Recent Advances in Organocatalyzed Domino C–C Bond-Forming Reactions

13 Pages·2017·2.83 MB·English

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.:[phone]
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]