Attempted Synthesis of Vinca Alkaloids Condensed with Three-Membered Rings

21 Pages·2017·2.15 MB·English

molecules
Article
Attempted Synthesis of Vinca Alkaloids Condensed
with Three-Membered Rings
AndrásKeglevich1,SzabolcsMayer1,RékaPápai2,ÁronSzigetvári3,ZsuzsannaSánta3,
MiklósDékány3,CsabaSzántayJr.3,PéterKeglevich1,*andLászlóHazai1
1 DepartmentofOrganicChemistryandTechnology,UniversityofTechnologyandEconomics,Budapest,
Hungary,H-1111Budapest,Gellérttér4.,Hungary;[email protected](A.K.);
[email protected](S.M.);[email protected](L.H.)
2 ComInnex,Inc.,GraphisoftPark(BuildingD),H-1031Budapest,Záhonyu.7.,Hungary;[email protected]
3 SpectroscopicResearchDepartment,GedeonRichterPlc.,H-1475Budapest10,P.O.Box27,Hungary;
[email protected](Á.S.);[email protected](Z.S.);[email protected](M.D.);
[email protected](C.S.J.)
* Correspondence:[email protected];Tel.:[phone]
(cid:1)(cid:2)(cid:3)(cid:1)(cid:4)(cid:5)(cid:6)(cid:7)(cid:8)(cid:1)
(cid:1)(cid:2)(cid:3)(cid:4)(cid:5)(cid:6)(cid:7)
Received:30August2018;Accepted:2October2018;Published:9October2018
Abstract: Oursuccessfulworkforthesynthesisofcyclopropanatedvinblastineanditsderivatives
bytheSimmons–Smithreactionwasfollowedtobuildupfurtherthree-memberedringsintothe
14,15-positionofthevindolinepartofthedimeralkaloid. Halogenated14,15-cyclopropanovindoline
waspreparedbyreactionswithiodoformandbromoform,respectively,inthepresenceofdiethylzinc.
Reactions of dichlorocarbene with vindoline resulted in the 10-formyl derivative. Unexpectedly,
inthecaseofthedimeralkaloidsvinblastineandvincristine,therearrangedproductscontainingan
oxiraneringinthecatharanthinepartwereisolatedfromthereactions. Theattemptedepoxidation
of vindoline and catharanthine also led to anomalous rearranged products. In the epoxidation
reactionofvindoline,ano-quinonoidderivativewasobtained,inthecourseoftheepoxidationof
catharanthine,ahydroxyindoleninetypeproductandaspiroderivativeformedbyringcontraction
reaction,wereisolated. Thecouplingreactionofvindolineandthespiroderivativeobtainedinthe
epoxidationofcatharanthinedidnotresultinabisindolealkaloid. Instead,twosurprisingvindoline
trimerswerediscoveredandcharacterizedbyNMRspectroscopyandmassspectrometry.
Keywords: halogencyclopropane; dichlorocarbene; epoxidation; vindoline; catharanthine; dimer
alkaloids;vindolinetrimer
1. Introduction
The“dimeralkaloids”vinblastine(vincaleukoblastine,VLB,1)andvincristine(VCR,2)(Figure1),
isolatedfromtheMadagascarperiwinkleCatharanthusroseus,belongtothefamilyoftheso-called
“bisindole”alkaloids[1–5]. Theirstructurecomprisestwoindole-related“monomers”: derivativesof
catharanthine(3)andvindoline(4). VLB(1),VCR(2)andsomeoftheiranalogsareanti-microtubule
drugsthathavebeenplayinganimportantroleincancerchemotherapyfordecades[6–10],andthere
are still many ongoing medicinal chemistry projects targeted at synthesizing new derivatives to
improvethetherapeuticeffectofthisfamilyofdrugsbyincreasingtheirselectivityorreducingtheir
toxicity[11,12].
Molecules2018,23,2574;doi:10.3390/molecules23102574 www.mdpi.com/journal/molecules
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MMoolleeccuulleess 22001188,, 2233,, xx FFOORR PPEEEERR RREEVVIIEEWW 22 ooff 2211

FFFiiiggguuurrreee 111... TTThhheee aaalllkkkaaallloooiiidddsss vvviiinnnbbblllaaassstttiiinnneee (((111))),,, vvviiinnncccrrriiissstttiiinnneee (((222))),,, cccaaattthhhaaarrraaannnttthhhiiinnneee (((333))) aaannnddd vvviiinnndddooollliiinnneee (((444)))...
It is interesting to note that relatively minor changes in the bisindole structure can result
IItt iiss iinntteerreessttiinngg ttoo nnoottee tthhaatt rreellaattiivveellyy mmiinnoorr cchhaannggeess iinn tthhee bbiissiinnddoollee ssttrruuccttuurree ccaann rreessuulltt iinn
in major changes in the biological activity. For example, one of the simplest such modification
mmaajjoorr cchhaannggeess iinn tthhee bbiioollooggiiccaall aaccttiivviittyy.. FFoorr eexxaammppllee,, oonnee ooff tthhee ssiimmpplleesstt ssuucchh mmooddiiffiiccaattiioonn iiss tthhee
is the catalytic hydrogenation of the olefinic bond in the vindoline part of VLB (1), leading to
ccaattaallyyttiicc hhyyddrrooggeennaattiioonn ooff tthhee oolleeffiinniicc bboonndd iinn tthhee vviinnddoolliinnee ppaarrtt ooff VVLLBB ((11)),, lleeaaddiinngg ttoo
14,15-dihydrovinblastine (5), whose antitumor activity is significantly lower than that of VLB (1)
1144,,1155--ddiihhyyddrroovviinnbbllaassttiinnee ((55)),, wwhhoossee aannttiittuummoorr aaccttiivviittyy iiss ssiiggnniiffiiccaannttllyy lloowweerr tthhaann tthhaatt ooff VVLLBB ((11))
(Figure2)[13]. Ontheotherhand,ifinsteadofonlybeingsaturated,thereisalsoamethylenebridge
((FFiigguurree 22)) [[1133]].. OOnn tthhee ootthheerr hhaanndd,, iiff iinnsstteeaadd ooff oonnllyy bbeeiinngg ssaattuurraatteedd,, tthheerree iiss aallssoo aa mmeetthhyylleennee bbrriiddggee
connectingC-14andC-15,theresultingcompound’sbioactivitychangesdramatically. Inourprevious
ccoonnnneeccttiinngg CC--1144 aanndd CC--1155,, tthhee rreessuullttiinngg ccoommppoouunndd’’ss bbiiooaaccttiivviittyy cchhaannggeess ddrraammaattiiccaallllyy.. IInn oouurr
work[14–16]wesynthesizeddifferentkindsofbisindolealkaloidscondensedwithacyclopropanering
pprreevviioouuss wwoorrkk [[1144––1166]] wwee ssyynntthheessiizzeedd ddiiffffeerreenntt kkiinnddss ooff bbiissiinnddoollee aallkkaallooiiddss ccoonnddeennsseedd wwiitthh aa
atposition14,15ofthevindolinepart,namelycyclopropanovinblastine(6),cyclopropanovincristine,
ccyycclloopprrooppaannee rriinngg aatt ppoossiittiioonn 1144,,1155 ooff tthhee vviinnddoolliinnee ppaarrtt,, nnaammeellyy ccyycclloopprrooppaannoovviinnbbllaassttiinnee ((66)),,
cyclopropanovinorelbin,andotherderivatives. Wereportedtheirsignificanttumorcellinhibiting
ccyycclloopprrooppaannoovviinnccrriissttiinnee,, ccyycclloopprrooppaannoovviinnoorreellbbiinn,, aanndd ootthheerr ddeerriivvaattiivveess.. WWee rreeppoorrtteedd tthheeiirr
activityondifferenttumortypesandtumorcelllines.
ssiiggnniiffiiccaanntt ttuummoorr cceellll iinnhhiibbiittiinngg aaccttiivviittyy oonn ddiiffffeerreenntt ttuummoorr ttyyppeess aanndd ttuummoorr cceellll lliinneess..

FFFiiiggguuurrreee 222... TTThhheee aaalllkkkaaallloooiiidddsss 111444,,,111555---dddiiihhhyyydddrrrooovvviiinnnbbblllaaassstttiiinnneee (((555))) aaannnddd 111444,,,111555---cccyyycccllloooppprrrooopppaaannnooovvviiinnnbbblllaaassstttiiinnneee (((666)))...
AAAsss aaa cccooonnntttiiinnnuuuaaatttiiiooonnn ooofff ttthhhaaattt wwwooorrrkkk,,, ooouuurrr ooobbbjjjeeeccctttiiivvveee iiisss ttthhheee sssyyynnnttthhheeesssiiisss ooofff fffuuurrrttthhheeerrr dddeeerrriiivvvaaatttiiivvveeesss ooofff pppooottteeennntttiiiaaallllllyyy
cccyyytttoootttoooxxxiiiccc dddiiimmmeeerrr aaalllkkkaaallloooiiidddsss cccooonnndddeeennnssseeeddd wwwiiittthhh,,, eee...ggg...,,, aaa hhhaaalllooogggeeennn sssuuubbbssstttiiitttuuuttteeeddd cccyyycccllloooppprrrooopppaaannneee ooorrr oooxxxiiirrraaannneee rrriiinnnggg...
IIInnn oououurrrr esrreeeassreecaahrrccghhr o uggprroo,utuhppe,,s etthmheeossleee cummleooslleehccauuvlleeessb ehheanavvaee m bbiseeseeinnn gaali nmmkiiisnssstiihnnegg anlliiannlkky siiisnno fttthhheee saatnrnuaacllyytussriisse -aoocfft ivttihhtyee
rssettrrlauutccitotuunrrseeh--aiapccttoiivvfiittthyye rrVeelilanattciiaoonanlsskhhaiilppo ioodffs .tthhSeey nVVtiihnneccatai caallskktuaalldooiiieddsssw.. SSeyyrennttnhhoeetttiioccn ssltytuupddeiieerfsso wwrmeerreeed nnooontt toohnnellydy ipmpeeerrrffooarrlmmkaeeldodi doonsn,
btthhueet ddaliismmoeeorrn aaltlkkhaaelliooriibddussi,, l bbduuintt gaallbsslooo cooknns t,thhi.eeeii.rr, cbbauutiihllddariinnanggt bbhllioonccekk(ss3,, ) ii..aeen..,,d ccaavttihhnaadrroaalnnintthheii(nn4ee) .((33)) aanndd vviinnddoolliinnee ((44))..
2. ResultsandDiscussion
22.. RReessuullttss aanndd DDiissccuussssiioonn
2.1. GenerationofHalogencyclopropaneRingwiththeSimmons–SmithReaction
22..11.. GGeenneerraattiioonn ooff HHaallooggeennccyycclloopprrooppaannee RRiinngg wwiitthh tthhee SSiimmmmoonnss––SSmmiitthh RReeaaccttiioonn
Our first purpose was to build up the halogencyclopropane ring in place of the C(14)=C(15)
OOuurr ffiirrsstt ppuurrppoossee wwaass ttoo bbuuiilldd uupp tthhee hhaallooggeennccyycclloopprrooppaannee rriinngg iinn ppllaaccee ooff tthhee CC((1144))==CC((1155))
carbon-carbon double bond of the vindoline ring (4). Based on the work of Beaulieu et al. [17],
ccaarrbboonn--ccaarrbboonn ddoouubbllee bboonndd ooff tthhee vviinnddoolliinnee rriinngg ((44)).. BBaasseedd oonn tthhee wwoorrkk ooff BBeeaauulliieeuu eett aall.. [[1177]],,
vindoline (4) was reacted with bromoform and iodoform in the presence of diethylzinc
vviinnddoolliinnee ((44)) wwaass rreeaacctteedd wwiitthh bbrroommooffoorrmm aanndd iiooddooffoorrmm iinn tthhee pprreesseennccee ooff ddiieetthhyyllzziinncc iinn
ddiicchhlloorroommeetthhaannee ((SScchheemmee 11)).. TThhee SSiimmmmoonnss––SSmmiitthh rreeaaccttiioonn rreessuulltteedd sstteerreeoossppeecciiffiiccaallllyy iinn 88
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in dichloromethane (Scheme 1). The Simmons–Smith reaction resulted stereospecifically in 8
14,15-bromocyclopropanovindoline(31%yield)and1014,15-iodocyclopropanovindoline(9%yield).
14,15-bromocyclopropanovindoline (31% yield) and 10 14,15-iodocyclopropanovindoline (9% yield).
By achieving the reaction with 10-bromovindoline (7) [18], the 9 bromocyclopropane and 11
By achieving the reaction with 10-bromovindoline (7) [18], the 9 bromocyclopropane and 11
iodocyclopropanederivativeswereobtainedinyieldsof40%and22%. Theconfigurationsofthe14,
iodocyclopropane derivatives were obtained in yields of 40% and 22%. The configurations of the 14,
15,and22carbonatomsweredeterminedbyNMRspectroscopy(14:(S),15:(R),and22:(S)).
15, and 22 carbon atoms were determined by NMR spectroscopy (14:(S), 15:(R), and 22:(S)).

SScchheemmee 11.. TThhee ffoorrmmaattiioonn ooff tthhee bbrroommoo-- aanndd iiooddooccyycclloopprrooppaannee rriinngg..
2.2. ReactionswithDichlorocarbene
2.2. Reactions with Dichlorocarbene
ThefollowingstepofourcurrentworkwastheinvestigationofthereactionsofVincaalkaloids
The following step of our current work was the investigation of the reactions of Vinca alkaloids
withdichlorocarbene. Dichlorocyclopropanoderivativesofmonomericanddimericalkaloidswere
with dichlorocarbene. Dichlorocyclopropano derivatives of monomeric and dimeric alkaloids were
aimedatasanextensionofourpreviouswork.
aimed at as an extension of our previous work.
First, the classical method of the reaction of dichlorocarbene with alkenes [19] was tried on
First, the classical method of the reaction of dichlorocarbene with alkenes [19] was tried on
vindoline(4)asamodelcompound(Scheme2). Achloroformsolutionofvindoline(4)wastreated
vindoline (4) as a model compound (Scheme 2). A chloroform solution of vindoline (4) was treated
with an aqueous solution of sodium hydroxide at room temperature in the presence of the phase
with an aqueous solution of sodium hydroxide at room temperature in the presence of the phase
transfercatalystbenzyltriethylammoniumchloride(TEBAC).Unexpectedly,thedichlorocyclopropano
transfer catalyst benzyltriethylammonium chloride (TEBAC). Unexpectedly, the
derivative(12)couldnotbedetectedinthereaction. However,aformylgroupwasbuiltinatposition
dichlorocyclopropano derivative (12) could not be detected in the reaction. However, a formyl group
10,resultingin10-formylvindoline(13),acompoundthatisalreadyknownintheliterature[20–22].
was built in at position 10, resulting in 10-formylvindoline (13), a compound that is already known
in the literature [20–22].
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MMoolleeccuulleess 22001188,, 2233,, xx FFOORR PPEEEERR RREEVVIIEEWW 44 ooff 2211

SSSccchhheeemmmeee 222... TTThhheee ccclllaaassssssiiicccaaalll mmmeeettthhhoooddd ooofff ttthhheee dddiiiccchhhlllooorrrooocccaaarrrbbbeeennneee rrreeeaaaccctttiiiooonnn wwwaaasss tttrrriiieeeddd ooonnn vvviiinnndddooollliiinnneee ( ((444))) fi ffiirrrsssttt...
TTThhheee aaabbbooovvveee---mmmeeennntttiiiooonnneeeddd dddiiiccchhhlllooorrrooocccaaarrrbbbeeennneee rrreeeaaaccctttiiiooonnn ooonnn ttthhheee dddiiimmmeeerrriiiccc aaalllkkkaaallloooiiidddsss vvviiinnnbbblllaaassstttiiinnneee (((111))) aaannnddd
vvviiinnncccrrriiissstttiiinnneee (((222))) wwwaaasss aaallslssooo iniinnvvveeessstttiigiggaaattteeeddd... IIInnn ttthhheeessseee rrreeeaaaccctttiiiooonnnsss,,, iiinnnsssttteeeaaaddd ooofff ttthhheee eeexxxpppeeecccttteeeddd dddiiiccchhhlllooorrrooocccaaarrrbbbeeennneee
aaadddddduuuccctttsss 111444 aaannnddd 111666,,, iiinnnttteeerrreeessstttiiinnnggg rrriiinnnggg---ooopppeeennneeeddd oooxxxiiirrraaannneee dddeeerrriiivvvaaatttiiivvveeesss (((111555 aaannnddd 111777))) wwweeerrreee iiisssooolllaaattteeeddd iiinnn vvvaaarrriiiooouuusss
yyyiiieeellldddsss (((SSSccchhheeemmmeee 333)))...

SSSccchhheeemmmeee 333... TTThhheee dddiiiccchhhlllooorrrooocccaaarrrbbbeeennneee rrreeeaaaccctttiiiooonnnsss ooonnn ttthhheee dddiiimmmeeerrriiiccc aaalllkkkaaallloooiiidddsss vvviiinnnbbblllaaassstttiiinnneee (((111))) aaannnddd vvviiinnncccrrriiissstttiiinnneee (((222)))
llleeeddd tttooo rrriiinnnggg---ooopppeeennneeeddd oooxxxiiirrraaannneee d ddeeerrriiivvvaaatttiiivvveeesss ( ((111555 a aannnddd1 11777)))...
AA ppllaauussiibbllee iinntteerrpprreettaattiioonn ooff tthhee ooxxiirraannee ffoorrmmaattiioonn iiss oouuttlliinneedd iinn SScchheemmee 44 ((wwhheerree VV ccaann
rreepprreesseenntt nnoonn--mmooddiiffiieedd aanndd ddiiffffeerreenntt kkiinnddss ooff mmooddiiffiieedd ““vviinnddoolliinnee”” uunniittss aass wweellll)).. FFiirrsstt,,
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A plausible interpretation of the oxirane formation is outlined in Scheme 4 (where V can
reelpercetrsoenpthniloicn d-micohdloifiroecdaarbnednde iafftetraecnkts ktihned nsuocflmeoopdhiifiliecd te“rvtiinadryo lainmei”nue nniittsroagsewne allt) .pFoisristti,oenl e4c’t,r loepahdiilnicg
dtoic halno raomcamrboennieumatt accokmspthoeunnudc aleso tphhei liinctteerrmtiaerdyiaatme.i nTehneintr othgee nhyatdprooxsiytilo gnr4o’u,ple aadt iCng-2t0o’ amniagmhtm boencioumme
cdoempprootuonndataesdt huenidneterr mbaesdiica tree.aTchtieonn thceonhdyditrioonxys,l gthroeu panaitoCni-c2 0m’moiigethyt baetctaocmkes dCe-p2r1o’t, onanatde dNu-n4d’ eirs
bnaesuictrraelaizcteido ndcuornindgit ioan hs,ettheeroalnyitoicn icclemaoviaegtye aotft aack csaCrb-2o1n’,-naintdroNge-4n’ ibsonnedu.t rFailnizaelldy,d uornien goaf hthetee rcohlylotirco
cgleroavuapgse mofaay cuarnbdoenr-gnoi trsougbesntitbuotniodn. Fwiniathll yO,oHn,e oanfdth ea chfolormroygl roguropuspm faoyrmunsd beryg othseu besltiimtuitniaotniowni tohf
OhHyd,raongdena cfohrlmoryidleg.r oupformsbytheeliminationofhydrogenchloride.

SScchheemmee 44.. TThhee pprrooppoosseedd mmeecchhaanniissmm ffoorr ooxxiirraanneef foorrmmaattiioonn..
2.3. AttemptedEpoxidationofVincaAlkaloidBuildingBlocks
2.3. Attempted Epoxidation of Vinca Alkaloid Building Blocks
Anotherobjectiveofourresearchwastheexplorationofthereactivityof“monomeric”alkaloids
Another objective of our research was the exploration of the reactivity of “monomeric”
(e.g., vindoline, catharanthine) towards epoxidizing agents. In the literature, only few oxirane
alkaloids (e.g., vindoline, catharanthine) towards epoxidizing agents. In the literature, only few
derivativesofVincaalkaloidsareknown. Forinstance,the3-oxoderivativeofcatharanthinecould
oxirane derivatives of Vinca alkaloids are known. For instance, the 3-oxo derivative of catharanthine
beepoxidizedwithm-chloroperoxybenzoicacid[23]. Anotherexample,mehranine,the14,15-epoxi
could be epoxidized with m-chloroperoxybenzoic acid [23]. Another example, mehranine, the
derivativeofaspidospermidine,wasisolatedfromTabernaemontanabovinaanditstotalsynthesiswas
14,15-epoxi derivative of aspidospermidine, was isolated from Tabernaemontana bovina and its total
recentlypresented[24].
synthesis was recently presented [24].
Thevindolineandcatharanthinederivativesbearinganoxiraneringwerealsotriedtobeobtained
The vindoline and catharanthine derivatives bearing an oxirane ring were also tried to be
insimilarreactions,andtheyitwasattemptedtousethemincouplingreactionstoaffordepoxidized
obtained in similar reactions, and they it was attempted to use them in coupling reactions to afford
bisindolealkaloids.
epoxidized bisindole alkaloids.
First,theoxidationof10-bromovindoline(7)withm-chloroperoxybenzoicacid(m-CPBA)was
First, the oxidation of 10-bromovindoline (7) with m-chloroperoxybenzoic acid (m-CPBA) was
studied. The reaction could be performed either in the presence or absence of perchloric acid,
studied. The reaction could be performed either in the presence or absence of perchloric acid, which
whichmayinfluencetheoutcomeoftheoxidation[25]. Whencarryingoutthereactioninmethanol
may influence the outcome of the oxidation [25]. When carrying out the reaction in methanol
withoutHClO ,noneoftheoxidatedproductscouldbeisolated. Surprisingly,whenHClO wasused
without HClO44, none of the oxidated products could be isolated. Surprisingly, when H4 ClO4 was
inthereaction,thedebrominationanddemethylationatthearomaticringoccurred. Ano-quinoidal
used in the reaction, the debromination and demethylation at the aromatic ring occurred. An
compound(19)wasisolatedin27%yield,butthedesiredoxirane18couldnotbeobtained(Scheme5).
o-quinoidal compound (19) was isolated in 27% yield, but the desired oxirane 18 could not be
Startingfromcompound19,thereactionhasbeendescribedinashortarticlepublishedlastyearby
obtained (Scheme 5). Starting from compound 19, the reaction has been described in a short article
us[26].
published last year by us [26].
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N
O
Br 14
N 15
O
Br
15
H CO N OCOCH
3 3
H OH
N H CO NCH3 COOCHO3COCH
3 3
Br MeOH H18 OH
N HClO CH3 COOCH3
4
Br MeOH 18
m-CPBA
HClO
H3CO N OCOCH3 50o4C N
H OH
m-CPBA
H3CO NCH3 COOCHO3COCH3 50oC O 10 N
H7 OH
CH3 COOCH3 O 10
7 O 11 N OCOCH
3
H OH
CH COOCH
O 11 N 3 O3COCH
3
27% H OH
CH3 19 COOCH3
27%
Scheme 5. The attempted epoxidation of 10-bromovindoline (7) in the presence of perchloric acid.
19
HSScechhreeemamfete e55r.. TtThhheee aaatttbteeommvpept-temedd eeenpptooixoxiniddeaadttii ootnnw oooff 11m00--ebbtrrhoomomdoosvv iionnfdd ooollxiinniede a((77t)i) oiinnn tthwheei tpphrr eemssee-nnCccePe oBoffA pp eewrrccehhrlleoo rriiaccl saaoccii ddt.r. ied on
catharanthine (3). In the absence of perchloric acid, the oxidation led to a mixture of two products:
HHeerreeaafftteerr tthhee aabboovvee--mmeennttiioonneedd ttwwoo mmeetthhooddss ooff ooxxiiddaattiioonn wwiitthh mm--CCPPBBAA wweerree aallssoo ttrriieedd oonn
catharanthine N4-oxide (20) in 34% yield (a similar preparation of 20 is known from the literature
ccaatthhaarraanntthhiinnee ((33)).. IInn tthhee aabbsseennccee ooff ppeerrcchhlloorriicc aacciidd, ,tthhee ooxxiiddaattiioonn lleedd ttoo aa mmiixxttuurree ooff ttwwoo pprroodduuccttss::
[18]), and a new compound (N4-oxide of 7-hydroxyindolenine catharanthine, 21) in 35% yield
ccaatthhaarraanntthhiinnee NN44--ooxxiiddee ((2200)) inin3 344%%y iyeiledld(a (sai msiimlairlaprr eppraepraatrioatnioonf 2o0f i2s0k niso kwnnofwronm frtohmel ittheera ltiuterrea[t1u8r]e),
(Scheme 6).
[a1n8d]),a annedw cao mnepwo ucnodm(pNo4u-onxdi d(eNo4f-o7x-ihdyed roofx y7i-nhdyodlreonxiyniencdaotlheanriannet hcianteh,a2r1a)nitnhi3n5e%, 2y1ie) ldin( S3c5h%em yeie6l)d.
N-Oxide 20 is known to be unstable, it easily undergoes a [2,3]-sigmatropic rearrangement,
(ScheNm-eO 6x)i.d e 20 is known to be unstable, it easily undergoes a [2,3]-sigmatropic rearrangement,
leading to isoxazolidine 22 [27,28]. This kind of rearrangement during the NMR measurements
leadiNng-Otoxiidsoe x2a0z oilsi dkinnoew22n [2to7 ,2b8e] .uTnhsitsabklien,d iot feraesailryra ungnedmeregnoteds uar in[2g,3t]h-esiNgmMaRtrmopeiacs ureraemrraenngtse(mroeonmt,
(room temperature, CDCl3 as solvent) was also observed. Although Langlois et al. provided 1H and
lteeamdpinegra ttuor eis,oCxDaCzolliadsinseo lv2e2n [t2)7w,2a8s]a. lTsohiosb skeirnvde do.fA rletahroruagnhgeLmanegnlto idsuertianlg. ptrhoev iNdeMdR1 Hmaenadsu13rCemNeMntRs
13C NMR spectral3 data for 22 [19], they could not give an unequivocal assignment of the NMR
(srppoeeoacmktrs at. elImdna ptthearisfao tpurar2ep2,e [Cr1,D 9w]C,etl 3hr aeesyp oscorotlu vtlehdnet n)uo wntaagmsiv baelisgaoun oouubnss ee1rqHvue iadvn.o dAc al1lt3hCaos-NsuiggMhnR mL aaensnsgtilgoonfismt heeetn aNtls.M pfoRrro pv2ie2da, ekwds .h1HiIcnh at hnhidas s
1p3Cap eNr,MwRe rseppeocrttrathl eduantaa mfobri g2u2o [u1s91],H thaenyd 1c3oCu-lNd MnoRt agssivigen mane nutnsefqorui2v2o,cwahl iacshshigansmbeecnotm oef atchhei eNvaMbRle
become achievable because of the advancements in NMR instrumentation and measurement
pbeeacakus.s eIno fththise paadpvearn, cweme erneptsoirnt NthMe Runianmstrbuigmueonutsa t1iHon aanndd 1m3Ce-aNsuMrRem aesnsitgtnecmhenniqtsu efosrs i2n2c,e w1h97ic6h. has
techniques since 1976.
become achievable because of the advancements in NMR instrumentation and measurement
techniques since 1976.

SScchheemmee6 6..T Thheeo oxxididaatitoionnw witihthm m-c-chhlolorrooppeerrooxxyybbeennzzooiicc aaccidid wwaasst rtrieieddo onnc caaththaarraannththininee( 3(3))w witihthoouutt

ppeercrchhlolorircica accididf oforrt htheefi frisrtstt itmime.e.
Scheme 6. The oxidation with m-chloroperoxybenzoic acid was tried on catharanthine (3) without
pOOenrnch tthlhoerei coo atthchieedrr f ohhraa tnnhdde ,,f iwwrsthh teeinmn epp. eerrcchhlloorriicc aaccidid isi sapappplileided dudruirnign gthteh eoxoidxiadtiaotnio nof ocfatchaatrhaanrtahnitnhei n(3e)
(3w)itwh itmh-mC-PCBPAB, At,wtow oanaonmomalaoluosu spprordoducutcst swweerere oobbttaaiinneedd. .TThhee mmaajojorr pprroodduucctt ((5588%% yyiieelldd)) wwaass
77ββ--hhOyydndr rotohxxeyy ioinntdhdoeolrle enhniainnneedc ,c aawtthhhaaerrnaan nptthehriincnheel( o(22r3i3c)), ,at thchiedem misini naoporrpp lpirerooddd uducucttr( i(1n12g2% %thy yeiei eoldlxd)i)dw waataisostn th heoefs spcpairitrohoad dreaernrivitvhaaitnitvieve e(23 24)4
w(S(Sictchhhe emmme-eC7 7P).)B. A, two anomalous products were obtained. The major product (58% yield) was
7β-hydroxyindolenine catharanthine (23), the minor product (12% yield) was the spiro derivative 24
(Scheme 7).
Molecules2018,23,2574 7of21
Molecules 2018, 23, x FOR PEER REVIEW 7 of 21

SScchheemmee 77.. TThhee ooxxiiddaattiioonn wwiitthh mm--cchhlloorrooppeerrooxxyybbeennzzooiicc aacciidd wwaass ttrriieedd oonn ccaatthhaarraanntthhiinnee ((33)) iinn tthhee
pprreesseennccee ooff ppeerrcchhlloorriicc aacciidd aass wweellll..
TThhee ssyynntthheessiiss ooff 77ββ--hhyyddrrooxxyyiinnddoolleenniinnee ccaatthhaarraanntthhiinnee ((2233)) iiss aallrreeaaddyy kknnoowwnn [[2299]].. TThhee aauutthhoorrss
uusseedd ssiinngglleett ooxxyyggeennt otoo oxxididizizeec actahtharaarnanththininee( 3()3.)T. hTehyeyd edteetremrminiendedth ethceo ncofingfuigrautriaotnioonf coof mcopmoupnodun2d3
a2t3 Ca-7t bCy-7N MbyR NspMecRtr osspcoecptyrousscionpgyn uucslienagr Onvuecrlheaaru sOerveefrfhecatu(sNerO Eef)fmecet as(NurOemE)e nmtse.aOsuurreimndeenptse.n dOeunrt
NinMdeRpeanssdigenntm NenMtsR, ianscsluigdnimngenthtse, dinetcelrumdiinngat itohne odfettheermreilnaatitvioens toefr etohceh reemlaitsitvrey sotfeoreuorcphreomduiscttr,yw oefr eouinr
fpurloldaugcret,e wmeernet iwn iftuhllt haogsreeermepeonrtt ewditihn tRheofseer ernecpeor[2te9d]. iHn yRderfoexreyninced o[2le9n].i nHeysdarroexaylisnodnoaletunrinalesp raorde uaclstso,
en.agt.u,trhael 15p,r2o0d-duichtys,d roe.dge.,r ivtahteiv e1o5f,2203-idsihknyodwron adsecroivroantiavreid inoef hy2d3 roxisy inkdnoolewnnin eaasn dcworaosnisaorildatiende
fhryodmroExryviantadmolieancionreon aanrdia wvaars. ipsloenlaate[3d0 f]r.om Ervatamia coronaria var. plena [30].
TToo uutitliilzizee2 323in iann aonx idoaxtiidvaeticvoeu pcloinugplrienagc trioenac[t2io2]nw [i2t2h]v winidtho livnien(d4o)lwinieth (t4h) ewpiutrhp othsee opfuorbptoaisnei nogf
nobewtaibniisningd noelwea blkisailnodidosl,e tahlekdaloouidbsle, tbhoen ddoautbNle- 1b–oCn-d2 haat sNto-1b–eCs-2a thuaras tteod ,bseu spaptuosraintegdt,h sautpthpeoscionugp tlihnagt
rtheaec tcioounprleinqug irreesacatisoenco rnedqauriyreasm ai nsoecgornodupar(yi .ea.m,Rin1Ro 2gNrHou)po n(it.he.e, cRa1tRh2aNraHn)t hoinn ethsiete c.aTthhuarsa,natrheidnuec stiioten.
oTfh2u3s,w a arsedauimcteiodna otfw 2i3t hwsaosd aiuimmedb oarto whyitdhr sidodeituomo bbtoarionhiytsdr1i,d2-ed tioh yodbtraoind eitrsi v1a,2ti-vdeih,ybdurtot hdeerrievaacttiivoen,
rbeustu tlhteed reinactthioene lriemsuinlatetido nino tfhteh eelihmydinraotxioynl gorfo tuhpe, hreytdurronxinylg girtotoupc,a rthetaurrannitnhgin iet t(o3 )c.atharanthine (3).
RRoossaammiinnee,, aa nnaattuurraall pprroodduucctt iissoollaatteedd ffrroomm CCaatthhaarraanntthhuuss rroosseeuuss,, wwaass rreeppoorrtteedd bbyy
AAttttaa--uurr--RRaahhmmaann eett aall.. wwiitthh tthhee ssaammee ccoonnssttiittuuttiioonn aass 2244 [[3311]],, aalltthhoouugghh tthheeyy ddiidd nnoott ssppeecciiffyy tthhee
ccoonnfifigguurraattiioonn ooff aannyy ooff tthhee sstteerreeooggeenniicc cceenntteerrss.. WWee ddeetteerrmmiinneedd tthhee rreellaattiivvee ccoonnfifigguurraattiioonn ooff 2244 bbaasseedd
oonn NNOOEE mmeeaassuurreemmeenntsts( F(Figiguurere3 )3,)b, ubtuwt weceo cuoldulndo ntodte cdiedceidife2 i4f w24a swraoss armosianme.inTeh.e Trheaes roenasfoornt hfoart wthaast
twhaesu tnhaev auinlaabvialiitlyaboiflirteyl ioafb lreeslipaebclter aslpdeacttraaflo drarotas afmori nreos(ainmRineefe r(ienn cRee[f3e1r]e,nocnel y[3t1h]e, 1oHnlyN MthRe 1cHhe NmMicaRl
schhiefmtsiacnald schoiuftpsl ianngdc oconustpalnintsgf ocronthsetamntest hfoyrl gthroeu mpsetahnydl Hgr-o21upwse raendgi vHe-n2)1, swoearree gliiavbelne)c,o smo paa rriesloianbolef
tchoemsppaercitsroanl doaf ttahoe fs2p4ecwtriathl dthaotas eofo 2f4ro wsaitmh itnheowsea osfn rootspamosisnibe lwe.as not possible.
TThhee sstteerreeooggeenniiccc ceenntetersrso off2 424a raerCe -C2,-2N, -N4,-4C,- 1C4-,1C4,- 1C6-1a6n danCd-2 C1-(2F1ig (uFriegu3)r.eS 3in).c Sei2n4ceh a2s4 ahraisg iad rciaggide
sctarguec tusrtreu(c2t-uarzea bi(c2y-aczloa[b2i.c2y.2c]looc[2ta.2n.e2)]occotnadneen) secdonwdiethnsaedsi x-wmitehm bae rseidx-rminegm,tbheereredl atriivnegc, otnhfieg urrealtaitoivnes
ocofnNf-i4g,uCra-1ti4o,nCs- 1o6f, Nan-d4, CC-2-114a, rCe-fi1x6e, dan(tdh eCc-o2n1fi agruer afitxioend a(tthCe- 2c1ocnafnigbueraatribointr aarti lCy-e2s1t acbalnis hbeed aarsbRitr,athrielny
Nes-t4a,bClis-1h4e,da ansd RC, -th16enm Nu-s4t, bCe-1R4,,R a,Rnd). CW-1it6h mthuissti bnem Ri,nRd,R,)t.h Wecitohn tfihgisu irna tmioinndo,f tCh-e2 cwonafsigduertaetrimonin oefd Ca-2s
fwoallso wdse.teTrhmeiNneOdE aSsY fcoolrlorewlast.i oTnhbee tNwOeeEnSYN Hco-r1r(e6la.6t0iopnp bme)twanedeno nNeHof-1th (e6p.6r0o tpopnmsa)t aCn-d17 o(1n.e9 5opf ptmhe)
ipmroptloienss thata tCt-h1e7 c(o1n.9fi5g uprpamtio) nimopfClie-2s itshRat (tohthe ecrownifsieguwreatwioonu lodf eCx-p2e icst Rco (rorethlaetriownisseb ewtwe eweonuNldH e-1xpaencdt
tchoerrperlaottioonnss abteCtw-5e),eann NdHth-e1 aacntuda tlhthe rpeero-dtoimnse nast ioCn-5a)l, satrnudc ttuhree aisctsuuaplp tohrrteeed-dbiymseenvseiroanlaol thsterruNctOurEeS iYs
csourprpeloarttieodn sby(F sigevuerera3l )o.ther NOESY correlations (Figure 3).
Molecules2018,23,2574 8of21
Molecules 2018, 23, x FOR PEER REVIEW 8 of 21

FFiigguurree 33.. TThhee tthhrreeee--ddiimmeennssiioonnaall ssttrruuccttuurree ooff tthhee ssppiirroo ddeerriivvaattiivvee ooff ccaatthhaarraanntthhiinnee ((2244))..
2.4. CouplingReactionoftheSpiroDerivativeofCatharanthineandVindoline
2.4. Coupling Reaction of the Spiro Derivative of Catharanthine and Vindoline
TThhee ccoouupplliinngg rreeaaccttiioonn ooff 2244 wwiitthh vviinnddoolliinnee ((44)) wwaass ccaarrrriieedd oouutt aaccccoorrddiinngg ttoo aa ggeenneerraall pprroocceedduurree
ffoorrmmeerrllyy uusseedd bbyyo ouurrr reesseeaarcrhchg groruouppin inth teheco cuorusresoe fosfy snytnhethsiezsiinzginVgL VBLdBe rdievraitvivateisv[e1s4 [,1145,]1,5w],h wichhiicsha ins
oaxni doaxtiidonatiinonth ienp rtehsee npcreesoefntrciefl uoof rotreitfhluaonrooleatnhdanFoelC al3nidn aFceiCdilc3 mine daicuidmic, fomlleodwiuedmb, yfothlleowreeddu cbtiyo nthoef
trheeduinctteiormn eodf itahtee iwntiethrmsoeddiiuatme wboitrho hsoyddiruidme b(Socrhoehmyder8i)d.e (Scheme 8).
IInnsstteeaadd oofft htehed edseirseidrebdi sbinisdionldeo2l6e, 2o6n,l younnlye xupneectxepdecptreodd upcrtosdwuecrtes fwouenred ifnouthnedr einac ttihoen rmeiaxcttuioren.
Wmeixetunrceo.u Wntee reendcothuanttevriendd othliante vcionudpolliende tcooiutspelelfd: atoc iattsieolnf:i ca tcraimtioenriicc vtriinmdeorliicn evi(n2d7)olainnde (a27tr) imanedr ica
vtriinmdeorliicn eviknedtoolninee( 2k8e)towneer e(2i8s)o wlaeterde .isTohlaetepdr.e sTehnec eproefseantchei rodf pa rtohdirudc tp,rNod-mucett,h Nyl-mquetahteyrln qauraytesranltaoryf
asaslpt iorfo ad sepriirvoa tdivereiv2a9tisvueg 2g9e sstusgtgheasttst hthearto tlheeo rfotlhee osf pthireo sdpeirroiv dateirvivea2t4ivien 2t4h ienr tehaec trieoanctmioing hmtibgehtt hbee
dtheem detehmyelathtiyolnatoiofnth oefm theseo mmeerso2m7.eTr o2s7u. pTpoo rstuopuproarts souumr patsiosunm, tphteiornea, ctthioen rweaacstiroenp ewataesd rwepitehaoteudt
awdidthinogutt haeddspinirgo tdheer isvpairtiov edeorfivcaatthivaer aonft hcainthea(r2a4n).thTinheis (w24a)y. ,Tohnilsy wOa-ym, eothnylyl aOte-dmtertihmyelaritcedv itnrdimoleinriec
(v2i7n)dcooliunled (b2e7)i scoolautledd baen disokleattoende a2n8dw kaestonnoet f2o8u nwdasin ntohte froeuancdti oinn mthixe turerea,ctwiohni cmhisxutubrseta, nwtihaitcehs
osuubrshtyanptoitahteess ios.ur hypothesis.
Molecules2018,23,2574 9of21
Molecules 2018, 23, x FOR PEER REVIEW 9 of 21
O N
O
N H
N N
H
NH H H3COOC
24 COOCH3 1)CF3CH2OH
HCl/H2O H3CO N H OHOCOCH3
FeCl3*6H2O CH3 COOCH3
+
26
2)NaBH /H O
0oC4 2 COOCH3
N CH3
HO H
H3COCO N OCH3
N
H CO N OCOCH
3 H OH 3
CH3 COOCH3 N OCH3
4
COOCH3 O N H OHOCOCH3
H3COCOHO H CNH3 OCH3 H3COOCH3CH N CH3 CH3 COOCH3
HO 7%
N
H COCO N
3
N OCH
3
O N OCOCH
H OH 3
H C
3H N CH3 COOCH3
H COOC
3
HO COOCH3
CH
H3COCO N HO H 3
H3COCO N OCH3
10%
28 N
N OCH
+ 3
O N OCOCH
O H3C H3C N CH3 CHH3 COOOHCH3 3
H
N H H COOC
3
HO
11% NH COOCHH3 H3COCO N
29 27

SScchheemmee8 8..T Thheec coouupplliinnggr reeaaccttioionno offt thhees sppirirood deerrivivaattiviveeo offc caatthhaarraanntthhininee( (2244))a annddv vininddoolilninee( (44))l eleddt oto
ssimimilialarrt rtrimimeerricicv vininddoolilnineed deerrivivaatitviveess..
3. ExperimentalSection
3. Experimental Section
3.1. General
3.1. General
Vinblastine, vincristine,andcatharanthinewerederivedfromthecorrespondingsulfatesalts;
Vinblastine, vincristine, and catharanthine were derived from the corresponding sulfate salts;
the bases were released directly before using them in the reactions. m-Chloroperoxybenzoic acid
the bases were released directly before using them in the reactions. m-Chloroperoxybenzoic acid
(m-CPBA)of77%assaywaspurchasedfromSigma-Aldrich(Budapest,Hungary)andwasusedas
(m-CPBA) of 77% assay was purchased from Sigma-Aldrich (Budapest, Hungary) and was used as
received. Melting points were measured on a VEB Analytik Dresden PHMK-77/1328 apparatus
received. Melting points were measured on a VEB Analytik Dresden PHMK-77/1328 apparatus
(Dresden, Germany) and are uncorrected. IR spectra were recorded on the Zeiss IR 75 and
(Dresden, Germany) and are uncorrected. IR spectra were recorded on the Zeiss IR 75 and 80
80 instruments (Thornwood, NY, USA). NMR measurements were performed on a Varian
instruments (Thornwood, NY, USA). NMR measurements were performed on a Varian VNMRS 800
VNMRS800MHzNMRspectrometerequippedwitha1H{13C/15N}TripleResonance13CEnhanced
MHz NMR spectrometer equipped with a 1H{13C/15N} Triple Resonance 13C Enhanced Salt Tolerant
SaltTolerantColdProbe,aVarianVNMRS500MHzNMRspectrometerequippedwitha1H{13C/15N}
Cold Probe, a Varian VNMRS 500 MHz NMR spectrometer equipped with a 1H {13C/15N} 5 mm PFG
5mmPFGTripleResonance13CEnhancedColdProbe(Varian,Inc.,PaloAlto,CA,USA),andaBruker
Triple Resonance 13C Enhanced Cold Probe (Varian, Inc., Palo Alto, CA, USA), and a Bruker Avance
AvanceIIIHDX500MHzNMRspectrometerequippedwitha1H{13C/15N}5mmTCICryoProbe
III HDX 500 MHz NMR spectrometer equipped with a 1H {13C/15N} 5 mm TCI CryoProbe (Bruker
(BrukerCorporation,Billerica,MA,USA).1HAnd13Cchemicalshiftsaregivenonthedeltascaleas
Corporation, Billerica, MA, USA). 1H And 13C chemical shifts are given on the delta scale as parts per
million (ppm) with tetramethylsilane (TMS) (1H, 13C) or dimethylsulfoxide-d6 (13C) as the internal
standard (0.00 ppm and 39.4 ppm, respectively). 1H-1H, direct 1H-13C, and long-range 1H-13C scalar
Molecules2018,23,2574 10of21
partspermillion(ppm)withtetramethylsilane(TMS)(1H,13C)ordimethylsulfoxide-d (13C)asthe
6
internalstandard(0.00ppmand39.4ppm,respectively). 1H-1H,direct1H-13C,andlong-range1H-13C
scalarspin-spinconnectiviteswereestablishedfrom2DCOSY,TOCSY,HSQC,andHMBCexperiments.
1H-1Hspatialproximitiesweredeterminedusingeithertwo-dimensionalNOESY/ROESYexperiments
ortheirselective1Dcounterparts.Allpulsesequenceswereappliedbyusingthestandardspectrometer
softwarepackage.Allexperimentswereperformedat298K.NMRspectrawereprocessedusingVnmrJ
2.2RevisionC(Varian,Inc. PaloAlto,CA,USA),BrukerTopSpin3.5pl6(BrukerCorporation,Billerica,
MA,USA)andACD/SpectrusProcessorversion2017.1.3(AdvancedChemistryDevelopment,Inc.,
Toronto,ON,Canada). HRMSandMSanalyseswereperformedonanLTQFTUltraaswellasanLTQ
XL(ThermoFisherScientific,Bremen,Germany)system. TheionizationmethodwasESIoperatedin
thepositiveionmode. FortheCID(collision-induceddissociation)experiment,heliumwasusedas
thecollisiongas,andthenormalizedcollisionenergy(expressedinpercentage),whichisameasure
oftheamplitudeoftheresonanceexcitationRFvoltageappliedtotheendcapsofthelineariontrap,
wasusedtoinducefragmentation. TheprotonatedmolecularionpeakswerefragmentedbyCIData
normalizedcollisionenergyof35–55%. Thesamplesweredissolvedinmethanol. Dataacquisition
andanalysiswereaccomplishedwithXcalibursoftwareversion2.0(ThermoFisherScientific,Bremen,
Germany). TLCwascarriedoutusingKieselgel60F (Merck,Budapest,Hungary)glassplates.
254
3.2. BromocyclopropanationofVindoline(4)
Vindoline(4)(228mg,0.50mmol)wasdissolvedindichloromethane(5mL)andunderArwith
1.28mL(1.28mmolin1Mhexanesolution)ofdiethylzincandthen88µL(1.00mmol)bromoformwas
injectedtothesolution. Afterstirringfor2hatroomtemperaturethereactionmixturewasfilteredand
thefiltratewasdilutedwithdichloromethane(50mL)andwashedwithwater(100mL).Theaqueous
phasewasextractedwithdichloromethane(4×50mL)andthecombinedorganicphasewasdried
overmagnesiumsulfate,filtered,andthefiltratewasevaporatedtodryness. Thecrudeproductwas
separatedbypreparativeTLC(dichloromethane-methanol19:1)and86mg(31%)ofproduct(8)was
isolated. Mp118–119◦C.
TLC(dichloromethane-methanol20:1);R =0.71.
f
IR(KBr)2963,1744,1617,1502,1230,1039cm−1.
1HNMR(499.9MHz,CDCl )δ(ppm)0.68(t,J=7.3Hz,3H,H -18),0.97(dd,J=9.7,3.8Hz,1H,
3 3
H-15),1.00(dq,J =14.4,7.3Hz,1H,H -19),1.62(ddddJ =9.7,3.8,3.5,0.7Hz,1H,H-14),1.91(dq,
x
J=14.4,7.3Hz,1H,H -19),2.21(s,3H,C(17)-OC(O)CH ),2.22–2.40(m,5H,H -6,H-21,H -3,H -5),
y 3 2 x x
2.63(s,3H,N(1)-CH ),3.23–3.33(brm,1H,H -5),3.44(brd,J=11.4Hz,1H,H -3),3.52(t,J=3.8Hz,
3 y y
1H,H-22),3.57(s,1H,H-2),3.78(s,3H,C(11)-OCH ),3.81(s,3H,C(16)-COOCH ),5.53(s,1H,H-17),
3 3
6.07(d,J=2.2Hz,1H,H-12),6.30(dd,J=8.2,2.2Hz,1H,H-10),6.84(d,J=8.2Hz,1H,H-9),7.96(brs,
1H,C(16)-OH).
13C NMR (125.7 MHz, CDCl ) δ (ppm) 8.2 (C-18), 21.6 (C(17)-OC(O)CH ), 23.3 (C-14),
3 3
23.5 (C-22), 28.0 (C-15), 34.4 (C-19), 38.7 (N(1)-CH ), 41.8 (C-20), 44.6 (C-6), 51.9 (C-3), 52.2 (C-7),
3
52.7(C(16)-COOCH ),53.5(C-5),55.6(C(11)-OCH ),69.6(C-21),76.3(C-17),78.9(C-16),83.7(C-2),
3 3
95.9(C-12),105.1(C-10),122.7(C-9),125.6(C-8),153.7(C-13),161.2(C-11),171.2(C(17)-OC(O)CH ),
3
171.9(C(16)-COOCH ).
3
HRMS:M+H=549.15965(C H O N Br,∆=0.3ppm). HR-ESI-MS-MS(CID=35%,rel. int.%):
26 34 6 2
489(100);457(1);429(1);314(1).
3.3. Bromocyclopropanationof10-Bromovindoline(7)
Thecompound10-Bromovindoline(7)(268mg,0.50mmol)wasdissolvedindichloromethane
(5mL)andunderArwith1.28mL(1.28mmolin1Mhexanesolution)ofdiethylzincandthen88µL
(1.00mmol),thebromoformwasinjectedtothesolution. Afterstirringfor3hatroomtemperature
thereactionmixturewasdilutedwithdichloromethane(40mL)andwashedwithwater(100mL).
Theaqueousphasewasextractedwithdichloromethane(2×50mL)andthecombinedorganicphase