Synthesis of Bisindole Alkaloids from the Apocynaceae

40 Pages·2016·7.21 MB·English

molecules
Review
Synthesis of Bisindole Alkaloids from the
Apocynaceae Which Contain a Macroline or
Sarpagine Unit: A Review
MdToufiqurRahman,VeeraV.N.PhaniBabuTiruveedhulaandJamesM.Cook*
DepartmentofChemistryandBiochemistry,UniversityofWisconsin-Milwaukee,3210N.CramerStreet,
Milwaukee,WI53201,USA;[email protected](M.T.R.);[email protected](V.V.N.P.B.T.)
* Correspondence:[email protected];Tel.:[phone];Fax:[phone]
AcademicEditor:MichaelWink
Received:29September2016;Accepted:4November2016;Published:14November2016
Abstract: Bisindole natural products consist of two monomeric indole alkaloid units as their
obligateconstituents. Bisindolesaremorepotentwithrespecttotheirbiologicalactivitythantheir
correspondingmonomericunits.Inaddition,thesynthesisofbisindolesarefarmorechallengingthan
thesynthesisofmonomericindolealkaloids. Hereinisreviewedtheenantiospecifictotalandpartial
synthesisofbisindolealkaloidsisolatedprimarilyfromtheAlstoniagenusoftheApocynaceaefamily.
Themonomericunitsbelongtothesarpagine,ajmaline,macroline,vobasine,andpleiocarpamine
series. An up-to-date discussion of their isolation, characterization, biological activity as well as
approachestotheirpartialandtotalsynthesisbymeansofbothsyntheticandbiosyntheticstrategies
arepresented.
Keywords: Alstoniagenus;Apocynaceaefamily;sarpagine;macroline;ajmaline;bisindolealkaloids;
biomimetic synthesis; partial and total synthesis; enantiospecific and regiospecific synthesis of
alkaloids;bioactiveindolealkaloids
1. Introduction
Indole alkaloids are of extraordinary significance due to their structural diversity, medicinal
propertiesandareanessentialpartofthedrugdiscoveryprocess(seetheMerckIndexfordetails)[1].
Theirmedicinalvaluesareevidentfromfolkloreandtheirethnopharmacologicalusesworldwide
stemfromancienttimes[2–5]. Manyofthealkaloidsaremarketeddrugs[6], andotherdrugsare
deriveddirectlyfromnaturalproductsortheyserveasleadcompoundsforfurtherdevelopment[7]
intoclinicalcandidatesrangingfromanti-bacterialtoanti-canceragents[8–15].
The activity and structures of bisindole alkaloids have been reviewed and the number of
isolated bisindole alkaloids are increasing [16–19]. This review is focused on the partial and total
synthesisofbisindoles,aswellassomedimericindolealkaloidswhereinatleastoneofthefollowing
monomericunitscontains,asitsobligateconstituent,thesarpagine,macroline,ajmaline,vobasine,
orpleiocarpaminesystems. Becauseofthecomplexityoftheirstructures, whicharecomprisedof
morethanonealkaloidalpartner,aconvergentapproachtowardtheirsynthesisislogicalsynthetically,
aswellasbiosynthetically. Thisbreaksdowntosynthesisofthemonomericalkaloidalunits,followed
by a biomimetic-type condensation to arrive at the bisindole framework. The number of isolated
bisindoleshasincreasedrecentlybecauseofmodernspectroscopictechniques(e.g.,Massspectrometry,
13C and 2D NMR, HMQC, HMBC, NOESY, and X-ray crystallography) which enable accurate
structure determination on milligram quantities of the bisindole. The synthesis of these complex
naturalproductscanbeginonlywhentheirstructuresareaccuratelyconfirmed[20]. Consequently,
the synthesis of bisindole alkaloids, of course, must lag behind the synthesis of monomers which
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comprisethem. Animportantapproach,definedaspartialsynthesis,istocombineanymonomeric
alkaloidavailable,eitherbysynthesis(includingthesynthesisfromanaturalproduct)orbyisolation,
withtheothernaturalmonomericunitusuallyinabiosyntheticstrategy. Thisprocessiscommonly
termed the biomimetic synthesis of bisindole alkaloids pioneered by Schmid, LeQuesne, Kutney,
Magnus,andothers.
In many studies, it has been shown that bisindole alkaloids exhibit more potent biological,
pharmacological and medicinal properties than the corresponding monomers which comprise
them [21,22], as mentioned above. There are many theories as to why this pattern of activity is
observed but, to date, no concrete evidence as to the mechanism of action (MOA) has emerged.
However,thisisnotsurprisingforonewouldnotexpectthesameMOAineachcase. Asalwaysoneof
themainhurdlesinnaturalproductrelateddrug-discoveryisthatmanynaturalproductsarepresent
inverysmallquantitiesandcannotbeisolatedinquantitieshighenoughtostudytheirbiological
activityletalonestructure-activityrelationships. Thissituationisexacerbatedinthecaseofbisindole
alkaloids. Consequently,itisessentialtodevelopbetterandeasieraccesstobisindolealkaloidseither
syntheticallyorbiosynthetically. Partialandtotalsynthesis,therebyrequireequalemphasisinthis
regard. Ifonecansynthesizethenaturalproductsinastereospecific,regiospecificandenantiospecific
senseviaapracticalsyntheticroute,thesealkaloidscouldbeobtainedinappropriateamountsfor
detailedstudiesoftheirbiologicalactivity. Onecouldthencondensethemismatchedpairsaswell
(i.e.,(+)(−);(+)(+);(−)(−);(−)(+)).
The discovery of the Vinca alkaloids vinblastine and vincristine, originally isolated from
Madagascarperiwinkle,Catharanthusroseus(formerlyknownasVincarosea)[23–26],markedamajor
milestone in natural product-based drug development as these two are the first clinically used
alkaloidalanti-canceragents. Moreover,itiswellknownthatthebisindolenatureofthesealkaloidsis
thekeyforthebisindolesaremuchmoreactivethanthemonomericalkaloidswhichcomprisethem.
Thesebisindole(indole-indoline)alkaloidsareoneofthebesttreatmentoptionsinvarioustypesof
cancersandhavebeensuccessfullyusedincombinationtherapiessincetheearly1960s[27–29].Besides,
theirMOA(interactionwithtubuline,microtubuleassemblyinhibition,andmitosisinhibition)isone
ofthemosteffectivetreatmentagainstcancer,whichpromotedrigorousresearchanddevelopment
ofvinblastineandvincristineresultinginmany(derivativesofvincristineandvinblastine)clinical
candidatestodate[6,8–15,30–36]. Asaconsequence,thesehaveprofoundlystimulatedthesearchand
developmentofalkaloidalnaturalproductbaseddrugs.
Thebisindoles(−)-accedinisine1and(−)-N(cid:48)-demethylaccedinisine2exhibitanti-leishmanial
activity,aswellasmoderateantibacterialactivityagainstgram-positiveB.subtilis[37,38]. Antimalarial
activity of numerous indole alkaloids against Palsmodium falciparum (cerebral) malaria have been
reported,manyofwhicharebisindolealkaloids[21,39–41].(−)-Macrocarpamine3and(+)-villalstonine
5werethemostactivebisindolesisolatedfromAlstoniamacrophyllaagainstbothEntamoebahistolytica
and Plasmodium falciparum [21,42]. These alkaloids 3 and 5 also exhibited potent anti-cancer
activityagainstlungcancercelllinesaswellasmelanoma, renalcellcarcinoma, breast, andcolon
adrenocarcinoma [22,40]. Villalstonine 5 was also active against murine leukemia cell lines [43].
(+)-Dispegatrine 7 and its related monomer, (+)-spegatrine exhibited potent hypotensive activity,
wherein the potency of the dimer was about an order of magniture greater than the monomer
toward α and α adrenergic receptors [44]. (+)-Macralstonine 9 has been reported to have
1 2
hypotensiveactivity[45,46]. Inanotherstudy,byKeawpradubetal. onthreeAlstoniaspeciesfrom
Thailand,bisindoles(+)-macralstonine9,(+)-O-acetylmacralstonine10,(+)-O-methylmacralstonine11,
(+)-villalstonine5,and(−)-macrocarpamine3,aswellasthemonomericalkaloids(+)-pleiocarpamine
14,(−)-alstonerine15,and(−)-alstophylline22exhibitedprofoundanti-Plasmodialactivity[47]. Itis
important to note that a minor change in the structure of (+)-macralstonine 9 by conversion into
the O-methyl ether 11 or O-acetyl ester 10, profoundly increased its anti-Plasmodial activity [47].
ThisincreaseinactivityofO-acetylandO-methylderivativesofmacralstoninemaybeduetothe
increasedlipophilicitywhichfacilitatedtheirtransportacrosscellmembranes. Accedinisine-related
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monomeric indole alkaloids (+)-pericyclivine (92, see later), (−)-perivine (43, see later) and
(−)-vobasine(notshown)exhibitedsignificantcytotoxicityagainstP388andKBcellsbutwereless
active than the bisindole alkaloids [20,48]. (+)-Pleiocarpamine 14 has recently been found to form
Molecules 2016, 21, 1525 3 of 40
anunprecedenteddimericstructure,(+)-bipleiophylline12,whereintwopleiocarpamine14unitswere
linkaerdomtoagtiect hsepracbeyr m(peyaroncsaotefchanuica raocmida)t. icThsipsa dceimr(epr ywroacsa ftoeuchndu ictoa cbied )v.eTryh iesffdeicmtiveer wagaasinfsotu dnrdugto- be
veryseenfsfeitcivtiev, eviangcariisntsinted rreusgis-tsaennts hituivmea,nv KinBc rainstdin Juerrkeasti scteallnst [4h9u]m. TahnisK fiBndainndg aJulsrok sautpcpelolrsts[ 4th9]e. aTrhguismfienndt ing
alsothsaut pbpisoirntdsotlhe ealakragluoimdse natret hmatorbei saicntdivoel ethaalnk atlhoeiidr sparoregemniotorres ascitnicvee (t+h)-apnletiohceairrpparmoigneen ditiodr snosti nce
(+)-pexlehiiobcita sripganmifiicnaentd aidctinvoittye [x2h1,i2b2it,4s7i]g. nificantactivity[21,22,47].
Illustrated in Figure 1 are representative bisindoles presented in this review. All of these alkaloids
IllustratedinFigure1arerepresentativebisindolespresentedinthisreview. Allofthesealkaloids
have originated from the combination of two monomeric indole alkaloids depicted in Figure 2.
haveoriginatedfromthecombinationoftwomonomericindolealkaloidsdepictedinFigure2.

FigFuigruer1e. 1R. eRperperseesnentatatitviveee exxaammpplleess ooff bbiiooaaccttivivee bbisiisninddoloel ealaklakloaildosid. s.
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Molecules 2016, 21, 1525 4 of 40
Molecules 2016, 21, 1525 4 of 40

FFiFgiigguuurreree2 22...M MMooonnnooommmeeerrriiiccc uuunnniiitttsss ppprrreeessseeennnttt iiinnn ttthhheee bbbiiisssiiinnndddooollleee aaallklkkaaallolooiididdss s rrereevvviieeiwewweededd hheherereerieinni.n. .
2. Biogenetic Relationship between Sarpagine/Macroline/Ajmaline Alkaloids
2.2.B Bioioggeenneettiicc RReellaattiioonnsshhiipp bbeettwweeeenn SSaarrppaaggiinnee/M/Maaccrorolilninee/A/Ajmjmalailnien eAAlklaklaoliodisd s
The macroline 19 and sarpagine 25 natural products are contained in one of the major classes of
ThTehem macarcorloilninee1 199a anndds saarrppaaggiinnee 2255 nnaattuurraall pprroodduuccttss aarree ccoonnttaainineedd inin oonne eofo tfhteh emmajaojro crlacslasessse osf of
indole alkaloids that originated from common biogenetic intermediates. Although macroline 19 has
inidnodloelea laklaklaoliodidsst hthaatto orirgigininaatteeddf frroomm ccoommmmoonn bbiiooggeenneettiicc iinntteerrmmeeddiaiatetes.s .AAltlhthouoguhg hmmacarcorloinlien 1e91 h9ahs as
not been isolated as an alkaloid itself, it is believed to be a biogenetic precursor for numerous
nontobte beneeinso ilsaoteladteads aans aalnk aalolkiadloitisde lift,sietlifs, bite liise vbeedlietovebde atob bioeg ean beitoicgpenreectiucr sporrecfourrsnourm foerr onuusmalekraoluosid s
alkaloids in this class. (+)-Ajmaline 26, a clinically and historically important alkaloid [20,50–52], is
inatlhkiaslocildasss i.n( +th)-iAs jcmlaaslsi.n (e+)2-6A,jamcalliinniec a2l6ly, aa ncldinhicisatlolyr iacnaldly hiimstoproirctaallnyt iamlkpaolortiadn[t2 a0l,k5a0l–o5i2d] ,[2is0,s5t0r–u5c2tu],r iasl ly
structurally related to the sarpagine alkaloids. These three major types of indole alkaloids are inter-
structurally related to the sarpagine alkaloids. These three major types of indole alkaloids are inter-
relatedtothesarpaginealkaloids. Thesethreemajortypesofindolealkaloidsareinter-relatedthrough
related through their biogenetic origin. To date, this group consists of more than 300 alkaloids which
related through their biogenetic origin. To date, this group consists of more than 300 alkaloids which
theirbiogeneticorigin. Todate,thisgroupconsistsofmorethan300alkaloidswhichcontainmorethan
contain more than 80 bisindole alkaloids [53,54]. A general strategy has been developed to access a
contain more than 80 bisindole alkaloids [53,54]. A general strategy has been developed to access a
80bisindolealkaloids[53,54]. Ageneralstrategyhasbeendevelopedtoaccessacommonintermediate
common intermediate to this series of natural products, the tetracyclic core of which consists of the
common intermediate to this series of natural products, the tetracyclic core of which consists of the
tothisseriesofnaturalproducts,thetetracycliccoreofwhichconsistsoftheazabicyclo[3.3.1]nonane
azabicyclo[3.3.1]nonane system with the (S) configuration at both C-3 and C-5 (Figure 3).
azabicyclo[3.3.1]nonane system with the (S) configuration at both C-3 and C-5 (Figure 3).
systemwiththe(S)configurationatbothC-3andC-5(Figure3).

Figure3.Thesarpagine,macroline,andajmalineindolealkaloids.ThebiogeneticnumberingofLeMen
anFFdiiggTuuarryee l o33r.. hTTahhsee b sseaaerrnppafaoggliilnnoeew,, emmdaa[cc5rr5oo]ll.iinnee,, aanndd aajjmmaalliinnee iinnddoollee aallkkaallooiiddss.. TThhee bbiiooggeenneettiicc nnuummbbeerriinngg ooff
LLeeMMeenn aanndd TTaayylloorr hhaass bbeeeenn ffoolllloowweedd [[5555]]..
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Molecules 2016, 21, 1525 5 of 40
Inasyntheticsense,sarpaginealkaloidscouldoriginatefromaMichael-typereactionoftheN(4)
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In a synthetic sense, sarpagine alkaloids could originate from a Michael-type reaction of the N(4)
nitrogenatomofmacroline19ontothe α,β-unsaturatedcarbonylsystematC-21eitherbya1,2or
nitrogen atom of macroline 19 onto the α,β-unsaturated carbonyl system at C-21 either by a 1,2 or a
a1,4-typeIna da dsyitniothnetrieca scetniosen, ,saasrpiallguinster aaltkeadloiindsF cigouulrde o4ri[g5i4n,a5t6e] f.rOomn ath Meiochthaeelr-thyapned re,athcteiosna orpf tahgei nNe(43)2 can
1,4-type addition reaction, as illustrated in Figure 4 [54,56]. On the other hand, the sarpagine 32 can
nitrogen atom of macroline 19 onto the α,β-unsaturated carbonyl system at C-21 either by a 1,2 or a
beconbev ecrotnevderintetdo imntaoc mroalcinroeli1n9e b1y9 bayr eat rroet-rMo-iMchicahealepl rporcoecsess,s,r ereppoorrtteedd iinn aa bbiioommiimmeetticic sseennses eoroirgiignianllayl lyby
1,4-type addition reaction, as illustrated in Figure 4 [54,56]. On the other hand, the sarpagine 32 can
LeQubeys nLeeQetueasl.n[e5 e7t] a.l. [57].
be converted into macroline 19 by a retro-Michael process, reported in a biomimetic sense originally
by LeQuesne et al. [57].

FigFuirgeur4e. 4In. Itnetrecrocnovnveersrsioionn ooff mmaaccrroolliinnee 1199 anand dsasraprapgaingei n2e5.2 5.
Figure 4. Interconversion of macroline 19 and sarpagine 25.
The biogenetic relationship between these series of alkaloids has been reported previously [58–61].
TShtӧeckbiigotg eetn ael.t iccornevlearttieodn s1h6-ieppib-veetwlloeseimntinhee s3e3as einriteos voinfoarliknael o35idas vhiaa dsebaeceentyrlevpinoorrtiende p34r euvsiionug salcyet[y5l8 –61].
The biogenetic relationship between these series of alkaloids has been reported previously [58–61].
StöckCigotAe dteapl.ecnodnenvte vrtinedor1in6e- espyin-vthealsloe s[i6m2–i6n4e].3 T3haisi nsttuodvyi ncoonrfiinrme3ed5a thvei acodnevaecrseitoynlv oifn tohrei ennedo3-4aludseihnygdea cetyl
Stӧckigt et al. converted 16-epi-vellosimine 33a into vinorine 35a via deacetylvinorine 34 using acetyl
CoAcdoenptaeinndinegn stavrpinaogrinine eskseylnettohna (s3e3[) 6in2t–o6 t4h]e. aTjhmiaslisnteu dskyelceotonnfi (r3m5)e udntdheer accoindvice crosniodnitioofnsth, aes esnudgog-easltdedeh yde
CoA dependent vinorine synthase [62–64]. This study confirmed the conversion of the endo-aldehyde
contaeinarinliegr sbayr pWaogoindewsakredl e(Ftoignu(r3e 35)) i[n5t8o]. theajmalineskeleton(35)underacidicconditions,assuggested
containing sarpagine skeleton (33) into the ajmaline skeleton (35) under acidic conditions, as suggested
earlieerabrlyierW boyo Wdwooadrwda(rFdi g(Fuirgeu5re) 5[5) 8[5].8].

Figure 5. Biosynthetic relationship between sarpagine and ajmaline reported by Stӧckigt et al. [62–64] .
F3i.g GuerenFe5ir.gauBlr iSeo st5ry. aBntiteohgseyytn ittchore eAtilcac rcteieolsanstis othnhispeh iTbpee bttwertaweceyenecnlsi sacar rCppaoaggreiinn 2ee 7aa nondfd athjamjema Slainaleirn preeapgroeirpnteoedr/M tbeyda ScbtrӧyoclkSiintgöte ce/kAt iagjlm.t [e6at2l–ian6l4.e][ .6 2–64].
Related Indole Alkaloids
3. General Strategy to Access the Tetracyclic Core 27 of the Sarpagine/Macroline/Ajmaline
3. GeneralStrategytoAccesstheTetracyclicCore27oftheSarpagine/Macroline/Ajmaline
RelatAedn aInzadboilcey cAlolk[3a.3lo.1i]dnso nane core system 27 is a common feature of the macroline/sarpagine/ajmaline
RelatedIndoleAlkaloids
type indole alakaloids. Thus, a general synthetic strategy for the synthesis of these alkaloids involved
An azabicyclo[3.3.1]nonane core system 27 is a common feature of the macroline/sarpagine/ajmaline
Athne sayznathbeicsiysc olfo t[h3i.s3 c.o1r]en sotnruacntuerec owrieths tyhset ceomrre2c7t sitseraeoccohmemmisotrny afet aptousirteioonfs Cth-3e, Cm-5a carnodl ianpep/rosparripaateg ine/
type indole alakaloids. Thus, a general synthetic strategy for the synthesis of these alkaloids involved
ajmaltfihunene scyttyinoptnheaelis nigsdr ooofu ltpehsias al cato kCrae- l1so5tri duancstd.u TrCeh- w1u6si t,fhoa trhg feeu cnrotehrrreaerlc ftsu syntnecrttehiooencthaicelimzsatirtsiatortyne .ga Tty pof oodsraittiteoh,n ems sCeyt-hn3o,t hCdes-5 sf iaosnr odaf cactphepserssoienpgar iltakhteae loids
involfvuendcttihoneasly gnrtohuepssi sato Cft-h15is acnodr eC-s1t6ru fcotru fruertwheitrh futnhceticoonrarleizcattsiotenr.e Tooc hdeamte,i smtreythaotdpso fsoirt iaocncessCsi-n3g, tCh-e5 and

appropriatefunctionalgroupsatC-15andC-16forfurtherfunctionalization. Todate,methodsfor
acces singthe(±)-azabicyclo[3.3.1]nonane27systemhasbeenreportedbyYoneda[65],Mashimo[66],
Kluge[67]andonlargescalebySoerensetal.[68].
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Molecules2016,21,1525 6of40
(±)-azabicyclo[3.3.1]nonane 27 system has been reported by Yoneda [65], Mashimo [66], Kluge [67]
and on large scale by Soerens et al. [68].
ThTehsey snytnhtehseissiso off tthhee ooppttiiccaallllyy aacctitvive e(−()−-te)-ttreatcryacclyicc cliocrec owraesw acahsieavcehdie bvye ZdhbayngZ ehta anl.g [6e9t] ainl. 1[96898] in
198in8 ian satesrteeoresopsepciefcici fifcasfhasiohnio wnhwichhic hememplopyloeyde dthteh easaysmymmmetreitcr iPciPctiectt-eStp-Sepnegnlegrl errearectaicotnio. nN.uNmuemroeuros us
adajudsjutmstemnetnsths ahvaeveb ebeenenm madadeet otob beettteterra acccceessss tthhiiss mmooiieettyy wwiitthh bbootthh NNaa-H-H aanndd NNa-aM-Me feufnucnticotnioanliatileisti es
ovoevrethr ethyee yaerasr.sT. hTehep prerseesenntts strtraatteeggyy iiss iilllluussttrraatteedd iinn SScchheemmee 11. .CCuurrrernetnlytl,y t,hteh ePiPctiectt-eSt-pSepnegnlegrl ererarcetaioctni on
iscisa rcrairerdieodu otuitn ino noenep poottu unnddeerrc coonnddiittiioonnss tthhaatt ppeerrmmiitt eeppiimmeerriizzaatitoionn aat tCC-1- 1tot oprporvoivdied oenolyn ltyheth deesdieresdir ed
tratnras-nds-idasiatestreeroemomerer3 83.8.D D--((++))--ttrryyppttoopphhaann mmeetthhyyl leessteter r3377 isi sccoommmmerecricailalyll yavaavilaaiblaleb lbeubt uctanca anlsaol sboe be
preppreapreadrefdr ofrmomD -D(+-()+-)t-rtyrypptotopphhaann3 366b byy FFiisscchheerr eesstteerriiffiiccaattiioonn oonn 440000 ggraramm scsaclael.e .

SScchheemmee 1. 1G.eneral Gsteranteergayl to satcrcaetses gthye tettoracyacclcice kssetonthese whtiecthr accoynctaliicn thke eatzoanbeicsyclow[3h.i3c.1h]nocnoanntea siynstemth.e
azabicyclo[3.3.1]nonanesystem.
The Nb-benzylation was done on amine 37 with benzaldehyde in methanol at room temperature,
folTlohweeNd b-yb ernedzyulcattiioonn owf tahsed soon feoromneadm iimnien3iu7mw iiothn bseanltz walidthe hsoyddieuimn mboertohhayndorlidaet raododmedt esmlopwelrya ttou re,
b
the mixture at −10 °C. Subsequently, trifluoroacectic acid was added to the mixture at 0 °C to bring
followed by reduction of the so formed iminium ion salt with sodium borohydride added slowly
totthhee pmHi xttou r7e. aAtft−er1 0re◦mCo.vSaul bosf etqhuee snotllvye,ntrt,i flmueotrhoyalecneec ticchlaocriiddew, tarsiflaudodroeadcettoict haceidm (iTxFtuAr)e aantd0 4◦,C4-to
dimethoxybutyrate were added to the mixture at 0 °C and this was stirred for 10 days at room
bring the pH to 7. After removal of the solvent, methylene chloride, trifluoroacetic acid (TFA)
antdem4,p4e-rdaitmureet htoo xyyibeuldt ytrhaet etrwanesr-ediaedstdere d38t oint h8e3%m ixytiuelrde aast 0th◦eC soalne dprthodisucwt a[s70s]t.i rTrehdis fcooru1ld0 dbea ys
accomplished in refluxing chloroform in one day in slightly lower yield. Next, the Dieckmann
atroomtemperaturetoyieldthetrans-diester38in83%yieldasthesoleproduct[70]. Thiscould
cyclization was done in the presence of a large excess of NaOMe and methanol in toluene at reflux for
be accomplished in refluxing chloroform in one day in slightly lower yield. Next, the Dieckmann
72 h (6 h for the Na-Me indole) to yield the cyclized product. At the completion of the reaction, the
cyclizationwasdoneinthepresenceofalargeexcessofNaOMeandmethanolintolueneatreflux
reaction mixture was cooled to 0 °C and the excess base was neutralized with glacial acetic acid and the
for72h(6hfortheN -Meindole)toyieldthecyclizedproduct. Atthecompletionofthereaction,
solvent was removeda under reduced pressure. After that, glacial acetic acid and aqueous hydrochloric
thereactionmixturewascooledto0◦Candtheexcessbasewasneutralizedwithglacialaceticacid
acid as well as water were added to the mixture and it was allowed to reflux under these strongly acidic
and the solvent was removed under reduced pressure. After that, glacial acetic acid and aqueous
conditions to furnish the product of decarboxylation. This gave Nb-benzyl tetracyclic ketone 39, in 80%
hyodvroercahlll oyriieclda coind laarsgwe seclallaes. Fwoar ttehre wNea-rMeea dsedreieds,t othteh teramnsi-xdtiuersetear n3d8 witaws maseathllyolwateedd utosirnegfl iuoxdoumndetehratnhee se
straonndg lsyodaicuidmic hcyodnrdidieti oinn DstMoFfu torn yiisehldt htheep Nroa-dMuec ttroafnds-edciaersbteorx 4y0l ainti o>9n5.%T hyiiselgda, vwehNicbh- buenndzeyr lthteet rsaacmyec lic
ketcoonned3it9io,nins 8a0s %38o gvaevrael lthyeie Nlda-oMnel atertgreacsycaclliec. kFeotrotnhee 4N1 ai-nM ae osneer-ipeso,tt hperotcreasnss.- dTiheisst eroru3t8e wisa sstimll eotnhey loaft ed
usitnheg iboedsto mroeuttheasn seinacned rseoadctiiuomns hcyadn rbidee dinonDe MonF tmouylitei-lhdutnhdereNda -gMraemtr asncasl-edsi easntedr d40o inno>t 9r5e%quyiriee ld,
which under the same conditions as 38 gave the N -Me tetracyclic ketone 41 in a one-pot process.
a

Thisrouteisstilloneofthebestroutessincereactionscanbedoneonmulti-hundredgramscales
and do not require protection of the N -H function. This is an enantioselective and regioselective
a
Molecules2016,21,1525 7of40
Molecules 2016, 21, 1525 7 of 40
processin>98%ee. Thisroutewithtwoonepotconversionsalsorequiresfewerstepsthanprevious
protection of the Na-H function. This is an enantioselective and regioselective process in >98% ee. This
routes [69–71]. In addition, the availability of D-(+)-tryptophan and the (−)-enantiomer provides
route with two one pot conversions also requires fewer steps than previous routes [69–71]. In addition,
a route to both enantiomers of the alkaloids including the ability to condense mismatched pairs,
the availability of D-(+)-tryptophan and the (−)-enantiomer provides a route to both enantiomers of the
asmentioned.
alkaloids including the ability to condense mismatched pairs, as mentioned.
4. PartialandTotalSynthesisofBisindoleAlkaloids
4. Partial and Total Synthesis of Bisindole Alkaloids
4.1. (−)-Alstonisidine
4.1. (−)-Alstonisidine
(−)-AlstonisidinewasisolatedfromthebarkofAlstoniamuellerianaDomin,alongwithseveral
(−)-Alstonisidine was isolated from the bark of Alstonia muelleriana Domin, along with several
otheralkaloidsbyElderfieldetal. andLeQuesneetal.[72,73]. Thestructureof(−)-alstonisidine13
other alkaloids by Elderfield et al. and LeQuesne et al. [72,73]. The structure of (−)-alstonisidine 13
wawsares preoprtoerdteidn i1n9 179272b ybyL eLQeQuuesensneee etta al.l.[ [7744,,7755]]
ThTehset rsutrcutuctrueroef o1f 313w wasasp proroppoosseedd,,i nina a bbiioommiimmeettiicc sseennssee,, ffoorr ((−−)-)a-lasltsotnoinsiidsiidnien ferofrmo mitsi ctsoncostnitsutietnute nt
momnoonmoemriecriucn uitnsi,ts(+, ()+-q)-uqeuberbarcahchididininee2 200a anndd( (++))--mmaaccrroolliinnee 1199.. TThhee ccrryysstatal lsstrtuructcuturer eofo (f−()−-a)l-satolsntoisnidisiindei ne
wawsausl tuimltiamtealtyelrye preoprtoerdtebdy bHy oHaordaridn i1n9 17977w7 hwichhiccho cnofinrfmirmededth tehset rsutrcutcutruerae sa1s 313(F (iFgiugruere6 )6[)7 [67]6.]W. Whheennt he
mitxhteu mreixotfu1r9e oafn 1d9 2a0ndw 2a0s wstaisr rsetidrriend0 in.2 0N.2 aNq auqeuoeuosuHs HCCl,l,t htheel laabbiillee hheemmiikkeettaall 4422 foformrmede,d a,sa isndinicdaitceadt ed
bybeyx aexmaimnaintiaotinono fotfh tehes pspecetcrtaralld daatata.. TThhee tteennttaattiivvee sstteerreeoocchheemmisistrtyry wwasa sbabsaesde dono nthteh setrsutrcutucrteu roef othfet he
bublkuylkqyu qeuberbarcahcihdiidnineeu unnititw whhicichhb boorree aa ––CCHH22–– ggrroouupp wwhhicichh sshhoouuldld ococcucpuyp ythteh eeqeuqautoartioarli aplopsiotisointi.o n.
ThTehhee hmemikiekteatlalw waasst trreeaatteedd wwiitthh bboorroonn trtirfilfluouroidried eetheethraetrea ttoe ytoielydi ealldstoanlsistoidniinsei dwinheichw shuigchgessutegdg tehset ed
thestsrturcutcutruer 4e24 a2sa asna inntienrtmeremdieadteia, tsein,csein ncoe rneoacrteioanct ioocncuorcrecdu rurenddeur nthdee rsathmee scaomndeictioonnds ibtieotwnseebne t(w+)e-en
quebrachidine 20 and (+)-macroline 19 [75].
(+)-quebrachidine20and(+)-macroline19[75].

FigFuigreur6e. 6S.t rSutrcutuctruerseos fo(f+ ()+-)q-quueebbaacchhididiinnee ((2200)),, ((++))--mmaaccrroolliinnee ((1199),) ,aanndd (−()−-a)l-satlosntoisnidisiindei n(1e3()1. 3).
ThTishbisio mbioimmeitmicestyicn tshyensitshoesfi(s− o)-fa l(s−to)-nailssitdoinniesi1d3ineem p13lo yeemdptlhoeybeido gtehnee tbiciopgreencuetrisco rpsr(e+c)u-mrsaocrrso l(i+n)e-19
macroline 19 and (+)-quebrachidine 20. Although macroline has never been isolated as a natural
and (+)-quebrachidine 20. Although macroline has never been isolated as a natural product,
product, it is widely agreed to be a biogenetic precursor for (−)-alstonerine [77], (−)-alstophylline [78], and
it is widely agreed to be a biogenetic precursor for (−)-alstonerine [77], (−)-alstophylline [78],
(+)-alstonisine [72] and may be present in very small steady-state concentrations in plants. Furthermore,
and (+)-alstonisine [72] and may be present in very small steady-state concentrations in plants.
the isolation of traces of (+)-quebrachidine from A. muelleriana further strengthened this proposed
Furthermore, the isolation of traces of (+)-quebrachidine from A. muelleriana further strengthened
biogenetic route. (+)-Quebrachidine 20 has been isolated from Vinca libanotica [79], Ochrosia acuminate [80],
this proposed biogenetic route. (+)-Quebrachidine 20 has been isolated from Vinca libanotica [79],
Alstonia muelleriana [77], and the leaves of Aspidosperma quebracho blanco Schletch [81] and its structure
Ochrosia acuminate [80], Alstonia muelleriana [77], and the leaves of Aspidosperma quebracho blanco
was proposed to be 20 based on the studies by NMR and mass spectroscopy [82]. Four aromatic
Schletch [81] and its structure was proposed to be 20 based on the studies by NMR and mass
proton multiplets (δ = 6.6 to 7.2) indicated it contained an unsubstituted aromatic ring, accompanied
spectroscopy [82]. Four aromatic proton multiplets (δ = 6.6 to 7.2) indicated it contained
by an ethylidene group. Examination of the Infrared spectrum indicated the presence of N-H (3590 cm−1),
anOu-nHs u(b33st7i0tu ctmed−1)a raonmd aati ccarrinbogm,aectchoomxypl a(n1i7e2d2,b 1y2a35n ecmth−y1 liadnedn e1Hg rsoiungpl.eEt xaat mδ in= a3t.i6o)n gorfotuhpe. IUnpfroanr ed
speaccetrtuylmatiionnd, itchaet ecdomthpeoupnreds geanvcee ao fdNiac-Heta(t3e5. 9A0ncamlys−i1s) o,fO th-He N(3M37R0, IcRm a−n1d) UanVd spaeccatrrab oomf theteh doixaycelt(a1t7e2 2,
123in5dcimca−te1da nthde1 pHressinengcleet oaft aδ =se3co.6n)dgarroyu pal.cUohpooln aancde tay ldaithioynd,rothinedcoolme pnoiturongdegna avteomad. Aianceatlaytseis. Aofn tahlye sis
ofmthaessN sMpeRct,rIuRma fnudrthUeVr sstpreencgtrtaheonfetdh tehde iparcoeptaotseedin sdtriucacttuedre tohfe (+p)r-eqsueenbcreacohfidainsee ctoon bdea 2r0y [a82lc]o. holand
adihydInro tihned boiloemniimtreotgice pnaarttioaml s.yAntnhaelsyiss iosf o(−f)t-halestmonaisssidsipnee c1t3r u[8m3],f u(+r)t-hmearcsrtorleinneg 1th9e wnaesd ptrheepaprreodp boys ed
strduecgturaredaotfio(n+ )o-qf uveilblarmacihnied (innoett oshboew2n0) [b8y2 ]t.he method of Schmid et al. [84]. (+)-Macroline 19 reacted
Molecules2016,21,1525 8of40
Inthebiomimeticpartialsynthesisof(−)-alstonisidine13[83],(+)-macroline19waspreparedby
Molecules 2016, 21, 1525 8 of 40
degradationofvillamine(notshown)bythemethodofSchmidetal.[84]. (+)-Macroline19reacted
wwiitthh nnaattuurraallllyy ooccccuurrrriinngg ((++))--qquueebbrraacchhiiddiinnee 2200 uunnddeerr mmiillddllyy aacciiddiicc ccoonnddiittiioonnss aatt 2200 °◦CC ((SScchheemmee 22))..
IInniittiiaallllyy mmaaccrroolliinneeu unnddeerwrweenntta aM Micihcahealerle raecaticotniown iwthitthh ethined ionldinoelinniet rnoigtreongaetno matoomfq uofe bqruaecbhridacinheidainnde
saunbds seuqbuseenqtulyenutnlyd uenrwdeernwteinnttr ianmtroamlecoulelacurlcayrc clyizcalitzioatniotno tfoo rfomrmth tehaem aminionoh ehmemikiketeatlal4 422..T Thhiiss hheemmiikkeettaall
ssppeecciieess wwaass ffoouunndd toto beb ehihgihglhyl ylablailbei lteo taociadc isdinscien icte reitverersveedr steod thtoe stthaertsintagr tminagtemriaaltse 1ri9a lasn1d9 2a0n udpo2n0
uwpaormnwinagr, masin wg,ealls aws eullnadseur nsdtreornsgteror nagceidriacc cidoincdciotinodnist iaonnds adnudridnugr cinhgrocmhraotomgartaopghrya.p Fhoy.rtFuonratutenlya,t enlyo,
notohoerth ceormcopmoupnodusn wdserwe eorbesoebrvseerdv eedxceexpct etphtet hstearsttianrgti nmgamteraitaelrsi a1l9s 1a9nda n2d0.2 T0.hTe hneenwe windinodleo l4e24 h2ahda da
ammoloecleucluarla wrweiegihgth otfo f69609 0anandd exexamamininataitoinon oof fththee IRIR ssppeeccttrruumm iinnddiiccaatteedd tthhee pprreesseennccee ooff oonnllyy oonnee
ccaarrbboonnyyll ppeeaakk ((11773355 ccmm−−11) )wwhhicichh iinnddiiccaatteedd tthhaatt aafftteerr tthhee iinniittiiaall 11,,44--ccoonnjjuuggaattee aaddddiittiioonn hhaadd ooccccuurreedd,,
tthhee ssoo ffoorrmmeedd kkeettoonnee oonn tthhee mmaaccrroolliinnee uunniitt rreeaacctteedd iinnttrraammoolleeccuullaarrllyy wwiitthh tthhee ––CCHH22OOHH ggrroouupp ttoo ffoorrmm
tthhee ccoorrrreessppoonnddiinngg hheemmii--kkeettaall pprreesseenntt iinn 4422.. WWhheenn hheemmiikkeettaall 4422 wwaass ttrreeaatteedd wwiitthh bboorroonn ttrriiflfluuoorriiddee aatt
00 ◦°CCf ofro6r h6, thhe, etlheec treolpechtirliocpahriolmic aatircosmubatsitcit ustuiobnsttiotuotkiopnla cteo,ookr thpolatoceth, eoartmhoin otog rtohuep aomfqinuoe bgrarcohuipd inoef
tqoufeobrrmacthhideitneetr taoh fyodrmro pthyer atentrwahhyicdhrowpaysriannd wishtiincghu wisahsa ibnldeifsrtoinmguthisehnaabtlue rfarollmy othcceu nrartiungraalllyst oocnciusirdriinnge
1a3ls(tSocnhiseimdien2e) 1f3r o(mSchAe.mmeu 2el)l efrrioamna A[7. 7m,8u3e]l.leriana [77,83].

SScchheemmee2 2..B Biioommiimmeettiiccp paarrttiaialls syynntthheessisiso off( (−−))--1133 bbyy LLeeQQuueessnnee eett aall. [[7755]]..
The total synthesis of (−)-alstonisidine has not been reported yet. Extensive work has been done
The total synthesis of (−)-alstonisidine has not been reported yet. Extensive work has been
toward its monomeric constituents 19 and 20. To date, The Milwaukee group has achieved the total
done toward its monomeric constituents 19 and 20. To date, The Milwaukee group has achieved
synthesis of (+)-macroline 19 [85–88] and the enantiomer of macroline as well [89]. Besides an
thetotalsynthesisof(+)-macroline19[85–88]andtheenantiomerofmacrolineaswell[89]. Besides
advanced intermediate for 20, the synthesis of quebrachidine diol (not shown) has been reported as
anadvancedintermediatefor20,thesynthesisofquebrachidinediol(notshown)hasbeenreported
well [90]. The partial synthesis of (−)-alstonisidine has been completed, to date, from synthetic (+)-
aswell[90]. Thepartialsynthesisof(−)-alstonisidinehasbeencompleted,todate,fromsynthetic
macroline 19 and natural (+)-quebrachidine 20. The total synthesis of bisindole 13 awaits the total
(+)-macroline19andnatural(+)-quebrachidine20. Thetotalsynthesisofbisindole13awaitsthetotal
synthesis of 20.
synthesisof20.
The earliest synthesis of (+)-macroline 19, a biomimetic synthesis, was done by LeQuesne et al.
Theearliestsynthesisof(+)-macroline19,abiomimeticsynthesis,wasdonebyLeQuesneetal. in
in 1980 [57] and the absolute configuration had been confirmed by X-ray crystallography by Hesse in
1980[57]andtheabsoluteconfigurationhadbeenconfirmedbyX-raycrystallographybyHessein
1981 [91]. In this synthesis, LeQuesne et al. converted (−)-perivine 43 to (+)-normacusine 44, according
1981[91]. Inthissynthesis,LeQuesneetal. converted(−)-perivine43to(+)-normacusine44,according
to the reported procedure by Gorman et al. (Scheme 3) [92]. The protection of the hydroxyl group (in
tothereportedprocedurebyGormanetal.(Scheme3)[92].Theprotectionofthehydroxylgroup(in44)
44) as the tert-butyldimethylsilyl ether, was followed by Na-methylation to furnish the sarpagine
asthetert-butyldimethylsilylether,wasfollowedbyN -methylationtofurnishthesarpaginesystem45.
a
system 45. Osmylation of olefin 45 with OsO4 and pyridine in THF gave an inseparable mixture which
Osmylationofolefin45withOsO andpyridineinTHFgaveaninseparablemixturewhichcontained
4
contained the diol 46, along with a related spirooxindole byproduct. The bulky TBDMS function rendered
the diol 46, along with a related spirooxindole byproduct. The bulky TBDMS function rendered
the osmylation sequence stereoselective, although marred by the formation of the spirooxindole side-
the osmylation sequence stereoselective, although marred by the formation of the spirooxindole
product. This mixture was treated with TsCl and Py, followed by NaH in THF to give the epoxide 47
side-product. ThismixturewastreatedwithTsClandPy,followedbyNaHinTHFtogivetheepoxide
that could be purified by crystallization. The epoxide underwent rearrangement on treatment with
47thatcouldbepurifiedbycrystallization. Theepoxideunderwentrearrangementontreatmentwith
freshly prepared MgBr2 to furnish the ketone 48. The methylation of the Nb function was performed
freshlypreparedMgBr tofurnishtheketone48. ThemethylationoftheN functionwasperformed
with dimethyl sulfate a2nd potassium carbonate, in refluxing benzene. This bwas followed by the retro-
with dimethyl sulfate and potassium carbonate, in refluxing benzene. This was followed by the
Michael reaction in base followed by desilylation with TBAF to provide (+)-macroline 19 [57].
retro-MichaelreactioninbasefollowedbydesilylationwithTBAFtoprovide(+)-macroline19[57].
Molecules2016,21,1525 9of40
Molecules 2016, 21, 1525 9 of 40

Scheme 3. Biomimetic partial synthesis of (+)-19 by LeQuesne et al [57].
Scheme3.Biomimeticpartialsynthesisof(+)-19byLeQuesneetal.[57].
In an enantiospecific synthetic approach to (+)-macroline [85,86], the readily available Nb-benzyl
Inanenantiospecificsyntheticapproachto(+)-macroline[85,86],thereadilyavailableN -benzyl
tetracyclic ketone [93–95] intermediate 41, available on 300 gram scale, was converted binto the
tetracyclic ketone [93–95] intermediate 41, available on 300 gram scale, was converted into the
corresponding Nb-methyl indole compound 49 by methylation with methyl triflate followed by
corresponding N -methyl indole compound 49 by methylation with methyl triflate followed by
catalytic debenzyblation to form the Nb-methyl system in 84% yield (Scheme 4). The ketone 49 was
catalytic debenzylation to form the N -methyl system in 84% yield (Scheme 4). The ketone 49
reacted with the anion of chloromethbyl phenyl sulfoxide (LDA, THF, −78 °C) to generate the
wasreactedwiththeanionofchloromethylphenylsulfoxide(LDA,THF, −78 ◦C)togeneratethe
corresponding chlorohydrin. This chlorohydrin, upon stirring in a heterogeneous solution of 10 N
correspondingchlorohydrin.Thischlorohydrin,uponstirringinaheterogeneoussolutionof10NKOH
KOH in THF at 25 °C for 24 h produced the corresponding spirooxirane and this was followed by
inTHFat25◦Cfor24hproducedthecorrespondingspirooxiraneandthiswasfollowedbytreatment
treatment with LiClO4 and PO(n-Bu)3 in refluxing toluene to produce the α,β-unsaturated aldehyde
with LiClO and PO(n-Bu) in refluxing toluene to produce the α,β-unsaturated aldehyde 50 [96].
50 [96]. Che4mo-selective red3uction of the aldehyde with lithium aluminum hydride in ether at −20 °C
Chemo-selectivereductionofthealdehydewithlithiumaluminumhydrideinetherat−20◦Cgave
gave the allylic alcohol 51. Michael addition of the alcohol to 3-butyn-2-one 52 provided the desired
theallylicalcohol51. Michaeladditionofthealcoholto3-butyn-2-one52providedthedesiredenone
enone ether 53 in 92% yield. The Claisen rearrangement of the enone ether produced the β-dicarbonyl
ether 53 in 92% yield. The Claisen rearrangement of the enone ether produced the β-dicarbonyl
compound 54, which was subsequently reduced with sodium borohydride to give the corresponding
compound54,whichwassubsequentlyreducedwithsodiumborohydridetogivethecorresponding
diol 55. The 1,3-diol functionality was protected as an acetonide 56 using acetone dimethyl acetal in
diol55. The1,3-diolfunctionalitywasprotectedasanacetonide56usingacetonedimethylacetalin
the presence of p-toluenesulfonic acid. The hydroboration of the olefin in 56 with 9-BBN occurred in
thepresenceofp-toluenesulfonicacid. Thehydroborationoftheolefinin56with9-BBNoccurredin
a stereospecific fashion and this was followed by oxidation with a basic solution of hydrogen peroxide,
astereospecificfashionandthiswasfollowedbyoxidationwithabasicsolutionofhydrogenperoxide,
under classical conditions, to furnish the C-17 primary alcohol 57. The hydroxyl group of monol 57 was
underclassicalconditions,tofurnishtheC-17primaryalcohol57. Thehydroxylgroupofmonol57
protected as the t-butyldimethylsilyl ether, and subsequent selective removal of the acetonide was done
wasprotectedasthet-butyldimethylsilylether,andsubsequentselectiveremovaloftheacetonidewas
using p-toluenesulfonic acid in dry methanol to provide diol 58. To access the α,β-unsaturated carbonyl
doneusingp-toluenesulfonicacidindrymethanoltoprovidediol58. Toaccesstheα,β-unsaturated
system in macroline, it was planned to use the tosylate of the C-18 hydroxyl group as the leaving group.
carbonylsysteminmacroline,itwasplannedtousethetosylateoftheC-18hydroxylgroupasthe
But the tosylation with tosyl chloride and pyridine in DCM was not successful, and mesylation took
leavinggroup. ButthetosylationwithtosylchlorideandpyridineinDCMwasnotsuccessful,and
place with very poor regioselectivity. Based upon a precedent by Helquist et al. [97], acetylation with
mesylationtookplacewithverypoorregioselectivity. BaseduponaprecedentbyHelquistetal.[97],
acetic anhydride worked both as a protecting group and leaving group. The so formed monoacetate
acetylationwithaceticanhydrideworkedbothasaprotectinggroupandleavinggroup.Thesoformed
was subjected to PDC oxidation. The acetate group underwent elimination spontaneously upon oxidation
monoacetatewassubjectedtoPDCoxidation.Theacetategroupunderwenteliminationspontaneously
to provide the stable TBDMS protected macroline equivalent 59a, which could be stored in a vial. The silyl
upon oxidation to provide the stable TBDMS protected macroline equivalent 59a, which could be
ether was deprotected with tetrabutylammonium fluoride in THF to provide (+)-macroline 19 identical to
storedinavial. ThesilyletherwasdeprotectedwithtetrabutylammoniumfluorideinTHFtoprovide
the natural material obtained from villamine by Schmid et al. [84].
(+)-macroline19identicaltothenaturalmaterialobtainedfromvillaminebySchmidetal.[84].
Molecules2016,21,1525 10of40
Molecules 2016, 21, 1525 10 of 40

SScchheemmee 44.. EEnnaannttiioossppeecciifificc ttoottaall ssyynntthheessiiss ooff ((++))--1199 bbyy BBii eett aall. [[8855]]..
In another more recent and improved approach (Scheme 5) [87,88], Nb-alkylation via SN2
In another more recent and improved approach (Scheme 5) [87,88], N -alkylation via S 2
substitution on (Z)-1-bromo-2-iodo-2-butene 61 in the presence of K2CO3 in refbluxing THF gave tNhe
substitution on (Z)-1-bromo-2-iodo-2-butene 61 in the presence of K CO in refluxing THF gave
2 3
vinyl iodide 62. The palladium catalyzed intramolecular cyclization of the enolate anion with the
thevinyliodide62. Thepalladiumcatalyzedintramolecularcyclizationoftheenolateanionwiththe
vinyl iodide took place in a stereospecific manner to yield the pentacyclic ketone 63. A one-carbon
vinyliodidetookplaceinastereospecificmannertoyieldthepentacyclicketone63. Aone-carbon
homologation via Wittig olefination with methoxymethyl triphenylphosphonium chloride with
homologation via Wittig olefination with methoxymethyl triphenylphosphonium chloride with
potassium tert-butoxide in benzene, followed by hydrolysis of the so formed enol ether 64 in aqueous
potassium tert-butoxide in benzene, followed by hydrolysis of the so formed enol ether 64 in
HCl/THF furnished the α-aldehyde 65 ((+)-Na-methylvellosimine; an alkaloid isolated from Alstonia
aqueousHCl/THFfurnishedtheα-aldehyde65((+)-N -methylvellosimine;analkaloidisolatedfrom
a
nitida [98]). The aldehyde was reduced with sodium borohydride to provide (+)-affinisine 66, another
Alstonianitida[98]). Thealdehydewasreducedwithsodiumborohydridetoprovide(+)-affinisine66,
alkaloid obtained from A. macrophylla [99]. The protection of the primary alcohol as the TIPS ether
anotheralkaloidobtainedfromA.macrophylla[99]. TheprotectionoftheprimaryalcoholastheTIPS
with triisopropylsilyl triflate and 2,6-lutidine gave indole 67. The hydroboration-oxidation of the
etherwithtriisopropylsilyltriflateand2,6-lutidinegaveindole67. Thehydroboration-oxidationofthe
olefin in 67 went smoothly to provide the secondary alcohol 68 in very good yield, accompanied by
olefin in 67 went smoothly to provide the secondary alcohol 68 in very good yield, accompanied
a small amount of the corresponding tertiary alcohol. An equivalent of BH3 is known to complex with
by a small amount of the corresponding tertiary alcohol. An equivalent of BH is known to
3
the Nb-nitrogen function which alters the electronic character in the vicinity of the olefin, which
complex with the N -nitrogen function which alters the electronic character in the vicinity of
presumably resulted bin the formation of the small amount of tertiary alcohol. The Dess-Martin
the olefin, which presumably resulted in the formation of the small amount of tertiary alcohol.
periodinane-mediated oxidation of the alcohol 68 to the ketone 69 took place in high yield. The
The Dess-Martin periodinane-mediated oxidation of the alcohol 68 to the ketone 69 took place in
hqiugahteyrineilzda.tTiohne oqfu tahteer Nnibz-antiitornogoefnt hweiNth -mniettrhoygle niowdiidthe mine TthHyFl iaotd 0id °eCi,n wTaHsF foaltlo0w◦Ced, wbays tfroelaltomweendt boyf
the so formed Nb-methiodide salt with bpotassium tert-butoxide in ethanol under modified conditions
treatmentofthesoformedN -methiodidesaltwithpotassiumtert-butoxideinethanolundermodified
to provide the stable macrolibne equivalent 59b. Again, this intermediate can be easily stored. The de-
conditions to provide the stable macroline equivalent 59b. Again, this intermediate can be easily
silylation with tetrabutylammonium fluoride resulted in the synthesis of (+)-macroline 19 identical
stored. Thede-silylationwithtetrabutylammoniumfluorideresultedinthesynthesisof(+)-macroline
to that obtained above in much higher overall yield and fewer steps. These reactions could be scaled
19identicaltothatobtainedaboveinmuchhigheroverallyieldandfewersteps. Thesereactionscould
up with ease as well.
bescaledupwitheaseaswell.