A Focus on Vinyl Selenones

molecules

Review ReviewModern Synthetic Strategies with Organoselenium Reagents: Modern Synthetic Strategies with Organoselenium Reagents: AA FocusFocus onon VinylVinyl SelenonesSelenones

Martina Palomba, Italo Franco Coelho Dias, Ornelio Rosati and Francesca Marini * Martina Palomba, Italo Franco Coelho Dias, Ornelio Rosati and Francesca Marini *

Department of Pharmaceutical Sciences (Group of Catalysis, Synthesis and Organic Green Chemistry), UniversityGroup of Catalysis, of Perugia, Synthesis Via del andLiceo, Organic 06123 GreenPerugia, Chemistry, Italy; [email protected] Department of Pharmaceutical (M.P.); Sciences, italo.francocoelhodias@studeUniversity of Perugia, Via delnti.unipg.it Liceo, 06123 (I.F.C.D.); Perugia, [email protected] Italy; [email protected] (O.R.) (M.P.); *[email protected] Correspondence: [email protected] (I.F.C.D.); [email protected] (O.R.) * Correspondence: [email protected]

Abstract: In recent years, vinyl selenones were rediscovered as useful building blocks for new syn- Abstract: In recent years, vinyl selenones were rediscovered as useful building blocks for new thetic transformations. This review will highlight these advances in the field of multiple-bond-form- synthetic transformations. This review will highlight these advances in the ﬁeld of multiple-bonding reactions, one-pot synthesis of carbo- and heterocycles, enantioselective construction of densely forming reactions, one-pot synthesis of carbo- and heterocycles, enantioselective construction of functionalized molecules, and total synthesis of natural products. densely functionalized molecules, and total synthesis of natural products. Keywords: selenium; domino reactions; heterocycles; natural products; spiro compounds; annula- Keywords: selenium; domino reactions; heterocycles; natural products; spiro compounds; annula- tions; enantioselective synthesis; organocatalysis tions; enantioselective synthesis; organocatalysis

Citation: Palomba, M.; Dias, I.F.C.; Rosati, O.; Marini, F. Modern Syn- thetic Strategies with Orga- noselenium Reagents: A Focus on 1. Introduction 1. Introduction Vinyl Selenones. Molecules 2021, 26, Selenium chemistry has rapidly grown over the past years and nowadays selenium Selenium chemistry has rapidly grown over the past years and nowadays sele- x. https://doi.org/10.3390/xxxxx reagents are recognized tools in the chemo-, regio-, and stereoselective synthesis of mol- Citation: Palomba, M.; Franco nium reagents are recognized tools in the chemo-, regio-, and stereoselective synthesis of ecules containing selenium or not [1–3]. In fact, selenium functionalities can be easily re- Coelho Dias, I.; Rosati, O.; Marini, F. molecules containing selenium or not [1–3]. In fact, selenium functionalities can be easily Academic Editors: Luana Bagnoli duced, eliminated or transformed into other functional groups with high stereocontrol. In Modern Synthetic Strategies with reduced, eliminated or transformed into other functional groups with high stereocontrol. and Vladimir A. Potapov Organoselenium Reagents: A Focus Inthis this field, field, over over the the past past decade, decade, the the chemistry chemistry of of vinyl vinyl selenones selenones has has been been the the object of on Vinyl Selenones. Molecules 2021, renewed interest, leading to the development of diverse and powerful methods with ap- Received: 30 April 2021 renewed interest, leading to the development of diverse and powerful methods with appli- 26, 3148. https://doi.org/10.3390/ plications in challenging fields of organic synthesis, such as the enantioselective synthesis Accepted: 21 May 2021 cations in challenging fields of organic synthesis, such as the enantioselective synthesis and molecules26113148 and the total synthesis of natural products. The chemistry of these hexavalent, tetra-coor- Published: 25 May 2021 the total synthesis of natural products. The chemistry of these hexavalent, tetra-coordinated seleniumdinated selenium compounds compounds shows interestingshows interesting analogies analogies with that with of that the correspondingof the corresponding vinyl Academic Editors: Luana Bagnoli vinyl sulfones. Both contain an electron-withdrawing group that stabilizes vicinal carban- Publisher’s Note: MDPI stays neu- sulfones. Both contain an electron-withdrawing group that stabilizes vicinal carbanions and Vladimir A. Potapov tral with regard to jurisdictional andions activatesand activates the double the double bond bond to conjugate to conjugate nucleophilic nucleophilic attack, attack, but the but weak the weak C-Se bondC-Se claims in published maps and insti- donatesbond donates to the to phenylselenonyl the phenylselenonyl moiety, moiety, a better a better leaving leaving group group character character for further for further sub- Received: 30 April 2021 tutional affiliations. stitutionsubstitution or elimination or elimination reactions. reactions. In thisIn this review, review, recent recent applications applications of vinylof vinyl selenones selenones in Accepted: 21 May 2021 in domino or sequential one-pot processes for the assembly of carbo- and heterocycles, Published: 25 May 2021 domino or sequential one-pot processes for the assembly of carbo- and heterocycles, the functionalizationthe functionalization of biomolecules, of biomolecules, and and the th organocatalyzede organocatalyzed enantioselective enantioselective construction construc- oftion all-carbon of all-carbon quaternary quaternary stereocenters stereocenters will bewill presented be presented and discussed and discussed (Figure (Figure1). Main 1). Publisher’s Note: MDPI stays neutral Copyright: © 2020 by the authors. Main advantages of such multiple-bond forming strategies are the mild and operationally with regard to jurisdictional claims in advantages of such multiple-bond forming strategies are the mild and operationally simple Submitted for possible open access simple reaction conditions, the good to excellent yields, and the high chemo-, regio-, and published maps and institutional affil- reaction conditions, the good to excellent yields, and the high chemo-, regio-, and stereo- publication under the terms and iations. selectivities.stereo-selectivities. Examples Examples of use ofof vinyluse of selenones vinyl selenones in the total in the synthesis total synthesis of natural of products natural conditions of the Creative Commons willproducts also bewill shown. also be shown. Attribution (CC BY) license (http://creativecommons.org/licenses /by/4.0/). SeO 2Ph Carbo- and heterocycles synthesis Functionalization Copyright: © 2021 by the authors. R1 R2 via Michael initiated ring closure reactions of carbohydrates and nucleotides Licensee MDPI, Basel, Switzerland.

This article is an open access article Asymmetric Total syn thesis of distributed under the terms and organocatalysis natural products conditions of the Creative Commons Attribution (CC BY) license (https:// Figure 1. Vinyl selenones as versatile reagentsreagents in organic synthesis. creativecommons.org/licenses/by/ 4.0/).

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2. Synthesis of Vinyl Selenones and Their Biological Activities Selenones are usually prepared by oxidation of the corresponding selenides [4,5]. The ﬁrst oxidation of selenides to selenoxides is fast, but the decreased electron density on the selenium atom makes selenoxides less prone to the second oxygen transfer. Even if, several strong oxidants convert selenides into selenones, i.e., KMnO4 [6], peroxyacids or their salts [6,7], H2O2 in the presence of benzenseleninic acid [8], HMPA peroxo complex ® of molybdenum [9], Oxone [10], and HOF·CH3CN complex [11], 3-chloroperoxybenzoic acid (m-CPBA) [12] is the reagent of choice for the oxidation of vinyl selenides (Scheme1, route a). It is used in excess in alcoholic, ethereal or halogenated solvents. Recently, the greener Oxone® was used to generate vinyl selenones [13] in water without addition of any catalyst or co-solvent.

Scheme 1 . Synthetic approaches toScheme vinyl selenones. 1. Synthetic approaches to vinyl selenones.

In recent years, selenium-containing compounds have showed interesting biological activities and a great potential in medicinal chemistry, particularly in cancer therapy [14]. Bioactive vinyl selenones were recently prepared through the multistep sequence described in Scheme1, route b. In this protocol the Wittig–Horner reaction between phenylse- leninylmethyl phosphonates and variously substituted aromatic aldehydes generated vinyl selenoxides which were transformed into the corresponding selenone by oxidation with m-CPBA [15]. These compounds were evaluated for their in vitro and in vivo anticancer activities. They showed tubulin polymerization inhibition and antiproliferative activity against several cancer cell lines. The structure of the most active compound is reported in Figure2 together with other diaryl or aryl alkylselenones with antiproliferative [ 16] or pesticide activities. [17,18].

Scheme 2 . Cyclopropanations of active methylene compounds with vinyl selenones.

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Figure 2. Biologically active selenones.

3. Michael-Initiated Ring Closures Michael initiated ring closure reactions ofof vinyl selenones demonstrated toto bebe highly efficientefficient inin thethe regio-regio- andand stereoselectivestereoselective synthesissynthesis ofof smallsmall cycles.cycles. CyclopropanesCyclopropanes havehave attracted great attention by the scientificscientific community.community. TheseThese smallsmall ringsrings are presentpresent asas keykey structural motifmotif inin severalseveral naturalnatural products products and and drugs drugs and and are are used used as as synthetic synthetic intermedi- interme- ates due to the easy ring opening. Since the seminal independent works by Kuwajima and diates due to the easy ring opening. Since the seminal independent works by Kuwajima Tiecco [19–21], vinyl selenones and several active methylene pronucleophiles, such as di- and Tiecco [19–21], vinyl selenones and several active methylene pronucleophiles, such alkyl malonates, β-ketoesters, and β-ketoamides, have been employed for the construction as dialkyl malonates, β-ketoesters, and β-ketoamides, have been employed for the con- of these small rings. Nitromethane was also a competent pronucleophile. The reactions struction of these small rings. Nitromethane was also a competent pronucleophile. The proceed in the presence of strong bases through a deprotonation/Michael addition, fol- Scheme 1 . Syntheticreactions approaches proceed to vinyl in selenones. the presence of strong bases through a deprotonation/Michael addi- lowed by a proton transfer and a ring closure reaction by nucleophilic displacement of the tion, followed by a proton transfer and a ring closure reaction by nucleophilic displace- selenium moiety. Thus, the electron-withdrawing benzenselenonyl group, first activates ment of the selenium moiety. Thus, the electron-withdrawing benzenselenonyl group, the alkene to the Michael addition and then promotes the cyclization acting as an excellent first activates the alkene to the Michael addition and then promotes the cyclization acting leaving group (Scheme2). Benzeneseleninic acid is generated as the by-product. as an excellent leaving group (Scheme 2). Benzeneseleninic acid is generated as the by- product.

Scheme 2. Cyclopropanations of active methylene compounds with vinyl selenones. Scheme 2 . Cyclopropanations of active methylene compounds with vinyl selenones. Scheme 2. Cyclopropanations of active methylene compounds with vinyl selenones.

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InIn 2009, 2009, this this strategy strategy was was applied applied to to the the as asymmetricymmetric synthesis synthesis of of cyclopropanes cyclopropanes start- start- inging from malonatesmalonates containingcontaining ((-)-bornyl−)-bornyl or or (-)-mentyl (−)-mentyl groups groups as as chiral chiral auxiliaries auxiliaries [22]. [22]. These reactions reactions occurred occurred with with low low diasteroselect diasteroselectivity,ivity, but but the themixtures mixtures of the of two the diaster- two di- eoisomersastereoisomers were were easily easily separated separated by bychromato chromatography,graphy, giving giving access access to to enantiomerically enantiomerically pure compounds. Some Some products products were were successfully successfully converted converted into into α-cyclopropane--cyclopropane-αα-- aminoamino acids acids (ACCs) (ACCs) in in two two steps. steps. Enantiopure Enantiopure ACCs ACCs find ﬁndinteresting interesting applications applications in phar- in macologypharmacology and bioorganic and bioorganic chemistry. chemistry. In fact, In fact,they theyare conformationally are conformationally constrained constrained ana- loguesanalogues of proteinogenic of proteinogenic aminoacids aminoacids and andplay playan important an important role in role the in synthesis the synthesis of pep- of tidomimeticspeptidomimetics and andfoldamers. foldamers. Very Very recently, recently, alkyl alkyl phenyl phenyl selenones selenones were were involved involved in an in interestingan interesting cyclopropanation cyclopropanation reaction reaction by by dearomatization dearomatization of of 1-nitronaphthalenes 1-nitronaphthalenes [23]. [23]. ContraryContrary to to the the previously previously mentioned mentioned processes, processes, this this domino domino reaction, reaction, employs employs alkyl alkyl selenonesselenones as asMichael Michael donors donors in in a aCorey–Chaykovsky Corey–Chaykovsky type type cyclopropanation cyclopropanation (Scheme (Scheme 33).). The experiments experiments demonstrated demonstrated that that sterically sterically demanding demanding substituents substituents at the at theselenium selenium nu- cleophilenucleophile favor favor the the formation formation of ofcyclopropa cyclopropanesnes and and suppress suppress the the competitive competitive formation ofof the alkylated products by a Michael/elimination sequence. sequence. The The reaction reaction has has been been suc- suc- cessfullycessfully extendedextended to 2-nitronaphtalenes,to 2-nitronaphtalenes 6-nitroquinoline,, 6-nitroquinoline, and isomeric and 5-nitroindazolines. isomeric 5-nitroindazolines.Mixtures of endo Mixturesand exo isomersof endo and were exo usually isomers isolated. were usually isolated.

Scheme 3. AlkylAlkyl selenone-mediated selenone-mediated cyclopropanations by dear dearomatizationomatization of nitronapht nitronaphthaleneshalenes and derivatives.derivatives.

InIn the the past past decade, decade, the the development development of new of new methods methods for the for synthesis the synthesis of spirocycles of spiro- becamecycles became a hot topic a hot in topic organic in organic synthesis. synthesis. The conformational The conformational rigidity, rigidity, the three-dimen- the three- sionaldimensional nature naturewith substituents with substituents in well-defined in well-defined spatial disposition, spatial disposition, the improved the improved physico- chemicalphysicochemical and pharmacokinetic and pharmacokinetic properties properties and the and relative the relative structural structural novelty novelty make spiro- make cyclesspirocycles attractive attractive leads leadsin drug in drugdiscovery discovery programs programs [24,25]. [24 In,25 fact,]. In compared fact, compared to flat to aro- flat maticaromatic compounds, compounds, they they seem seem to have to have more more chances chances to maximize to maximize specific specific interactions interactions with biomolecules.with biomolecules. A number A number of new of newprotocols protocols have have been been described described as a as mean a mean for forgenerating generat- structuraling structural diversity diversity and/or and/or impart impart efficiency efficiency and andstereoselectivity stereoselectivity to the to cyclization. the cyclization. In this In field,this field, Marini Marini and andco-workers co-workers used used 2-oxindoles 2-oxindoles as pro-nucleophiles as pro-nucleophiles for fora facile a facile assembly assembly of spirocyclopropyloxindolesof spirocyclopropyloxindoles [26]. [26 The]. The synthesis synthesis of spirocyclopropyl of spirocyclopropyl oxindoles oxindoles has hasbeen been de- velopeddeveloped in aqueous in aqueous basic basic conditions conditions in the in presence the presence of catalytic of catalytic cetyltrimethylammonium cetyltrimethylammo- bromidenium bromide (CTAB). (CTAB). As reported As reported in Scheme in Scheme 4, variously4, variously substituted substituted spirocyclopropyl spirocyclopropyl oxin- dolesoxindoles with withthree threepoint pointof diversity of diversity were isolated were isolated in good in to goodexcellent to excellent yields. High yields. diastere- High oselectivitiesdiastereoselectivities were observed were observed starting from starting the fromβ-aryl the substitutedβ-aryl substituted vinyl selenones, vinyl selenones, probably π π dueprobably to the due stabilizing to the stabilizing π-π interactions- interactions between the between oxindole the ring oxindole and the ring neighboring and the neigh- ar- omaticboring aromaticring in the ring transition in the transition state. Some state. selected Some selected spiro-compounds spiro-compounds demonstrated demonstrated anti- HIV-1anti-HIV-1 activity. activity.

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Scheme 4. Spirocyclopropyl oxindoles via a Michael addition/cyclization cascade. Scheme 4. Spirocyclopropyl oxindoles via a Michael addition/cyclization cascade. cascade. Aqueous basic conditions were also successfully employed for the construction of a challengingAqueousAqueous spiro basic basic 2,2-substituted conditions conditions were were oxetane also also successf motif successfully inully moderate employed employed to good for for the yields the construction construction [27]. The ofMi- ofa challengingchaela challenging addition/intramolecular spiro spiro 2,2-substituted 2,2-substituted etherification oxetane oxetane motif cascade motif in moderate in was moderate performed to good to good withyields yields N-protected [27]. [ 27The]. TheMi- or chaelunprotectedMichael addition/intramolecular addition/intramolecular 3-hydroxy isatins etherificationand etheriﬁcation the phenyl cascade vinyl cascade selenonewas was performed performed without with addition with N-protected N-protected of surfac- or unprotectedtantsor unprotected (Scheme 3-hydroxy 5). 3-hydroxy This reaction isatins isatins andis anda valid the the phenyl alternative phenyl vinyl vinyl to selenone photochemical selenone without without [2+2] addition addition cycloadditions of of surfac- surfac- tants(Paternò–Buchitants (Scheme (Scheme 55).). reactions) ThisThis reactionreaction or ismultistepis aa validvalid alternativealternative protocols totoinvolving photochemicalphotochemical intramolecular [2+2][2+2] cycloadditionscycloadditions Williamson (Paternò–Buchietherifications(Paternò–Buchi inreactions) reactions) the preparation or or multistep of spiroox protocols indole involving oxetane. intramolecular Limitations ofWilliamson these ap- etherificationsproachesetheriﬁcations are the inin thenarrowthe preparation preparation substrate of spirooxindolescopeof spiroox and thindolee oxetane.poor oxetane. yields, Limitations respectively.Limitations of these ofAuthors approaches these alsoap- proachesperformedare the narrow are comparative the substrate narrow studies scopesubstrate and among scope the poor the and vinyl yields, the poorselenone respectively. yields, and respectively. its Authors more common also Authors performed sulfur also performedanalogue,comparative vinyl comparative studies sulfone. among studiesEqual the vinylamounts among selenone the of thvinyle and two selenone its chalcogenones more common and its weremore sulfur allowedcommon analogue, to sulfur vinylreact analogue,withsulfone. a limiting Equal vinyl amountsamountsulfone. of Equal of the the 3-hydroxy amounts two chalcogenones of isat thin.e two Vinyl werechalcogenones sulfone allowed showed to were react a poorerallowed with areactivity limitingto react withasamount Michael a limiting of acceptor the amount 3-hydroxy and of a thecomplete isatin. 3-hydroxy Vinyl inability sulfoneisatin. to Vinyl cyclize showed sulfone under a poorer showed the standard reactivity a poorer reaction as reactivity Michael con- acceptor and a complete inability to cyclize under the standard reaction conditions. asditions. Michael acceptor and a complete inability to cyclize under the standard reaction conditions.

Scheme 5. Synthesis of spirooxindole oxetanes: cross-over experiment between vinyl selenone and sulfone. Scheme 5. Synthesis of spirooxindole oxetanes: cross-over experiment between vinyl selenone and sulfone. A simple simple synthesis synthesis of of methoxyoxetanes methoxyoxetanes has has been been previously previously described described by Kuwajima by Kuwa- [28].jima AIn [28 simple this]. In telescopic this synthesis telescopic protocol, of methoxyoxetanes protocol, the 1-alkyl the 1-alkyl-3-phenylseleno-2-propen-1-ols-3-phenylseleno-2-propen-1-ols has been previously described were by Kuwajima wereoxidized oxi- [28].withdized Inm with -CPBAthis mtelescopic-CPBA and then and protocol, treated then treated thewith 1-alkyl NaOH with-3-phenylseleno-2-propen-1-ols NaOH in MeOH. in MeOH. The methoxide The methoxide ion were adds ion oxidized to adds vinyl to withselenonesvinyl m selenones-CPBA generating and generating then oxa-Michael treated oxa-Michael with adducts NaOH adducts that in MeOH. after that afterproton The proton methoxide transfer transfer and ion andintramolecular adds intramolec- to vinyl selenonesnucleophilicular nucleophilic generating substitution substitution oxa-Michael gave gave methoxyoxeta adducts methoxyoxetanes thatnes after in proton ingood good transferyields, yields, asand as 2:1 2:1intramolecular mixtures mixtures of nucleophilic substitution gave methoxyoxetanes in good yields, as 2:1 mixtures of

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unseparableunseparable ciscis andand transtrans diastereoisomers,diastereoisomers, independentlyindependently ofof thethe geometrygeometry ofof thethe startingstarting unseparableunseparableselenideselenide (Scheme(Scheme ciscis andand 6).6). transtrans diastereoisomers,diastereoisomers, independently independently of the geometry geometry of the starting starting selenideselenide (Scheme (Scheme 66).).

SchemeScheme 6.6. Oxidation/oxa-Michael/etherificationOxidation/oxa-Michael/etherification cascadecascade ofof 1-alkyl-3-phenylseleno-2-propen-1-ols.1-alkyl-3-phenylseleno-2-propen-1-ols. SchemeScheme 6.6. Oxidation/oxa-Michael/etheriﬁcationOxidation/oxa-Michael/etherification cascade cascade of of 1-alkyl-3-phenylseleno-2-propen-1-ols. 1-alkyl-3-phenylseleno-2-propen-1-ols. InIn 2010,2010, aa one-potone-pot synthesissynthesis ofof aziridinesaziridines fromfrom vinylvinyl selenonesselenones andand primaryprimary amines,amines, aminoalcoholsaminoalcoholsInIn 2010, 2010, a a one-pot one-potoror diaminesdiamines synthesis synthesis waswas ofdescribed ofdescribed aziridines aziridines [29].[29]. from from TheThe vinyl vinyl aza-Michaelaza-Michael selenones selenones InitiatedInitiated and and primary primary RingRing amines, Closure amines,Closure aminoalcoholsaminoalcoholsreactionreaction (aza-MIRC)(aza-MIRC) or or diamines waswas performedperformed was described bothboth inin[29]. [29 toluenetoluene]. The The aza-Michael aza-Michaeloror inin aqueousaqueous Initiated Initiated suspensionsuspension Ring Ring orClosureor Closure emul-emul- reactionreactionsion,sion, withoutwithout (aza-MIRC) additionaddition waswas ofof performed performed anyany catalystcatalyst both both oror in addiaddiin toluene toluenetivetive inin or orgoodgood in in aqueous aqueous yields.yields. suspension TheThe suspension mainmain limitation orlimitation emulsion,or emul- ofof sion,withoutthisthis protocolprotocolwithout addition wasadditionwas of thethe any lacklack catalystof any ofof reactivityreactivity catalyst or additive or ofof addiin aromaticaromatic goodtive yields. in amines.amines. good The yields. InIn main thisthis limitation Thecase,case, main waterwater of limitation this alsoalso protocol playedplayed of thiswasaa beneficialbeneficial protocol the lack role,wasrole, of reactivity thesincesince lack higherhigher of reactivity aromatic reactionreaction amines.of raterate aromaticss werewere In this amines. observedobserved case, In water inthisin aqueousaqueous alsocase, played water media.media. also a beneficial ItIt played seemsseems arole,reasonablereasonable beneficial since higher thatrole,that water watersince reaction mayhighermay rates bebe reaction responsible wereresponsible observed rate sfofo wererr inaa faster aqueousfaster observed protonproton media. in transfer. transfer.aqueous It seems Moreover, Moreover,media. reasonable It seemsthethe that H-H- reasonablewaterbondingbonding may networknetwork bethat responsible water cancan may facilitatefacilitate for be a fasterresponsible eithereither proton thethe fo transfer. rcoco anjugate njugatefaster Moreover, proton additionaddition transfer. the or H-bondingor thethe Moreover, cyclizationcyclization network the step stepcanH- bondingfacilitate(Scheme(Scheme either 7).network7). the conjugatecan facilitate addition either or the cyclizationconjugate stepaddition (Scheme or 7the). cyclization step (Scheme 7).

SchemeScheme 7.7. AziridinesAziridinesAziridines byby aza-Michaelaza-Michael by aza-Michael InitiaInitiated Initiatedted RingRing ClosureClosure Ring Closure (aza-MIRC)(aza-MIRC) (aza-MIRC) ofof ββ-substituted-substituted of β-substituted vinylvinyl Schemevinylselenones.selenones. selenones. 7. Aziridines by aza-Michael Initiated Ring Closure (aza-MIRC) of β-substituted vinyl selenones. TheThe one-potone-pot synthesissynthesis ofof αα,,,αα-disubstituted-disubstituted γγ-lactams-lactams from from vinyl vinyl selenones selenones and and N- N- phenylphenylThe substitutedsubstituted one-pot synthesis amidesamidesamides hashasofhas α beenbeenbeen,α-disubstituted reportedreportedreported (Scheme(Scheme(Scheme γ-lactams8 8).).8). Lactams LactamsLactams from vinyl were werewere selenones obtained obtainedobtained in andinin good goodgood N- phenyltoto excellentexcellent substituted yieldsyieldsyields viaviaamidesvia aaa MichaelMichaelMichael has been addition/intramolecularaddition/intramolecularaddition/intramolecular reported (Scheme 8). N-alkylationLactams N-alkylation were cascade cascadecascade obtained [30]. [[30].30 in]. good to excellent yields via a Michael addition/intramolecular N-alkylation cascade [30].

Scheme 8. Synthesis of γ-lactams. SchemeScheme 8.8. SynthesisSynthesis ofof γγ-lactams.-lactams. Scheme 8. Synthesis of γ-lactams. TheThe choicechoicechoice of ofof the thethe proper properproper base basebase was waswas crucial crucialcrucial for fofo therr thethe success successsuccess of ofof the thethe process. process.process. In In fact,In fact,fact, due duedue to thetoto thethe bidentateThe bidentatebidentate choice nature of naturenature the of proper ofof the thethe nucleophilic nucleophilicnucleophilicbase was crucial amide, amamide,ide, fo ther the thethe formation formationformation success of of ofof the C-N C-NC-N process. or oror C-O C-OC-O bondsIn bondsbonds fact, gave gaveduegave to the bidentate nature of the nucleophilic amide, the formation of C-N or C-O bonds gave access to lactams or imidates, respectively. Both Et3N and K2CO3 gave consistent amount of

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access to lactams or imidates, respectively. Both Et3N and K2CO3 gave consistent amount ofthe the imidates, imidates, whereas whereas 2 equivalents 2 equivalents of the of strongerthe stronger base, base, 1,8-diazabicyclo[5.4.0]undec-7-ene 1,8-diazabicyclo[5.4.0]undec- 7-ene(DBU), (DBU), afforded afforded lactams lactams in high in yieldshigh yields as the as sole the reaction sole reaction products. products. This This approach approach was wasextended extended to the to synthesis the synthesis of spirolactams of spirolactams containing containing a cyclopentanone, a cyclopentanone, indanone, indanone, tetralone, tetralone,or oxindole or oxindole scaffold. scaffold. In 2016, Zhu reported that alkyl isocyanidesisocyanides react with phenyl vinyl selenone in the presence of 1 equivalent of water and a catalytic amount of Cs2CO3 affording oxazolidin- presence of 1 equivalent of water and a catalytic amount of Cs2CO3 affording oxazolidin-2- 2-onesones in in good good yields yields [31 [31].]. In In this this reaction reaction four four new newbonds bonds werewere generatedgenerated andand thethe phenyl selenenonyl group group acted acted not not only only as asan anactivating activating and and a leaving a leaving group, group, but also but as also a latent as a oxidant.latent oxidant. The plausible The plausible mechanism, mechanism, reported reported in Scheme in Scheme 9, was9, wassupported supported by control by control ex- 13 13 18 18 perimentsexperiments carried carried out out with with nBuNnBuNC andC and H2 HO.2 WaterO. Water adds adds to phenyl to phenyl vinyl vinyl selenone selenone un- derunder basic basic conditions conditions to togenerate generate an an oxa-Michael oxa-Michael adduct adduct that that in in small small amounts amounts cyclizes cyclizes to give an oxirane (observed by 1313C-NMR experiment) and benzen benzenseleninicseleninic acid. The latter compound, in in equilibrium equilibrium with with its its anhydride anhydride (B (BSA),SA), is responsible is responsible of the ofthe oxidation oxidation of the of isocyanidethe isocyanide to isocyanate. to isocyanate. The nucleophilic The nucleophilic addition addition of the of Michael the Michael adduct adduct onto the onto isocy- the anateisocyanate generates generates a carbamate a carbamate which which can cyclize can cyclize to oxazolidinone to oxazolidinone by the by extrusion the extrusion of ben- of zenseleninicbenzenseleninic acid. acid.

Scheme 9. One-pot synthesis of oxazolidin-2-ones.

Interesting domino processes for the access to sixsix oror seven-memberedseven-membered heterocyclesheterocycles were developed by Bagnoli and co-workers in 2011 [[32].32]. 1,4-Dioxanes, oxazines, thiazines and piperazines were synthesized through th thee formation of two new carbon-heteroatom bonds using vinyl selenones and commerciallycommercially availableavailable chiralchiral 1,2-diols,1,2-diols, NN-protected-protected amino alcohols, alcohols, thiols thiols or or diamines diamines without without loss loss of ofenantiomeric enantiomeric purity. purity. The The access access to en- to antiopureenantiopure piperazines piperazines is particularly is particularly interesting. interesting. This privileged This privileged scaffold scaffold is present is present in sev- eralin several pharmacologically pharmacologically active compounds, active compounds, but there but is therea paucity is a of paucity reliable of and reliable stereose- and lectivestereoselective approaches approaches to carbon-substituted to carbon-substituted piperazines piperazines since most since of the most methods of the methods give ac- cessgive only access to onlycompounds to compounds with substituents with substituents at the nitrogen at the nitrogenatoms. Moreover, atoms. Moreover, 1,4-Benzoxa- 1,4- zepines,Benzoxazepines, and 1,4-benzodiazepines and 1,4-benzodiazepines were prepared were prepared (Scheme (Scheme10). 10). Scheme 11 shows similar one-pot conjugate addition/cyclization strategies for the synthesis of fused benzenes [33], indoles and pyrroles [34,35]. Such condensed heterocycles are very common in drugs and natural products. Carboxamides derived from enantiopure amino esters or amines (ee > 98%) also gave chiral pyrazino fused indoles and pyrroles

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Molecules 2021, 26, x FOR PEER REVIEW 8 of 26 in good yields. The addition of the complexing agent 18-crown-6 was essential to obtain products with high chemo- and regio-selectivity in the synthesis of oxazino[4,3-a]indoles.

Scheme 10. Synthesis of oxygen, nitrogen and/or sulfur-containing 6- and 7-membered heterocycles.

Scheme 11 shows similar one-pot conjugate addition/cyclization strategies for the synthesis of fused benzenes [33], indoles and pyrroles [34,35]. Such condensed heterocycles are very common in drugs and natural products. Carboxamides derived from enantiopure amino esters or amines (ee > 98%) also gave chiral pyrazino fused indoles and pyrroles in good yields. The addition of the complexing agent 18-crown-6 was essential to obtain products with high chemo- and regio-selectivity in the synthesis of oxazino[4,3- Scheme 10. Synthesisa]indoles. of oxygen, nitrogen and/or sulfur sulfur-containing-containing 6- 6- and and 7-membered 7-membered heterocycles. heterocycles.

Scheme 11. Synthesis of oxazino[4,3-a]indolesoxazino[4,3-a]indoles and pyrazino[1,2-a]indoles.

Vinyl selenone-modiﬁed nucleosides or monosaccharides were deeply investigated as substrates for the diversity-oriented synthesis (DOS) of enantiopure, structurally and functionally complex molecular scaffolds. In early reports, Chattopadhyaya et al. [36–39] described the synthesis of 20,30-modiﬁed uridine derivatives as part of a drug discovery

Scheme 11. Synthesis of oxazino[4,3-a]indoles and pyrazino[1,2-a]indoles.

Molecules 2021, 26, x FOR PEER REVIEW 9 of 26

Vinyl selenone-modified nucleosides or monosaccharides were deeply investigated Molecules 2021, 26, 3148 as substrates for the diversity-oriented synthesis (DOS) of enantiopure, structurally9 ofand 25 functionally complex molecular scaffolds. In early reports, Chattopadhyaya et al. [36–39] described the synthesis of 2′,3′-modified uridine derivatives as part of a drug discovery program concerning new types of selective inhibitorsinhibitors of thethe HIV-reverse-transcriptaseHIV-reverse-transcriptase (Scheme 1212).).

Scheme 12. Uridine analogues synthesized throug throughh selenone-based transformations.transformations.

Once again, the formation of the products can be explained by the bis electrophilic properties of the 20,30-ene-20-phenyl selenone which undergoes sequential Michael addi- Molecules 2021, 26, x FOR PEER REVIEW 10 of 26

Molecules 2021, 26, 3148 10 of 25 Once again, the formation of the products can be explained by the bis electrophilic properties of the 2′,3′-ene-2′-phenyl selenone which undergoes sequential Michael addition and nucleophilic nucleophilic substitution substitution of of the the selenonyl selenonyl group. group. The The C2=O C2=O group group of of the the uracil uracil is sometimesis sometimes involved involved as asthe the internal internal nucleophile. nucleophile. The Thecombination combination of the of chirality the chirality of car- of bohydratescarbohydrates with with the thehigh high reactivity reactivity of viny of vinyll selenones selenones can can offer offer interesting interesting opportunities opportuni- forties generating for generating new new stereochemically stereochemically define deﬁnedd and andstructurally structurally complex complex compounds. compounds. Re- cently,Recently, Pathak Pathak designed designed D-xyloseD-xylose or D or-fructose-derivedD-fructose-derived alkenyl alkenyl selenones selenones to explore to explore Mi- chael-initiatedMichael-initiated functionalizations functionalizations of sugars of sugars [40,41] [40 with,41] withsmall small carbo carbo and heterocyclic and heterocyclic rings. Moreover,rings. Moreover, furanoside furanoside and pyranoside and pyranoside rings were rings decorated were decorated with five-membered with ﬁve-membered N-het- eroaromaticN-heteroaromatic compounds compounds through through Michael Michael addition/elimination addition/elimination sequences. sequences. Some exam- Some plesexamples with D with-fructose-derivativesD-fructose-derivatives are collected are collected in Scheme in Scheme 13. 13.

SchemeScheme 13. 13.Vinyl Vinyl selenone-based selenone-based functionalizations functionalizations of of carbohydrates. carbohydrates.

These reactions nicelynicely complementcomplement vinyl vinyl sulfone-mediated sulfone-mediated transformations transformations of of sugars. sugars.In fact, In fact, the easy the removaleasy removal of the of selenonyl the selenonyl moiety moiety gave access gave toaccess completely to completely different different reaction pathwaysreaction pathways [42,43]. [42,43]. In 2017, Tiwari described the N-heterocyclic carbene (NHC)/base catalyzed addition of aromatic aldehydes and ketones to vinyl selenones for the formation of multifunctionalized

Molecules 2021, 26, x FOR PEER REVIEW 11 of 26

Molecules 2021, 26, 3148 11 of 25 In 2017, Tiwari described the N-heterocyclic carbene (NHC)/base catalyzed addition of aromatic aldehydes and ketones to vinyl selenones for the formation of multifunction- alizedtetrahydrofuranes tetrahydrofuranes [44]. This[44]. This unprecedented unprecedented three-component three-component reaction reaction gave gave access access to tochallenging challenging 2,3-dihydroxy-2,3-diaryltetrahydrofurans 2,3-dihydroxy-2,3-diaryltetrahydrofurans with with two two contiguous contiguous oxygenated oxygen- quaternaryated quaternary stereocenters stereocenters (Scheme (Scheme 14). 14).

O Mes = 2,4,6-trimethylphenyl Ar SeO2Ph Stetter-type products N not formed N Mes N O BF4 Ar Ar SeO2Ph 20 mol% O R1 OH Ar H DIBAL-H 2 equiv. O R2 Cs CO or 1,1,3,3-tetramethylguanidine O O O OH 2 3 Ar Ar R2 R1 (1.5 equiv.) CH3CN, rt, 24h 23 examples 17—71% yield

Suggested mechanism: I

O O H3C N N Ar Ar H Ar N OH CH 3 SeO Ph 2 II base O Michael addition H C Ar 3 N Ar N SeO Ph OH 2 HO OH N Ar CH3 Ar Ar NHC O base H O O Ar H 1 Ar R (H) Ar O 2 SeO Ph Ar R (Ar) OH 2 O -PhSeO H 2 1 Ar O R O or O R2 Ar H SchemeScheme 14.14. FunctionalizedFunctionalized 2,3-diaryltetrahydrofurans2,3-diaryltetrahydrofurans byby NHC/baseNHC/base mediated multicomponent reactions.

The following reaction steps can explain the formation of the products: (a) the NHC- catalyzed synthesis synthesis of of the the benzoin benzoin I fromI from two two molecules molecules of arom of aromaticatic aldehyde, aldehyde, (b) the (b) base the promotedbase promoted Michael Michael addition addition of the ofbenzoin the benzoin to the vinyl to the selenone vinyl selenone to generate to generatethe interme- the diateintermediate II, (c) theII, reaction (c) the reaction of II with of II acetonewith acetone or 2,2,2-trifluoro or 2,2,2-trifluoro acetophenone acetophenone to generate to generate tetrahydrofuro[2,3-tetrahydrofuro[2,3-d][1,3]dioxoles.d][1,3]dioxoles. A Athird third molecule molecule of of aldehyde aldehyde can can also also react react with with II inin place ofof aa ketone.ketone. Once Once again, again, results results highlight highligh thet the different different reactivity reactivity of the of vinylthe vinyl selenones sele- nonesin respect in respect to vinyl to sulfonesvinyl sulfones and vinyl and vinyl phosphonates, phosphonates, which which simply simply generate generate Stetter-type Stetter- products under similar conditions. The bicyclic products gave the corresponding 2,3- dihydroxytetrahydrofuranes by treatment with DIBAL-H at room temperature for 24 h.

Molecules 2021, 26, x FOR PEER REVIEW 12 of 26

Molecules 2021, 26, 3148 12 of 25 type products under similar conditions. The bicyclic products gave the corresponding 2,3- dihydroxytetrahydrofuranes by treatment with DIBAL-H at room temperature for 24 h. Interestingly,Interestingly, little little changing changing in inthe the substr substrateate can can completely completely alter alter the the reactivity. reactivity. For For instance,instance, isatins isatins in inplace place of ofthe the above above mentio mentionedned ketones ketones gave gave not not access access to tothe the expected expected spirospiro compounds. compounds. Alkenylation Alkenylation products products we werere obtained obtained as asa consequence a consequence of ofthe the NHC- NHC- catalyzedcatalyzed redox redox reaction reaction described described in inScheme Scheme 15 15 [45].[ 45 The]. The intermediate intermediate I, generatedI, generated when when thethe aldehyde aldehyde reacts reacts with with the the N-carbeneN-carbene catalyst, catalyst, undergoes undergoes a hydride a hydride transfer transfer to togenerate generate thethe intermediate intermediate II IIandand the the anion anion IIIIII. The. The reaction reaction between between intermediates intermediates IIII andand IIIIII affordsaffords a a 2-benzoyl2-benzoyl isatin isatin IV that reactsreacts withwith vinylvinyl selenone selenone via via a a CsF-assisted CsF-assisted Michael Michael addition. addition. The Thefollowing following elimination elimination of of benzenseleninic benzenseleninic acid acid gives gives variously variously substituted substituted vinyl vinyl oxindoles oxin- dolesin moderate in moderate to good to good yields. yields.

R3 O R2 R1 O N

O O R2

N not obtained O N Mes N BF O 4 O SeO2Ph 3 O R 20 mol% 2 O N R3 R 1 R CsF, TMG, DMSO, r.t., 24h O O N R2 H R1 25 examples 45—81% yield

Suggested mechanism:

N N N O II N N O R3 SeO2Ph O O 2 N O R2 R 3 O 2 R R2 H R O N CsF O O N R1 N R1 O N IV N N O R1 2 III I H R hydride transfer

O N R1 SchemeScheme 15. 15. SynthesisSynthesis of of1-substituted 1-substituted 3-vinyl 3-vinyl oxindoles. oxindoles. Molecules 2021, 26, x FOR PEER REVIEW 13 of 26

Molecules 2021, 26, 3148 13 of 25

4. Enantioselective Organocatalytic Transformations 4. Enantioselective Organocatalytic Transformations Enantioselective organocatalysis consists in the conversion of prochiral or racemic Enantioselective organocatalysis consists in the conversion of prochiral or racemic substratessubstrates intointo highlyhighly enantioenrichedenantioenriched productsproducts byby effecteffect of of aa chiralchiral organocatalyst.organocatalyst. InIn thethe lastlast yearsyears thisthis approachapproach acquiredacquired greatgreat popularitypopularity asas aa robustrobust andand powerfulpowerful strategystrategy forfor thethe synthesissynthesis ofof chiralchiral buildingbuilding blocks,blocks, naturalnatural products,products, andand pharmaceuticallypharmaceutically relevantrelevant moleculesmolecules asas singlesingle enantiomersenantiomers [[46].46]. CommonCommon advantagesadvantages ofof organocatalystsorganocatalysts are:are: easyeasy handling,handling, lowlow cost,cost, poorpoor toxicity,toxicity, airair andand waterwater stability.stability. Moreover,Moreover, thethe metal-freemetal-free condi-condi- tionstions areare particularlyparticularly usefuluseful inin thethe productionproduction ofof pharmaceutical pharmaceutical intermediates. intermediates. InIn thisthis ﬁeld,field, privilegedprivileged chiralchiral organocatalystsorganocatalysts withwith non-covalentnon-covalent activationactivation mode,mode, suchsuch asas ureas,ureas, thioureas,thioureas, C6C60-hydroxyl′-hydroxyl cinchona cinchona derivatives, derivatives, or or squaramides squaramides have have been been conveniently conveniently em- ployedemployed in Michael-type in Michael-type reactions reactions between between vinyl vinyl selenones selenones and differentand different pro-nucleophiles pro-nucleo- constructingphiles constructing all-carbon all-carbon quaternary quaternary stereocenters stereocenters and/or multipleand/or multiple stereocenters stereocenters with ex- cellentwith excellent levels of levels enantioselectivity. of enantioselectivity. These organocatalysts These organocatalysts are bifunctional are bifunctional small molecules small bearingmolecules a hydrogen bearing a bondhydrogen donor bond group donor (in group red in (in the red following in the following schemes) schemes) besides abesides basic sitea basic (in bluesite (in in blue the following in the following schemes) schemes) on a chiral on a scaffold.chiral scaffold. Usually, Usually, a tertiary a tertiary amine amine at the basicat the site basic generates site generates the nucleophile the nucleophile by deprotonation, by deprotonation, while awhile weak a Brønsted weak Brønsted acid group acid activatesgroup activates the electrophile the electrophile through through hydrogen hydr bonding.ogen bonding. Thus, Thus, the catalyst the catalyst simultaneously simultane- orientsously orients and activates and activates both the both Michael the Michael donor donor and the and acceptor the acceptor allowing allowing that the that addition the ad- occursdition occurs with an with excellent an excellent level oflevel stereocontrol. of stereocontrol. The ﬁrstThe organocatalyzedfirst organocatalyzed conjugate conjugate additionaddition of of vinyl vinyl selenones selenones was was reported reported by by Marini Marini etet al.al. in in 2009 2009 [47]. [47]. The The reaction reaction was was an anα-functionalizationα-functionalization of 2-aryl-2-cyanoacetates of 2-aryl-2-cyanoacetates (Scheme (Scheme 16). After16). After a careful a careful screening, screening, it was itclear was that clear the that reaction the reaction is best carried is best out carried in the out nonpolar in the nonpolar aprotic solvent aprotic toluene solvent and toluene in the andpresence in the of presence 4Å molecular of 4Å sieves. molecular Products sieves. co Productsntaining all-carbon containing quaternary all-carbon stereocenter quaternary stereocenterwere obtained were at obtained−70 °C with at − a70 thioureidic◦C with a thioureidiccatalyst in catalystgood to inexcellent good to yields excellent and yields high andenantiomeric high enantiomeric excesses. excesses.A lower yield A lower (53%) yield an (53%)d a poorer and aenantioselectivity poorer enantioselectivity (70%) was (70%) ob- wasserved observed with 2-allyl-2-cyanoacetate. with 2-allyl-2-cyanoacetate. The Mich Theael Michaeladducts adductswere transformed were transformed into syntheti- into syntheticallycally valuable valuable chiral intermediates, chiral intermediates, not direct notly directlyaccessible accessible via conjugate via conjugate addition, addition, without withoutloss of enantiomeric loss of enantiomeric excess. The excess. formation The formation of the all-carbon of the all-carbon quaterna quaternaryry stereocenter stereocen- bear- tering bearing a terminal a terminal double doublebond is bond particularly is particularly interesting. interesting. In fact, In the fact, α-vinylation the α-vinylation of active of activemethylene methylene compounds compounds is still isin stillgreat in demand, great demand, due to duethe lack to the of lackmethods of methods for the forenanti- the enantioselectiveoselective installation installation of alkenyl of alkenyl groups groups at sterically at sterically hindered hindered positions. positions.

SchemeScheme 16.16. Enantioselective addition addition of of 2-aryl-2-cyano 2-aryl-2-cyanoacetatesacetates to to the the vinyl vinyl phenyl phenyl selenone selenone and and chemicalchemical transformations.transformations.

ReactionsReactions carriedcarried outout withwith thethe lessless reactivereactive ββ-substituted-substituted vinylvinyl selenonesselenones atat roomroom temperaturetemperature werewere usedused forfor thethe synthesissynthesis ofof enantioenrichedenantioenriched cyclopropanescyclopropanes withwith vicinalvicinal tertiarytertiary andand quaternaryquaternary stereocentersstereocenters [[48].48]. TheThe sequentialsequential one-potone-pot strategystrategy isis basedbased onon thethe nucleofugacitynucleofugacity of of the the selenonyl selenonyl group group and and the th abilitye ability of the of samethe same group group to control to control the regio- the andregio- stereoselectivity and stereoselectivity of the conjugateof the conjugate addition. addition. Enantioenriched Enantioenriched Michael Michael adducts adducts were generatedwere generated under control under of control a bifunctional of a ureidicbifunctional catalyst ureidic and cyclized catalyst by intramolecularand cyclized nu-by

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cleophilicintramolecular displacement nucleophilic of the displacement phenylselenonyl of the group phenylselenonyl induced by a de-ethoxycarbonylationgroup induced by a de- process.ethoxycarbonylation Two different process. conditions Two different were used conditions for the de-ethoxycarbonylationwere used for the de-ethoxycar- step: a Krapcho-typebonylation step: protocol a Krapcho-type with LiCl in protocol HMPA orwith the LiCl more in eco-friendly HMPA or treatmentthe more witheco-friendly EtONa intreatment EtOH (Scheme with EtONa 17). Z in-Cyclopropanes EtOH (Scheme were 17). recoveredZ-Cyclopropanes as single were isomers recovered in moderate as single to highisomers yields in moderate and acceptable to high to yields good enantiomericand acceptable excesses. to good enantiomeric excesses.

Scheme 17.17. One-pot organocatalyzedorganocatalyzed enantioselective enantioselective conjugate conjugate addition/cyclopropanation addition/cyclopropanation cascade. cascade. Organocatalyzed Michael-initiated cyclizations for the enantioselective synthesis of polycyclicOrganocatalyzed compounds, Michael-initiated such as spirolactones cyclizations [49 for] and the enantioselectiveβ-aminoesters [synthesis50] with of a tetrahydroindeno[1,2-polycyclic compounds,b ]pyrrolesuch as spirolactones core, were also [49] developed and β-aminoesters by the same [50] authors. with a Intetrahy- these reactions,droindeno[1,2- the selenonylb]pyrrole group core, were also actsalso asdeveloped a traceless by agent the same able authors. to activate In andthese control reactions, the additionthe selenonyl step. group The key also step acts of as both a traceless synthetic agent protocols able to is theactivate conjugate and control addition the of addition a cyclic tertstep.-butyl- The βkey-ketoester step of toboth vinyl synthetic phenyl protoc selenone,ols is catalyzed the conjugate by a O-9-phenantryladdition of a cyclic C60 -OHtert- quinidinebutyl-β-ketoester or quinine-derivative, to vinyl phenyl that selenone, generates catalyzed highly by enantioenriched a O-9-phenantryl Michael C6′-OH adducts. quini- Indine the or first quinine-derivative, process, the addition that generates of silica highly gel after enantioenr the Michaeliched reaction,Michael adducts. promoted In thethe ringfirst process, closurethrough the addition nucleophilic of silica gel displacement after the Michael of the reaction, SeO2Ph bypromoted the carbonyl the ring ester. closure The presencethrough nucleophilic of the tert-butyl displacement residue, which of the can SeO be2Ph easily by the removed carbonyl by theester. free The silanol presence groups of ofthe the tert silica,-butyl wasresidue, essential which for can an be efficient easily removed cyclization. by the The free use silanol of pseudo-enantiomeric groups of the silica, 0 0 catalystswas essential O-phenantryl for an efficient C6 OH-QD cyclization. and C6 TheOH-Q, use havingof pseudo-enantiomeric opposite configurations catalysts at C8O- Molecules 2021, 26, x FOR PEER REVIEW 15 of 26 andphenantryl C9, provided C6′OH-QD spirolactones and C6′OH-Q, with comparablehaving opposite yields config and enantiomericurations at C8 excesses,and C9, pro- but oppositevided spirolactones enantioselectivity with comparable (Scheme 18 yields). and enantiomeric excesses, but opposite enantioselectivity (Scheme 18).

SchemeScheme 18. One-pot organocatalyzedorganocatalyzed enantioselective enantioselective Michael Michael addition/cyclization addition/cyclization cascade cascade for for the the synthesis synthesis of spirolactones. of spirolactones.

Alternatively, the Michael adducts were transformed into alkyl azides by an inter- molecular nucleophilic substitution with sodium azide. The following Staudinger/intramolecular aza-Wittig sequence gave access to dihydroindeno[1,2-b]pyrroles. The three steps were carried out telescopically, with the exclusion of purification steps. Products were isolated by column chromatography in 60–85% yield and 93–98% enantiomeric excess. Cyclic β-aminoesters were obtained by reduction with sodium borohydride in MeOH (Scheme 19).

Scheme 19. Telescopic organocatalyzed synthesis of enantioenriched dihydroindeno[1,2-b]pyrroles.

Interestingly, a catalyst loading of only 5 mol% did not compromise the chemical and optical yields, albeit longer reaction times were needed. In more recent papers, the tri- fluoroacetic acid deprotection of the racemic β-amino esters obtained by a modified protocol that employs Na2CO3 in place of the chiral catalyst, gave access to β-amino acids. These compounds were resolved by amylase or zwitterionic cinchona alkaloid-based chiral stationary phases [51,52]. In 2013 Zhu and coworkers developed the asymmetric conjugate addition of 2-aryl-2-isocyanoacetates to vinyl phenyl selenone with the C6′-OH quinine-derived catalyst (C6’OH-Q-OnBu), bearing a n-butoxy group reported in Scheme 20

Molecules 2021, 26, x FOR PEER REVIEW 15 of 26

MoleculesScheme2021, 2618., 3148One-pot organocatalyzed enantioselective Michael addition/cyclization cascade for the synthesis of spirolac-15 of 25 tones.

Alternatively, the the Michael Michael adducts adducts were were transformed transformed into into alkyl alkyl azides azides by byan aninter- in- moleculartermolecular nucleophilic nucleophilic substitution substitution with with sodium sodium azide. azide. The following The following Staudinger/intra- Staudinger/ molecularintramolecular aza-Wittig aza-Wittig sequence sequence gave gave access access to todihydroindeno[1,2- dihydroindeno[1,2-b]pyrroles.b]pyrroles. The The three steps were carried out telescopically, with thethe exclusionexclusion ofof puriﬁcationpurification steps.steps. Products were isolated byby columncolumn chromatography chromatography in in 60–85% 60–85% yield yield and and 93–98% 93–98% enantiomeric enantiomeric excess. excess.Cyclic Cyclicβ-aminoesters β-aminoesters were obtainedwere obtained by reduction by redu withction sodium with sodium borohydride borohydride in MeOH in MeOH(Scheme (Scheme 19). 19).

SchemeScheme 19. TelescopicTelescopic organocatalyzed synthesis of enantioenrichedenantioenriched dihydroindeno[1,2-b]pyrroles.dihydroindeno[1,2-b]pyrroles.

Interestingly,Interestingly, a a catalyst catalyst loading loading of of only only 5 mol% 5 mol% did did not not compromise compromise the chemical the chemical and opticaland optical yields, yields, albeit albeit longer longer reaction reaction times times were were needed. needed. In more In more recent recent papers, papers, the thetri- fluoroacetictriﬂuoroacetic acid acid deprotection deprotection of the of theracemic racemic β-aminoβ-amino esters esters obtained obtained by a bymodified a modiﬁed pro- tocolprotocol that that employs employs Na Na2CO2CO3 in3 placein place of ofthe the chiral chiral catalyst, catalyst, gave gave access access to to ββ-amino-amino acids. acids. These compounds werewere resolvedresolved byby amylase amylase or or zwitterionic zwitterionic cinchona cinchona alkaloid-based alkaloid-based chiral chi- ralstationary stationary phases phases [51 ,52[51,52].]. In 2013 In 2013 Zhu Zhu and and coworkers coworkers developed developed the asymmetric the asymmetric conjugate con- 0 jugateaddition addition of 2-aryl-2-isocyanoacetates of 2-aryl-2-isocyanoacetates to vinyl to vinyl phenyl phenyl selenone selenone with with the C6 the-OH C6′-OH quinine- qui- nine-derivedderived catalyst catalyst (C6’OH-Q-O (C6’OH-Q-OnBu), bearingnBu), bearing a n-butoxy a n-butoxy group reportedgroup reported in Scheme in Scheme 20[ 53]. 20 In the same scheme, a possible transition state consistent with the observed enantioselectivity was also reported. The presence of electron-donating or electron-withdrawing groups at ortho, meta, or para position of the α-aryl substituent as well as the presence of heteroaromatic rings were well tolerated. In all the cases, the products were obtained in good to excellent yields and enantiomeric excesses ≥74%.

Scheme 20. Enantioselective addition of 2-aryl-2-isocyanoacetates to the vinyl phenyl selenone. Scheme 20. Enantioselective addition of 2-aryl-2-isocyanoacetates to the vinyl phenyl selenone. This method offers a facile access to versatile building blocks in a high enantioenriched form. Scheme 21 shows their easy transformation into pharmaceutically relevant heterocycles.

Scheme 24. Synthesis of 1,3-oxazinan-2-ones. Molecules 2021, 26, x FOR PEER REVIEW 16 of 26

[53]. In the same scheme, a possible transition state consistent with the observed enantioselectivity was also reported. The presence of electron-donating or electron-withdrawing groups at ortho, meta, or para position of the α-aryl substituent as well as the presence of heteroaromatic rings were well tolerated. In all the cases, the products were obtained in good to excellent yields and enantiomeric excesses ≥ 74%.

Scheme 20. Enantioselective addition of 2-aryl-2-isocyanoacetates to the vinyl phenyl selenone.

This method offers a facile access to versatile building blocks in a high enantioen- Molecules 2021, 26, 3148 riched form. Scheme 21 shows their easy transformation into pharmaceutically relevant16 of 25 heterocycles.

SchemeScheme 21.21. SynthesisSynthesis ofof chiralchiral 3,3-disubstituted3,3-disubstituted oxindoleoxindole andand pyrrolidinone.pyrrolidinone.

TheThe new methodology also also found found nice nice applic applicationsations in inthe the total total synthesis synthesis of natural of nat- Molecules 2021, 26, x FOR PEER REVIEW 17 of 26 uralproducts. products. The first The example ﬁrst example is referred is referred to the enantioselective to the enantioselective synthesis synthesis of (+)-Trigono- of (+)- Trigonoliimineliimine A (Scheme A (Scheme 22). 22).

Scheme 22. TotalTotal synthesis of (+)-trigonoliimine A.

ThisThis alkaloid, alkaloid, with with an an unusual unusual hexacyclic hexacyclic skeleton skeleton and and a a quaternary quaternary carbon carbon center, center, waswas isolated isolated from from the the extract extract of of the the leaves leaves of of TrigonostemonTrigonostemon Li. ItIt is is known known for for the the modest anti-HIV activity. After the Michael addition and the substitution of the phenylselenonyl group with sodium azide, the synthetic sequence proceeds with the hydrolysis of the isonitrile. The next step was the reductive amination with 2-(1H-indole-3-yl)acetaldehyde in the presence of NaBH(OAc)3. Then, a Staudinger reduction was performed to directly produce a lactam. Finally, the reduction of the nitro group followed by treatment of the resulting diamine with trimethyl orthoformate and piridinium p-toluensulfonate, and the Bischler-Napieralski reaction furnished (+)-trigonoliimine in 7.5% overall yield and 84% ee. It is noteworthy that, employing a quinidine-derived bifunctional catalyst and following exactly the same procedure, (–)-trigonoliimine A could be obtained in 6.8% overall yield and 73% ee [54]. The catalytic asymmetric Michael addition of methyl α-(2-nitrophenyl)-α-isocyano acetate to phenyl vinyl selenone in the presence of a quinidine-derived bifunctional catalyst was the key step for the enantioselective construction of the (+)-Hinckdentine A (Scheme 23). This is a marine alkaloid isolated from the bryozoan Hincksinoflustra denticulata collected from Tasmania’s eastern coast [55].

Molecules 2021, 26, 3148 17 of 25

anti-HIV activity. After the Michael addition and the substitution of the phenylselenonyl group with sodium azide, the synthetic sequence proceeds with the hydrolysis of the isonitrile. The next step was the reductive amination with 2-(1H-indole-3-yl)acetaldehyde in the presence of NaBH(OAc)3. Then, a Staudinger reduction was performed to directly produce a lactam. Finally, the reduction of the nitro group followed by treatment of the resulting diamine with trimethyl orthoformate and piridinium p-toluensulfonate, and the Bischler-Napieralski reaction furnished (+)-trigonoliimine in 7.5% overall yield and 84% ee. It is noteworthy that, employing a quinidine-derived bifunctional catalyst and following exactly the same procedure, (–)-trigonoliimine A could be obtained in 6.8% overall yield and 73% ee [54]. The catalytic asymmetric Michael addition of methyl α-(2-nitrophenyl)-α-isocyano acetate to phenyl vinyl selenone in the presence of a quinidine-derived bifunctional catalyst was the key step for the enantioselective construction of the (+)-Hinckdentine A (Scheme 23). Molecules 2021, 26, x FOR PEER REVIEW 18 of 26 This is a marine alkaloid isolated from the bryozoan Hincksinoﬂustra denticulata collected from Tasmania’s eastern coast [55].

Scheme 23.23. CatalyticCatalytic asymmetricasymmetric Michael Michael addition addition of of methyl methylα-(2-nitrophenyl)- α-(2-nitrophenyl)-α-isocyanoacetateα-isocyanoacetate to vinylto vinyl phenyl phenyl selenone sele- asnone key as step key for step the for total the synthesistotal synthesis of (+)-Hinckdentine of (+)-Hinckdentine A. A.

In 2014, 2014, Zhu Zhu reported reported the the reactions reactions of of 2- 2-substitutedsubstituted isocyanoacetates, isocyanoacetates, alkenyl alkenyl sele- se- noneslenones and and water water to afford to afford 4,4-disubstituted 4,4-disubstituted 1,3-oxazinan-2-ones 1,3-oxazinan-2-ones in good in goodto excellent to excellent yields [56].yields In[ 56this]. process In this processfour new four bonds new are bonds formed. are 1,3-Oxazinan-2-one formed. 1,3-Oxazinan-2-one ring is a privileged ring is a scaffoldprivileged found scaffold in bioactive found inand bioactive natural andcompounds natural compoundsdisplaying antibacterial, displaying antibacterial, anti-inflam- matory,anti-inﬂammatory, anti-diabetes, anti-diabetes, and anti-HIV and activities anti-HIV. The activities. process was The carried process out was in two carried steps out by treatmentin two steps with by a treatment catalytic withamount a catalytic of a base amount followed of aby base the followedaddition byof thehydrated addition p-tol- of . uenesulfonichydrated p-toluenesulfonic acid (PTSA.H2 acidO). Based (PTSA onH2 theO). Basedresults on of thecontrol results experiments of control experiments carried out withcarried 18O out labeled with water,18O labeled the following water, the reaction following steps reaction were suggested: steps were (a) suggested:the Michael (a) addi- the tion,Michael (b) the addition, partial (b)hydrolysis the partial of the hydrolysis isocyanide of thewhich isocyanide generates which the formamide, generates the (c) for-the nucleophilicmamide, (c) thedisplacement nucleophilic of the displacement phenylselenonyl of the phenylselenonylgroup by the amide group oxygen by the with amide for- mationoxygen withof a 5,6-dihydro-4 formation of aH 5,6-dihydro-4-1,3-oxazine Hand-1,3-oxazine release of and benzenseleninic release of benzenseleninic acid (in equilib- acid rium(in equilibrium with the benzeneseleninic with the benzeneseleninic anhydride, anhydride, BSA), (d) BSA), a second (d) a secondaddition addition of water of under water acidicunder condition acidic condition to generate to generate a 1,3-oxazinan-2-ol a 1,3-oxazinan-2-ol,, (e) the (e)formation the formation of the seleninate of the seleninate by re- actionby reaction with withBSA BSAand andfinally, ﬁnally, (f) the (f) theoxidation oxidation to 1,3-oxazinan-2-one to 1,3-oxazinan-2-one with with elimination elimination of benzeneselenenicof benzeneselenenic acid acid (Scheme (Scheme 24). 24 ).

Scheme 24. Synthesis of 1,3-oxazinan-2-ones.

Scheme 20. Enantioselective addition of 2-aryl-2-isocyanoacetates to the vinyl phenyl selenone. Molecules 2021, 26, 3148 18 of 25

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Scheme 24. Synthesis of 1,3-oxazinan-2-ones.Scheme 24. Synthesis of 1,3-oxazinan-2-ones.

Thus, the phenyl selenonyl group acts consec consecutivelyutively as an alkene activator, a leaving group and a latent oxidant. The The asymmetric asymmetric va variantriant of of this this reaction reaction employed employed a a quinine- quinine- derived bifunctional organocatalyst to generategenerate the 4,4-disubstituted 1,3-oxazinan-2-one with an excellent enantiocontrol (Scheme 2525).).

Scheme 25. One-pot enantioselective sy synthesisnthesis of a 1,3-oxazinone.

InIn 2016, Simlandy and Mukherjee develope developedd the enantioselective vinylogous addi- addi- tiontion of of deconjugated deconjugated substituted substituted butenolides butenolides to tovinyl vinyl selenones selenones [57]. [57 The]. The reaction reaction was wascat- alyzedcatalyzed by bya thiourea a thiourea derivative derivative and and gave gave access access to to γγ, ,γγ-disubstituted-disubstituted butenolides butenolides as as the Michael adducts in in good good yield yield and and enantioselectivity enantioselectivity starting starting from from both both alkyl alkyl or or aryl aryl sub- sub- stituted compounds. Interestingly,Interestingly, the the vinyl vinyl phenyl phenyl sulfone sulfone resulted resulted completely completely unreactive unreactive(Scheme (Scheme 26) 26) under under the the condition condition employed. employed. On On the the contrary,contrary, thethe vinylvinyl (1-phenyl-1 HH-- tetrazol-5-yl)sulfonetetrazol-5-yl)sulfone gave gave the the adduct adduct in in comparable comparable yield yield and and enantioselectivity enantioselectivity with with the seleniumthe selenium reagent. reagent. As reported As reported in the in same the samescheme, scheme, the selenone the selenone adduct adduct was practically was prac- convertedtically converted into an azide into an and azide finally and into ﬁnally a tria intozole a by triazole Cu-catalyzed by Cu-catalyzed click-reaction click-reaction with phenylacetylene.with phenylacetylene. In 2019, Zhu and coworkers developed a highly enatioselective conjugate additionbe- tween 2-alkyl-2-nitroacetates and phenyl vinyl selenones in the presence of a 60-OH quinine derived bifunctional catalyst [58]. The Michael adducts could be further transformed into quaternary α-aminoacids or other densely functionalized compounds due to the chemical versatility of the nitro and phenyselenonyl functionalities. The adducts were obtained in 67–99% yield and 74–96% ee. In another experiment, the phenyselenonyl group was reduced into a selenide retaining the unmodiﬁed nitro group with an excellent level of chemoselectivity. Alternatively, this group was reductively removed with the simultaneous reduction of the nitro group. These and other transformations are reported in Scheme 27.

Scheme 26. Enantioselective vinylogous addition of deconjugated substituted butenolides to vinyl chalcogenones.

In 2019, Zhu and coworkers developed a highly enatioselective conjugate additionbe- tween 2-alkyl-2-nitroacetates and phenyl vinyl selenones in the presence of a 6′-OH quinine derived bifunctional catalyst [58]. The Michael adducts could be further transformed into quaternary α-aminoacids or other densely functionalized compounds due to the chemical versatility of the nitro and phenyselenonyl functionalities. The adducts were obtained in 67–99% yield and 74–96% ee. In another experiment, the phenyselenonyl group was reduced into a selenide retaining the unmodified nitro group with an excellent level of chemoselectivity. Alternatively, this group was reductively removed with the simultaneous reduction of the nitro group. These and other transformations are reported in Scheme 27.

Molecules 2021, 26, x FOR PEER REVIEW 19 of 26

Thus, the phenyl selenonyl group acts consecutively as an alkene activator, a leaving group and a latent oxidant. The asymmetric variant of this reaction employed a quinine- derived bifunctional organocatalyst to generate the 4,4-disubstituted 1,3-oxazinan-2-one with an excellent enantiocontrol (Scheme 25).

Scheme 25. One-pot enantioselective synthesis of a 1,3-oxazinone.

In 2016, Simlandy and Mukherjee developed the enantioselective vinylogous addition of deconjugated substituted butenolides to vinyl selenones [57]. The reaction was catalyzed by a thiourea derivative and gave access to γ, γ-disubstituted butenolides as the Michael adducts in good yield and enantioselectivity starting from both alkyl or aryl substituted compounds. Interestingly, the vinyl phenyl sulfone resulted completely unreactive (Scheme 26) under the condition employed. On the contrary, the vinyl (1-phenyl-1H- tetrazol-5-yl)sulfone gave the adduct in comparable yield and enantioselectivity with the selenium reagent. As reported in the same scheme, the selenone adduct was practically Molecules 2021, 26, 3148 converted into an azide and finally into a triazole by Cu-catalyzed click-reaction with19 phe- of 25 nylacetylene.

Molecules 2021, 26, x FOR PEER REVIEW 20 of 26

Scheme 26. Enantioselective vinylogous additionaddition of deconjugated substituted butenolides toto vinylvinyl chalcogenones.chalcogenones.

Scheme 27. Enantioselective addition of 2-alkyl-2-nitroacetates to phenyl vinyl selenones and chemical transformations.

Finally, hydrogen-bond-mediated hydrogen-bond-mediated catalytic catalytic pr processesocesses with with vinyl vinyl selenone selenone in ionic in ionic liq- uidsliquids were were reported reported [59]. [59 ].Vari Variouslyously substituted substituted 2-oxindoles 2-oxindoles were were added added to to phenyl vinyl selenone at room room temperature in the presence of a Cinchona-derived thiourea catalyst in a pyridine-based ionic liquid with good good yields yields and and an an excellent excellent enantiocontrol enantiocontrol (Scheme (Scheme 28).28). Easy transformations of an enantioenriched Michael adduct furnished the corresponding pyrroleindoline without loss of enantiomeric purity. This heterocyclic scaffold is typical of (−)-physostigmine and other biologically active compounds.

Scheme 28. Enantioselective organocatalyzed Michael additions in ionic liquid and application to the synthesis of a pyrroloindoline.

Easy transformations of an enantioenriched Michael adduct furnished the corresponding pyrroleindoline without loss of enantiomeric purity. This heterocyclic scaffold is typical of (-)-physostigmine and other biologically active compounds.

5. Cycloaddition Reactions of Vinyl Selenones As reported from previous discussion, vinyl selenones have been well investigated as Michael acceptors, but few methods refer to their use as 2π partners in cycloaddition reactions. Seminal examples were described by Chattopadhyaya et al. in 1990 [39] using a 5′-O-protected vinyl selenone-modified nucleoside and sodium azide at 20 °C for 5 h

Molecules 2021, 26, x FOR PEER REVIEW 20 of 26

Scheme 27. Enantioselective addition of 2-alkyl-2-nitroacetates to phenyl vinyl selenones and chemical transformations.

Finally, hydrogen-bond-mediated catalytic processes with vinyl selenone in ionic liq- uids were reported [59]. Variously substituted 2-oxindoles were added to phenyl vinyl Molecules 2021, 26, 3148 selenone at room temperature in the presence of a Cinchona-derived thiourea catalyst20 ofin 25 a pyridine-based ionic liquid with good yields and an excellent enantiocontrol (Scheme 28).

Scheme 28. EnantioselectiveEnantioselective organocatalyzed organocatalyzed Mich Michaelael additions additions in ionic in ionic liquid liquid and a andpplication application to the to sy thenthesis synthesis of a pyr- of aroloindoline. pyrroloindoline.

5. CycloadditionEasy transformations Reactions of of an Vinyl enantioenriched Selenones Michael adduct furnished the corre- spondingAs reported pyrroleindoline from previous withou discussion,t loss of enantiomeric vinyl selenones purity. have This been heterocyclic well investigated scaffold Molecules 2021, 26, x FOR PEER REVIEWis typical of (-)-physostigmine and other biologically active compounds. 21 of 26 as Michael acceptors, but few methods refer to their use as 2π partners in cycloaddition reactions. Seminal examples were described by Chattopadhyaya et al. in 1990 [39] using 5.a 5Cycloaddition0-O-protected vinylReactions selenone-modiﬁed of Vinyl Selenones nucleoside and sodium azide at 20 ◦C for 5 h (SchemeAs reported 29).29). A A triazole triazole from previous was was recovered recovered discussion, with with vinyl an acceptable selenones yieldhave (64%) been wellthrough investigated a [3+2]- ascycloaddition Michael acceptors, followed but by few elimination methods of refer benzenseleninc to their use acid.as 2π In partners the same in papercycloaddition authors ◦ reactions.also explored Seminal the Dies-Alderexamples were reaction described with cyclopentadiene.cybyclopentadiene. Chattopadhyaya After et al. fo four urin 1990days [39] at 60 using °C,C, a 5product′-O-protected was obtained vinyl selenone-modified in 64% yield. nucleoside and sodium azide at 20 °C for 5 h

O O O NH NH NH N O N O N O TBDMSO O TolO O PGO O NaN3 toluene DMSO N N PhO2Se N 64% 64% H SchemeScheme 29.29. EarlyEarly examplesexamples ofof cycloadditionscycloadditions withwith vinylvinyl selenones.selenones.

More recently,recently, inin 2014, 2014, Pathak Pathak and and co-workers co-workers described described the the synthesis synthesis of enantiomeri- of enantio- mericallycally pure pure 1,4,5-trisubstituted-1,2,3-triazoles 1,4,5-trisubstituted-1,2,3-triazoles starting starting from from four differentfour different vinyl vinyl selenones sele- nonesderived derived from D from-xylose D-xylose and D -glucoseand D-glucose [60]. The[60]. cascade The cascade transformation transformation is initiated is initiated by a byregioselective1,3-dipolar a regioselective1,3-dipolar cycloaddition cycloaddition with with organic organic azides azides followed followed by by elimination elimination of ofbenzenseleninic benzenseleninic acid. acid. The The method method did did not not require require any any catalyst catalyst or or metal. metal. TheThe openingopening of the sugar ring, due to the cleavage of the acet acetalal bond, afforded the trisubstituted triazoles (Scheme 3030).). In 2021 a multicomponent [3+2] cycloaddition/elimination cascade for the synthesis of spirooxindole pyrrolizines has been developed [61]. The reaction tolerates the presence of a range of functional groups. Reactions were performed in 1,4-dioxane at reﬂux with in situ generated azomethine ylides and vinyl selenones as dipolarophiles (Scheme 31).

Scheme 30. Vinyl selenones-modified carbohydrates for the synthesis of 1,2,3-triazoles.

In 2021 a multicomponent [3+2] cycloaddition/elimination cascade for the synthesis of spirooxindole pyrrolizines has been developed [61]. The reaction tolerates the presence of a range of functional groups. Reactions were performed in 1,4-dioxane at reflux with in situ generated azomethine ylides and vinyl selenones as dipolarophiles (Scheme 31).

Molecules 2021, 26, x FOR PEER REVIEW 21 of 26

(Scheme 29). A triazole was recovered with an acceptable yield (64%) through a [3+2]- cycloaddition followed by elimination of benzenseleninc acid. In the same paper authors also explored the Dies-Alder reaction with cyclopentadiene. After four days at 60 °C, a product was obtained in 64% yield.

O O O NH NH NH N O N O N O TBDMSO O TolO O PGO O NaN3 toluene DMSO N N PhO2Se N 64% 64% H Scheme 29. Early examples of cycloadditions with vinyl selenones.

More recently, in 2014, Pathak and co-workers described the synthesis of enantiomerically pure 1,4,5-trisubstituted-1,2,3-triazoles starting from four different vinyl selenones derived from D-xylose and D-glucose [60]. The cascade transformation is initiated by a regioselective1,3-dipolar cycloaddition with organic azides followed by elimination of benzenseleninic acid. The method did not require any catalyst or metal. The opening of Molecules 2021, 26, 3148 the sugar ring, due to the cleavage of the acetal bond, afforded the trisubstituted triazoles21 of 25 (Scheme 30).

Molecules 2021, 26, x FOR PEER REVIEW 22 of 26

SchemeScheme 30. 30.Vinyl Vinyl selenones-modiﬁed selenones-modified carbohydrates carbohydrates for for the the synthesis synthesis of of 1,2,3-triazoles. 1,2,3-triazoles.

SchemeScheme 31.31. ThreeThree componentcomponent [3+2][3+2] cycloaddition/elimination re reactionaction for the synthesis of spiro oxindoles.

The 1,3-dipole was obtained by decarboxylative condensation of of isatins isatins and and a a secondary α-aminoacids.-aminoacids. Products Products were were obtained obtained in in good good to to excellent excellent yields yields and and high high dias- di- teroselectivity,asteroselectivity, regardless regardless of the of thenature nature and andposition position of the of substituent the substituent on the on isatin the deriv- isatin ative.derivative. L-prolineL-proline gave gavebetter better yields yields in respect in respect to other to other secondary secondary aminoacids aminoacids such such as the as transthe trans-4-hydroxy--4-hydroxy-L-proline,L-proline, L-thioproline,L-thioproline, and and sarcosine. sarcosine. Excellent Excellent regioselectivity regioselectivity were observed with aryl-substituted selenones. By analogy with other dipolarophiles, the three- component cycloaddition can proceed through the following steps: (a) the condensation between the isatin and the α-aminoacid to generate an iminium ion in equilibrium with a cyclic intermediate, (b) the decarboxylation for the formation of the azomethine ylide, (c) the [3+2]-cycloaddition, (d) the spontaneous loss of benzenseleninic acid to generate a double bond. The elimination step is not common with other dipolarophiles. Experiments with other chalcogen-containing functional groups, such as selenoxide, sulfoxide, and sulfones, were unsuccessful.

6. Transition-Metal Catalyzed Cross-Coupling of Vinyl Selenones The investigation of vinyl selenones as electrophiles in transition-metal catalyzed cross-coupling reactions has been explored by Beng in 2015. Scheme 32 shows the iron catalyzed α-carbofunctionalization of piperidine and azepane ene-formamides or carbamates with alkenyl, aryl, heteroaryl, and allyl Grignard reagents (route a).

Molecules 2021, 26, 3148 22 of 25

observed with aryl-substituted selenones. By analogy with other dipolarophiles, the three- component cycloaddition can proceed through the following steps: (a) the condensation between the isatin and the α-aminoacid to generate an iminium ion in equilibrium with a cyclic intermediate, (b) the decarboxylation for the formation of the azomethine ylide, (c) the [3+2]-cycloaddition, (d) the spontaneous loss of benzenseleninic acid to generate a double bond. The elimination step is not common with other dipolarophiles. Experiments with other chalcogen-containing functional groups, such as selenoxide, sulfoxide, and sulfones, were unsuccessful.

6. Transition-Metal Catalyzed Cross-Coupling of Vinyl Selenones The investigation of vinyl selenones as electrophiles in transition-metal catalyzed cross- coupling reactions has been explored by Beng in 2015. Scheme 32 shows the iron catalyzed Molecules 2021, 26, x FOR PEER REVIEWα-carbofunctionalization of piperidine and azepane ene-formamides or carbamates23 of 26 with

alkenyl, aryl, heteroaryl, and allyl Grignard reagents (route a).

Scheme 32. 32. αα- and- and β functionalizationβ functionalization of piperidine of piperidine or azepane or azepane ene-formamides ene-formamides or carbamates. or carbamates.

TheThe electron-withdrawing electron-withdrawing nature nature of the selenonyl of the selenonylgroup also facilitated group also the β facilitated-func- the βtionalization-functionalization of the aza-heterocycles of the aza-heterocycles by lithiation by lithiationand trapping and with trapping selenium with electro- selenium elec- trophilesphiles (route (route b). The b). Theaza-hetero aza-heterocyclescycles were then were vicinally then vicinally difunctionalized difunctionalized with different with different carbon partners partners (route (route c-d), c–d), taking taking advantage advantage of the ofdiverse the diverse reactivity reactivity of the two of selenyl- the two seleny- ated functional groups [62]. In fact, the coupling between the β-selenyl group and the aryl lated functional groups [62]. In fact, the coupling between the β-selenyl group and the aryl bromide required warming to 40 °C. bromide required warming to 40 ◦C. 7. Conclusions 7. Conclusions In this review, we discussed recent developments in vinyl selenone chemistry. The reactivityIn this of vinyl review, selenones we discussed has been recentexplored developments in a variety of in Michael-initiated vinyl selenone multiple chemistry. The reactivitybond-forming of vinylreactions, selenones cycloadditions has been and explored coupling in reactions. a variety The of Michael-initiatedsimple preparation, multiple bond-formingthe ease of handling, reactions, and the cycloadditions variety of possible and transformations coupling reactions. make the The vinylselenones simple preparation, theinteresting ease of building handling, blocks and with the varietyuseful applications of possible in transformations (hetero)cycle synthesis, make the total vinylselenones syn- interestingthesis of natural building products blocks and with modular useful construction applications of drug-like in (hetero)cycle molecules. synthesis, Organocata- total synthe- sislyzed of protocols natural products with cinchona and modular derivatives construction or other privileged of drug-like organocatalysts molecules. gave Organocatalyzed access protocolsto densely withfunctionalized cinchona compounds derivatives with or a other high level privileged of enantiocontrol. organocatalysts We hope gave that access to denselythe chemistry functionalized described in compounds this review can with stimulate a high levelfurther of investigations enantiocontrol. in the We under- hope that the chemistryexplored field described of selenone-media in this reviewted transformations can stimulate further (Scheme investigations 33). in the underexplored ﬁeld of selenone-mediated transformations (Scheme 33).

Scheme 33. Vinyl selenones as reactive species in organic synthesis.

Molecules 2021, 26, x FOR PEER REVIEW 23 of 26

Scheme 32. α- and β functionalization of piperidine or azepane ene-formamides or carbamates.

The electron-withdrawing nature of the selenonyl group also facilitated the β-functionalization of the aza-heterocycles by lithiation and trapping with selenium electrophiles (route b). The aza-heterocycles were then vicinally difunctionalized with different carbon partners (route c-d), taking advantage of the diverse reactivity of the two selenyl- ated functional groups [62]. In fact, the coupling between the β-selenyl group and the aryl bromide required warming to 40 °C.

7. Conclusions In this review, we discussed recent developments in vinyl selenone chemistry. The reactivity of vinyl selenones has been explored in a variety of Michael-initiated multiple bond-forming reactions, cycloadditions and coupling reactions. The simple preparation, the ease of handling, and the variety of possible transformations make the vinylselenones interesting building blocks with useful applications in (hetero)cycle synthesis, total synthesis of natural products and modular construction of drug-like molecules. Organocata- lyzed protocols with cinchona derivatives or other privileged organocatalysts gave access to densely functionalized compounds with a high level of enantiocontrol. We hope that Molecules 2021, 26, 3148 the chemistry described in this review can stimulate further investigations in the under-23 of 25 explored field of selenone-mediated transformations (Scheme 33).

Scheme 33. VinylVinyl selenones as reactive species in organic synthesis.

Author Contributions: M.P. and F.M. conceived the review; all the authors contributed selecting and analyzing the literature; writing—original draft preparation, M.P., I.F.C.D. and F.M.; writing—review and editing, M.P., O.R. and F.M. All authors have read and agreed to the published version of

the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Acknowledgments: This manuscript is part of the disseminative activity of the International Network Selenium, Sulfur, Redox and Catalysis (SeSRedCat). Conﬂicts of Interest: The authors declare no conﬂict of interest.

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