone to aryl β-nitroolefins, albeit in moderate results [111]. the addition of of acetone acetone and and acetophenone acetophenone to to aryl aryl ββ-nitroolefins,-nitroolefins, albeit albeit in in moderate moderate results results [111]. [111 ].

Figure 16. 16. SimpleSimple chiral chiral amine amine organocatalysts organocatalysts usedused in the in Michael the Michael addition addition of ketones of ketonesto trans-β tonitrostyrenes.trans-β-nitrostyrenes.

Finally, accessibleaccessible amino-Cinchona derivatives combined to acid additives have been used as catalytic system for diverse Michael processes. Thus, epi-cinchonidine-cinchonidine amine amine 9191 was used as chiral organocatalyst in the addition of different 1-acetylcycloalkene1-acetylcycloalkene derivatives to nitroalkenes, providing products 92 inin moderatemoderate enantioselectivitiesenantioselectivities (Scheme(Scheme 2121). Subsequent treatment of these productsproducts with tetramethylguanidine gave the expected bicyclicbicyclic compounds, after a new Michael addition process [[112].112].

Scheme 21. Asymmetric organocatalyzed addition of 1-acetylcycloalkenes to β-nitrooleﬁns. Scheme 21. Asymmetric organocatalyzed addition of 1-acetylcycloalkenes to β-nitroolefins.

The remote ε-regioselective 1,4-addition of cyclic 2,5-dienones to nitroalkenes has been accomplished throughthrough inin situsitu generation generation of of chiral chiral trienamine trienamine species species derived derived from fromCinchona Cinchonaamine amine93, 93combined, combined to benzoicto benzoic acid, acid, leading leading to to products products94 94 withwith moderate results results (S (Schemecheme 22). 22 ).Addition Addition of tetramethylguanidineof tetramethylguanidine to the to achieved the achieved products products 94, gave94, rise gave to an rise intramolecular to an intramolecular Michael addition Michael leadingaddition to leading the formation to the formation of chiral of chiral spirocyclic, spirocyclic, or even or even bis-spirocyclic, bis-spirocyclic, compounds compounds as as single diastereomers [[113].113].

Molecules 2017,, 22, 895 23 of 51 Molecules 2017, 22, 895 23 of 51

Scheme 22. Organocatalyzed bisvinylogous 1,4-addition of cyclic 2,5-dienones to β-nitrooleﬁns. Scheme 22. Organocatalyzed bisvinylogous 1,4-addition of cyclic 2,5-dienones to β-nitroolefins. Scheme 22. Organocatalyzed bisvinylogous 1,4-addition of cyclic 2,5-dienones to β-nitroolefins. Although not directly involving aa ketoneketone pro-nucleophiles,pro-nucleophiles, the catalytic asymmetricasymmetric dearomatizationAlthough not (CADA) directly reaction involving of phenol a derivativesderivatiketone vespro-nucleophiles, is a procedure which the leadscatalytic to the asymmetric generation ofdearomatization substituted cyclic (CADA) enones reaction [114 [114]. Recently, of phenol 2-naphthols derivatives is have a procedure been successfully which leads used to as the nucleophiles generation inof substituted anan organocatalyticorganocatalytic cyclic enones conjugateconjugate [114 addition].addition Recently, toto 2-naphthols nitroethylene,nitroethylene, have affordingaffording been successfully enantioenrichedenantioenriched used as functionalizedfunctionalized nucleophiles 2-naphthalenonesin an organocatalytic throughthrough conjugate a dearomatizationa additiondearomatization to nitroe processthylene, process [115]. affording Thus, [115]. Takemoto’s enantioenrichedThus, thioureaTakemoto’s functionalized organocatalyst thiourea 732-naphthalenonesorganocatalyst catalyzes this 73 reaction catalyzesthrough affording thisa dearomatization reaction the corresponding affording process the products corresponding [115]. 95 withThus, high productsTakemoto’s enantioselectivities 95 withthiourea high (Schemeorganocatalystenantioselectivities 23). A 73 proposed catalyzes(Scheme highly 23).this A orderedreaction proposed transition affording highly state,ordered the wherecorresponding transition a bifunctional state, products where hydrogen-bonding 95a bifunctional with high activationenantioselectivitieshydrogen-bonding of the naphthol (Schemeactivation by the23). of tertiaryAthe proposed naphthol amine, highly andby the the ordered tertiary electrophile transition amine, by theand state, thiourea, the where electrophile facilitates a bifunctional by the theRe facehydrogen-bondingthiourea, attack facilitates of the nucleophile. theactivation Re face ofattack the ofnaphthol the nucleophile. by the tertiary amine, and the electrophile by the thiourea, facilitates the Re face attack of the nucleophile.

Scheme 23. Asymmetric dearomatization of 2-naphthols through an organocatalyzed conjugate Schemeaddition 23.to nitroethylene. AsymmetricAsymmetric dearomatization dearomatization of of 2-naphthols through an organocatalyzed conjugate addition to nitroethylene. 2.3. 1,3-Dicarbonyl Compounds 2.3. 1,3-Dicarbonyl Compounds The asymmetric addition of 1,3-dicarbonyl compounds onto nitroolefins has experienced an exponentialThe asymmetric asymmetric growth since addition addition the beginning of of 1,3-dicarbonyl 1,3-dicarbonyl of this 21st co compoundscentury.mpounds The onto ontospectacular nitroolefins nitroolefins blossoming has has experienced experienced of research an anexponentialarticles exponential dealing growth growthwith since this since the beginningtransformation the beginning of this ofar 21stises this century. 21stwith century. theThe developmentspectacular The spectacular blossoming of the blossoming asymmetric of research of researcharticlesorganocatalysis dealing articles through dealingwith thishydrogen-bond with transformation this transformation activation. arises arisesTh withis fact with the somehow thedevelopment development occurred ofafter of the the the asymmetricasymmetricpublication organocatalysisin 2003 by Takemoto through of a hydrogen-bond novel bifunctional activation.activation. thiourea-based ThisThis fact somehow organocatalyst occurred (73) afterable the to catalyze publication the inenantioselective 2003 by Takemoto addition ofof aa novelofnovel malonates bifunctionalbifunctional to nitroolef thiourea-basedthiourea-basedins with excellent organocatalyst yields ( and73) ableenantioselectivities to catalyze the enantioselective[116]. Thus, the additiongreataddition performance of of malonates malonates of tohydrogen-bon to nitroolefins nitroolefins withding with excellent organocatalysts excellent yields yields and in enantioselectivitiesandthis enantioselectivitiestransformation [116 has]. Thus,[116].prompted theThus, great research the performance great groups performance worldwide of hydrogen-bonding of hydrogen-bon for the develo organocatalystsdingpment organocatalysts of new in this organic transformation in entitiesthis transformation able has to prompted catalyze has researchpromptedsuch process groups research as worldwidewell groups as for worldwide forbroa thedening development for the the scope develo of newof pmentdicarbonyl organic of new entities compounds organic able toentities employed. catalyze able such toIn catalyze processthe last assuchyears, well process different as for as broadening wellorganocatalysts as for the broa scope deninghave of dicarbonylbeen the scopedescri compoundsofbed dicarbonyl to efficiently employed. compounds catalyze In the employed. the last addition years, In different theof 1,3-last organocatalystsyears,diketones different and β -keto haveorganocatalysts esters been described to nitroalkenes, have to been efficiently as descri it is catalyzechronologicallybed to efficiently the addition illustrated catalyze of 1,3-diketones in the Scheme addition 24. and ofβ-keto 1,3- estersdiketones to nitroalkenes, and β-keto esters as it is to chronologically nitroalkenes, as illustrated it is chronologically in Scheme 24illustrated. in Scheme 24.

Molecules 2017, 22, 895 24 of 51 Molecules 2017, 22, 895 24 of 51

SchemeScheme 24. 24.Asymmetric Asymmetric addition addition ofof 1,3-dicarbonyl1,3-dicarbonyl co compoundsmpounds to tonitroolefins nitrooleﬁns using using different different organocatalysts.organocatalysts.

For example, catalyst 97 bearing sulfonamide/2-aminoDMAP moieties in its structure has Forproven example, to act as catalyst bifunctional97 bearing acid/base sulfonamide/2-aminoDMAP organocatalyst in this reaction, moieties obtaining in its the structure corresponding has proven to actadducts as bifunctional in good yields acid/base and enantioselectivities organocatalyst in [117]. this reaction, Working obtaining in this idea, the was corresponding published more adducts in goodrecently yields the and synthesis enantioselectivities and evaluation of [117 catalyst]. Working 98, formed in this by the idea, combination was published of squaramide more recently and 2- the synthesisaminoDMAP and evaluation on a trans of-cyclohexane-1,2-diamine catalyst 98, formed by theas chiral combination scaffold [118]. of squaramide The resulting and catalyst 2-aminoDMAP was on a moretrans -cyclohexane-1,2-diamineactive and able to reach similar as yields chiral and scaffold levels of [118 enantioselection]. The resulting in the catalyst Michael wasproducts more 96 active, and ablebut using to reach only similar 1 mol % yields loading. and In levels addition, of enantioselection organocatalyst 99, in composed the Michael by BINOL, products quinine96, but and using squaramide moieties, has turned out to be an extremely active catalyst for the enantioselective only 1 mol % loading. In addition, organocatalyst 99, composed by BINOL, quinine and squaramide addition of a wide variety of 1,3-diketones and 1,3-keto esters onto nitroalkenes, since as low as 0.5 moieties, has turned out to be an extremely active catalyst for the enantioselective addition of a wide mol% catalyst loading was enough to promote such transformation in high yields, good to excellent varietydiastereoselectivities of 1,3-diketones and and 1,3-keto excellent esters ee’s [119]. onto Bifunctional nitroalkenes, organocatalysts since as low as 100 0.5, which mol% is catalyst based loadingon was enoughrosin-derived to promote indane such amine transformation has also demonstrated in high yields,its high good efficiency to excellent by promoting diastereoselectivities the addition of and excellentacetylacetoneee’s [119 ].onto Bifunctional a wide variety organocatalysts of nitroalkenes100 (even, which aliphatic is based ones). onMoreover, rosin-derived 100 is also indane able to amine has alsocatalyze demonstrated the enantioselective its high efﬁciencyaddition of by 2-hydroxy- promoting1,4-naphthoquinone the addition of on acetylacetoneto the same ontoMichael a wide varietyacceptors of nitroalkenes [120]. (even aliphatic ones). Moreover, 100 is also able to catalyze the enantioselective addition of1,3-Diamine-tethered 2-hydroxy-1,4-naphthoquinone guanidinium salt-thiourea onto the same 101 Michaelacted as acceptorsa bifunctional [120 ].catalyst able to 1,3-Diamine-tetheredefficiently catalyze this transformation guanidinium leading salt-thiourea to adduct101 96acted (Figure as 17). a bifunctionalIn this case, the catalyst use of an able to external organic base like Et3N was necessary to accomplish good results [121]. In addition, the efﬁciently catalyze this transformation leading to adduct 96 (Figure 17). In this case, the use of bifunctional thiourea-pyrrolidine catalyst 102, synthesized from inexpensive L-proline in nine steps, an external organic base like Et3N was necessary to accomplish good results [121]. In addition, the bifunctional thiourea-pyrrolidine catalyst 102, synthesized from inexpensive L-proline in nine steps, also promotes addition of dicarbonyl compounds. Under optimized conditions, good to high yields and excellent enantioselectivities were achieved for adducts 96. However, when non-symmetrically Molecules 2017, 22, 895 25 of 51 Molecules 2017, 22, 895 25 of 51 also promotes addition of dicarbonyl compounds. Under optimized conditions, good to high yields and excellent enantioselectivities were achieved for adducts 96. However, when non-symmetrically substituted dicarbonyl compounds were employed, the diastereoselectivitiesdiastereoselectivities varied from poor to high [[122].122]. Finall Finally,y, organocatalyst 103,, basedbased onon aa (diaminomethylene)malononitrile(diaminomethylene)malononitrile attached to a Cinchona motif has been reported for the asymmetric ad additiondition of acetylacetone to to aryl nitroalkenes. Using suchsuch organocatalystorganocatalyst in in combination combination with with benzoic benzoic acid, acid, moderate moderate to high to high yields yields along along with goodwith enantioselectivitiesgood enantioselectivities are obtained are obtained for the for addition the addition adducts adducts96 [123 96]. [123].

Figure 17.17. Organocatalyts employed in the asymmetric addition of 1,3-dicarbonyl1,3-dicarbonyl compounds to nitrooleﬁnsnitroolefins leadingleading toto 9696..

Organocatalysts 104 or 105 have been reported for the asymmetric addition of different Organocatalysts 104 or 105 have been reported for the asymmetric addition of different malonates and malononitrile to aryl nitroalkenes. These catalysts, which are synthesized from malonates and malononitrile to aryl nitroalkenes. These catalysts, which are synthesized from pentaerythritrol-based tetrabromide, showed high effectiveness in only 1 mol% loading, affording pentaerythritrol-based tetrabromide, showed high effectiveness in only 1 mol% loading, affording excellent yields and enantioselectivities for adducts 106 (Scheme 25). excellent yields and enantioselectivities for adducts 106 (Scheme 25).

Scheme 25.25. AsymmetricAsymmetric addition addition of of malonates malonates and and malononitriles malononitriles onto nitroolefins nitrooleﬁns using organocatalysts 104104 and 105105..

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The use of a stoichiometric amount of base was mandatory for for reaching reaching such such results. results. This This fact, fact, along withwith thethe presence presence of quaternaryof quaternary ammonium ammonium salts, salts, point topoint an ion-pair to an ion-pair activation activation of the substrates, of the substrates,although H-bond although interaction H-bond interaction cannot be ruledcanno out,t be especiallyruled out, withespecially catalyst with104 catalystbearing 104 an bearing OH group an OHin its group structure in its [124 structure]. Two organocatalysts[124]. Two organocatalysts based on the based use of on calyx[4]arene the use of calyx[4]arene as scaffold have as scaffold recently havebeen employedrecently been for thisemployed conjugate for addition this conjugate reaction addition (Figure 18reaction). Thus, (Figure catalyst 18).107 ,Thus, bearing catalyst a thiourea 107, bearingmoiety wasa thiourea employed moiety for the was enantioselective employed for addition the enantioselective of 1,3-diketones addition and malonates of 1,3-diketones to nitrooleﬁns, and malonatesachieving moderateto nitroolefins, to high achieving yields and moderate enantioselectivities to high yields of the and ﬁnal enantioselectivities adducts [125]. Similar of the results final adductswere obtained [125]. forSimilar the addition results ofwere 1,3-diketones obtained fo whenr the catalyst addition108 of, bearing1,3-diketones a squaramide when catalyst moiety in108 its, bearingstructure a wassquaramide used [126 moiety]. in its structure was used [126].

Figure 18. Calix[4]arene-basedCalix[4]arene-based organocatalysts for the en enantioselectiveantioselective addition of 1,3-diketones and malonates to nitroolefins. nitrooleﬁns.

As shownshown in in previous previous examples, examples, organocatalysts organocatalysts involving involving a hydrogen-bond a hydrogen-bond activation activation normally normallyrequire the require use of the non-polar use of non-polar aprotic solvents aprotic to solvents obtain good to obtain results. good Thus, results. hydrocarbons, Thus, hydrocarbons, ethers and etherschlorinated and chlorinated compounds compounds are the main are solvents the main employed. solvents In employed. this sense, In an this important sense, breakthroughan important breakthroughwas the use ofwas these the organocatalystsuse of these organocatalysts in brine as environmentally in brine as environmentally benign reaction benign media. reaction This media.highly polarThis highly solvent polar was not solvent only toleratedwas not foronly the to Michaellerated for addition the Michael of dicarbonyl addition compounds of dicarbonyl onto compoundsnitroalkenes, onto but turnednitroalkenes, out to bebut beneﬁcial turned out for to the be reaction, beneficial since for highthe reaction, yields and since enantioselectivities high yields and enantioselectivitiesof adducts 110 were of obtained adducts in 110 short were reaction obtained times in at short room reaction temperature timesusing at room low temperature catalyst loading using of lowhydroquinine-squaramide catalyst loading of hydroquinine-squaramide derivative 109 (2 mol %) derivative (Scheme 26 109a) (2 [127 mol]. The%) (Scheme catalyst loading26(a)) [127]. could The be catalystreduced loading to 0.01 mol%could inbe some reduced cases. to The0.01 scopemol% of in this some ‘on cases. water’, The protocol scope of was this successfully ‘on water’, expanded protocol wasto the successfully addition of expanded dithiomalonates to the toadditionβ,β-disubstituted of dithiomalonates nitroalkenes, to β allowing,β-disubstituted the one-pot nitroalkenes, synthesis allowingof GABA-analogs the one-pot bearing synthesis an all-carbon of GABA-analogs quaternary stereocenterbearing an all-carbon starting from quaternary the resulting stereocenter adducts starting111. In thisfrom latest the case,resulting a higher adducts loading 111. ofIn 109this(15 latest mol case, %) was a higher required loading along of with 109 the(15 needmol %) for was the requiredaddition ofalongo-xylene with asthe additive need for (Scheme the addition 26b) [128 of]. o-xylene This unexpected as additive behavior (Scheme was 26(b)) probably [128]. due This to unexpectedthe so-called behavior hydrophobic was probably hydration due effect. to the As so-c a matteralled ofhydrophobic fact, the same hydratio reactionn effect. carried As out a matter with the of fact,less hydrophobicthe same reaction quinine-squaramide carried out analoguewith the proceeded less hydrophobic with lower quinine-squaramide yields and enantioselectivities. analogue proceeded with lower yields and enantioselectivities.

Molecules 2017, 22, 895 27 of 51 Molecules 2017, 22, 895 27 of 51

Molecules 2017, 22, 895 27 of 51

Scheme 26. Asymmetric organocatalyzed addition of malonates and thiomalonates to nitroalkenes in brine. Scheme 26. Asymmetric organocatalyzed addition of malonates and thiomalonates to nitroalkenes in brine.The use of a tertiary amine/squaramide derived organocatalyst 112 supported on an ionic liquid, allowed the use of pure water as solvent for the addition of acetylacetone to different nitroolefins due TheSchemeto its use amphiphilic 26. of Asymmetric a tertiary nature. organocatalyzed amine/squaramide The reaction addition proceeded of malonate derived in sshort and organocatalyst thiomalonates reaction times to112 nitroalkenes withsupported high in yields brine. on anand ionic liquid,enantioselectivities allowed the use (Scheme of pure 27). The water extraction as solvent of the Michael for the adducts addition 113 ofwith acetylacetone an ether/n-hexane to different(8:2 v/v) mixtureThe use permitted of a tertiary the amine/squaramide catalyst recycling over derived 30 times organocatalyst without a significant 112 supported loss of on activity an ionic [129]. liquid, nitrooleﬁnsallowed duethe use to of its pure amphiphilic water as solvent nature. for the The addi reactiontion of acetylacetone proceeded to in different short reaction nitroolefins times due with highto yields its amphiphilic and enantioselectivities nature. The reaction (Scheme proceeded 27). The in extraction short reaction of the times Michael with adductshigh yields113 andwith an ether/enantioselectivitiesn-hexane (8:2 v /(Schemev) mixture 27). permittedThe extraction the of catalyst the Michael recycling adducts over 113 30with times an ether/ withoutn-hexane a signiﬁcant (8:2 loss ofv/v activity) mixture [ 129permitted]. the catalyst recycling over 30 times without a significant loss of activity [129].

Scheme 27. Enantioselective Michael addition ‘on water’ using recyclable organocatalyst 112.

As previously mentioned, one of the remaining challenges in the organocatalytic asymmetric addition of dicarbonyl compounds to nitroalkenes is the search for new pro-nucleophiles which allow furtherScheme elaborationScheme 27. Enantioselective27. Enantioselective of the resulting Michael Michael adducts addition addition for the ‘onsearch water’ water’ of bioactiveusing using recyclable recyclable compounds. organocatalyst organocatalyst Thus, the112 .quinine- 112. squaramide derivative 114 has turned out to be an efficient organocatalyst for the enantio- and As previously mentioned, one of the remaining challenges in the organocatalytic asymmetric

Asaddition previously of dicarbonyl mentioned, compounds one ofto nitroalkenes the remaining is the challenges search for new in thepro-nucleophiles organocatalytic which asymmetric allow additionfurther of elaboration dicarbonyl ofcompounds the resulting adducts to nitroalkenes for the search is the of bioactive search forcompounds. new pro-nucleophiles Thus, the quinine- which allowsquaramide further elaboration derivative of114 the has resulting turned out adducts to be foran efficient the search organocatalyst of bioactive for compounds. the enantio-Thus, and the

Molecules 2017, 22, 895 28 of 51

Molecules 2017, 22, 895 28 of 51 quinine-squaramideMolecules 2017, 22, 895 derivative 114 has turned out to be an efficient organocatalyst for the enantio-28 of 51 and diastereoselective conjugate addition of β-ketoamides to aryl- and alkyl-nitroolefins, to afford adducts diastereoselective conjugate addition of β-ketoamides to aryl- and alkyl-nitroolefins, to afford 115 (Scheme 28)[130]. These starting β-ketoamides, despite being more difficult to activate due to adducts 115 (Scheme 28) [130]. These starting β-ketoamides, despite being more difficult to activate the lower acidity of the hydrogen placed in α-position,α present some advantages compared to other due to the lower acidity of the hydrogen placed in α-position, present some advantages compared to dicarbonyl compounds. Thus, the lower acidity prevents a possible epimerization of the resulting other dicarbonyl compounds. Thus, the lower acidity prevents a possible epimerization of the Michael adducts. In addition, the presence of two substituents on the nitrogen allow to tune their resulting Michael adducts. In addition, the presence of two substituents on the nitrogen allow to tune steric and electronic properties more easily than other common 1,3-dicarbonyl pro-nucleophiles. their steric and electronic properties more easily than other common 1,3-dicarbonyl pro-nucleophiles.

Scheme 28. Organocatalyzed enantioselective addition of β-ketoamides to nitroalkenes. SchemeScheme 28. 28.Organocatalyzed Organocatalyzedenantioselective enantioselective addition of of ββ-ketoamides-ketoamides to to nitroalkenes. nitroalkenes.

The addition of α-substituted monothiomalonates to aryl nitroolefins have been recently TheThe addition addition of αof-substituted α-substituted monothiomalonates monothiomalonates to aryl to nitrooleﬁnsaryl nitroolefins have beenhave recently been recently described described by using bifunctional Cinchona alkaloid-urea organocatalysts 116. The corresponding byadducts using bifunctional 117 were obtainedCinchona withalkaloid-urea excellent organocatalystsee’s along with 116diastereoselectivities. The corresponding ranging adducts from117 wereadducts obtained 117 withwere excellentobtained eewith’s along excellent with diastereoselectivitiesee’s along with diastereoselectivities ranging from moderate ranging tofrom good moderate to good (Scheme 29) [131]. (Scheme 29)[131].

Scheme 29. Organocatalyzed enantioselective addition of β-ketoamides. SchemeScheme 29. 29.Organocatalyzed Organocatalyzed enantioselectiveenantioselective addition addition of of ββ-ketoamides.-ketoamides.

The aforementioned thiourea-L-pyrrolidine derived tertiary amine 102, has also demonstrated TheThe aforementioned aforementioned thioureathiourea-L-pyrrolidineL-pyrrolidine derived derived tertiary tertiary amine amine102 102,, has has also also demonstrated demonstrated its its effectiveness in the Michael addition of other dicarbonyl compounds, such as dithiomalonates effectivenessits effectiveness in the in Michael the Michael addition addition of other of othe dicarbonylr dicarbonyl compounds, compounds, such such as dithiomalonates as dithiomalonates [132 ] [132] (Scheme 30(a)) and 2-oxochroman-3-carboxylate esters (Scheme 30(b)) [133] to nitroalkenes. The (Scheme[132] (Scheme 30a) and 30(a)) 2-oxochroman-3-carboxylate and 2-oxochroman-3-carboxylate esters (Scheme esters (Scheme 30b) [133 30(b))] to nitroalkenes.[133] to nitroalkenes. The resulting The resulting adducts 118 and 119, respectively, were obtained in excellent yields and enantioselectivities, adductsand can118 beand elaborated119, respectively, obtaining bioactive were obtained motifs. in Organic excellent molecules yields andwith enantioselectivities, a quaternary stereocenter and can beand elaborated can be elaborated obtaining bioactiveobtaining motifs.bioactive Organic motifs. moleculesOrganic molecules with a quaternary with a quaternary stereocenter stereocenter bearing a bearing a fluorine atom are very attractive motifs for medicinal chemistry in the search of fluorinated ﬂuorine atom are very attractive motifs for medicinal chemistry in the search of ﬂuorinated analogs of analogs of bioactive compounds, their construction being challenging. bioactive compounds, their construction being challenging.

Molecules 2017, 22, 895 29 of 51 Molecules 2017, 22, 895 29 of 51

Molecules 2017, 22, 895 29 of 51

Scheme 30. Enantioselective Michael addition of dithiomalonates and 2-oxochroman-3-carboxylate Scheme 30. Enantioselective Michael addition of dithiomalonates and 2-oxochroman-3-carboxylate esters organocatalyzed by 102. estersScheme organocatalyzed 30. Enantioselective by 102 Michael. addition of dithiomalonates and 2-oxochroman-3-carboxylate esters organocatalyzed by 102. The use of unsymmetrically substituted 2-fluoro-1,3-dicarbonyl compounds as pronucleophiles The use of unsymmetrically substituted 2-ﬂuoro-1,3-dicarbonyl compounds as pronucleophiles in in MichaelThe additionsuse of unsymmetrically to nitroolefins substituted would render 2-fluoro the-1,3-dicarbonyl formation of compounds these enantioenriched as pronucleophiles compounds Michael additions to nitrooleﬁns would render the formation of these enantioenriched compounds 120, 120in, also Michael bearing additions two consecutiveto nitroolefins all would carbon render stereocenters the formation (Scheme of these 31).enantioenriched compounds also120 bearing, also bearing two consecutive two consecutive all carbon all carbon stereocenters stereocenters (Scheme (Scheme 31 31).).

Scheme 31. Organocatalyzed enantioselective Michael addition of fluorinated pro-nucleophiles to Scheme 31. Organocatalyzed enantioselective Michael addition of ﬂuorinated pro-nucleophiles nitroolefins. to nitrooleﬁns. Scheme 31. Organocatalyzed enantioselective Michael addition of fluorinated pro-nucleophiles to nitroolefins.

Molecules 2017, 22, 895 30 of 51

Organocatalyst 121 has proven to be quite efficient in such purpose, allowing the reaction betweenOrganocatalyst 2-fluoro-1,3-diketones121 has proven onto to nitroalkenes be quite efficient in good in such yields purpose, and allowingenantioselectivities the reaction but between with 2-fluoro-1,3-diketonesmoderate diastereoselectivities onto nitroalkenes [134]. More in good rece yieldsntly, fluorinated and enantioselectivities monothiomalonates but with have moderate been diastereoselectivitiessuccessfully added to nitroolefins [134]. More in recently, the presence fluorinated of 1 mol monothiomalonates % of organocatalyst have116, obtaining been successfully excellent addedenantio- to and nitroolefins diastereoselectivities in the presence for ofthe 1 molcorrespo % ofnding organocatalyst products.116 Such, obtaining thioesters excellent are more enantio- labile andthan diastereoselectivitiesthe corresponding esters for theand corresponding hence easier to products. be further Such transformed. thioesters In are fact, more after labile the reduction than the correspondingof the nitro group, esters the and correspo hence easiernding tofluorinated be further lactams transformed. were Insynthesized fact, after thein straightforward reduction of the nitroway group,[135]. the corresponding fluorinated lactams were synthesized in straightforward way [135]. Similarly, the use of α-fluoro-fluoroβ β-ketophosphonates-ketophosphonates asas activeactive methylenemethylene compoundscompounds able to act as nucleophiles in this transformation has been also recently reported. Thus, both Cinchona-thiourea derivative 122 [[136]136] and squaramide-basedsquaramide-based catalyst 123 [[137]137] have proven to efficientlyefficiently accomplishaccomplish such purpose.purpose. AlthoughAlthough good good yields yields were were observed observed using using both catalysts,both catalysts,122 turned 122 turned out to be out superior to be insuperior terms ofin enantio-terms of andenantio- diastereoselection and diastereoselection (Scheme 31(Scheme). 31). Versatility and excellentexcellent performanceperformance as organocatalystorganocatalyst hashas shownshown epiepi-quinine-derived-quinine-derived squaramide 124 in this kind of transformations, as as illust illustratedrated in in the the examples examples depicted depicted in in Scheme Scheme 32.32. Thus, the synthesis of densely functionalized dihydropyrans 126 by dehydration of tetrahydropyrans 125,, whichwhich areare obtainedobtained fromfrom thethe additionaddition ofof 1,3-dicarbonyl1,3-dicarbonyl compoundscompounds ontoonto α-hydroxymethylated nitroolefins,nitroolefins, is is shown. shown. The The reaction reaction proceeds proceeds via via a domino a domino Michael-hemiacetalization Michael-hemiacetalization sequence, sequence, and andthe final the finalheterocycles heterocycles are obtained are obtained in high in yields high yieldsand enantioselectivities and enantioselectivities with a moderate with a moderate to high todiastereoselectivity high diastereoselectivity (Scheme 32(a)) (Scheme [138]. 32More(a)) rece [138ntly,]. and More based recently, on the andsame basedidea, the on synthesis the same of idea,O-acyl-protected the synthesis γ-hydroxy-nitroketones of O-acyl-protected γ -hydroxy-nitroketones127 has been described.127 hasThus, been the described. corresponding Thus, theenantioenriched corresponding tetrahydropyrans enantioenriched tetrahydropyrans125 were submitted125 wereto an submitted intramolecular to an intramolecular Claisen-type Claisen-typefragmentation, fragmentation, catalyzed by catalyzed photochemica by photochemicallylly activated Fe(0) activated complex. Fe(0) Products complex. 127 Products were obtained127 were obtainedin moderate in moderate yields with yields high with enantio- high and enantio- diastereoselectivities and diastereoselectivities (Scheme 32(b)) (Scheme [139]. 32b) [139].

α SchemeScheme 32. OrganocatalyzedOrganocatalyzed enantioselec enantioselectivetive Michael addition onto α-hydroxymethylnitrooleﬁns.-hydroxymethylnitroolefins.

Finally, it is important to remark that the same catalyst 124 has been used for the synthesis of complex molecules bearing up to six consecutive stereocenters in a one-pot multicomponent reaction.

Molecules 2017, 22, 895 31 of 51

Finally, it is important to remark that the same catalyst 124 has been used for the synthesis of Molecules 2017,, 22,, 895895 31 of 51 complex molecules bearing up to six consecutive stereocenters in a one-pot multicomponent reaction. Thus, highly functionalized cyclohexane-derivatives 128128 cancan be obtained obtained starting starting from from an an asymmetricasymmetric organocatalyzed 1,4-addition1,4-addition of of 1,3-dicarbonyl 1,3-dicarbonyl to nitrooleﬁns, to nitroolefins,nitroolefins, followed followedfollowed by a 1,6-/1,2 by a addition1,6-/1,2 sequenceaddition sequencein the presence in the ofpresence an achiral of an organic-base. achiral organic-base Despite..the DespiteDespite complexity thethe complexitycomplexity of the products, ofof thethe products,products, moderate moderatemoderate to good yieldstoto goodgood were yieldsyields obtained werewere obtainedobtained along with alongalong excellent withwith excellentexcellent enantioselectivities enantioselectivitiesenantioselectivities in products inin productsproducts128, using 128 only,, usingusing 1 mol onlyonly % of 11 molorganocatalyst % of organocatalyst (Scheme 33 (Scheme)[140]. 33) [140].

Scheme 33.33.Multicomponent MulticomponentMulticomponent reaction reactionreaction based basedbased onthe onon organocatalyzed thethe organocatalyzed enantioselective enantioselective Michael additionMichael additionof 1,3-dicarbonyl of 1,3-dicarbonyl compounds compounds to nitrooleﬁns to nitroolefins catalyzed catalyzed by 124. by 124..

2.4. Nitroalkanes The asymmetric Michael Michael addition addition of of αα-fluoro--fluoro-αα-nitro-nitro esters esters to to nitroolefins nitroolefins for for the the preparation preparation of compoundsof compounds 130130 hashashas recentlyrecently recently beenbeen been reportedreported reported employingemploying employing aa CinchonaCinchona-alkaloid-amino acid-thioureaacid-thiourea structure 129 asas organocatalystorganocatalyst (Scheme(Scheme 3434))[ [141].141]. Differ Differentent conditions for for the nitro reduction of compounds 130130 were werewere assayed assayedassayed to toto obtain obtainobtain the thethe corresponding correspondingcorrespondingα-fluoro- α-fluoro-α-aminoα-amino acid acid derivatives, derivatives, but only but only the use of H2 in the presence of Pd/BaSO4 gave partial success (20% yield). Denitration of one of onlythe use the of use H 2ofin H the2 in presence the presence of Pd/BaSO of Pd/BaSO4 gave4 gave partial partial success success (20% (20% yield). yield). Denitration Denitration of one of one of the of theadductsthe adductsadducts130 130was waswas accomplished accomplishedaccomplished using usingusing radical radicalradical conditions. conditions.conditions.

Scheme 34.34. Asymmetric Michael addition of α-fluoro--ﬂuoro--fluoro-α-nitro-nitro esters esters to to nitroalkenesnitroanitroalkeneslkenes catalyzed catalyzed by by anan alkaloid-threonine-thiourea derivative.derivative.

A chiral bifunctional alkaloid-squaramide organocatalyst 131 has been used for the Michael A chiral bifunctional alkaloid-squaramide organocatalyst 131131 has been used for the Michael addition of 1-nitropropane to different nitroalkenes [142]. The conjugate addition products 132 were addition of 1-nitropropane to different nitroalkenesnitroalkenes [[142].142]. The conjugate addition products 132 were obtained in high to excellent yields and stereoselectivities, being insensitive to the electronic nature obtained in highhigh toto excellentexcellent yieldsyields and and stereoselectivities, stereoselectivities, being being insensitive insensitive to to the the electronic electronic nature nature of of the aromatic ring (Scheme 35). ofthe the aromatic aromatic ring ring (Scheme (Scheme 35 ).35).

Molecules 2017, 22, 895 32 of 51 Molecules 2017, 22, 895 32 of 51 Molecules 2017, 22, 895 32 of 51

SchemeScheme 35. 35.Asymmetric Asymmetric Michael Michael additionaddition ofof 1-nitropropane1-nitropropane to to nitroalkenes nitroalkenes organocatalyzed organocatalyzed byby an an alkaloid-squaramideSchemealkaloid-squaramide 35. Asymmetric derivative. derivative. Michael addition of 1-nitropropane to nitroalkenes organocatalyzed by an alkaloid-squaramide derivative. 2.5.2.5. Heterocyclic Heterocyclic Compounds Compounds 2.5. HeterocyclicChiral oxindoles Compounds have attracted significant attention in asymmetric catalysis and medicinal Chiral oxindoles have attracted significant attention in asymmetric catalysis and medicinal chemistry due to their prevalence in a variety of natural and biologically active compounds [143,144]. chemistryChiral due oxindoles to their prevalence have attracted in a varietysignificant of natural attention and in biologically asymmetric active catalysis compounds and medicinal [143,144 ]. Particularly, chiral 3,3-disubstituted oxindole derivatives are considered crucial scaffolds in several Particularly,chemistry due chiral to their 3,3-disubstituted prevalence in oxindolea variety of derivatives natural and are biologically considered active crucial compounds scaffolds [143,144]. in several Particularly,drugs [145,146]. chiral Thus, 3,3-disubstituted 3-functionalized oxindole oxindoles derivatives have been are efficientlyconsidered used crucial as nucleophilesscaffolds in several in the drugs [145,146]. Thus, 3-functionalized oxindoles have been efficiently used as nucleophiles in drugsconjugate [145,146]. addition Thus, to nitrostyrene3-functionalized derivatives. oxindoles As ha usual,ve been the efficientlyreaction is used organocatalyzed as nucleophiles by inchiral the the conjugate addition to nitrostyrene derivatives. As usual, the reaction is organocatalyzed by conjugatebifunctional addition organocatalysts to nitrostyrene involving derivatives. a dual BrønstedAs usual, base/hydrogenthe reaction is organocatalyzedbonding activation by ofchiral the chiral bifunctional organocatalysts involving a dual Brønsted base/hydrogen bonding activation bifunctionalnucleophile andorganocatalysts the electrophile. involving An exampla duale Brønsted is the thiourea-tertiary base/hydrogen aminebonding catalyst activation 133 whichof the of the nucleophile and the electrophile. An example is the thiourea-tertiary amine catalyst nucleophilepromotes the and conjugate the electrophile. addition of An 3-aminooxindo example is theles tothiourea-tertiary nitroolefins, affo aminerding catalyst the corresponding 133 which 133promotesderivativeswhich promotesthe 134 conjugate bearing the addition conjugatea quaternary of 3-aminooxindo addition stereogenic of 3-aminooxindolesles tocenter nitroolefins, with high toaffo nitroolefins, rdingyields, the diastereo-corresponding affording and the correspondingderivativesenantioselectivities 134 derivatives bearing (Scheme134 a bearing36)quaternary [147]. a quaternaryInterestingly, stereogenic stereogenic high center selectivities centerwith high with (>99/1 highyields, dr, yields, 87% diastereo- ee diastereo-) were alsoand and enantioselectivitiesenantioselectivitiesobtained for aliphatic (Scheme (Scheme nitroolefins 36 36))[ 147[147]. such]. Interestingly, Interestingly,as (E)-(2-nitrovinyl)cyclohexane high selectivities (>99/1 (>99/1(R3 = drcyclohexyl),,dr 87%, 87% ee)ee were )although were also also 3 obtainedobtainedin low foryields for aliphatic aliphatic (30%). nitroolefinsA nitroolefins dual and such simultaneoussuch asas (E(E)-(2-nitrovinyl)cyclohexane)-(2-nitrovinyl)cyclohexane Brønsted base/hydrogen (R (Rbonding3 = =cyclohexyl), cyclohexyl), activation althoughalthough of the ininnucleophile low low yields yields (30%).and (30%). electrophile, A A dual dual and respectively,and simultaneous simultaneous has been BrønstedBrønsted proposed base/hydrogen based on related bonding bonding activation activation activation models of and ofthe the nucleophilenucleophilethe observed and and product electrophile, electrophile, stereochemistry, respectively, respectively, as hasdepictedhas beenbeen in proposed the model based based I (Scheme on on related related 36). activation activation models models and and thethe observed observed product product stereochemistry, stereochemistry, as as depicted depicted inin thethe modelmodel I (Scheme(Scheme 36). 36).

Scheme 36. Asymmetric organocatalytic conjugate addition of 3-aminooxindoles to nitroolefins. SchemeScheme 36. 36.Asymmetric Asymmetric organocatalytic organocatalytic conjugate addition addition of of 3-aminooxindoles 3-aminooxindoles to tonitroolefins. nitrooleﬁns.

Molecules 2017, 22, 895 33 of 51

Molecules 2017, 22, 895 33 of 51 A range of chiral 3-pyrrolyl-3,3’-disubstituted oxindoles have been prepared via conjugate A range of chiral 3-pyrrolyl-3,3’-disubstituted oxindoles have been prepared via conjugate addition of 3-pyrrolyloxindoles to β-nitrostyrene organocatalyzed by the Cinchona-alkaloid addition of 3-pyrrolyloxindoles to β-nitrostyrene organocatalyzed by the Cinchona-alkaloid squaramide-based organocatalyst 135 [148]. The reaction affords the corresponding products squaramide-based organocatalyst 135 [148]. The reaction affords the corresponding products in high in high yields, moderate diastereoselectivities, and good to excellent enantioselectivities for yields, moderate diastereoselectivities, and good to excellent enantioselectivities for the major the major diastereoisomer. The usefulness of the methodology has been demonstrated by the diastereoisomer. The usefulness of the methodology has been demonstrated by the synthesis of synthesis of different optically active compounds, such as the pyrrolidinoindoline derivative 136, different optically active compounds, such as the pyrrolidinoindoline derivative 136, with a core with a core structure related to interesting natural products, such as (−)-physostigmine and structure related to interesting natural products, such as (−)-physostigmine and (−)- (−)-pseudophrynaminol (Scheme 37). pseudophrynaminol (Scheme 37).

OMe N

NH N O NH

O CF3

135 F3C

Ph N Ph N N Ph NO2 N O 135 (5 mol%) O N N N CH2Cl2,0ºC N Me 2 2 Me Me 54 h Me N H + 97%, 87/13 dr, 94% ee Me Ph Recryst. Ph >99/1 dr, >99% ee 136 NO2 >99/1 dr, >99% ee 136 >99/1 dr, >99% ee

Scheme 37. Asymmetric organocatalytic conjugate addition of 3-aminooxindoles to nitrooleﬁns. Scheme 37. Asymmetric organocatalytic conjugate addition of 3-aminooxindoles to nitroolefins.

The asymmetric Michael addition reaction of 3-alkyloxindoles [149] [149] or 3-chlorooxindoles [[150]150] to nitroalkenes nitroalkenes has has been been explored explored recent recentlyly using using as asorganocatalysts organocatalysts the theguanidine guanidine 137 137and andthe thesquaramide squaramide 138,138 respectively., respectively. The The reaction reaction conditions, conditions, yields yields and and stereoselectivities stereoselectivities of of thethe corresponding adducts areare shownshown inin FigureFigure 1919..

Figure 19. OrganocatalystsOrganocatalysts employed employed for for the the conjugate conjugate ad additiondition reactions reactions of of3-alkyloxindoles 3-alkyloxindoles and and 3- 3-chlorooxindoleschlorooxindoles to to nitroolefins. nitrooleﬁns.

Molecules 2017, 22, 895 34 of 51

Molecules3-Alkylideneoxindoles 2017, 22, 895 have also been studied in the conjugate addition to nitroolefins34 of 51 [151 ]. The ability3-Alkylideneoxindoles of 3-alkylideneoxindoles have also to been react studied as electron-poor in the conjugate acceptors addition to converts nitroolefins these [151]. substrates The in challengingability of 3-alkylideneoxindoles nucleophiles. Thus, to dihydroquinine-derived react as electron-poor acceptors thiourea converts organocatalyst these substrates139 promotes in the asymmetricchallenging nucleophiles. vinylogous MichaelThus, dihydroquinine-derived addition of a variety thiourea of 3-alkylideneoxindoles organocatalyst 139 topromotesβ-nitrostyrene the derivativesasymmetric through vinylogous a bifunctional Michael activationaddition of mechanism,a variety of to3-alkylideneoxindoles afford the corresponding to β-nitrostyrene products 140 withderivatives excellent through regio- and a bifunctional stereoselectivities, activation nomechanism, olefin isomerization to afford the corresponding being observed products (Scheme 140 38). In addition,with excellent thiourea regio-139 andalso stereoselectivities, organocatalyzed no the olefin conjugate isomerization addition being of α observed-alkylidenepyrazolidinones (Scheme 38). In to nitroolefinsaddition, thiourea [152]. 139 also organocatalyzed the conjugate addition of α-alkylidenepyrazolidinones to nitroolefins [152].

SchemeScheme 38. 38.Asymmetric Asymmetric organocatalyzed organocatalyzed conjugateconjugate addition addition of of 3-alkylideneoxindoles 3-alkylideneoxindoles to nitroolefins. to nitrooleﬁns.

Due to the frequent occurrence of the pyrazolone core in many important naturally occurring Due to the frequent occurrence of the pyrazolone core in many important naturally occurring compounds and drug molecules, great efforts have been made for their chiral synthesis [153]. So far, compounds and drug molecules, great efforts have been made for their chiral synthesis [153]. So far, numerous works have been reported on the pyrazolone addition, taking advantage of the aromatic numerous works have been reported on the pyrazolone addition, taking advantage of the aromatic character acquired by these substrates after deprotonation. Interestingly, challenging nitroolefins characterhave acquiredbeen used by as these electrophiles substrates for after the deprotonation. conjugate addition. Interestingly, For instance, challenging the N nitrooleﬁns-sulfinylurea have beenorganocatalyst used as electrophiles 141 has been for theemployed conjugate to promote addition. the Foradditi instance,on of different the N-sulﬁnylurea 3-substituted organocatalystpyrazolone 141 hasderivatives been employed to nitroalkenes to promote bearing the an additionoxetane or of azetidine different ring 3-substituted at the β-position pyrazolone (Scheme derivatives 39) [154]. to nitroalkenesThe nitroalkane bearing anpyrazolone oxetane oradducts azetidine 142 ring areat obtained the β-position with moderate (Scheme 39to)[ 154good]. Theyields nitroalkane and pyrazoloneenantioselectivities. adducts 142 are obtained with moderate to good yields and enantioselectivities.

SchemeScheme 39. 39.Asymmetric Asymmetric organocatalyzedorganocatalyzed conjugate conjugate ad additiondition of ofpyrazolones pyrazolones to tofour-member four-member heterocycle-containingheterocycle-containing nitrooleﬁns. nitroolefins.

Molecules 2017, 22, 895 35 of 51 Molecules 2017, 22, 895 35 of 51 Chiral squaramide 143 has been successfully used as organocatalyst in the conjugate addition of 3-substituted pyrazolones to β-trifluoromethyl β-disubstituted nitroolefins to afford the Chiral squaramide 143 has been successfully used as organocatalyst in the conjugate addition of corresponding Michael adducts 144 in moderate to good yields and good to excellent 3-substituted pyrazolones to β-triﬂuoromethyl β-disubstituted nitrooleﬁns to afford the corresponding enantioselectivities [155] (Scheme 40). However, the reaction is quite unpredictable in terms of Michael adducts 144 in moderate to good yields and good to excellent enantioselectivities [155] electronic effects. For instance, β-nitrostyrenes with both strong electron-withdrawing (-CF3) or (Scheme 40). However, the reaction is quite unpredictable in terms of electronic effects. For instance, donating (-OMe) groups at the para position of the phenyl ring do not show any reactivity in the β-nitrostyrenes with both strong electron-withdrawing (-CF ) or donating (-OMe) groups at the para process. Also, striking effects on the reaction yield and 3enantioselectivity have been observed position of the phenyl ring do not show any reactivity in the process. Also, striking effects on the depending on the electronic features of the substituents of the phenyl ring at the 1-position of the reaction yield and enantioselectivity have been observed depending on the electronic features of the pyrazolinone. Thus, halogenated (4-ClC6H4, 4-BrC6H4) as well as electron-donating (4-MeOC6H4) para substituents of the phenyl ring at the 1-position of the pyrazolinone. Thus, halogenated (4-ClC H , substituents afforded the addition products in moderate to good yields and excellent6 4 4-BrC6H4) as well as electron-donating (4-MeOC6H4) para substituents afforded the addition products enantioselectivities, while strong electron-withdrawing groups (-CF3) led to low yields. A in moderate to good yields and excellent enantioselectivities, while strong electron-withdrawing bifunctional activation of the deprotonated tautomer of the nucleophile and the electrophile by the groups (-CF ) led to low yields. A bifunctional activation of the deprotonated tautomer of the chiral catalyst3 is proposed in the reaction transition state. nucleophile and the electrophile by the chiral catalyst is proposed in the reaction transition state.

Scheme 40. Organocatalyzed asymmetric conjugate addition of pyrazolones to triﬂuoromethylated Scheme 40. Organocatalyzed asymmetric conjugate addition of pyrazolones to trifluoromethylated nitrooleﬁns. nitroolefins.

Chiral urea- and thiourea-based organocatalysts 145145–147–147 have been reported to organocatalyze the conjugate addition ofof oxazolonesoxazolones [[156],156], thiazolonesthiazolones [[157],157], oxazolidindiones [[158],158], and thiazolidindiones [[159]159] toto nitroalkenes nitroalkenes leading leading to to the the corresponding corresponding adducts adducts 148 148 (Scheme (Scheme 41, 41, Figure Figure 20). 20).In general, In general, high high yields yields and and selectivities selectivities are are observed observed for for all all the the tested tested nucleophiles nucleophiles andand ββ-arylated nitroalkenes, whereas the use of aliphatic nitroolefin nitrooleﬁnss usually affords low yields irrespective of the employed nucleophile (Figure 2020).).

Scheme 41.41.Asymmetric Asymmetric organocatalyzed organocatalyzed conjugate conjugate addition ofaddition oxazolones, of thiazolones,oxazolones, oxazolidindiones thiazolones,, and thiazolidindiones to nitrooleﬁns. oxazolidindiones, and thiazolidindiones to nitroolefins.

Molecules 2017, 22, 895 36 of 51 Molecules 2017, 22, 895 36 of 51

Molecules 2017, 22, 895 36 of 51

FigureFigure 20. 20.Organocatalysts Organocatalysts employedemployed in the conjugate conjugate addition addition of ofoxazolones, oxazolones, thiazolones, thiazolones, oxazolidindiones,oxazolidindiones, and and thiazolidindiones thiazolidindiones to to nitroolefins nitroolefins leading to to 148148. . Figure 20. Organocatalysts employed in the conjugate addition of oxazolones, thiazolones, oxazolidindiones, and thiazolidindiones to nitroolefins leading to 148. Lactones [160,161], azlactones [162], phthalides [163], cyclic hemiacetals [164], and Lactones [160,161], azlactones [162], phthalides [163], cyclic hemiacetals [164], and benzofuranones [165] have shown as suitable pro-nucleophiles in the asymmetric organocatalytic benzofuranonesLactones [ 165[160,161],] have shownazlactones as suitable[162], pro-nucleophilesphthalides [163], incyclic the asymmetrichemiacetals organocatalytic[164], and benzofuranonesconjugate addition [165] to nitroolefins.have shown Concerning as suitable lactones,pro-nucleophiles the direct in asymmetric the asymmetric vinylogous organocatalytic conjugate conjugate addition to nitroolefins. Concerning lactones, the direct asymmetric vinylogous conjugate conjugateaddition of addition γ-aryl-substituted to nitroolefins. deconjugated Concerning butenolides lactones, tothe β -alkyldirect andasymmetric β-aryl substituted vinylogous nitroolefins conjugate addition of γ-aryl-substituted deconjugated butenolides to β-alkyl and β-aryl substituted nitroolefins additionhas been of performedγ-aryl-substituted using deconjugatedchiral thioureas butenolides 149 and to β150-alkyl as and organocatalysts, β-aryl substituted to nitroolefinsafford the has beenhascorresponding performedbeen performed chiral using lactones chiralusing thioureas151chiral bearing thioureas149 adjacentand 149150 quaternary andasorganocatalysts, 150 andas organocatalysts,tertiary tostereocenters afford to the affordwith corresponding good the chiralcorrespondingisolated lactones yields,151 chiralhighbearing diastereoselectivities, lactones adjacent 151 bearing quaternary andadjacent excellent and quaternary tertiary enantioselectivi stereocenters and tertiaryties [160]stereocenters with (Scheme good isolatedwith 42). good yields, highisolated diastereoselectivities, yields, high diastereoselectivities, and excellent enantioselectivities and excellent enantioselectivi [160] (Schemeties [160] 42). (Scheme 42).

Scheme 42. Asymmetric organocatalyzed direct vinylogous conjugate addition of deconjugated butenolides to nitroolefins. SchemeScheme 42. 42.Asymmetric Asymmetric organocatalyzed organocatalyzed directdirect vinylogo vinylogousus conjugate conjugate addition addition of deconjugated of deconjugated butenolides to nitroolefins. butenolidesChiral phthalides to nitrooleﬁns. are present in numerous natural products and drugs [166]. An interesting asymmetricChiral phthalidesorganocatalyzed are present conjugate in numerous addition natuof phthalideral products derivatives and drugs to nitroolefins[166]. An interesting has been Chiralasymmetricrecently phthalides reported organocatalyzed [163]. are The present reaction,conjugate in numerous catalyzed addition by naturalof quinine-derivedphthalide products derivatives andthiourea drugs to nitroolefins122 [,166 is carried]. An has interestingout been in asymmetricrecently organocatalyzedreported [163]. The conjugate reaction, catalyzed addition by of quinine-derived phthalide derivatives thiourea to122 nitrooleﬁns, is carried out has in been recently reported [163]. The reaction, catalyzed by quinine-derived thiourea 122, is carried out in dichloroethane (DCE) at room temperature, the corresponding functionalized 3,3-disubstituted phthalide derivatives 152 being obtained in high yields, diastereo- and enantioselectivities (Scheme 43). Molecules 2017, 22, 895 37 of 51 dichloroethane (DCE) at room temperature, the corresponding functionalized 3,3-disubstituted Moleculesphthalide2017 derivatives, 22, 895 152 being obtained in high yields, diastereo- and enantioselectivities (Scheme37 43). of 51

Scheme 43. Asymmetric organocatalyzed Conjugate addition of phthalide derivatives to nitroolefins. nitrooleﬁns.

A highly enantioselective Michael addition of cycl cyclicic hemiacetals to nitroolefins nitrooleﬁns has recently been reported using the Hayashi-Jørgensen proline-derivedproline-derived catalystcatalyst 1313 [[164].164]. This methodology allows the preparation of optically active 3-substituted tetrahydrofurans and tetrahydropyrans 153, which are compounds not as easily accessible as thethe 2-substituted2-substituted derivatives. This catalytic methodology is of high synthetic utility, allowing the synthesissynthesis of 2,3-disubstituted cyclic ethers, αα-substituted-substituted lactones, lactones, and analogues of the antidepressant venlafaxinevenlafaxine (Scheme(Scheme 4444).).

Scheme 44. Organocatalytic enantioselective addition of cyclic hemiacetals to nitrooleﬁns.nitroolefins.

3. Nitrogen Nucleophiles The organocatalytic organocatalytic aza-Michael aza-Michael reaction reaction has has attr attractedacted considerable considerable attention attention in recent in recentyears years[167–171]. [167 –Among171]. Amongthe employed the employed nucleophiles, nucleophiles, the most frequently the most frequentlystudied have studied been carbamates, have been carbamates,benzotriazoles, benzotriazoles, pyrazolinones, pyrazolinones, hydrazones hydrazonesand hydroxylamines. and hydroxylamines. More recently, More recently,the use theof useorganocatalysts of organocatalysts having a having tertiary a amine tertiary and amine a thiourea and a moiety thiourea has moiety allowed has the allowed Michael the addition Michael of additionnitrogen nucleophiles, of nitrogen nucleophiles, a double activation a double role activation being assigned role being to these assigned catalysts. to these Thus, catalysts. Takemoto’s Thus, Takemoto’sorganocatalyst organocatalyst 73 has been 73employedhas been in employed the addition in the of additionacylhydrazines of acylhydrazines to nitroalkenes to nitroalkenes giving the givingproducts the 154 products (Scheme154 45).(Scheme Both electron-rich 45). Both electron-rich and electron-poor and electron-poor aryl nitroalkenes aryl nitroalkeneswere successfully were successfullyemployed obtaining employed good obtaining enantios goodelectivities, enantioselectivities, whereas rather whereas poor rather results poor were results obtained were obtained using usingaliphatic aliphatic nitroalkenes nitroalkenes [172]. [172].

Scheme 45. Asymmetric aza-Michael addition of acylhydrazi acylhydrazinesnes to nitroalkenes nitroalkenes by using using Takemoto’s Takemoto’s thiourea catalystcatalyst 73..

Nitrogen containing heterocycles, such as phthalimide and benzotriazole have been added successfully to nitrooleﬁns mediated by a Cinchona-alkaloid thiourea organocatalyst. Thus, Molecules 2017, 22, 895 38 of 51

Nitrogen containing heterocycles, such as phthalimide and benzotriazole have been added successfullyMolecules 2017to , 22nitroolefins, 895 mediated by a Cinchona-alkaloid thiourea organocatalyst.38 Thus,of 51 4- Molecules 2017, 22, 895 38 of 51 nitrophthalimideMolecules 2017, 22, 895 reacted with a variety of nitroalkenes in the presence of the alkaloid-thiourea38 of116 51 Nitrogen containing heterocycles, such as phthalimide and benzotriazole have been added to give the corresponding Michael adducts 155 (Scheme 46) [173]. Activity test showed that some of successfullyNitrogen to containing nitroolefins heterocycles, mediated bysuch a asCinchona phthalimide-alkaloid and thiourea benzotriazole organocatalyst. have been Thus, added 4- these products have moderate or good herbicidal activity against cole and barnyard grass. 4-nitrophthalimidesuccessfullynitrophthalimide to nitroolefins reacted reacted with mediated a a variety variety byof ofnitroaa nitroalkenesCinchonalkenes-alkaloid in the in presence the thiourea presence of organocatalyst.the ofalkaloid-thiourea the alkaloid-thiourea Thus, 116 4- 116 tonitrophthalimideto give give thethe correspondingcorresponding reacted with Michael Michael a variety adducts adducts of nitroa155155 (Schemelkenes(Scheme in46) the [173].46 presence)[173 Activity]. Activityof thetest alkaloid-thioureashowed test showed that some that 116 of some of thesetothese give products products the corresponding have have moderatemoderate Michael or or goodgood adducts herbicidal herbicidal 155 (Scheme activity activity 46) against [173]. against cole Activity coleand barnyard andtest showed barnyard grass. that grass. some of these products have moderate or good herbicidal activity against cole and barnyard grass.

Scheme 46. Asymmetric aza-Michael addition of 4-nitrophthalimide to nitroalkenes using an alkaloid-thiourea derivative as organocatalyst. SchemeScheme 46. 46.Asymmetric Asymmetric aza-Michael aza-Michael additionaddition of of 4-nitrophthalimide 4-nitrophthalimide to tonitroalkenes nitroalkenes using using an an Scheme 46. Asymmetric aza-Michael addition of 4-nitrophthalimide to nitroalkenes using an alkaloid-thioureaalkaloid-thiourea derivative derivative as as organocatalyst. organocatalyst. The formationalkaloid-thiourea of quaternary derivative as stereogenic organocatalyst. cent ers has been achieved using organocatalyst 74 via an aza-MichaelThe formation addition of quaternary of benzotriazole stereogenic tocent theers hasalkoxycarbonylated been achieved using nitroalkenesorganocatalyst 74[174], via the The formationThe formation of quaternary of quaternary stereogenic stereogenic centers centers has has been been achievedachieved using organocatalyst organocatalyst 7474 viavia an correspondingan aza-Michael adducts addition 156 ofbeing benzotriazole obtained to inthe moderatealkoxycarbonylated to high nitroalkenesyields and [174], with the high aza-Michaelan aza-Michael addition addition of benzotriazole of benzotriazole to the alkoxycarbonylated to the alkoxycarbonylated nitroalkenes nitroalkenes [174], the corresponding[174], the enantioselectiviticorrespondinges (Schemeadducts 47).156 being obtained in moderate to high yields and with high adductscorrespondingenantioselectiviti156 being obtainedadductses (Scheme in156 moderate47). being toobtained high yields in moderate and with to high high enantioselectivities yields and with (Scheme high 47). enantioselectivities (Scheme 47).

SchemeScheme 47. Asymmetric 47. Asymmetric aza-Michael aza-Michael addition addition ofof benzotriazolebenzotriazole to to β,ββ,-disubstitutedβ-disubstituted nitroalkenes nitroalkenes by by SchemeScheme 47. Asymmetric 47. Asymmetric aza-Michael aza-Michael additi additionon ofof benzotriazole to to β ,β-disubstituted,β-disubstituted nitroalkenes nitroalkenes by by usingusing an alkaloid-thiourea an alkaloid-thiourea derivative. derivative. usingusing an alkaloid-thiourea an alkaloid-thiourea derivative. derivative. 5-Aminopent-2-enoate derivatives have been employed as nitrogen nucleophiles in the aza- 5-Aminopent-2-enoate derivatives have been employed as nitrogen nucleophiles in the 5-Aminopent-2-enoateMichael5-Aminopent-2-enoate addition to nitrostyrenes. derivatives derivatives The have have formed beenbeen adductemployedployed underwent as as nitrogen nitrogen a second nu cleophilesnucleophiles Michael in additionthe in aza-the aza- Michaelaza-MichaelMichaelmediated addition addition additionby the to sametonitrostyrenes. tonitrostyrenes. catalyst nitrostyrenes. to giveThe The tetrasubstituted formedformed The formedadduct piperidines underwentunderwent adduct underwent157 a asecond[175]. second Different Michael a Michael second Cinchona-addition addition Michael mediatedadditionmediatedalkaloid-based mediatedby theby thesame thioureas by same thecatalyst catalyst samewere testedto catalystto give give as organocatalyststetrasubstituted tetrasubstituted to give tetrasubstituted in piperidines piperidinesthis transformation, piperidines157 157 [175]. [175]. giving Different157 Different similar[175 Cinchona-]. results: Cinchona- Different Cinchonaalkaloid-basedalkaloid-basedlow-alkaloid-based diastereoselectivity thioureas thioureas thioureas were and were testedhigh tested were enantioselectivity. as as testedorganocatalysts organocatalysts as organocatalysts Catalyst inin this this 116 transformation, transformation, proved in this to transformation, be slight giving givingly similarsuperior similar giving results: to the results: similar lowresults: diastereoselectivitylowothers lowdiastereoselectivity in the diastereoselectivity asymmetric and and cascadehigh high enantioselectivity. and enantioselectivity.aza-Michael/Michael high enantioselectivity. Catalyst addition 116 116 usingproved Catalystproved nitroalkenes to tobe116 beslight slightproved ly(Scheme superiorly superior to 48). be to The the slightly to the others in the asymmetric cascade aza-Michael/Michael addition using nitroalkenes (Scheme 48). The otherssuperiorobtained in tothe the asymmetricdiastereoisomers others in thecascade asymmetric 157 aza-Michael/Michael were cascadeinseparable, aza-Michael/Michael additionwhich represents using nitroalkenes additiona drawback using (Scheme for nitroalkenes this48). The obtained diastereoisomers 157 were inseparable, which represents a drawback for this (Schemetransformation. 48). The obtained diastereoisomers 157 were inseparable, which represents a drawback for obtainedtransformation. diastereoisomers 157 were inseparable, which represents a drawback for this transformation.this transformation.

Scheme 48. Asymmetric cascade aza-Michael/Michael addition for the synthesis of piperidines by SchemeSchemeusing 48. anAsymmetric 48.alkaloid-thiourea Asymmetric cascade cascade derivative. aza-Michael/Michael aza-Michael/ Michael addition addition for for the the synthesis synthesis of piperidines of piperidines by by usingusing an alkaloid-thiourea an alkaloid-thiourea derivative. derivative. Scheme 48. Asymmetric cascade aza-Michael/Michael addition for the synthesis of piperidines by

4. Oxygenusing an Nucleophiles alkaloid-thiourea derivative. The asymmetric conjugated addition of oxa-nucleophiles has been described by means of alkaloid based thiourea organocatalysts, being a very straightforward approach in the formation Molecules 2017, 22, 895 39 of 51

4. OxygenMolecules Nucleophiles2017, 22, 895 39 of 51 MoleculesThe2017 asymmetric, 22, 895 conjugated addition of oxa-nucleophiles has been described by means39 of of 51 4. Oxygen Nucleophiles alkaloid based thiourea organocatalysts, being a very straightforward approach in the formation of The asymmetric conjugated addition of oxa-nucleophiles has been described by means of carbon-oxygenof carbon-oxygen bonds bonds [171]. [171 Oximes]. Oximes have have proved proved to be tosuitable be suitable oxygen-centered oxygen-centered nucleophiles nucleophiles in the Michaelalkaloid addition based thiourea to nitroalkenes organocatalysts, bearing being aa verytrifluoromethyl straightforward substituent approach in[176]. the formation Among of the in thecarbon-oxygen Michael addition bonds [171]. to nitroalkenesOximes have proved bearing to be a triﬂuoromethylsuitable oxygen-centered substituent nucleophiles [176]. in Among the organocatalysts tested, 74 gave the best yields and stereoselectivities in the addition of 4- theMichael organocatalysts addition tested,to nitroalkenes74 gave bearing the best a yieldstrifluoromethyl and stereoselectivities substituent [176]. in theAmong addition the of methoxybenzaldehyde oxime to a variety of β,β-disubstituted nitroalkenes, affording adducts 158 4-methoxybenzaldehydeorganocatalysts tested, oxime74 gave to athe variety best yields of β,β and-disubstituted stereoselectivities nitroalkenes, in the affordingaddition of adducts 4- 158(Scheme(Schememethoxybenzaldehyde 49). 49 Analogous). Analogous catalysts oxime catalysts to bea varietyaring bearing urea of urea β ,orβ-disubstituted orsquaramide squaramide nitroalkmoieties moietiesenes, instead instead affording of of the the adducts thiourea thiourea 158 unit resulted(Scheme less 49). productive Analogous in termscatalysts ofof be conversionconversionaring urea and andor squaramide selectivity.selectivity. moieties instead of the thiourea unit resulted less productive in terms of conversion and selectivity. R F3C OH R NO2 N R 74 (10 mol%) F3CO OH+ NO NO2 N R 2 Mesitylene,74 (10 mol%) 0 ºC ON PMP F+3C NO2 N PMP F3C Mesitylene,72-96 h 0 ºC PMP R = aryl, alkyl 72-96 h PMP 158 R = aryl, alkyl 13158 examples 1352-87% examples yield 52-87%46-90% yieldee 46-90% ee Scheme 49. Asymmetric oxa-Michael addition of 4-methoxybenzaldehyde4-methoxybenzaldehyde oxime to nitroalkenes by Scheme 49. Asymmetric oxa-Michael addition of 4-methoxybenzaldehyde oxime to nitroalkenes by using an alkaloid-thiourea derivative. using an alkaloid-thiourea derivative.

TheThe same same Cinchona Cinchona-derived-derived thiourea thiourea organocatalyst organocatalyst 7474 has has been been employed employed in inthe the preparation preparation of of chromanschromans by by meansmeans means ofof of anan an oxa-Michael/Michaeloxa-Michael/Michael oxa-Michael/Michael cascade reactionreaction [177]. [[177].177 ].Thus, Thus, Thus, aryl aryl aryl 2-(2-hydroxy- 2-(2-hydroxy- 2-(2-hydroxy- phenyl)vinylphenyl)vinyl ketones ketones ketones reacted reacted reacted with withwith nitroalkenes nitroalkenes in in an an apolarapolar apolar solvent, solvent, solvent, such such suchas astoluene, toluene, as toluene, favoring favoring favoring the the activationthe activation of ofthe of the thesubstrates substrates by by byhydrogen-bonding. hydrogen-bonding. hydrogen-bonding. TheThe The adductsadducts adducts 159 159159 were werewere obtained obtained obtained with with with high high selectivitiesselectivities independently independently of of the the substituents substituents inin thethe nitrostyrenes,nitrostyrenes, although althoughalthough electron-withdrawing electron-withdrawingelectron-withdrawing groupsgroups enhanced enhanced the the reactivity, reactivity, yielding yielding the the expected expected productsproducts in in shorter shorter shorter reaction reaction reaction times times times (Scheme (Scheme (Scheme 50). 50).50). On the contrary, the substituents on the ketone did not show any effect in the outcome of the reaction. On the the contrary, contrary, the the substituents substituents on onthe theketone ketone did not did show not showany effect any in effect the outcome in the outcome of the reaction. of the This asymmetric synthesis of chromans has also been performed using β-CF3-nitroalkenes as Thisreaction. asymmetric This asymmetric synthesis synthesis of chroma of chromansns has also has alsobeen been performed performed using using ββ-CF-CF3-nitroalkenes-nitroalkenes as electrophiles, using a Cinchona-derived squaramide as organocatalyst [178]. 3 electrophiles, using a Cinchona-derived squaramide asas organocatalystorganocatalyst [[178].178].

SchemeScheme 50. 50.Asymmetric Asymmetric cascade cascade oxa-Michael/Michaeloxa-Michael/Michael addition addition by by using using an analkaloid-thiourea alkaloid-thiourea derivativederivative as organocatalyst.as organocatalyst. Scheme 50. Asymmetric cascade oxa-Michael/Michael addition by using an alkaloid-thiourea 5. Sulfur5.derivative Sulfur Nucleophiles Nucleophiles as organocatalyst.

5. SulfurTheThe asymmetricNucleophiles asymmetric sulfa-Michael sulfa-Michael addition addition toto activated olefins oleﬁns allows allows the the preparation preparation of S-centered of S-centered opticallyoptically active active compounds, compounds, thioacetic thioacetic acidacid beingbeing commonly employed employed as assulfur sulfur nucleophile nucleophile [171]. [171 ]. Thus,Thus,The thioacetic asymmetric thioacetic acid acid sulfa-Michael has has beenbeen added added addition to to nitroalkenes nitroalkenesto activated using olefins using the amine-thioureaallows the amine-thiourea the preparation organocatalyst organocatalyst of S-centered 160, 160optically,yielding yielding active the the compounds,corresponding corresponding thioacetic adducts adducts 161acid 161with beinwith moderateg commonly moderate enantioselecti enantioselectivitiesemployedvities as su(Schemelfur (Schemenucleophile 51) [179]. 51 )[ In[171].179 ]. addition, the alkaloid-thiourea 74 has also shown to be active and selective in the addition of thioacids Thus,In addition, thioacetic the acid alkaloid-thiourea has been added74 hasto nitroalkenes also shown using to be the active amine-thiourea and selective organocatalyst in the addition 160 of, to trisubstituted nitroalkenes [180]. Thus, oxetane and azetidine nitroalkenes reacted with thioacetic and yieldingthioacids the to trisubstitutedcorresponding nitroalkenesadducts 161 [180with]. moderate Thus, oxetane enantioselecti and azetidinevities (Scheme nitroalkenes 51) [179]. reacted In thiobenzoic acids at low temperature (−78 °C), giving the corresponding 1,2-nitrothioesters 162–164 with withaddition, thioacetic the alkaloid-thiourea and thiobenzoic 74 has acids also at shown low temperatureto be active and (− selective78 ◦C), givingin the addition the corresponding of thioacids to trisubstituted nitroalkenes [180]. Thus, oxetane and azetidine nitroalkenes reacted with thioacetic and 1,2-nitrothioesters 162–164 with high yield and enantioselectivities (Figure 21). The nitroalkene bearing thiobenzoica 4-membered acids ring at low gave temperature rise to the ( higher−78 °C), reactivity, giving the whereascorresponding the reaction 1,2-nitrothioesters with substrates 162–164 bearing with − ◦ 6-membered ring or acyclic moieties needed a higher temperature ( 25 C) to give the corresponding addition products. Molecules 2017, 22, 895 40 of 51 high yield and enantioselectivities (Figure 21). The nitroalkene bearing a 4-membered ring gave rise to the higher reactivity, whereas the reaction with substrates bearing 6-membered ring or acyclic Molecules 2017, 22, 895 40 of 51 moieties needed a higher temperature (−25 °C) to give the corresponding addition products.

Scheme 51. Asymmetric sulfa-Michael addition of thioacetic acid to nitroalkenes by using a tertiary amine-thiourea derivative as organocatalyst.

Figure 21.21.Enantioenriched Enantioenriched 1,2-nitrothioesters 1,2-nitrothioesters via addition via ofaddition thioacids of to nitroalkenesthioacids to organocatalyzed nitroalkenes organocatalyzedby 74. by 74.

Different aryl and alkyl thiols have been added to 1,2-disubstituted nitroalkenes using the DDifferentifferent aryl and alkyl thiols have been added to 1,2-disubstituted1,2-disubstituted nitroalkenes using the modified Cinchona alkaloid 165 in a nonpolar solvent. Sulfa-Michael adducts 166 were obtained in modifiedmodiﬁed Cinchona alkaloidalkaloid 165165 inin a a nonpolar nonpolar solvent. solvent. Sulfa-Michael Sulfa-Michael adducts adducts 166166 werewere obtained obtained in excellent yields with good diastereoselectivities and high enantioselectivities, independently of the excellentin excellent yields yields with with good good diastereoselectivities diastereoselectivities and and high high enantioselectivities, enantioselectivities, independently independently of of the substitution pattern on the nitro compound or the S-nucleophile (Scheme 52) [181]. substitution pattern on the nitro compound or the S-nucleophile (Scheme(Scheme 5252))[ [181].181].

Scheme 52. Asymmetric sulfa-Michael addition of thiols to nitroalkenes by using an alkaloid derivative. Scheme 52. Asymmetric sulfa-Michael addition of thiols to nitroalkenes by using an alkaloid derivative. The enantioselective synthesis of chroman and thiochroman derivatives has been achieved by an asymmetric cascade sulfa-Michael/Michael addition starting from different thiophenol derivatives,

squaramide-based organocatalysts being employed in both transformations. Thus, the synthesis Molecules 2017, 22, 895 41 of 51

The enantioselective synthesis of chroman and thiochroman derivatives has been achieved by MoleculesThe2017 enantioselective, 22, 895 synthesis of chroman and thiochroman derivatives has been achieved41 of by 51 an asymmetric cascade sulfa-Michael/Michael addition starting from different thiophenol derivatives, squaramide-based organocatalysts being employed in both transformations. Thus, the synthesisof chromans of chromans167 has been 167 has achieved been achieved using organocatalyst using organocatalyst143 (Scheme 143 (Scheme53), although 53), although other tertiary other tertiaryamine-squaramide amine-squaramide catalysts catalysts also showed also showed good activity good [activity182]. [182].

Scheme 53.53. Asymmetric cascade sulfa-Michael/Michael addition addition leading leading to to chromans chromans by by using a cyclohexanediamine-squaramide organocatalyst.

Among the squaramide-based organocatalysts, the alkaloid-squaramide catalyst 135 has Among thethe squaramide-based squaramide-based organocatalysts, organocatalysts, the alkaloid-squaramidethe alkaloid-squaramide catalyst catalyst135 has provided135 has provided the best results in the preparation of thiochromans 168 (Scheme 54a) [183]. Following the providedthe best results the best in results the preparation in the preparation of thiochromans of thiochromans168 (Scheme 168 (Scheme 54a) [183 54a)]. Following[183]. Following the same the same idea and type of catalyst, the sulfa-Michael addition to a nitroalkene can be followed by a Henry sameidea andidea typeand type of catalyst, of catalyst, the the sulfa-Michael sulfa-Michael addition addition to to a nitroalkenea nitroalkene can can be be followed followed byby a Henry reaction, allowing the preparation of thiopyran motifs in an enantioselective manner as described in reaction, allowing allowing the the preparation preparation of of thiopyran thiopyran moti motifsfs in in an an enantioselective enantioselective manner manner as asdescribed described in the synthesis of dihydrothiopyrano[2,3-b]quinolines 169 (Scheme 54b) [184]. For the latter case, the thein the synthesis synthesis of dihydrothiopyrano[2,3- of dihydrothiopyrano[2,3-b]quinolinesb]quinolines 169 169(Scheme(Scheme 54b) 54 [184].b) [184 For]. Forthe latter the latter case, case, the use of another alkaloid-based organocatalysts has allowed to reverse the diastereoselectivity of the usethe useof another of another alkaloid-based alkaloid-based orga organocatalystsnocatalysts has hasallowed allowed to reverse to reverse the thediastereoselectivity diastereoselectivity of the of transformation. transformation.the transformation.

Scheme 54. Asymmetric cascade sulfa-Michael/Michael addition leading to thiochromans by using Scheme 54. Asymmetric cascadecascade sulfa-Michael/Michael sulfa-Michael/Michael addition addition leading leading to to thiochromans thiochromans by by using using an an alkaloid-thiourea derivative as organocatalyst. analkaloid-thiourea alkaloid-thiourea derivative derivative as organocatalyst.as organocatalyst.

6. Phosphorous Nucleophiles 6. Phosphorous Nucleophiles The phospha-Michael addition to nitroalkenes has been recently described using The phospha-Michael addition to nitroalk nitroalkenesenes has been recently described using diphenylphosphite as P-centered nucleophile [185]. Thus, a tertiary amine-squaramide and a tertiary diphenylphosphite as as P-centered P-centered nucleophile nucleophile [185]. [185 Thus,]. Thus, a tertiary a tertiary amine-squaramide amine-squaramide and a tertiary and a amine-thiourea have been assayed as bifunctional organocatalysts in this asymmetric reaction in a amine-thioureatertiary amine-thiourea have been have assayed been assayed as bifunctional as bifunctional organocatalysts organocatalysts in this in asymmetric this asymmetric reaction reaction in a supercritical carbon dioxide medium. The squaramide unit exhibited better activity and selectivity in supercriticalin a supercritical carbon carbon dioxide dioxide medium medium.. The The squaramide squaramide unit unit exhibited exhibited better better activity activity and and selectivity selectivity in this transformation, the best catalytic performance being obtained when using squaramide 43 as thisin this transformation, transformation, the the best best catalytic catalytic perfor performancemance being being obtained obtained when when using using squaramide squaramide 4343 as

Molecules 2017, 22, 895 42 of 51

Molecules 2017, 22, 895 42 of 51 organocatalyst. Following this procedure, nitrophosphonates 170 have been obtained in high yields organocatalyst.and enantioselectivities Following (Scheme this procedure, 55). nitrophosphonates 170 have been obtained in high yields and enantioselectivities (Scheme 55).

Scheme 55. Asymmetric phospha-Michael addition of diphenylphosphite to nitroalkenes by using a tertiary amine-squaramide derivativederivative as organocatalyst.

5.7. Conclusions Asymmetric organocatalysisorganocatalysis is is a verya very powerful powerful synthetic synthetic tool that, tool when that, applied when toapplied the conjugate to the conjugateaddition ofaddition nucleophiles of nucleophiles to nitroalkenes to nitroalkenes can prepare can prepare valuable valuable final products final products in high in high yields yields and andstereoselectivities, stereoselectivities, usually usually employing employing a simple a simple methodology. methodology. Those Those final final adductsadducts bearbear aa nitro functionality, whichwhich is amenableis amenable of further of further synthetic synthetic transformations transformations towards interesting towards compounds.interesting Thiscompounds. revision This has shownrevision how has active shown is nowadays how active this is field. nowadays A huge arraythis field. of organocatalysts A huge array have of organocatalystsbeen developed have recently been todeveloped perform recently this conjugate to perform addition this conjugate reaction addition employing reaction many employing different manynucleophiles different and nucleophiles achieving impressive and achieving results impre in manyssive cases.results However, in many manycases.challenges However, persistmany challengesand still improvements persist and still are improvements necessary. Thus, are nece usuallyssary.the Thus, higher usually enantioinductions the higher enantioinductions are achieved whenare achieved using β -arylatedwhen using nitroolefins β-arylated as electrophiles, nitroolefins their as electrophiles, alkylated counterparts their alkylated frequently counterparts being less frequentlyeffective. Inbeing addition, less effective. polysubstituted In addition, nitroalkenes polysubstituted have been nitroalkenes less explored. have Moreover,been less explored. although Moreover,numerous organocatalystsalthough numerous have orga beennocatalysts developed, have many been times developed, they are many only employedtimes they inare model only employedreactions. Additionalin model reactions. research concerningAdditional theresearch development concerning of organocatalysts the development able of toorganocatalysts promote high ablestereoselectivities to promote high using stereoselectivities different nucleophiles using different and nitroolefins, nucleophiles low loadingsand nitroolefins, and environmentally low loadings andfriendly environmentally conditions is necessary.friendly conditions Recoverable is necess and reusableary. Recoverable catalytic systems and reusable would addcatalytic an additional systems valuewould toadd the an methodology, additional value increasing to the the methodology, possibility of increasing industrial applications.the possibility Withof industrial all these applications.considerations, With no doubtall these that considerations, asymmetric organocatalytic no doubt that conjugateasymmetric addition organocatalytic to nitroolefins conjugate will additioncontinue to nitroolefins be a fast-forwarding will continue topic to in be the a nextfast-forwarding future. topic in the next future.

Acknowledgments: We thank thank the the financial financial support support from the from Spanish the SpanishMinisterio Ministerio de Economía, de Industria Economí a,y CompetitividadIndustria y Competitividad (CTQ2015-66624-P) (CTQ2015-66624-P) and the University and the of UniversityAlicante (UAUSTI16-03, of Alicante (UAUSTI16-03, AUSTI16-10, VIGROB-173, AUSTI16-10, VIGROB-173, VIGROB-285). VIGROB-285). Conflicts of Interest: The authors declare no conflict of interest. Conflicts of Interest: The authors declare no conflict of interest. References References 1. Dalko, P.I. Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Applications; Wiley-VCH: 1. Dalko, P.I. Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Applications; Wiley-VCH: Weinheim, Germany, 2013. Weinheim, Germany, 2013. 2. Alemán, J.; Cabrera, S. Applications of asymmetric organocatalysis in medicinal chemistry. Chem. Soc. Rev. 2. Alemán, J.; Cabrera, S. Applications of asymmetric organocatalysis in medicinal chemistry. Chem. Soc. Rev. 2013, 42, 774–793. [CrossRef][PubMed] 2013, 42, 774–793. 3. Atodiresei, I.; Vila, C.; Rueping, M. Asymmetric organocatalysis in continuous flow: Opportunities for 3. Atodiresei, I.; Vila, C.; Rueping, M. Asymmetric organocatalysis in continuous flow: Opportunities for impacting industrial catalysis. ACS Catal. 2015, 5, 1972–1985. [CrossRef] impacting industrial catalysis. ACS Catal. 2015, 5, 1972–1985. 4. Krause, N.; Hoffmann-Roder, A. Recent advances in catalytic enantioselective Michael additions. Synthesis 4. Krause, N.; Hoffmann-Roder, A. Recent advances in catalytic enantioselective Michael additions. Synthesis 2001, 2001, 0171–0196. [CrossRef] 2001, volume, 171–196. 5. Jha, S.C.; Joshi, N.N. Catalytic, enantioselective Michael addition reactions. ARKIVOC 2002, viii, 167–196. 5. Jha, S.C.; Joshi, N.N. Catalytic, enantioselective Michael addition reactions. ARKIVOC 2002, viii, 167–196. [CrossRef] 6. Christoffers, J.; Baro, A. Construction of quaternary stereocenters: New perspectives through 6. Christoffers, J.; Baro, A. Construction of quaternary stereocenters: New perspectives through enantioselective enantioselective Michael reactions. Angew. Chem. Int. Ed. 2003, 42, 1688–1690. Michael reactions. Angew. Chem. Int. Ed. 2003, 42, 1688–1690. [CrossRef][PubMed] 7. Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Conjugate additions of nitroalkanes to electron- 7. Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Conjugate additions of nitroalkanes to electron-poor poor alkenes: Recent results. Chem. Rev. 2005, 105, 933–971. alkenes: Recent results. Chem. Rev. 2005, 105, 933–971. [CrossRef][PubMed] 8. Almasi, D.; Alonso, D.A.; Najera, C. Organocatalytic asymmetric conjugate additions. Tetrahedron: Asymmetry 2007, 18, 299–365.

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