molecules Review Recent Advances in Organocatalyzed Domino C–C Bond-Forming Reactions CleoS.EvansandLindseyO.Davis* DepartmentofChemistryandBiochemistry,BerryCollege,P.O.Box495016,Mt.Berry,GA30149,USA; [email protected] * Correspondence:[email protected];Tel.:+1-706-236-2237 Received:11December2017;Accepted:22December2017;Published:23December2017 Abstract: Reactions that form a C–C bond make up a foundational pillar of synthetic organic chemistry. In addition, organocatalysis has emerged as an easy, environmentally-friendly way to promote this type of bond formation. Since around 2000, organocatalysts have been used in a variety of C–C bond-forming reactions including Michael and aldol additions, Mannich-type reactions,andDiels–Alderreactions,tonameafew. Manyofthesemethodologieshavebeenrefined andfurtherdevelopedtoincludecascadeanddominoprocesses. Thisreviewwillfocusonrecent advancesinthisareawithanemphasisonmethodologieshavingapplicationsinthesynthesisof biologically-significantcompounds. Keywords: organocatalysis;domino;tandem;Henry;aldol;Mannich 1. Introduction Reactionsthatformcarbon–carbonbondsareanimportanttoolforasyntheticorganicchemist. Sincetheearly2000s,thefieldoforganocatalysishasdevelopedasanattractivealternativetotraditional metal Lewis acid catalysis [1]. As the field of organocatalysis has matured, chemists have found methodsformanyorganocatalyzeddominoprocessesallowingforthesynthesisofcomplexmolecules inanefficientmanner[2]. Theaimofthismini-reviewistohighlighttheworkdoneoverthepast twoyearsinorganocatalyzeddominoprocessesthatinvolvetheformationofacarbon–carbonbond. Inparticular,wewillfocusonreportsthathaveledtothesynthesisofcompoundswithbiologicaland medicinalsignificance. Also,wehavetriedtoavoidreviewingliteraturethathasbeenrecentlycited elsewhere[3]. 2. Mannich TheMannichreactionisanextensively-studiedandsignificanttoolinthesynthesisofβ-amino ketones, sometimes referred to as Mannich bases [4,5]. Organocatalyzed, asymmetric variants of thisreactionweredevelopedintheearly2000s,primarilyutilizingprolineanditsderivativesasthe organocatalyst[6],althoughCinchonaalkaloids[7,8],(DHQD) -basedcatalysts(dihydroquinidine)[9], 2 thioureas [10], and phosphoric acid derivatives [11] have been employed as well. Tandem organocatalyzed Mannichreactionshave beenreportedin thesynthesis ofbiologically-significant compounds[12],butmanyofthesereactionshavebeenreviewedelsewhere[13]. Thefocusofthis sectionwillbetandemMannichreactionsreportedbetween2016andlate2017. Spirocyclic oxindole scaffolds are found in a variety of biological molecules [14–18]. Yu and co-workers recently reported a synthesis of spirooxindole benzoquinolizines utilizing a Michael–Mannich–hemiaminalization–dehydrationcascade(Scheme1)[19]. TheJørgensen–Hayashi catalyst (1) was used to catalyze the reaction and 10 mol % PhCO H was used an additive. 2 AfterscreeningvariousbasesfortheMannichreaction,DABCO(1,4-diazabicyclo[2.2.2]octane)was Molecules2018,23,33;doi:10.3390/molecules23010033 www.mdpi.com/journal/molecules Molecules2018,23,33 2of13 Molecules 2017, 23, 33 2 of 13 Molecules 2017, 23, 33 2 of 13 chobseesnt basasteh,e abs ecsotmbpasaere,das toco DmIPpEarAe d(Nto,ND-dIPiiEsoApr(oNp,yNle-dthiiysloapmrionpey),l eKt2hCyOla3m, oirn eP)P,hK3 2aCmOo3n,go rotPhPehrs3. aTmheo ng othbsecerosspt. ebT aohsfee , tashcse o cproeemacoptfaiortnehd,e mtroea aDdceItP iouEnpA, o(mNf a,1Nd9-e deuixispaompoprfol1eps9y, leeinxthcalymuladpmeldeisn ,beo)i,nt hKcl 2uCedlOeec3dt,r oobrno -PtdhPohne3al eatimcntgroo nnagn- dodto henelaerstci.t nrToghnea- nd elecswtcriootphned- wroaifwt htihndegr a rgweraioncutgipogsn r,ao tum ptahsdeae t ptuhhpeen poyfhl e1rni9ny gel xroainfm gtpholeef sti,hm eiinnicmelu,i ndaeelt,dha olbuthogtohhu gnehole cnstotrroosntnr-god noegnleaectlitenrcogtn r-oawnndi-tw heditlrehacdwtrroainwng-i ng wgriothudprsa wweirneg e mgrpoluopyse da.t I nth aed dpihtieonny, la rginragm o sfc athlee syimntihnees, isa lwthaosu agchh ienvoe dst wrointhg geoloecdt ryoienl-dw (i6th5%dr yawielidn)g, groupswereemployed. Inaddition,agramscalesynthesiswasachievedwithgoodyield(65%yield), gshroouwpins gw perreo memispel fooyre tdh.i Isn r eaadcdtiitoino nm, ae tghroadmo lsocgayle tsoy bneth uesseisd w ina sc oamchmieevrecdia wl pitrho gdouocdti oynie. ld (65% yield), showingpromiseforthisreactionmethodologytobeusedincommercialproduction. showing promise for this reaction methodology to be used in commercial production. Scheme1.Michael–Mannich–hemiaminalization–dehydrationcascade. Scheme 1. Michael–Mannich–hemiaminalization–dehydration cascade. Scheme 1. Michael–Mannich–hemiaminalization–dehydration cascade. CaCtaalytaslty1st h1a hsaasl saolsroe rceecnetnlytlyb ebeenenu useseddt otoc caatatalylyzzee aa MMiicchhaaeell//MMaannnnicihc h[3[ 3+ +2]2 c]yccylocalodadditdioitni ocnasccaasdcea de rearcetaiocntiCobanet atbwleyteswte n1ee hαna -sαβ -a-βuls-nuo snrasetacuteurnartaltyete dbde aaellndd euehhsyeyddd eetsos aacnnatdda lttyrrziifflel uuao oMrrooimcmheaethethly/yMl-ls-ausnbunsbticisthtui tt[ue3d t+e id2m]i imcnyoicnmlooaamldodanliaottinoesna ttceoas sftcooardmfoe rm triflrtrueiaofclrutoioomrno embtehetywthl-eyselun-sb uαsb-tβist-tuuittnuestdaetdpu yprarytrreordlo ildaildidnienehesys(d S(Secsch haeenmmde et r22i))fl [[u22o00r]]o.. methyl-substituted iminomalonates to form tr ifluoromethyl-substituted pyrrolidines (Scheme 2) [20]. Scheme 2. Michael–Mannich cascade followed by Wittig olefination. ScShcehmemee2 .2.M Micichhaaeell––MMaannnniicchh ccaassccaaddee ffoolllloowweedd bbyy WWitittitgi goloelfeinfiantaiotino. n. Substituted pyrrolidines are found in many bioactive natural products and pharmaceutical agenStsu [b2s1ti,2tu2t]e. dP aprytircruollaidrliyn,e tsh ea raed fdoiutinodn oinf tmhea ntryi fbluiooaroctmiveet hnyal tugrroalu pp rtood tuhcetsse apnydr rpohliadrimneasc emuatikceasl Substituted pyrrolidines are found in many bioactive natural products and pharmaceutical athgeemnt sa t[t2r1a,c2t2iv].e Ptaarrgtiectusl faorrly s,y tnhteh eatdicd oitrigoann oicf cthheem triisftlsu [o2r3o,m24e].t hTyhli sg mroeutph otdoo tlhoegsye ppryorvriodleids ian esys nmthaekseiss agents [21,22]. Particularly, the addition of the trifluoromethyl group to these pyrrolidines makes tohf ecmh iartatlr atcritfilvueo traormgeettsh fyolra tseydn tphyertirco olirdgianneisc wchitehm gisotso d[2 3y,i2e4ld]. Tahnids mexectehlolednotl odgiyas pterroevoidseelse cat isvyintyth aensids theoemnf acanhtttiirroaascle tltierviceftliutvaoirtrygo.em tIsnetf hoayrdldsaytitenidot hnpe, yttirhcreoo lrridgeaaincnetiisco ncwh ipethrmo cgiseoteosdd[e2 dy3 i,2seml4d]o .aoTnthhdil sye mxwceeittlhhle onedtl eodcltoiragosynte-prweroiotshvedilderecatswivaiintsgyy naatnnhdde sis of ceehnleaicrntartloiontsr-eidflloeucntoaivrtiointmyg. e gItrnho yualpdasdt eaidtpioppney,n rdtrheoedl i rdtoeia ntcheteiso αnw, βipt-hruoncgseoaetoduderadyt eisedml daolodatenhhdlyyd ewex.ci tehl leelnetctdroians-tweritehodsrealwecitnigv itaynda nd enaenletciotrIsonen lae-ddcdotinivtaiiottiynn. gto Ig nprroaoudlpidnsie ta-idpoepnre,invtdehdeed or rteoga atchntieoo cαna,tβap-luryonsctssea,e tuudrreeadate-ddsme arliodvoeetdhhy oldyregw.a nitohcaetalelyctsrtso nh-awveit bhederna wusiendg ina nd elecdtormoniIn-ndo ao drnedaaitctiitnoiognn gtsor. opZurhpoolsuina eap-npddee rnciodv-eewdd ootrorkgetahrnse orαcea,cβtea-nluytlnsyts sad, tueuvrreeaalto-edpdeerdai vldaened h aoysrdygmea.nmoecatrtiacl yMstus khaaivyea mbeae–nM uasnendi cinh dreoaImnctiainodond rbieteiaotcwntieoteonnsp .f rlZuohloiorniune -aadtneeddr i cvsoiel-ydwl ooerrngkoaelrn seo trhceaectreasn lyatlnsytd sd ,keuevrteeimlao-ipdneeedsr iavcanet daalsoyyrzmgeadmn beoytcr aiact ahMlyyudsktrsoaiqhyuaaivmneianb–eeM edanenruinvsiecedhd in domrbeiifanuconticortneio abnceattilwo unersee.na Z cfalhutoaoulryisnatan 2tde (dSc cosh-ilewymlo eer nk3oe) rl[ s2e5trh]e.e cresn atlnydd keevtiemloipneesd caantaalyszyemd mbye tari chyMdruokqauiyinaimnea d–Meriavnend ich reabcitfiuonncbtieotnwale uenreafl ucaotrailnyastt e2d (Sscihlyelmeen 3o)l [e2t5h].e rs andketimines catalyzed by a hydroquinine derived bifunctionalureacatalyst2(Scheme3)[25]. Scheme 3. Formation of fluorinated benzosultam derivatives. Scheme 3. Formation of fluorinated benzosultam derivatives. Molecules 2017, 23, 33 2 of 13 best base, as compared to DIPEA (N,N-diisopropylethylamine), K2CO3, or PPh3 among others. The scope of the reaction, made up of 19 examples, included both electron-donating and electron- withdrawing groups at the phenyl ring of the imine, although no strong electron-withdrawing groups were employed. In addition, a gram scale synthesis was achieved with good yield (65% yield), showing promise for this reaction methodology to be used in commercial production. Scheme 1. Michael–Mannich–hemiaminalization–dehydration cascade. Catalyst 1 has also recently been used to catalyze a Michael/Mannich [3 + 2] cycloaddition cascade reaction between α-β-unsaturated aldehydes and trifluoromethyl-substituted iminomalonates to form trifluoromethyl-substituted pyrrolidines (Scheme 2) [20]. Scheme 2. Michael–Mannich cascade followed by Wittig olefination. Substituted pyrrolidines are found in many bioactive natural products and pharmaceutical agents [21,22]. Particularly, the addition of the trifluoromethyl group to these pyrrolidines makes them attractive targets for synthetic organic chemists [23,24]. This methodology provides a synthesis of chiral trifluoromethylated pyrrolidines with good yield and excellent diastereoselectivity and enantioselectivity. In addition, the reaction proceeded smoothly with electron-withdrawing and electron-donating groups appended to the α,β-unsaturated aldehyde. In addition to proline-derived organocatalysts, urea-derived organocatalysts have been used in domino reactions. Zhou and co-workers recently developed an asymmetric Mukaiyama–Mannich Molecules2018,23,33 3of13 reaction between fluorinated silyl enol ethers and ketimines catalyzed by a hydroquinine derived bifunctional urea catalyst 2 (Scheme 3) [25]. ScShcehmemee3 .3F. Foormrmaatitoionn ooff flfluuoorriinnaatteedd bbeennzzoossuultlatamm ddereirvivataivtievse. s. MoBleecunlezso 2s01u7l,t 2a3m, 33 b ased Cα-tetrasubstituted α-amino acid derivatives, the products 3o off 13t his reaction, have been shown as valuable chiral auxiliaries and reagents [26–29] and found in Benzosultam based Cα-tetrasubstituted α-amino acid derivatives, the products of this reaction, biologically-significantcompounds[30,31]. Throughacatalystscreening,theauthorsdeterminedthat have been shown as valuable chiral auxiliaries and reagents [26–29] and found in biologically- botshigNni–fHicabnot ncdomsopfotuhnedus r[e3a0,c3a1t]a. lTyhsrtowuegrhe an ceacteaslsyasrt yscfroereancinhgie, vthineg auenthaonrtsi odfeatceiramlcinoendtr tohla.tT bhoeths uNb–sHtr ate scobpoenidnsc oluf dtheed udrieflau coartoaelynsot xwyesrilea nneecsewssiatrhy afporp eacnhdieevdinegle ecntraonnti-odfoanciaatli ncognatrnodl. eTlheec tsruonbs-twraitteh dscroapwei ng groiunpclsu;dheodw deivfleur,oaroliepnhoaxtyicsidlaiflneuso wrinitaht eadppeennodlesdil yelleectthreorns-dwoenraetninogt arenadc teilveecternono-uwgihthtdorgaiwveinag sgurbosutpasn;t ial amhoouwnetvoefr,p arliopdhuatcitc. dTifhlueorrienaactteido nenwola ssilyslc eatlhaebrlse wtoerea n3o.t0 remacmtiovle secnaolueg,hs htoo gwivine ga stuhbestpaontteianl taiamlooufntt his meothf opdroodlougcyt. fTohrep rreaaccttiicoanl swyanst hsceatilcabplue rtpoo as e3s.0. Imnmadodl sitciaolne, tsohdowifliunogr tihnea tpeodtesnutbiaslt roaft eths,ism moentohfloudoolroingayt ed enofolr spilryalcteictahle srysntwheetriec paulsropossuesc.c Iens safdudlitsiounb sttor adtiefsluoinrintahteisd rseuabcsttiroante,s, pmroodnoufcluinogrinmatoedn oeflnuool rsiinlyalt ed benezthoesrusl twamerep raoldsou cstuscicneshsifguhl syuieblsdtr(a7t8es– 9i9n% thyiise lrde)acatniodng, oporoddsuecleincgti vmitoyn(o>f2lu0o:1ridnrataendd b9e0n–z9o2s%ulteaem). products in high yield (78–99% yield) and good selectivity (>20:1 dr and 90–92% ee). 3. HenryReactions 3. Henry Reactions The nitro-aldol reaction, or Henry reaction, has been established as a powerful methodology The nitro-aldol reaction, or Henry reaction, has been established as a powerful methodology for fortheformationofcarbon–carbonbondsbetweennitroalkenesandketonesoraldehydes[32–34]. the formation of carbon–carbon bonds between nitroalkenes and ketones or aldehydes [32–34]. Though Though the Henry reaction was discovered in 1896, a chiral variant was not developed until the the Henry reaction was discovered in 1896, a chiral variant was not developed until the 1990s [35,36]. 1990s[35,36]. AsymmetricorganocatalystswereemployedinboththeHenryreactionandaza-Henry Asymmetric organocatalysts were employed in both the Henry reaction and aza-Henry reaction in reaction in the early 2000s [37,38]. Since then, researchers have sought to expand the reaction the early 2000s [37,38]. Since then, researchers have sought to expand the reaction scope and reaction scopeandreactionconditions,testingnewchiralorganocatalystssuchassquaramide[39],thiourea conditions, testing new chiral organocatalysts such as squaramide [39], thiourea derivatives [40], derivatives [40], proline derivatives [41], and bipyridine derivatives [42]. Like the aldol reaction, proline derivatives [41], and bipyridine derivatives [42]. Like the aldol reaction, Henry reactions are Henry reactions are often used in tandem with Michael reactions [40,41,43,44]. The following often used in tandem with Michael reactions [40,41,43,44]. The following syntheses involve Michael– synthesesinvolveMichael–Henryordouble-Michael–Henrycascadesthatproceedviadifferentchiral Henry or double-Michael–Henry cascades that proceed via different chiral organocatalysts to form orgnaenwo craintagl ysystsstetmosfo wrmithn mewultriipnlge sstyesrteeomgesnwici cthenmteursl.t iplestereogeniccenters. XieXaien dancdo- wcoo-wrkoerrkserresp roerpteodrteddia sdtiearsetoerdeiovdeirvgeerngtesnyt nstyhnetsheessoesf 2oHf -2tHhi-othpiyorpaynroa[n2o,3[2b,]3qbu]qinuoinloonloensews ith threweitcho tnhtrigeeu coounstisgteuroeuosc setnetreeroscevniatearsd voima ain doomMiincoh aMeli–chHaeenl–rHyernearyc trieoanct(iSocnh (eSmchee4m)e[ 445) ][.45]. ScShcehmeem4e. 4S. ySnytnhtehseissiso offc chhiriraallf fuunnccttiioonnaalliizzeedd qquuiinnoolliinneess vviaia MMicihcaheale–lH–Henernyr ryearectaicotnio. n. Both the quinolone ring and thiopyran functional group have potential as biological and pharmaceutical targets [46–51]. Quinoline-derived organocatalysts had previously been identified as successful catalysts for conjugate additions [52–54]. Unsurprisingly, the authors could identify two viable catalysts for the tandem Michael–Henry reaction, quinolines 3 and 4. They discovered that the diastereoselectivity of these catalysts were complementary to each other, where catalyst 3 produced the 1,2-anti diastereomer and catalyst 4 gave the 1,2-syn diastereomer. Using a starting material previously synthesized by the group, O-thiocyanato-(E)-cinnamaldehyde [55], nitroolefin, and two different quinoline-derived organocatalysts, the group was able to obtain excellent yields, enantioselectivity, and diastereoselectivity in 8 h at −30 °C using 20 mol % of catalyst and two equivalents of nitroolefin. Liu and coworkers also used a bifunctional organocatalyst, guanidinium derivative 5, in a Michael/Michael/Henry cascade (Scheme 5) [56]. Remarkably, this is the first example of a single chiral organocatalyst being employed to create cyclohexanes with six vicinal stereogenic centers. Molecules2018,23,33 4of13 Both the quinolone ring and thiopyran functional group have potential as biological and pharmaceuticaltargets[46–51]. Quinoline-derivedorganocatalystshadpreviouslybeenidentifiedas successfulcatalystsforconjugateadditions[52–54]. Unsurprisingly,theauthorscouldidentifytwo viablecatalystsforthetandemMichael–Henryreaction,quinolines3and4. Theydiscoveredthatthe diastereoselectivityofthesecatalystswerecomplementarytoeachother,wherecatalyst3producedthe 1,2-antidiastereomerandcatalyst4gavethe1,2-syndiastereomer. Usingastartingmaterialpreviously synthesized by the group, O-thiocyanato-(E)-cinnamaldehyde [55], nitroolefin, and two different quinoline-derivedorganocatalysts,thegroupwasabletoobtainexcellentyields,enantioselectivity, anddiastereoselectivityin8hat−30◦Cusing20mol%ofcatalystandtwoequivalentsofnitroolefin. Liu and coworkers also used a bifunctional organocatalyst, guanidinium derivative 5, in a Michael/Michael/Henrycascade(Scheme5)[56]. Remarkably,thisisthefirstexampleofasingle Molecules 2017, 23, 33 4 of 13 chiralorganocatalystbeingemployedtocreatecyclohexaneswithsixvicinalstereogeniccenters. Prior tothispublication,acombinationoforganocatalysts[57]oraLewisacidcatalystwithanorganicbase Prior to this publication, a combination of organocatalysts [57] or a Lewis acid catalyst with an co-coargtaalnyisct sba[s5e8 ]cow-ceartearlyesqtus i[r5e8d] wtoearec hreieqvueirtehdi stot raacnhsifeovrem thaitsi otrna.nsformation. SchSecmheem5e. S5.y Snythntehseissios focfh cihriarlacl ycyclcolohheexxaannee vviiaa MMiicchhaaeell//MMicihchaeale/lH/eHneryn rcyasccaasdcea.d e. The reaction tolerated a variety of electron-donating and electron-withdrawing groups on the The reaction tolerated a variety of electron-donating and electron-withdrawing groups on aryl substituent of the nitroalkene, although the electronic characteristics played a role in the yield. the aryl substituent of the nitroalkene, although the electronic characteristics played a role in the Those aryl groups with electron-withdrawing substituents typically gave higher yields of the yield. Thosearylgroupswithelectron-withdrawingsubstituentstypicallygavehigheryieldsofthe cyclohexane product. The scope of the reaction with respect to the α-ketoester included alkyl, alkenyl, cycalonhde axraynl esupbrsotidtuuecnt.tsT whieths cliottplee eofffetcht eorne tahcet iyoineldw oitrh serelescptievcittyt.o Wthheileα t-hkee tuoteilsittye roifn tchleu pdreoddualcktsy hl,aasl nkoetn yl, andbeaerny lfusullby srteiatulieznedts, twhiist hrelpitotlret pefrfoevcitdoens at hreemyaierlkdabolre seexlaemctpivleit oy.f Wanh oirlgeatnhoecuattailliytzyeodf dthomepinroo dreuaccttsiohna. snot beenfulAlynroethaleirz nedot,etwhiosrtrheyp oexrtamprpolve iodfe asna orregmanaorckaatabllyezeexda dmopmlienoof Haennoryrg raeancotcioanta wlyazse rdecdenomtlyi nreoproeratecdti on. byA Lnino tahnedr ncoo-tweworokrethrsy. Aex saqmuparleamofidaen doerrgiavnatoivcaet 6a lwyzaesd foduonmd itnoo cHateanlyrzyer tehaec tfiiorsnt wtaansdreemce vnitnlyyloregpoourst ed byMLiinchaanedl c(Vo-MwAo)r/kHeerns.ryA rseqauctaioranm inidveoldveinrigv aat ikveeto6nwe amsofoieutyn dtot osycanttahleyszizeet hteetrfiarhsytdtaronfldueomrevni-n9-yolnoegso us Mic(Shcaheelm(Ve M6)A [5)9/]H. Tehnirsy clraesasc otifo cnominpvooulvnidn gwaask ientcoonrepomraotieedt yinttoo smynedthiceinsiezse utseetdra thoy tdreraotfl aunodr erned-9u-coen es (Schbreamine a6n)d[ s5p9i]n.aTl ihnijsurcileass ass oefarcloy masp thoeu 1n9d70ws,a asnidn icso srtipllo prhaatermdaincetuotimcaelldyi rceilneevsanuts [e6d0].t oWtirthea at caonmdbirneeddu ce bra2in3 eaxnadmsppleisn, atlhien sjucorpiees oafs tehaisr lryeaacstiothne in1c9l7u0dse,da nnidtroisalksteinllesp hwaitrhm aarcyel urtiincgasl lywirtehl evvaarinotus[6 e0l]e.ctWronit-h a donating and electron-withdrawing substituents. The 1,3-indandione-derived substrate typically combined23examples,thescopeofthisreactionincludednitroalkeneswitharylringswithvarious tolerated aryl and alkyl groups. electron-donating and electron-withdrawing substituents. The 1,3-indandione-derived substrate typicallytoleratedarylandalkylgroups. Scheme 6. Synthesis of tetrahydrofluoren-9-ones via Michael/Michael/Henry cascade. Molecules 2017, 23, 33 4 of 13 Prior to this publication, a combination of organocatalysts [57] or a Lewis acid catalyst with an organic base co-catalysts [58] were required to achieve this transformation. Scheme 5. Synthesis of chiral cyclohexane via Michael/Michael/Henry cascade. The reaction tolerated a variety of electron-donating and electron-withdrawing groups on the aryl substituent of the nitroalkene, although the electronic characteristics played a role in the yield. Those aryl groups with electron-withdrawing substituents typically gave higher yields of the cyclohexane product. The scope of the reaction with respect to the α-ketoester included alkyl, alkenyl, and aryl substituents with little effect on the yield or selectivity. While the utility of the products has not been fully realized, this report provides a remarkable example of an organocatalyzed domino reaction. Another noteworthy example of an organocatalyzed domino Henry reaction was recently reported by Lin and co-workers. A squaramide derivative 6 was found to catalyze the first tandem vinylogous Michael (VMA)/Henry reaction involving a ketone moiety to synthesize tetrahydrofluoren-9-ones (Scheme 6) [59]. This class of compound was incorporated into medicines used to treat and reduce brain and spinal injuries as early as the 1970s, and is still pharmaceutically relevant [60]. With a combined 23 examples, the scope of this reaction included nitroalkenes with aryl rings with various electron- donating and electron-withdrawing substituents. The 1,3-indandione-derived substrate typically Molecules2018,23,33 5of13 tolerated aryl and alkyl groups. SchSecmheem6.e S6y. nSythnethsiessiosf otfe tteratrhayhdyrdorflofuluoorerenn-9-9-o-onneess vviiaa MMiicchhaaeell//MMicihchaeale/lH/eHneryn rcyasccaasdcea.d e. Molecules 2017, 23, 33 5 of 13 Inadditiontoawidescope,theauthorswerealsoabletoprovidepreliminaryresultsthatshowed In addition to a wide scope, the authors were also able to provide preliminary results that showed thethgee ngeenraelriatlyityo fotfh tehein idnadnadndioionnee-d-deerriivveedd pprroonnuucclleeoopphhiilleess. .AAnontohtehre Mr Michicahela ealccaecpcteoprt, oar ,oaxionxdionlde ole derdievraivtiavteive(F (iFgiugurere1 1)) wwaass uusseedd inin ththisi sreraecaticotnio, na,nda nwdithw sitlhighstlliyg hmtloydimfieodd irfieaecdtiornea ccotniodniticoonns,d tihtieo ns, thepprorodduuctcst swwereer memadaed ien ihnighhig yhieyldie (l9d2–(9928–%9)8 a%n)da mndodmeroadtee reantaenetinoasnelteioctsievlietyct (i8v1it–y83(8%1)–. 83%). Figure 1. An oxindole derivative used as a Michael acceptor in a VMA/Aldol reaction cascade. Figure1.AnoxindolederivativeusedasaMichaelacceptorinaVMA/Aldolreactioncascade. Hong et al. constructed highly functionalized Hajos–Parrish-ketones (HPKs) containing five to sixH coonngtiegtuaolu.sc osntesrteruogcteendich cigehntlyerfsu tnhcrtoioungahl izaend oHrgaajonso–cPataarlryitsihc -keentaonntieoss(eHlePctKivse) cMonicthaianeiln/Mgificvheaetlo/ six conHtiegnuroy uresasctteiroeno (gSecnhiecmcee n7t)e [r6s1]t.h HroPuKgsh haanveo brgeaenn oucsaetda layst iicmepnoarntatniot sseylnetchtiovnes Mfoirc ah avealr/ieMtyi cohf anealt/uHraeln ry reapcrtoiodnuc(tSsc [h62e]m, aend7) a[r6e 1o]n.e HofP thKes hhisatvoericbael eonriguinsesd ofa osrgimanpoocarttaalnytsissy [n63th,6o4n].s Thfoer Joargveanrsieenty–Hoafynaashtui ral procdatuaclytsst[ 6w2a],s aunsdeda irne ao bniepohfastihce syhsistetomr iocfa wloartiegri:ancseotofnoirtrgialen aotc 2a:t1a loyvseirs a[6 s3e,v6e4n]. toT hfoeuJrotregenen dsaeyn p–Heraioyda shi cataatl yrsotowma tseumspederiantuareb.i pThhaes aicqusyesotuesm pohfaswea atlelro:waceedto fnoirt rtihlee ante2ce:1ssoavreyr daissseovleuntioton foofu crytecelonpdeanytapdeiorinoed at roormeagteenmt.p Ae rvaatruiertey. oTf hHePKaqs uweeorue ssypnhthaesseizaeldlo (w10e edxafomrptlhese) nweitche smsaordyerdaitses tool guotioodn yoiefldc yancldo epxecnetlalednito ne reaegneanntt.iosAelevcatirvieittyy. of HPKs were synthesized (10 examples) with moderate to good yield and excellentenantioselectivity. Scheme 7. Synthesis of Hajos–Parrish-type ketones via double-Michael/Henry reaction. It is noteworthy that the synthesized HPKs have five to six contiguous stereocenters and two quaternary carbons. This report provides a hallmark example of the utility of domino reactions to create complex products efficiently. 4. Aldol Reactions The aldol reaction is arguably one of the most researched and versatile C–C bond-forming reactions in all of organic chemistry [65–67]. Not surprisingly, there are many examples of organocatalyzed aldol reactions, typically catalyzed by proline and its derivatives [68–70]. Aldol reactions have commonly been incorporated in domino reactions and reviewed somewhat recently [71,72]; therefore, we will focus on reports from this year only. Rios and co-workers developed a double Michael addition to α,β-unsaturated aldehydes, followed by an intramolecular aldol reaction to synthesize pyridine derivatives using a chiral secondary amine catalyst 1 (Scheme 8) [73]. Molecules 2017, 23, 33 5 of 13 In addition to a wide scope, the authors were also able to provide preliminary results that showed the generality of the indandione-derived pronucleophiles. Another Michael acceptor, a oxindole derivative (Figure 1) was used in this reaction, and with slightly modified reaction conditions, the products were made in high yield (92–98%) and moderate enantioselectivity (81–83%). Figure 1. An oxindole derivative used as a Michael acceptor in a VMA/Aldol reaction cascade. Hong et al. constructed highly functionalized Hajos–Parrish-ketones (HPKs) containing five to six contiguous stereogenic centers through an organocatalytic enantioselective Michael/Michael/ Henry reaction (Scheme 7) [61]. HPKs have been used as important synthons for a variety of natural products [62], and are one of the historical origins of organocatalysis [63,64]. The Jorgensen–Hayashi catalyst was used in a biphasic system of water:acetonitrile at 2:1 over a seven to fourteen day period at room temperature. The aqueous phase allowed for the necessary dissolution of cyclopentadione reagent. A variety of HPKs were synthesized (10 examples) with moderate to good yield and excellent Molecules2018,23,33 6of13 enantioselectivity. Scheme 7. Synthesis of Hajos–Parrish-type ketones via double-Michael/Henry reaction. Scheme7.SynthesisofHajos–Parrish-typeketonesviadouble-Michael/Henryreaction. It is noteworthy that the synthesized HPKs have five to six contiguous stereocenters and two ItisnoteworthythatthesynthesizedHPKshavefivetosixcontiguousstereocentersandtwo quaternary carbons. This report provides a hallmark example of the utility of domino reactions to quaternarycarbons. Thisreportprovidesahallmarkexampleoftheutilityofdominoreactionsto create complex products efficiently. createcomplexproductsefficiently. 4. Aldol Reactions 4. AldolReactions The aldol reaction is arguably one of the most researched and versatile C–C bond-forming reactions in Tahll eofa oldrgoalnrice achcteimonistirsy a[6r5g–u6a7b].l Nyootn seuropfristhineglmy, othsterree asreea mrcahneyd eaxanmdpvleesr soaf toilregaCno–cCatbaloynzedd-f aolrdmoli ng rearcetaioctniosnsi,n typailclalolyf caotraglyazneidc bcyh permoliisnter yand[6 i5ts– d6e7r]i.vatiNveos t[68s–u7r0p]r. iAsildnogll yre,actthioenres haarvee cmomamnyonelyx baemenp les of ionrcgoarpnoorcaatetadl yinz dedomainldoo rlearcetaiocntsio annsd, rteyvpieiwcaeldly socmaetawlyhzate rdecbenytlyp r[7o1li,7n2e]; athnedrefiotsred, werei vwaitlilv feoscu[s6 8o–n7 0]. Aldreoplorretasc ftrioomns thhias vyeeacro omnlmy.o nly been incorporated in domino reactions and reviewed somewhat recentlyR[i7o1s ,a7n2d]; ctoh-ewreofrokreer,s wdeevweloilplefdo cau dsoounblree Mpoicrhtsaefrl oamddtithioisny toe aαr,βo-nulnys.aturated aldehydes, followed byR aino sinatrnadmocloe-cwuloarr kaeldrsol dreeavcetiloonp etod syandthoeusibzlee pMyriidchinaee dleardivdaittiivoens utsoinαg ,aβ -cuhnirsaal tsuercaotneddarayl damehinyed es, catalyst 1 (Scheme 8) [73]. followedbyanintramolecularaldolreactiontosynthesizepyridinederivativesusingachiralsecondary aminecatalyst1(Scheme8)[73]. Molecules 2017, 23, 33 6 of 13 CHO R 1 (20 mol %) R CN + CN R N CHO CH2Cl2, r.t. N PhCO H (20 mol%) 2 R= H, Me, NO , CN, F, Cl, Br 2 33-72% yield 3:1 to 6:1 dr 87-99% ee Scheme 8. Synthesis of pyridine derivative by Michael/Michael/Aldol reaction. Scheme8.SynthesisofpyridinederivativebyMichael/Michael/Aldolreaction. Remarkably, this cascade resulted in the formation of three C–C bonds with moderate yield and Remarkably, this cascade resulted in the formation of three C–C bonds with moderate yield diastereoselectivity and excellent enantiopurity. Enals with appended electron-withdrawing groups and(e.dgi.a, spt-enrietroos,e ple-ccytiavnioty) wanerde eexxcceelllleenntt seunbasntrtaiotepsu, writhye.reEans aelnsawl siuthbsatrpapteesn wdeitdh esluebcsttriotunt-ewdi thhadlorgaewni ng groautopmss( ep.rgo.v,ipd-endi tthroe, fipn-acly parnodou)cwtse inre onexlyc melloednetrastue bysietlrda t(e63s,–7w2%he).r Ueansfoerntuanlastuelbys, itfr aante eslewctritohn-sduobnsattiitnugt ed halgorgoeunp asutochm ass panro avliipdheadtict haledefihnyadlep wroasd eumctpsloinyeodn alsy thme osudbesrtaratete,y tiheeld re(a6c3ti–o7n2 g%av).e aU cnofmorptluexn matiexltyu,rief. an elecNterovenr-tdhoelneasst,i nthgisg rreopuoprt spurcohviadsesa anna elixpcehlaletnict aexldamehpyled oefw thaes peomwpelro oyfe tdhea asldthoel rseuabctsitorna tien, ath deormeaincoti on gavperoacceossm. plexmixture. Nevertheless,thisreportprovidesanexcellentexampleofthepowerofthe aldolreTachtei o(Sn)-iTnMaSd-doimariynlporpolrioncoel scsa.talyst 1 has also been used recently to catalyze a Michael/Michael/aldol coTnhdeens(aSti)o-nT MtoS -pdroiavriydlep rtroilciyncolilc cchartoamlyasntes1 beharaisng afolsuor cboenetinguouusse dsterreeocgeenntilcy cetnotersc,a toanley zoef a which is tetrasubstituted (Scheme 9) [74]. Chromanes are a commonly-found scaffold in a variety of Michael/Michael/aldol condensation to provide tricyclic chromanes bearing four contiguous natural products, some of which have anticancer and antibacterial [75,76], antifungal [77], analgesic [78], stereogeniccenters,oneofwhichistetrasubstituted(Scheme9)[74].Chromanesareacommonly-found and antimalarial properties [79,80]. This methodology has a large reaction scope. Nitrochromenes scaffold in a variety of natural products, some of which have anticancer and antibacterial [75,76], with appended electron-neutral (H), electron-donating, or electron-withdrawing groups at the C6 or C7 antifungal [77], analgesic [78], and antimalarial properties [79,80]. This methodology has a position were excellent substrates in this reaction. In addition, dihalogenated 3-nitro-2H-chromenes at large reaction scope. Nitrochromenes with appended electron-neutral (H), electron-donating, the C6 and C8 positions provided products in moderate yield and excellent enantioselectivity. Many orelectron-withdrawinggroupsattheC6orC7positionwereexcellentsubstratesinthisreaction. aliphatic aldehydes were also used as substrates, with moderate yield of chromene products; however, In addition, dihalogenated 3-nitro-2H-chromenes at the C6 and C8 positions provided products isovaleraldehyde and tert-butyl acetaldehyde were not successful substrates even after five days of reaction. The authors also screened different α,β-unsaturated aldehydes, where aliphatic aldehydes (e.g., acrylaldehyde) provided the desired product in good yield and excellent diastereoselectivity and enantioselectivity. The selectivity remained high for aromatic α,β-unsaturated aldehydes bearing electron-neutral, electron-donating, and electron-withdrawing groups. It is noteworthy that this methodology was shown to be viable on a gram scale, demonstrating the applicability of this protocol. Scheme 9. A Michael–Michael–aldol condensation to produce chromanes. Pan and co-workers recently reported a method for the synthesis of 3-acyloxypyrazoles from unsaturated pyrazolones and α-nitroketones through an asymmetric Michael/Hemiketalization/ retro-aldol reaction to product 3-acyloxy pyrazoles (Scheme 10) [81]. Molecules 2017, 23, 33 6 of 13 CHO R 1 (20 mol %) R CN + CN R N CHO CH2Cl2, r.t. N PhCO H (20 mol%) 2 R= H, Me, NO , CN, F, Cl, Br 2 33-72% yield 3:1 to 6:1 dr 87-99% ee Scheme 8. Synthesis of pyridine derivative by Michael/Michael/Aldol reaction. Remarkably, this cascade resulted in the formation of three C–C bonds with moderate yield and diastereoselectivity and excellent enantiopurity. Enals with appended electron-withdrawing groups (e.g., p-nitro, p-cyano) were excellent substrates, whereas enal substrates with substituted halogen atoms provided the final products in only moderate yield (63–72%). Unfortunately, if an electron-donating group such as an aliphatic aldehyde was employed as the substrate, the reaction gave a complex mixture. Nevertheless, this report provides an excellent example of the power of the aldol reaction in a domino process. The (S)-TMS-diarylprolinol catalyst 1 has also been used recently to catalyze a Michael/Michael/aldol condensation to provide tricyclic chromanes bearing four contiguous stereogenic centers, one of which is tetrasubstituted (Scheme 9) [74]. Chromanes are a commonly-found scaffold in a variety of natural products, some of which have anticancer and antibacterial [75,76], antifungal [77], analgesic [78], Molaecnudle sa2n01ti8m,2a3l,a3r3ial properties [79,80]. This methodology has a large reaction scope. Nitrochromen7eos f13 with appended electron-neutral (H), electron-donating, or electron-withdrawing groups at the C6 or C7 position were excellent substrates in this reaction. In addition, dihalogenated 3-nitro-2H-chromenes at in moderate yield and excellent enantioselectivity. Many aliphatic aldehydes were also used as the C6 and C8 positions provided products in moderate yield and excellent enantioselectivity. Many substrates, with moderate yield of chromene products; however, isovaleraldehyde and tert-butyl aliphatic aldehydes were also used as substrates, with moderate yield of chromene products; however, acetaldehydewerenotsuccessfulsubstratesevenafterfivedaysofreaction. Theauthorsalsoscreened isovaleraldehyde and tert-butyl acetaldehyde were not successful substrates even after five days of diffreeraecntitonα., βT-huen asuatthuorrast eadlsoa lsdcereheyndeeds ,dwiffhereernet aαli,pβ-huantsicataulrdaetehdy daledseh(ey.dge.,sa, cwrhyelareld aelhipyhdaeti)c parlodvehidyeddest he des(ier.egd., apcrroydlaulcdteihnydgeo)o pdroyvieidldeda nthde edxecseirlleedn ptrdoidaustcetr ieno gsoeoledc tyiiveiltdy aanndd eexncealnletniot sdeilaesctteirveiotys.elTechteivsietyle acntidv ity remenaiannetidosheilegchtivfoitry.a rTohme astiecleαct,iβv-ituyn sraemtuarianteedd ahlidghe hfyodr easrboemaartiinc gαe,lβe-cutnrsoantu-nraetuetdr aal,ldeelehcytdreosn -bdeoanriantgi ng, andeleelcetcrotrno-nne-wutirtahld, realwecitnrogng-droonuaptsin.gIt, isanndo teewlecotrrtohny-wthitahtdtrhaiwsimnge thgoroduoplos.g yItw iass nshootewwnorttohyb etvhiaatb ltehios na grammetshcoadleo,lodgeym woanss tsrhaotwinng toth beea vpiapblliec aobni lai tgyraomf tshciaslep, rdoetmocoonls.trating the applicability of this protocol. Scheme 9. A Michael–Michael–aldol condensation to produce chromanes. Scheme9.AMichael–Michael–aldolcondensationtoproducechromanes. Pan and co-workers recently reported a method for the synthesis of 3-acyloxypyrazoles from Pan and co-workers recently reported a method for the synthesis of unsaturated pyrazolones and α-nitroketones through an asymmetric Michael/Hemiketalization/ 3-arceytlroox-aylpdyolr arezaoclteisonf rtoo mproudnuscat t3u-aracytelodxyp pyyrarazzoololense (sScahnemdeα 1-0n) i[t8ro1]k. etones through an asymmetric Michael/Hemiketalization/retro-aldolreactiontoproduct3-acyloxypyrazoles(Scheme10)[81]. Molecules 2017, 23, 33 7 of 13 CF 3 tBu S R1 N N N CF3 O2N R1 H H O + 10 mol% N N O R3 NO2 PhCF , 0 °C, 5 days N N OCOR3 3 R2 R2 R3=Ar, HetAr, Alk R1, R2=Ar 57-94% yield 85-99% ee Scheme 10. Synthesis of 3-acyloxy pyrazoles through Michael/Hemiketalization/retro-aldol. Scheme10.Synthesisof3-acyloxypyrazolesthroughMichael/Hemiketalization/retro-aldol. Pyrazoles are particularly important nitrogen containing motifs because they are found in a wide Pyrazolesareparticularlyimportantnitrogencontainingmotifsbecausetheyarefoundinawide variety of bioactive compounds [82,83]. A wide variety of pyrazolones having different benzylidene varsiuebtystoitfubeinotas cwtievree tcoolmerpatoeudn ind sth[i8s2 r,e8a3c]t.ioAn.w Biodteh velaercitertoyn-odfopnyartainzgo laonnde eslehcatvroinng-wditihffderraewntinbge ngzroyulipdse ne subast ttihtue eonrtthsow-, emreetat-o, laenrda tpedarai-npotshitiisonr eoafc tthioe na.rylB gorothupe laeffcotrrdoend-d thoen aptyinragzoalensd ine elexccterlloenn-tw yiiethlddsr aanwdi ng groeunpanstiaosteltehcetivoitrieths.o I-n, amddetitaio-,n,a vnadriopuas rpay-praozsoitloionnes owfitthh eN-asurybsltigturtoiounps (aef.fgo.,r d4-eMdeCth6He4)p wyrearez oallesso in excseulclecenstsfyuile sludbsstarantdes ewnitahn ytiioelsdesl eocf tpiyvriatizeosl.es Irnanagdindgi ftrioomn, 8v1%ar itoo u93s%p wyritahz eoxlocenlleesntw enitahntNios-seulebctsitviittuietsi.o ns (e.gT.h,e4 g-MeneeCralHity )ofw theer ereaalcstioons uwcacse sfusfruthlers udbemstroantsetsrawtedit has ythieel dscsopoef opfy nriatrzookleetsonreasn ignicnlugdferdo mvar8io1u%s to 6 4 93%thowseit whiethx caeplpleenntdeedn aanrytli ogsreoluepcst,i vhiettieerso.arTohmeagtice nrienrgasl,i tayndo faltkhyel grreoaucptiso. n was further demonstrated asthescopeofnitroketonesincludedvariousthosewithappendedarylgroups,heteroaromaticrings, 5. Other Reactions andalkylgroups. 5.1. Knoevenegal/Diels-Alder Reactions 5. OtherReactions Estévez-Braun and co-workers have recently reported two examples of Knoevenegal/Hetero- 5.1. Knoevenegal/Diels-AlderReactions Diels–Alder domino reactions (DKHDA) in the synthesis of embelin derivatives (Scheme 11) [84,85]. Embelin, a biologically-active compound derived from a plant, has been reported to be a promising Estévez-Braun and co-workers have recently reported two examples of Knoevenegal/ structural backbone for potential drug candidates [86]. Hetero-Diels–Alder domino reactions (DKHDA) in the synthesis of embelin derivatives R2 R2 O O O OH CHO O 9 9 + EDDA 10 mol% HO HO O O O R1 DCE, MW, 120 °C, 10 min. Embelin R1= Br, Cl, H, OCH , CO Et R1 3 2 R2= H, NO , OCH , OH, CF 38-100% yield 2 3 3 Scheme 11. Synthesis of embelin derivatives via organocatalyzed Knoevenegal/Hetero-Diels–Alder domino reactions (DKHDA) reaction. This report is particularly significant because it is the first time intramolecular DKHDA reactions with non-terminal alkynes type O-(arylpropynloxy)-salicylaldehydes have been used. Thirty-five aryl-substituted alkynyl ethers were prepared using this methodology, with the majority of reactions giving moderate to high yields of product. The reaction tolerated a variety of electron-donating and electron-withdrawing groups on either aryl ring. The authors hypothesized that the added molecular complexity, introduced with ease because of the domino process, may result in more active and selective biological molecules when compared to embelin. 5.2. Wittig Reactions Organocatalyzed Michael/Wittig reactions have been used in the synthesis of pyrazoles [87] and trisubstituted cyclohexene carboxylates [88]. Recently, Ghorai and co-workers reported the use of Molecules 2017, 23, 33 7 of 13 CF 3 tBu S R1 N N N CF3 O2N R1 H H O + 10 mol% N N O R3 NO2 PhCF , 0 °C, 5 days N N OCOR3 3 R2 R2 R3=Ar, HetAr, Alk R1, R2=Ar 57-94% yield 85-99% ee Scheme 10. Synthesis of 3-acyloxy pyrazoles through Michael/Hemiketalization/retro-aldol. Pyrazoles are particularly important nitrogen containing motifs because they are found in a wide variety of bioactive compounds [82,83]. A wide variety of pyrazolones having different benzylidene substituents were tolerated in this reaction. Both electron-donating and electron-withdrawing groups at the ortho-, meta-, and para-position of the aryl group afforded the pyrazoles in excellent yields and enantioselectivities. In addition, various pyrazolones with N-substitutions (e.g., 4-MeC6H4) were also successful substrates with yields of pyrazoles ranging from 81% to 93% with excellent enantioselectivities. The generality of the reaction was further demonstrated as the scope of nitroketones included various those with appended aryl groups, heteroaromatic rings, and alkyl groups. 5. Other Reactions 5.1. Knoevenegal/Diels-Alder Reactions Molecules2018,23,33 8of13 Estévez-Braun and co-workers have recently reported two examples of Knoevenegal/Hetero- Diels–Alder domino reactions (DKHDA) in the synthesis of embelin derivatives (Scheme 11) [84,85]. (Scheme11)[84,85]. Embelin,abiologically-activecompoundderivedfromaplant,hasbeenreported Embelin, a biologically-active compound derived from a plant, has been reported to be a promising tobeapromisingstructuralbackboneforpotentialdrugcandidates[86]. structural backbone for potential drug candidates [86]. R2 R2 O O O OH CHO O 9 9 + EDDA 10 mol% HO HO O O O R1 DCE, MW, 120 °C, 10 min. Embelin R1= Br, Cl, H, OCH , CO Et R1 3 2 R2= H, NO , OCH , OH, CF 38-100% yield 2 3 3 Scheme 11. Synthesis of embelin derivatives via organocatalyzed Knoevenegal/Hetero-Diels–Alder Scheme11.SynthesisofembelinderivativesviaorganocatalyzedKnoevenegal/Hetero-Diels–Alder domino reactions (DKHDA) reaction. dominoreactions(DKHDA)reaction. This report is particularly significant because it is the first time intramolecular DKHDA reactions wTithh isnorenp-toerrtmisinpaal ratilckuylnaersl ytyspigen Oifi-c(aarnytlbperocapuysneloixtyis)-tshaelicfiyrlsatldtiemhyedinest rhamavoel ebceuelna ruDseKdH. TDhAirtrye-afcivtieo ns witahrynlo-snu-btestrimtuitnedal aalklkyynnyle esthtyeprse wOe-r(ea pryrelppraorepdy unsloinxgy t)h-sisa lmiceytlhaolddoelhoygdye, swhitahv teheb meeanjouristye do.f rTeahcitritoyn-fis ve arygl-isvuinbgs tmituotdeedraatlek tyon hyilgeht hyeierlsdws oefr eprpordeupcatr. eTdhue srienagcttiohnis tmoleertahtoeddo al ovgayr,iewtyi tohf tehleecmtroanjo-rdiotynaotfinrge aacntdio ns giveinlegctmroond-weriathtedrtaowhiinggh gyroieuldpss oonf epirtohderu acrty.lT rhinegr. eTahcet iaounthtoolresr haytepdotahevsaizrieedt ythoaft ethleec atdrodne-dd monoaleticnuglaar nd elecctormonp-lwexiitthyd, rianwtroindgucgerdo uwpistho neaesieth beercaaruysler ionf gt.hTe hdeoamuitnhoo rpsrohcyepsos,t hmeasiyz erdestuhlta tinth meaodred eadctimveo laencdu lar comseplelecxtiivtye, biinotlorogdicualc emdolweciuthlese awsheebne ccoamupsearoefd tthoe emdobmeliinn.o process, may result in more active and selectivebiologicalmoleculeswhencomparedtoembelin. 5.2. Wittig Reactions 5.2. WittigReactions Organocatalyzed Michael/Wittig reactions have been used in the synthesis of pyrazoles [87] and trisubstituted cyclohexene carboxylates [88]. Recently, Ghorai and co-workers reported the use of Organocatalyzed Michael/Wittig reactions have been used in the synthesis of pyrazoles [87] Molecules 2017, 23, 33 8 of 13 and trisubstituted cyclohexene carboxylates [88]. Recently, Ghorai and co-workers reported the useboiffunbcitfiuonnaclt isoqnuaalrasmquidaer/athmioiudree/a tchaitoaulyrset ainc aa tWaliyttsitg/ionxaa-MWicithtaigel/ roexacat-iMoni ctoh asyelntrheeasciztieo bnentozosxyanbothroelsei ze bendzeorxivaabtoivroesle (Sdcehreivmaet i1v2e)s [8(S9c].h eme12)[89]. Scheme 12. Reaction scope of o-formyl aryl boronic acids. Scheme12.Reactionscopeofo-formylarylboronicacids. Benzoxaboroles have been shown to have many potential pharmaceutical applications because ofB theneizro axnatbi-opraoralessitihca, avnetbimeeanlarsihaol,w anntit-oinhflaavmemmaatonryy,p aontteibnatciatelrpiahla, armnda acneutivtiicraall paproppleicratiteiso n[9s0b]. eTchaeu se of tbhiefuirncatniotin-apla orargsaitnico,caatnatlyimsta ilsa rthiaolu,gahntt it-oin cfloaomrdminaattoe rtyo, tahnet icbaarcbtoenryial l,ofa nthde asnubtisvtirraatelsp trhorpoeurgthie sth[e9 0]. Thesqbuifauranmctiidoen/athlioorugraean ofucantcatliyonstali sgtrhoouupsg hotf ttohec ocoartadliynsat t(ethteo pthuell)c,a arnbdo ntyhle otfertthiaerysu nbistrtoragteens othf rtohue gh thecsaqtaulayrsat mcoiodred/inthaitoesu troe athfeu nbcotrioonn ainl gthroe uspubssotrfatthee pcraotvaildyisntg( tthhee “ppuulls)h,”a.n Tdhteh seutbesrttiitaurtiyonn iotrno gtheen aorfylt he catamlyosiettcyo woradsi nfoautensdt otot hbee bqouritoen gienntehrael,s uasb setlreactteropnr-odvoindaitninggt haned“ peuleschtr”o.nT-wheithsdurbaswtiitnugt iosunbostnitutheentasr yl mowieotyrkweda swfeollu, nredsutoltibnge iqnu tihtee igseonlaetiroanl, oafs theele bcetrnozno-xdaboonraotliensg ina enxdceellleencttr yoinel-dw ainthdd ernaawntiinogsesleucbtisvtiittiuees.n ts worTkheed awutehlol,rrse aslusolt iwngerien atbhlee tioso ulsaeti tohne obfenthzeoxbaebnozrolexsa abso sruolbesstrianteesx icne ltlheen styyniethldesaisn odf ecnhairnatli oβs-helyedcrtoivxiyti es. Thekaeutotnheosr sina glsooowd yerieeldab alnedt oenuasnettiohseebleecntizvoitxya (bSocrhleemsaes 1s3u).b stratesinthesynthesisofchiralβ-hydroxy ketonesingoodyieldandenantioselectivity(Scheme13). Scheme 13. Synthesis of β-hydroxy ketones. Acknowledgments: The authors would like to acknowledge Berry College for their financial support. Conflicts of Interest: The authors declare no conflict of interest. References 1. Scheffler, U.; Mahrwald, R. Recent Advances in Organocatalytic Methods for Asymmetric C–C Bond Formation. Chem. Eur. J. 2013, 19, 14346–14396, doi:10.1002/chem.201301996. 2. Rueping, M.; Atodiresei, I. 6.13 C–C Bond Formation: Cascade or Domino Reaction. In Comprehensive Chirality; Elsevier: Amsterdam, The Netherlands, 2012; pp. 345–373, ISBN 978-0-08-095168-3. 3. Gasperi, T.; Miceli, M.; Campagne, J.-M.; Marcia de Figueiredo, R. Non-Covalent Organocatalyzed Domino Reactions Involving Oxindoles: Recent Advances. Molecules 2017, 22, 1636, doi:10.3390/molecules22101636. 4. Arend, M.; Westermann, B.; Risch, N. Modern Variants of the Mannich Reaction. Angew. Chem. Int. Ed. 1998, 37, 1044–1070, doi:10.1002/(SICI)1521-377337:8<1044::AID-ANIE1044>3.0.CO;2-E. 5. Córdova, A. The Direct Catalytic Asymmetric Mannich Reaction. Acc. Chem. Res. 2004, 37, 102–112, doi:10.1021/ar030231l. 6. Verkade, J.M.M.; van Hemert, L.J.C.; Quaedflieg, P.J.L.M.; Rutjes, F.P.J.T. Organocatalysed asymmetric Mannich reactions. Chem. Soc. Rev. 2008, 37, 29–41, doi:10.1039/B713885G. Molecules 2017, 23, 33 8 of 13 bifunctional squaramide/thiourea catalyst in a Wittig/oxa-Michael reaction to synthesize benzoxaborole derivatives (Scheme 12) [89]. Scheme 12. Reaction scope of o-formyl aryl boronic acids. Benzoxaboroles have been shown to have many potential pharmaceutical applications because of their anti-parasitic, antimalarial, anti-inflammatory, antibacterial, and antiviral properties [90]. The bifunctional organocatalyst is thought to coordinate to the carbonyl of the substrates through the squaramide/thiourea functional groups of the catalyst (the pull), and the tertiary nitrogen of the catalyst coordinates to the boron in the substrate providing the “push”. The substitution on the aryl moiety was found to be quite general, as electron-donating and electron-withdrawing substituents worked well, resulting in the isolation of the benzoxaboroles in excellent yield and enantioselectivities. MolTechuele sa2u0t1h8o,2r3s, a3l3so were able to use the benzoxaborles as substrates in the synthesis of chiral β-hydrox9yo f13 ketones in good yield and enantioselectivity (Scheme 13). SSchcheemmee1 133.. SSyynntthheessiiss ooff ββ--hhyyddrrooxxyy kketeotonense.s . Acknowledgments: The authors would like to acknowledge Berry College for their financial support. AckCnoonwflliectdsg omf eInnttesr:eTsth: eTahue tahuotrhsowrs oduelcdlalriek enoto coanckflnicot wofl eindtgeereBste.r ryCollegefortheirfinancialsupport. ConflictsofInterest:Theauthorsdeclarenoconflictofinterest. References Ref1e. renSccehseffler, U.; Mahrwald, R. Recent Advances in Organocatalytic Methods for Asymmetric C–C Bond Formation. Chem. Eur. J. 2013, 19, 14346–14396, doi:10.1002/chem.201301996. 1. Scheffler, U.; Mahrwald, R. Recent Advances in Organocatalytic Methods for Asymmetric C–C Bond 2. Rueping, M.; Atodiresei, I. 6.13 C–C Bond Formation: Cascade or Domino Reaction. In Comprehensive Formation.Chem.Eur.J.2013,19,14346–14396.[CrossRef][PubMed] Chirality; Elsevier: Amsterdam, The Netherlands, 2012; pp. 345–373, ISBN 978-0-08-095168-3. 2. 3. RuGepaisnpge,riM, T..;; MAitcoedlii,r Mes.e; iC,aIm. 6p.a1g3nCe,– JC.-MB.o; nMdarFcoiar mdea Ftiiogune:irCeadsoc, aRd. eNoonr-DCoovmailnenot ROergacatnioocna.taIlnyzCedom Dpormehinenos ive ChiRraelaitcyti;oEnlss eInvvieorl:viAnmg Ostxeirnddaomle,sT: RheecNenett Ahedrvlaanndcess,. 2M01o2le;cpulpes. 3240157–,3 2723,, 1I6S3B6N, d9o7i:81-00.-30389-00/9m5o1l6e8c-u3l.es22101636. 3. 4. GaAspreernid,,T .M;M.; iWceelsi,teMrm.;aCnanm, Bp.a; gRnisec,hJ.,- MN.. ;MMoadrecrina dVearFiiagnutse ioref dthoe, RM.aNnonnic-hC oRveaalcetniotnO. Argnagneowc. aCtahleymz.e IdntD. oEmd. ino Rea1c9t9i8o,n 3s7I, n1v04o4lv–1in0g70O, dxoini:d10o.l1e0s0:2R/(eScIeCnIt)1A52d1v-a37n7c3e3s7.:M8<o1l0e4c4u:l:eAsI2D0-1A7N,2I2E,1106434>63..[0C.CroOs;s2R-Ee.f ][PubMed] 4. 5. AreCnódr,dMov.a;,W Aes. teTrhme aDnnir,eBct. ;CRaistachly,tNic .AMsoydmemrnetVraicr iaMnatnsnoifcthh eRMeaactnionnic. hARcec.a cCtihoenm.. ARnegs.e w2.0C04h,e m37.,I n1t0.2E–d11.21,9 98, 37,d1o0i4:140–.11002710/.a[rC03ro02ss3R1le. f] 5. 6. CóVrdeorkvaad,eA, .J.MTh.Me.D; viraenc tHCeamtaelryt,t iLc.JA.Cs.y; mQumaeedtrfilcieMg, aPn.Jn.Lic.Mh.R; eRaucttjeios,n F..PA.Jc.cT.. OCrhgeamn.ocRateasl.ys2e0d0 4a,sy3m7,m1e0t2ri–c1 12. [CrMosasnRneifc]h[ rPeuabctMioends.] Chem. Soc. Rev. 2008, 37, 29–41, doi:10.1039/B713885G. 6. Verkade, J.M.M.; van Hemert, L.J.C.; Quaedflieg, P.J.L.M.; Rutjes, F.P.J.T. Organocatalysed asymmetric Mannichreactions.Chem.Soc.Rev.2008,37,29–41.[CrossRef][PubMed] 7. Li,W.;Song,B.;Bhadury,P.S.;Li,L.;Wang,Z.;Zhang,X.;Hu,D.;Chen,Z.;Zhang,Y.;Bai,S.;etal.Chiral CinchonaAlkaloid-DerivedThioureaCatalystforEnantioselectiveSynthesisofNovelβ-aminoEstersby MannichReaction.Chirality2012,24,223–231.[CrossRef][PubMed] 8. Yeboah,E.M.O.;Yeboah,S.O.;Singh,G.S.RecentApplicationsofCinchonaAlkaloidsAndTheirDerivatives AsCatalystsInMetal-FreeAsymmetricSynthesis.Tetrahedron2011,67,1725–1762.[CrossRef] 9. Poulsen,T.B.;Alemparte,C.;Saaby,S.;Bella,M.;Jørgensen,K.A.DirectOrganocatalyticandHighlyEnantio- andDiastereoselectiveMannichReactionsofα-Substitutedα-Cyanoacetates.Angew.Chem.Int.Ed.2005,44, 2896–2899.[CrossRef][PubMed] 10. Han, B.; Li, J.-L.; Xiao, Y.-C.; Zhou, S.-L.; Chen, Y.-C. Thiourea-Catalyzed Asymmetric Mannich-Type Reactions.Curr.Org.Chem.2011,15,4128–4143.[CrossRef] 11. Hatano, M.; Ishihara, K. Highly Practical BINOL-Derived Acid-Base Combined Salt Catalysts for the AsymmetricDirectMannich-TypeReaction.Synthesis2010,2010,3785–3801.[CrossRef] 12. Smith,A.B.;Kanoh,N.;Minakawa,N.;Rainier,J.D.;Blase,F.R.;Hartz,R.A.TremorgenicIndoleAlkaloids. StudiesDirectedtowardtheAssemblyoftheA,F,andIRingsofPenitremD: ObservationofanUnexpected StereochemicalOutcome.Org.Lett.1999,1,1263–1266.[CrossRef][PubMed] 13. Akiyama,T.6.3C–CBondFormation:MannichReaction.InComprehensiveChirality;Elsevier:Amsterdam, TheNetherlands,2012;pp.69–96,ISBN978-0-08-095168-3. 14. Hong, L.; Wang, R. Recent Advances in Asymmetric Organocatalytic Construction of 3,3(cid:48)-Spirocyclic Oxindoles.Adv.Synth.Catal.2013,355,1023–1052.[CrossRef] 15. Ball-Jones,N.R.;Badillo,J.J.;Franz,A.K.StrategiesfortheEnantioselectiveSynthesisofSpirooxindoles. Org.Biomol.Chem.2012,10,5165–5181.[CrossRef][PubMed] 16. Trost,B.M.;Brennan,M.K.AsymmetricSynthesesofOxindoleandIndoleSpirocyclicAlkaloidNatural Products.Synthesis2009,2009,3003–3025.[CrossRef] Molecules2018,23,33 10of13 17. Marti, C.; Carreira, E.M. Construction of Spiro[pyrrolidine-3,3(cid:48)-oxindoles]—Recent Applications to the SynthesisofOxindoleAlkaloids.Eur.J.Org.Chem.2003,2003,2209–2219.[CrossRef] 18. Galliford, C.V.; Scheidt, K.A. Pyrrolidinyl-Spirooxindole Natural Products as Inspirations for the DevelopmentofPotentialTherapeuticAgents. Angew. Chem. Int. Ed. 2007, 46, 8748–8758. [CrossRef] [PubMed] 19. Tan, Y.; Feng, E.-L.; Sun, Q.-S.; Lin, H.; Sun, X.; Lin, G.-Q.; Sun, X.-W. Enantioselective synthesis of spirooxindole benzoquinolizines via organo-catalyzed cascade reactions. Org. Biomol. Chem. 2017, 15, 778–781.[CrossRef][PubMed] 20. Zhi, Y.; Zhao, K.; Liu, Q.; Wang, A.; Enders, D. Asymmetric Synthesis of Functionalized Trifluoromethyl-Substituted Pyrrolidines Via an Organocatalytic Domino Michael/Mannich [3 + 2] Cycloaddition.Chem.Commun.2016,52,14011–14014.[CrossRef][PubMed] 21. Li,X.;Li,J.RecentAdvancesintheDevelopmentofMMPIsandAPNIsBasedonthePyrrolidinePlatforms. MiniRev.Med.Chem.2010,10,794–805.[CrossRef][PubMed] 22. O’Hagan,D.Pyrrole,Pyrrolidine,Pyridine,PiperidineandTropaneAlkaloids. Nat. Prod. Rep. 2000,17, 435–446.[CrossRef][PubMed] 23. Fukui, H.; Shibata, T.; Naito, T.; Nakano, J.; Maejima, T.; Senda, H.; Iwatani, W.; Tatsumi, Y.; Suda, M.; Arika, T. Synthesis and Antibacterial Activity of Novel 7-(3-Substituted-3 or 4-Trifluoromethyl-1-Pyrrolidinyl)-8-Methoxyfluoroquinolones. Bioorg. Med. Chem. Lett. 1998, 8, 2833–2838.[CrossRef] 24. Jlalia,I.;Lensen,N.;Chaume,G.;Dzhambazova,E.;Astasidi,L.;Hadjiolova,R.;Bocheva,A.;Brigaud,T. Synthesis of an MIF-1 Analogue Containing Enantiopure (S)-α-Trifluoromethyl-Proline and Biological EvaluationonNociception.Eur.J.Med.Chem.2013,62,122–129.[CrossRef][PubMed] 25. Yu,J.-S.;Zhou,J.OrganocatalyticEnantioselectiveMukaiyama–MannichReactionofFluorinatedEnolSilyl EthersandCyclicN-sulfonylKetimines.Org.Chem.Front.2016,3,298–303.[CrossRef] 26. Oppolzer,W.;Wills,M.;Kelly,M.J.;Signer,M.;Blagg,J.ChiralToluene-2,α-sultamAuxiliaries:Asymmetric Diels-AlderReactionsofN-enoylDerivatives.TetrahedronLett.1990,31,5015–5018.[CrossRef] 27. Takeuchi, Y.; Suzuki, T.; Satoh, A.; Shiragami, T.; Shibata, N. N-Fluoro-3-cyclohexyl-3- methyl-2,3-dihydrobenzo[1,2-d]isothiazole1,1-Dioxide: AnEfficientAgentforElectrophilicAsymmetric FluorinationofEnolates.J.Org.Chem.1999,64,5708–5711.[CrossRef][PubMed] 28. Sun, H.M.; Liu, Z.P.; Tang, L.Q. Synthesis of Novel Chiral Fluorinating Agents, (+)- and (−)-N-fluoro-3-methyl-3-(4-methylphenyl)-2H-benzo[e][1,2]thiazine-1,1,4-triones.Chin.Chem.Lett.2008,19, 907–910.[CrossRef] 29. Davis,F.A.;Chen,B.C.AsymmetricHydroxylationofEnolateswithN-sulfonyloxaziridines. Chem. Rev. 1992,92,919–934.[CrossRef] 30. Zhang,S.;Li,L.;Hu,Y.;Zha,Z.;Wang,Z.;Loh,T.-P.BifunctionalAminoSulfonohydrazideCatalyzedDirect AsymmetricMannichReactionofCyclicKetimineswithKetones:HighlyDiastereo-andEnantioselective ConstructionofQuaternaryCarbonStereocenters.Org.Lett.2015,17,1050–1053.[CrossRef][PubMed] 31. Wrobel,J.; Dietrich,A.; Woolson,S.A.; Millen,J.; McCaleb,M.; Harrison,M.C.; Hohman,T.C.; Sredy,J.; Sullivan, D. Novel Spirosuccinimides with Incorporated Isoindolone and Benzisothiazole 1,1-Dioxide MoietiesasAldoseReductaseInhibitorsandAntihyperglycemicAgents.J.Med.Chem.1992,35,4613–4627. [CrossRef][PubMed] 32. Drabina,P.;Harmand,L.;Sedlak,M.EnantioselectiveHenryReactionCatalyzedbySupportedTransition MetalComplexes.Curr.Org.Synth.2014,11,879–888.[CrossRef] 33. Boruwa,J.;Gogoi,N.;Saikia,P.P.;Barua,N.C.CatalyticasymmetricHenryreaction.TetrahedronAsymmetry 2006,17,3315–3326.[CrossRef] 34. Luzzio,F.A.TheHenryreaction:Recentexamples.Tetrahedron2001,57,915–945.[CrossRef] 35. Sasai,H.;Suzuki,T.;Arai,S.;Arai,T.;Shibasaki,M.BasicCharacterofRareEarthMetalAlkoxides.Utilization inCatalyticCarbon-CarbonBond-FormingReactionsandCatalyticAsymmetricNitroaldolReactions.J.Am. Chem.Soc.1992,114,4418–4420.[CrossRef] 36. Yamada,K.-I.;Harwood,S.J.;Groger,H.;Shibasaki,M.TheFirstCatalyticAsymmetricNitro-Mannich-Type Reaction Promoted by a New Heterobimetallic Complex. Angew. Chem. Int. Ed. 1999, 38, 3504–3506. [CrossRef]