molecules 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. Molecules 2017, 22, 895; doi:10.3390/molecules22060895 www.mdpi.com/journal/molecules Molecules 2017, 22, 895 2 of 51 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