bark conquer the world

8/12/2019 Bark Conquer the World

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) le&end since re+uted4 lon& held that the S,anish Countess o+ ChinchGn* -i+e o+ a vicero" o+ eru* -as cured

o+ malaria thans to a bre- o+ cinchona bar. 8he ne-s o+ this cure so im,ressed the S-edish botanist Carl von

;innH 17079177I4 that he con+erred u,on the &enus to -hich the cinchona tree belon&s* the name o+ the

Countess. ne h -as lost su,,osedl" throu&h a t",o&ra,hic error* so the corres,ondin& &enus -as o++iciall"desi&nated Cinchonaat the ;ondon nternational :otanic Con&ress o+ 1I66* a name that still a,,lies toda" B1.

2. Cinchona 8rees

Cinchona trees can &ro- to a hei&ht o+ 30 m nearl" 100 +t4. 8he" are ever&reens* distin&uished b" a rounded

cro-n surmountin& a slender trun. 8he leaves ma" be u, to 20 cm ca. I n4 lon&* althou&h the blossoms ,in

or red4 are small* and occur as terminal ,anicles.

)s alread" indicated* the bar o+ these trees is an im,ortant source o+ uinine and other alaloids. ) +irst

harvestin& can be undertaen -hen a tree is 697 "ears old.


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t -as le+t to the Jrench a,othecaries ierre Dose,h elletier 17II91IM24 and Dose,h :ienaimH Caventou

17L591I774 to +urther develo, the isolation ,rocedure o+ 'omes and thereb" achieve the +irst ,re,aration o+

,ure uinine.

n their ,ublication in 1I20 the latter t-o scientists called u,on collea&ues to test* in ,ractice* the thera,eutic

,ro,erties o+ this ,ure uinine B3. Since elletier and Caventou described ver" ,recisel" their isolation

,rocedure* ,h"sicians and a,othecaries ever"-here +ound themselves in a ,osition to isolate +or themselves a

su,,l" o+ uinine* startin& -ith cinchona bar. 8his ,ure and ,recisel" dis,ensable substance -as indeed +oundto be hi&hl" e++ective* and it uicl" dis,laced ,ulveriFed bar as a remedial a&ent. :ecause o+ the hi&h demand

+or ,ure uinine* the +irst uinine +actories -ere soon established* re,resentin& in e++ect the advent o+ the

modern ,harmaceutical industr".

M. 8he+t o+ SeedsN ) Crime ;eadin& Oirectl" to a Kni&hthood

Cinchona bar -as such a ,ro+itable eA,ort +or the )ndean states :olivia* Columbia* Ecuador* and eru that* in

the mid#1Lth centur"* total bans -ere declared -ith res,ect to the eA,ort o+ an" ve&etable matter related to the

cinchona tree* this as a means o+ ,reservin& absolute mono,ol" ,ositions. $iolations o+ the eA,ort ban -ere

subject to the death ,enalt". 8he inevitable result o+ such eA,ort controls -as a shar, increase in the -orld ,rice

+or cinchona bar.

Euro,e had become heavil" de,endent on the bitter medicine a&ainst malaria* es,eciall" the major colonial

,o-ers a+ter their anneAation o+ eAtensive tro,ical re&ions in+ested -ith the disease. 8his led in turn to ever#

increasin& demand. 8he Outch -ere es,eciall" conscious o+ the im,ortance o+ havin& cinchona ,lantations on

land under their o-n control* so that in 1I51 the Outch minister o+ colonial a++airs commissioned a botanical

eAcursion -ith an es,eciall" adventurous &oal B1N des,ite threats o+ the death ,enalt"* this team -as sent o++ to

collect betterN steal4 seeds and seedlin&s o+ the cinchona tree +or the ,ur,ose o+ ,lantin& them in the Outch

colonies in ndonesia* thereb" breain& the mono,ol" o+ the South )mericans. )s +ormal justi+ication +or this

criminal act* a marvelousl" altruistic eAcuse -as develo,edN the honorable ,ur,ose underl"in& the endeavor

-as rescue o+ the cinchona tree +rom its other-ise ,otential eAtinction* to be accom,lished throu&h tar&eted

cultivation else-here.

8he 'erman botanist Dustus Karl %assarl 1I1191ILM4 -as entrusted -ith this delicate Outch assi&nment. %e

had alread" s,ent ten "ears in the Outch ndies as director o+ the :uitenFor& :otanical 'arden on Dava* -here

he studied the +lora and ecolo&" o+ that island. n 1I52 %assarl traveled to eru* learned the local lan&ua&e*

,rocured letters o+ recommendation and a,,ro,riate o++icial ,asses* and set o++ on a lon& hie throu&h the

)ndes. %e -andered* inco&nito* +or a total o+ t-o "ears throu&h the +orests and jun&les o+ the mountainous

re&ion. :" Dune* 1I53* %assarl -as able to send a small boA o+ the delicate seeds bac to %olland Ji&. 24. n


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,romisedN onl" about 10 P o+ the cultivated trees -ere ultimatel" +ound to ,rovide a su++icientl" hi&h level o+

uinine. 8he rest -ere disa,,ointin&l" useless.

),art +rom eA,editions or&aniFed b" &overnments* there -ere also inde,endent adventurers -ho set out to

trac do-n and steal the valuable ,lant material. 8he En&lishman Charles ;ed&er 1I1I91L054 read in a

ne-s,a,er that the En&lish &overnment -as ,lannin& an eA,edition +or 1I56 in search o+ cinchona seeds and

,lants. ;ed&er -as himsel+ interested in botan"* and thus* accom,anied eAclusivel" b" natives* he embared on

his o-n uest +or seeds o+ the cinchona tree. n his case* ho-ever* the &oal -as seeds eAclusivel" +rom trees-hose bar -as alread" no-n to have a hi&h uinine content. 8he seeds he recovered -ere +irst o++ered to the

En&lish &overnment* -ithout success* so he also later turned to the Outch* -ho re-arded him -ith 100 &ulden

B1* 5.

>sin& ;ed&er@s seeds* the eAistin& ,lantation on Dava -as reconstituted a+ter 1I65* based eAclusivel" on the

ne- cinchona s,ecies* -hich in his honor no- bears the name C. ledgerianaC. calisaya4. ncidentall"* ;ed&erhad +inanced his eA,edition himsel+* but in the end he earned ver" little +rom it. nce the ,romised

s,ectacularl" hi&h uinine "ield -as con+irmed* the Outch re,ortedl" ,aid ;ed&er an additional 500 &ulden.

;ed&er himsel+* in a letter to his brother* acno-led&ed receivin& a +irst ,a"ment* albeit o+ onl" Q50* -ith a

second installment o+ Q100. %e com,lained in a letter to his brotherN Investors are always losers.evertheless* he -ent on also to -rite that he -as ,roud that one o+ his dreams had been +ul+illedN Europe isno longer dependent on eru or Bolivia for its supply of life-giving quinia. B6

*(CinchonaConquers the World

)lthou&h the ,lantin& o+ cinchona trees +or harvestin& their bar -as initiall" treated as a state mono,ol"* b"

the end o+ the 1Lth centur" ,rivate investors and +armers increasin&l" sou&ht their +ortunes here. n 1I76 the

+irst cinchona bar +rom a ,rivate source -as mareted. Cultivation* harvest* and ,rocessin& o+ the bar -ere

+urther o,timiFedN &ra+tin& o+ uinine#rich ,lants on to varieties that -ere seemin&l" uite robust made it

,ossible to develo, es,eciall" resistant "et hi&hl" ,roductive strains. ndeed* the uinine content o+ bar in

individual cases reached values as hi&h as 20 P B1.

$arious alternative harvestin& techniues -ere also eAamined and introduced. n the 1L30s* the cultivation o+

cinchona trees on Dava -as ,er+ected to such a de&ree that L7 P o+ the uinine utiliFed -orld-ide ori&inated in

the ca. 10 million ilo&rams o+ bar +rom this one source.

Startin& around 1I70* the eAtremel" lucrative cultivation o+ cinchona -as ,romoted in other ne- re&ions as

-ellN hu&e ,lantations a,,eared in Ce"lon* ndia* )+rica* and even the >nited States. )s ever more cinchona

bar -as thrust u,on the -orld maret* the ,rice inevitabl" crashed. !here in 1II0 a ilo&ram o+ uininesul+ate sold +or 3I5 R


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Koch@s industrial eAtraction ,rocedure o+ 1I23/2M led not onl" to &ood "ields* but -as in +act so e++ective and

economical that* in ,rinci,le* it is still ,racticed toda" Ji&. 34. %is success +rom an economic stand,oint -as

trul" over-helmin&* so in 1I50 Koch sold his ,harmac" and o,ened a ,harmaceutical +actor" in ,,enheim* a

cit" on the u,,er Rhine bet-een


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B1 D. %ermann*harm. !. online),,1* 1I. ;in"#nf flan$en ver%ndern die &elt* %. %obhouse* dtv*


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o-e* the +inal ,rice bein& de,endent u,on the uinine level. n essence* -e reimburse on the basis o+ the

amount o+ uinine -e are ,urchasin&* not the uantit" o+ crude bar. 8his obviousl" encoura&es our

intermediaries to ,a" attention to ualit"* and it stron&l" discoura&es* +or eAam,le* an" miAin& in o+ -orthless

eucal",tus bar* -hich loos ver" similar to cinchona bar. t is the develo,ment* over the course o+ man"

"ears* o+ a stron& sense o+ con+idence in terms o+ the dealers -ith -hom -e -or that maes this sort o+

transaction ,ossible?one that is +air to both ,arties.

Vou can* o+ course* ima&ine that* &iven the insecure ,olitical situation* -e al-a"s need to maintain here on sitean adeuate reserve o+ barN in the order o+ a "ear@s su,,l".

%o- do "ou then ,rocess the barT

n our eAtraction ,lant the bar is +irst +inel" &round* a+ter -hich it is di&ested -ith uiclime and dilute sodium

h"droAide solution. 8he s-ollen bar ,o-der obtained in this -a" is then eAtracted +or several hours -ith

toluene. 8he resultin& or&anic ,hase contains all the cinchona alaloids* as -ell as +ats and resins that are

eAtracted simultaneousl". 8he miAture is then +iltered.

8he +ilter residue* still moist -ith toluene* is neAt treated -ith steam as a -a" o+ drivin& o++ and recoverin& thetoluene. 8he +inal bar residue* -hich is ,ermitted to contain at most 2 ,,m o+ le+tover toluene i.e.* 2 & o+

toluene ,er ton o+ bar material4* is combusted in an a,,ro,riate -a" as a heat source.

8he toluene ,hase +rom above is treated -ith dilute sul+uric acid in a set o+ liuid/liuid eAtractors. Since the

cinchona alaloids are amines* and thus basic* the" are converted b" the sul+uric acid into salts* causin& them to

,ass into the aueous ,hase* -hereas +ats and resins remain in the toluene. 8he or&anic ,hase is se,arated*

toluene is recovered b" distillation* and the remainin& dar bro-n* oil" resins and +ats are dis,osed o+?a&ain

in a ,ro,er -a"* ultimatel" -ith incineration.

8he aueous ,hase* -hich contains all o+ the cinchona alaloids* is -ored u, +urther in the chemical ,lant.

Jollo-in& ,recise modi+ication o+ the ,%* a,,roAimatel" 70 P o+ the uinine ,resent cr"stalliFes out in this

ver" +irst ste,. n the end -e mana&e to isolate ca. 309M0 & o+ uinine +rom ever" ton o+ bar.

)s su&&ested* the mother liuor contains additional uinine* to&ether -ith other cinchona alaloids* -hich are

isolated and ,uri+ied via a number o+ +urther cr"stalliFation ste,s. n addition to uinine* uinidine* cinchonine*

and cinchonidine -e also isolate uinic acid* as -ell as various s"nthetic ,roducts derived +rom the cinchona

alaloids. Jor more in+ormation* see ---.uinine#buchler.com/indeA.htm.

Cr"stalliFates that are intended to constitute end ,roducts +rom the chemical division are subjected to care+ul

anal"tical tests +or ,urit" and residual solvent content the" are acce,ted +or +urther ,rocessin& in the

,harmaceutical division onl" -hen the" con+orm to established +iAed criteria +or ,urit".

Vou a,,ear to mae a shar, distinction bet-een "our chemical and ,harmaceutical o,erations.

!hat is the si&ni+icance o+ thatT

8he t-o divisions are indeed entirel" se,arate* and are in +act housed in se,arate buildin&s. n the

,harmaceutical division -e -or eAclusivel" -ith -ater as a solvent* so that it is no lon&er necessar" +or those

rooms to be ,rotected a&ainst eA,losions.

)bove all* ho-ever* this com,lete se,aration became necessar" in the 1L70s* -hen stricter reuirements -ere

introduced re&ardin& ,harmaceutical ,roduction centers* insisted u,on es,eciall" b" the >nited States. :ecause
http://www.quinine-buchler.com/index.htmhttp://www.quinine-buchler.com/index.htmhttp://www.quinine-buchler.com/index.htm


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the >S) re,resented our most im,ortant maret +or uinine and uinidine* it -as essential that -e ada,t our

o,erations accordin&l". Still toda" -e are audited on a re&ular basis b"* amon& others* the JO) Jood and

Oru& )dministration4.

!hat does all this mean in ,racticeT

n our ,harmaceutical division -e o,erate strictl" accordin& to the standards o+ '


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From Pharmacy to the Pub A Bark Conquers the World: Part &

DOI: 10.1002/chemv.20130007I

Author: Klaus Roth and Sabine Streller

Published Date: 02 li,iec 2013

ource ! Publisher: Chemie in unserer eit/!ile"#$C%

Co"yri#ht: !ile"#$C% $erla& 'mb% ( Co. K'a)* !einheim

Cinchona$ or quina$ re%ers to a #enus o% about &' s"ecies in the %amilyRubiaceae* +irst +ound in +orests o+the tro,ical )ndes. Kno-n to natives in eru as uinauina bar o+ the bars4* it is ,erha,s the &reatest &i+t

+rom the e- !orld to the ld !orld. n ,articular* its bar "ielded the +irst e++ective remed" +or malaria* one

o+ the most dan&erous o+ in+ectious diseases. 8he chie+ com,onent o+ cinchona bar* uinine* is still used as a

medication* but also +or ,re,arin& tonic -ater and :itter ;emon.

8here is thus &ood reason +or havin& a closer loo +rom a chemical ,oint o+ vie- at this bitter tree bar. ... )nd

the lon& road +rom the structure determination to the total s"nthesis o+ uinine is an eAcitin& detective stor".

7. Jrom


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)+ter )dol,h Strecer in 1I5M corrected the uinine molecular +ormula to C20%2M22B12* 13* one o+

%o+mann@s ,u,ils* William Perkin* -ho at the time -as onl" 1I "ears old* seiFed u,on the idea once a&ainand* in accord -ith the ne- molecular +ormula* selected a startin& material -ith +our additional h"dro&en

atoms* namel"5#all"ltoluidine. %is ,lan -as to oAidiFe the amine -ith ,otassium dichromate* to &ive uinineaccordin& to the +ollo-in& euationN

2 C10%13 X 3 Y C20%2M22X %2

5#all"ltoluidine X oA"&en Y uinine X -ater

erin attem,ted to carr" out the trans+ormation in his o-n ver" modest ,rivate laborator"* -hereb" he

acuired?instead o+ the ho,ed +or -hite uinine?an insoluble* noncr"stalliFable* red#bro-n ,reci,itate. :ut

erin did not &ive u,. %e ,ro,osed &ettin& to the bottom o+ this trans+ormation* so he decided to re,eat the

oAidation reaction -ith the sim,ler amine aniline* -hich -as readil" available +rom coal tar. t must have been

clear to him that uinine itsel+ could not be ,roduced +rom aniline* but ,resumabl" he ho,ed that +rom reaction

o+ the sim,ler startin& material he could &ain insi&ht into the course o+ the ,rocess.

8he reaction ,roduct?a blac* amor,hous residue?at +irst &lance looed useless. :ut erin -as ,ersistent*and -ith the aid o+ alcohol he -as able to isolate +rom the blac mass a dee, violet substance. !ith this

,i&ment he carried out ,reliminar" d"e eA,eriments* usin& one o+ his sister@s -hite sil blouses* and later* in

1I6I* he ,atented his violet d"e* -hich eventuall" acuired the name mauve.

erin himsel+ ultimatel" determined that his mauve must be a miAture o+ at least t-o com,ounds* and that the

aniline he had started -ith contained rather lar&e amounts o+ o# andp#toluidine* so that these structuralelements must o+ necessit" have +ound their ,lace in the reaction ,roducts. 8he structural +ormula ,resent +or

decades in the literature +or mauve ,roved in 1LLM to be -ron&. 8hat re,roduced above is the correct +ormula

+or the ,rinci,al com,onent o+ erin@s mauve. B1M* 15

8his rather audacious chemical a,,roach?as seen from today6s perspective?led to the +irst o+ the aniline d"es*and the chance discover" mared the be&innin& o+ the almost unbelievable ascent o+ the coal tar or aniline4 d"e

industr"

:ut that -as onl" the be&innin&= t later turned out that not onl" teAtiles* but also microor&anisms 'ram

stainin& test +or bacteria4 and subcellular com,onents chromosomes* -here chromais 'ree +or color4 canalso be d"ed. 8he neAt ste, -as a,,lication o+ d"e derivatives as chemothera,eutics. 8he major 'erman

cor,orations Jarb-ere %oechst )' %oechst O"e !ors nc.4* )&+a )tien&esellscha+t +Zr )nilin,rodution[ Cor,oration +or )niline roduction4* and :)SJ :adische )nilin und Soda Jabri [ :aden )niline and Soda

Jactor"4 ,oint to this ori&in in their ver" names.


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/() tructure Determination %or 2uinine

Oeterminin& the com,lete structures +or uinine and other cinchona com,onents e,t &enerations o+ chemists

bus". Jrom the man" small ,ieces* the 'erman chemist aul Rabe -as able to solve the structural ,uFFle in

1L0I* and ,ro,ose the ultimatel" con+irmed constitutional +ormula +or uinine Ji&. M* 14 B16. n this ,rocess*

uinine -as disassembled* -ith +ull retention o+ con+i&uration?in other -ords ver" care+ull"* and observin& all

the rules o+ the art?until one +inall" had in hand eAclusivel" smaller molecules* the con+i&urations o+ -hich-ere alread" no-n.

Fi#ure .(Structure o+ uinine.

uinine turned out to be a methoA"#substituted uinoline rin& Ji&. M* red4* bound b" -a" o+ a carbon atom to a

bic"clic uinuclidine blue4 B1791L. Even the nitro&en atom 1 is stereo&enic* in that its +ree electron ,air*

directed out-ards* can be re&arded +ormall" as a +ourth substituent. Oue to the ri&idit" o+ the bic"clic

uinuclidine rin& s"stem* the con+i&urations o+ the t-o brid&eheads 1 and CM must be identical* hence* thereis no need to mae eA,licit re+erence to the 7con+i&uration o+ 1.

8he stor" o+ establishin& the con+i&uration* and a &reat deal else about uinine as -ell* and has been ,resented

in -onder+ull" readable +orm b" JritF Eiden B17* 1I.

t -as not until 1L50 throu&h the -or o+ relo& and %\+li&er B1L* and their establishment o+ the con+i&uration

o+ CL* that the structure o+ uinine could be de+initivel" re&arded as +ull" determined Ji&. M4 B20922. 8he

relative con+i&urations* ,reviousl" established strictl" b" chemical means* -ere con+irmed b" ]#ra" structural

anal"sis in 1L55.

/(& 3he 4on# 5ourney to the First 3otal ynthesis o% 2uinine

Strictl" s,eain&* a totals"nthesis o+ a natural ,roduct should commence -ith a set o+ elements dra-n +rom the,eriodic table. n ,ractice* ho-ever* one does not start -ith elemental carbon* oA"&en* h"dro&en* and nitro&en*

but taes advanta&e instead o+ the tremendous reservoir o+ com,ounds alread" ,re,ared b" &enerations o+

chemists. 8he &oal then becomes ,re,aration usin& the +e-est ,ossible ste,s* startin& +rom sim,ler* readil"

available?,erha,s commerciall" available?,reviousl" s"nthesiFed com,onents.

8he total s"nthesis o+ uinine evolved over the course o+ nearl" a centur"* and re+lects increasin& no-led&e

about the chemistr" o+ uinine* alon& -ith develo,ments in s"nthetic methodolo&".


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Fi#ure *(8he lon& road to a total s"nthesis o+ uinine.

1'*&:t all started -ith 4ouis Pasteur* -ho* b" -armin& uinine in dilute acid* rearran&ed it to the isomeric

uinotoAine )4* thou&h he had no idea about the actual chemical structures o+ either one Ji&. 54 B23.

1-1':Paul +abesucceeded in establishin& the correct molecular +ormula +or uinine* and to&ether -ith Karl

Kindler converted uinotoAine )4 bac into uinine 14 via a three#ste, reaction seuence Ji&. 54 B23.

1-.&: 6( Pro7tenikand 8( Prelo#dismantled uinonine .4?another com,onent o+ cinchona bar* one -hich

is closel" related to uinine?into X4#homomerouinene &4 B25* -hich to&ether -ith uinic acid *4 the" thenconverted into X4#uinotoAine )4 Ji&. 54.

) cou,lin& o+ this sort -ith uinic acid had been described earlier b" Rabe and Kindler in their s"nthesis o+ the

analo&ous dih"dro#uinotoAine B26. 8hus* a uinotoAine ,artial s"nthesis -as accom,lished +rom uinonine*

another natural ,roduct. 8he authors also ,ointed the -a" to-ard a total s"nthesisN

17ince 8 the transformation of quinoto3ine into 8 quinine 8 was accomplished some time ago by Rabe and9indler2 all that remains for a total synthesis of quinine is solution of the problem of synthetic preparation ofhomomeroquinene.4

1-..:recisel" this &oal -as achieved b" +( B( Wood9ardand W( ( Doerin#in the +orm o+ a brilliant

s"nthesis. Startin& -ith 7#h"droA"isouinoline ;4 the" +irst s"nthesiFed racemic homomerouinene &4 B27*

2I* -hich the" converted -ith uinic acid b" the method o+ ro^teni and relo& into racemic uinotoAine )4.!ith the aid o+ a O#tartaric acid derivative* )4 -as se,arated into its t-o enantiomers. Since Rabe and Kindler

had in 1L1I alread" converted X4#uinotoAine into uinine 14* !ood-ard and Ooerin& entitled their,ublication :he :otal 7ynthesis of ;uinine. 8oda" one -ould s,ea more ,recisel" o+ a +ormal totals"nthesis* since the authors themselves had not actuall" carried out the last three ste,s.

cienti%ically$ the 3otal ynthesis o% 2uinine 9as a Bombshell

n onl" sli&htl" more than a "ear* these t-o 26#"ear#old )merican chemists had* in about 20 s"nthetic ste,s*

,re,ared one o+ the most sou&ht#a+ter o+ all natural ,roducts Ji&. 64.


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Fi#ure ;( 8he !ood-ard and Ooerin& +ormal4 total s"nthesis o+ uinine.

8he outstandin& creativit" o+ !ood-ard@s s"nthetic ,lannin& -as +reuentl" re+erred to in the chemical

,ro+essional literature B2L. ne thin& stood out immediatel" at even a su,er+icial &lanceN in the +irst hal+ o+ the

s"nthesis one -ould never &uess -here the -hole thin& -as headed. !h"* +or eAam,le* did !ood-ard and

Ooerin& introduce the meth"l &rou, sho-n in red in Ji&. 6 into the isouinoline rin&T

8his ste, turns out to re,resent an es,eciall" di++icult s"nthetic tas* since the reaction o+ /to 'resisted,roceedin& correctl". nl" a+ter 16 hours o+ heatin& -ith sodium methanolate at 220 _C in an autoclave =4 -as

it +inall" accom,lished* in 65 P "ield. t is a miracle that under these drastic conditions an"thin& at all

remained. nl" at the end does it become a,,arent -h" so much e++ort -as eA,ended hereN this meth"l &rou,

-as to become a ,art o+ the reuisite vin"l &rou,.

aul Rabe* -ho +irst &ained access to this ,ublication onl" a+ter the end o+ the Second !orld !ar* hand-rote

in 1LMI a movin& letter to !ood-ard* re,roduced in B30. 8he ,artial translation that +ollo-s also +rom B304 isb" . 8. :en+e" and R. %uis&enN studied "our +irst ,a,er -ith admiration. am deli&hted that have lived to

see the total s"nthesis o+ uinine* and send "ou m" sincere con&ratulations. Vour thou&ht -as certainl" a

+ruit+ul one to increase the +our carbon atoms o+ the benFene nucleus o+ isouinoline b" an additional one and

then -ith the hel, o+ these +ive carbon atoms to create the rest o+ the ,ro,ionic acid and the vin"l &rou,=


15/26

Still toda"* s"nthetic chemists s,ea o+ this s"nthesis -ith hi&h re&ard B31. t -as !ood-ard@s +irst total

s"nthesis* -as admired* -as at the time an im,ortant and un,recedented achievement* and remained a scienti+ic

milestone. 8he !ood-ard9Ooerin& s"nthesis o+ uinine -as also &roundbreain& +or or&anic s"nthesis in the

decades that +ollo-ed U 8his achievement made him in his +ield almost a demi&od.

8he total s"nthesis o+ uinine in 1LMM -as not just anys"nthesis* ho-ever in the middle o+ the Second !orld

!ar it -as also an im,ortant -artime achievement +rom a strate&ic ,oint o+ vie-. ) lar&e +raction o+ the)merican +orce -as de,lo"ed in Southeast )sia* and their -ellbein& in malaria#in+ested re&ions -as de,endent

u,on this dru&. 8he major cinchona bar eA,ortin& lands* lie Dava* at that time a Outch colon"* as -ell as the

sea ,assa&es* -ere all controlled b" the Da,anese enem"* so the >nited States su++ered +rom a chronic shorta&e

o+ this medication so vital +or the troo,s. ne can onl" ima&ine the elation on the home +ront -hen a success+ul

laborator" s"nthesis -as +inall" achieved* somethin& totall" inde,endent o+ enem" su,,l" sources. 8he

)merican media raised !ood-ard and Ooerin& overni&ht to su,erstars. 8he5ew this? step because we kept losing a key o3ygen atom. @ord knows where it went2 but it wasn6tthere.


16/26

-ent home at three ).


17/26

-ith res,ect to its scienti+ic value* a stir -as created b" a ,articular +ootnote* one that raised serious uestions

re&ardin& the total s"nthesis o+ uinine b" !ood-ard and Ooerin& 50 "ears earlierN

&oodward and 'oering did not claim to have confirmed RabeDs FG report2 in a few lines2 that he hadsucceeded in converting quinoto3ine to quinine >although the basis of their characteri$ation of RabeDsclaim as 1established4 is unclear?2 nor is there any evidence that they produced any quinine in their ownlaboratories. But this was wartime2 and the H.7. had been cut off from the 'utch East Indies2 its maor

source of cinchona bark. :he resulting an3iety may e3plain press accounts2 notable for enthusiasm

rather than for sober analysis2 which created the quasiuniversal impression that the construction ofhomomeroquinene in FJJ meant that quinine had been synthesi$ed.

t must be em,haticall" acno-led&ed that 'ilbert Stor never eA,ressed the sli&htest doubt re&ardin& the

brilliance o+ their total s"nthesis o+ homomerouinene. %e -rote in a letter to the editor o+ Chemical andEngineering 5ewsin 2001 B36N18 A:he synthesis is beautiful and inspiring 8 and 'oering6s superb andinsufficiently acknowledged mastery of the far from trivial e3perimental difficulties is what makes thehomomeroquinene synthesis a masterpiece4.

+abe and ?indler=s Work >ot +e"roducible@

Stor@s criticism a,,lied above all to the +inal ,ara&ra,h o+ !ood-ard and Ooerin&@s ,ublicationN 1In view ofthe established conversion of quinoto3ine to quinine2 A,J with the synthesis of quinoto3ine the total synthesisis complete4. n +act it -as the adjective established that Stor -as un-illin& to acce,t. n his o,inion* thetrans+ormation o+ uinotoAine into uinine -as +ar +rom established* in that Rabe and Kindler in their short

communication B2M had not ,rovided an" eA,erimental details* and even later had not done so. n la"in& claim

to a total s"nthesis* !ood-ard and Ooerin& should necessaril" have veri+ied eA,erimentall" Rabe and

Kindler@s s"nthetic ste,s.

Jor Stor* +ootnote 1M -as the best ,art o+ his -or B37.


18/26

Since the ,assionate discussion re&ardin& !ood-ard and Ooerin&@s uinine s"nthesis has died do-n

some-hat* thans to tem,oral distance* -e can in the meantime anal"Fe the +acts as these are no- understood*

and come to our o-n conclusions.

/(* Who Can 3rust Whom$ and in Whom Can We Place Our 3rust@

n the controversial communication Lber die partielle 7ynthese des Chinins /n the artial 7ynthesis of;uinine4* Rabe and Kindler re,orted their trans+ormation o+ uinotoAine into uinine Ji&. I4. Rabe had alread"

,resented in detail in 1L11 the ,re,arative eAecution o+ the +irst t-o ste,s in an analo&ous trans+ormation o+

uinotoAine into cinchoninone BM1. n the third ste, the" introduced a ne- reduction method involvin&

aluminum ,o-der in sodium ethanolate/ethanol* -hich in their jud&ment re,resented* a si&ni+icant advance in

s"ntheses in the cinchona alaloid series.

Fi#ure '(8he Rabe9Kindler ,artial s"nthesis o+ uinine +rom uinotoAine.

8he actual eA,erimental ,rocedure is eAtremel" tersel" described* ho-everN 16.3 & o+ ,reviousl" s"nthesiFed

uininone toda"N uinidinone4 ,roduced* u,on treatment -ith the stated reduction miAture Baluminum ,o-der

in sodium ethanolate/ethanol* alon&side 0.L & o+ uinidine* the uinine in a "ield o+ 2 & o+ anal"ticall" ,ure

substance.

n alaline solution* uininone 11a4 is in euilibrium -ith the isomeric uinidinone 11b4. Since uinidinone is

less soluble* it ,reci,itates +irst. 8hus* Rabe did not isolate uininone* but rather uinidinone. 8his is actuall"

irrelevant +or the subseuent reduction* ho-ever* since in alaline medium an euilibrium bet-een the t-o

isomers is a&ain established. n the structural +ormulas o+ Ji&. I -e indicate this euilibrium bet-een the

isomers.


19/26

M?attac double bonds. resumabl"* Rabe believed that -ith this &eneral ,rocedure* asannotated* he had also described thorou&hl" enou&h the reduction o+ uininone to uinine.

8his ,resum,tion -as con+irmed b" Rabe and Kindler in their 1L3L article !u 7ynthesen in der Reihe derChina-)lkaloide Regarding 7yntheses in the Cinchinone 7eries4 BM3. 8he" had develo,ed ne- ,rocedures +orse,aratin& epi#uinine 1&4 and epi#uinidine 1.4 +rom com,leA miAtures* and U this circumstance ,ut us ina ,osition to terminate the stud" initiated in 1L1I. )t that time -e -ere success+ul* thans namel" to discover"

o+ a ne- non#catal"tic method o+ h"dro&enation* in a ,artial s"nthesis o+ the ,air uinine and uinidine* startin&

thereb" -ith uinotoAine* -hich still laced a closed uinuclidine rin&.

8he" then too u, once a&ain the over 200 & residue +rom the "ear 1L1I. n actual +act the" isolated this time*

in addition to uinine 14 and uinidine 1)4* the non#natural stereoisomers 1&4 and 1.4 +rom the old reaction

miAture.


20/26

)lso in this article the" once more eAtolled the de+initive advanta&e o+ the non#catal"tic reduction method

involvin& aluminum ,o-der in sodium ethanolate/ethanolN !e used +or h"dro&enation namel" aluminum

,o-der in alcoholic solution in the ,resence o+ sodium ethoAide* a reducin& a&ent that can indeed attac the

carbon"l &rou,* but not?or onl" -ith su++icient di++icult"?another unsaturated &rou,* the vin"l &rou,* -hich

is readil" reduced b" catal"ticall" activated h"dro&en.

t is thus uneuivocall" the case that Rabe and Kindler actuall" did carr" out the ,artial s"nthesis o+ uinine+rom uinotoAine. ublication o+ the eA,erimental details +or the last three ste,s -as sim,l" dela"ed* +or

reasons -hich remain unno-n. 8his ,ublication behavior -as unusual +or Rabe* but one cannot someho- tae

that to be a si&n o+ untrust-orthiness. verall one also cannot accuse !ood-ard and Ooerin& o+ havin& had so

much doubt re&ardin& the -or o+ Rabe and Kindler that the" needed to re,eat these ste,s. Ooerin& commented

in 2007 -ith res,ect to thisN !e relied on the -or o+ one o+ 'erman"s best or&anic chemists to com,lete the

conversion. 8here -as no earthl" reason to doubt the validit" o+ Rabes -or. BMM.

/(; Paul +abe and ?arl ?indler+est in Peace

Jinall"* the "ears#lon& heated debate re&ardin& the uinine total s"nthesis motivated the chemistr" historian

De++ Seeman to revie- the bac&round in a com,rehensive and meticulous -a"* and then ,resent us -ith his

insi&hts in an amusinto#read +ashion B30.

;ast but not least* in 200I the Rabe9Kindler reaction seuence +rom uinotoAine to uinine -as reconstructed

in terms o+ the laborator" techniues o+ 1LMM* b" Smith and !illiams BM5. 8he result came as no sur,riseN in a

rou&h#and#read" +ashion* uinine can indeed be ,re,ared +rom uinotoAine b" the Rabe9Kindler method. 8he

bi&&est ,roblem -as that modern aluminum ,o-der turned out to be unsuitable because it -as too +resh* and

had to be a&ed +or a -ee or t-o in air. 8he results a,,eared in )ngewandte Chemieunder the unusuall"melodramatic title 1Rabe Rest in eaceN Confirmation of the Rabe(9indler Conversion of d-;uinoto3ine to;uinine. E3perimental )ffirmation of the &oodward('oering "ormal :otal 7ynthesis of ;uinine.

8his ,ublication* -hich -as su,,osed to?once and +or all?,ut an end to the tem,est in a tea,ot* -as

addressed b" Stor as +ollo-sN thin !illiams and Smith did an eAcellent job o+ +i&urin& out ho- to modi+"

aluminum ,o-der so the" could re,roduce the Rabe9Kindler ,ortion o+ the !ood-ard9Ooerin& route to

uinine.

8oo bad* thou&h* that Stor couldn@t re+rain +rom stoin& the +ire one more time BM6N t@s a shame that this

-asn@t done b" !ood-ard and Ooerin&.

Com"leity o% the Chemical +esearch Process

) revie- o+ the uinine total s"ntheses sho-s that research results are the ,roduct not onl" o+ su,,osedl"

objective laborator" -or* but also o+ ,eo,le -ith color+ul characters* -orin& in a socio#,olitical settin& at a

,articular ,oint in time. 8hus* the uinine s"nthesis can serve as an e,istemolo&ical lesson in the com,leAit" o+

the ,rocess o+ chemical research BM7.

Jrom a less aloo+ ,oint o+ vie- -e mi&ht sim,l" enjo" the reco&nition that chemists?even the &reat ones?don@t al-a"s thin and deal as strictl" rationall" as the" o+ten believe the" must ,ur,ort* but instead do so

emotionall" and +ull o+ ,assion. 8his is in +act -hat actuall" maes them into endearin& ,eo,le.


21/26

+e%erences

B11 !. %. erin*. Chem. 7oc.1'-;* +F* 5L69637. ON 10.103L/C8IL66L005L6

B12 . %. Srau,*Ber. 'tsch. Chem. Oes. 1'/'* * 15169151L. ON 10.1002/cber.1I7I0110265B13 . %. Srau,*@iebigs )nn.Chem. 1'/-* FF* 3MM935L. ON 10.1002/jlac.1I7L1LL020LB1M .


22/26

From Pharmacy to the Pub A Bark Conquers the World: Part .

DOI: 10.1002/chemv.2013000IL

Author: Klaus Roth and Sabine Streller

Published Date: 06 sier,ie 2013

ource ! Publisher: Chemie in unserer eit/!ile"#$C%

Co"yri#ht: !ile"#$C% $erla& 'mb% ( Co. K'a)* !einheim

I. !hat Ooes uinine Oo 8o Counteract


23/26

biomineraliFation* all the iron centers in the heme are coordinativel" saturated and the heme bound in the

cr"stalline hemoFoin is no lon&er toAic BM69MI.

Fi#ure -(:iomineraliFation o+ heme in blood cells in+ected -ithlasmodium. O. Sullivan to, ri&ht4* E. %em,elmann bottom ri&ht4* both -iimedia commons

n terms o+ the human host* an in+ection o+ this sort can ultimatel" ,rove lethalN the enormous loss o+ red blood

cells* mentioned above* -ill lead to acute anemia and the sur+aces o+ in+ected blood cells are altered such that

the" readil" obstruct the victim@s ca,illaries* es,eciall" in the brain.

2uinine as an Antimarial A#entuinine@s ,harmacolo&ical activit" as an antimalarial a&ent is based on hindrance o+ the biomineraliFation o+

heme* thus inhibitin& +ormation o+ cr"stalline hemoFoin. 8he ,recise mechanism remains unclearN that is*

-hether uinine bonds to the dimeric heme com,leA and thus ,revents +urther a&&re&ation* or i+ it creates a sort

o+ ,rotective la"er over the ra,idl" &ro-in& cr"stal sur+ace BML. Re&ardless o+ mechanistic details* in an

in+ected blood cell treated -ith uinine thelasmodium,atho&en continues to ,roduce such a hi&hconcentration o+ heme throu&h hemo&lobin de&radation that it ultimatel" ensures its o-n demise.

uinine* -hich is to sa" cinchona bar* -as +or centuries the onl" e++ective antimalarial a&ent no-n. n 1L3M*

chlorouine Resochin4* the +irst hi&hl" success+ul s"nthetic a&ent +or combatin& the disease -as discovered.

8his -as +ollo-ed in 1LM0 b" sul+adoAin/,"rimethamine* and in the 1L70s b" me+louine ;ariam4 and

artemisinin B50. )s a result* uinine -as almost com,letel" dis,laced +rom the maret o+ malaria thera,eutic

a&ents. n the meantime* ho-ever* the ,atho&en has develo,ed si&ni+icant resistance to these ne-er com,ounds*

so dru& combinations are commonl" used +or both ,ro,h"laAis and thera,". n di++icult cases -here these still

,rove ine++ective* ho-ever* uinine is even toda" administered* to some eAtent in combination -ith other

in&redients.

L. 18 in the event that it is needed1

%istoricall"* the im,ortance o+ uinine as a ,ro,h"lactic and thera,eutic a&ent a&ainst malaria increased -ith

each ne- conuest b" the Euro,eans in )+rica* )sia* and )merica. t -as standard ,ractice +or all the colonial


24/26

,o-ers to ,rovide their militar" ,ersonnel* &overnment o++icials* trade re,resentatives* and missionaries -ith

uinine in the +orm o+ either ,o-der or tablets.

Countless additives -ere tried over the "ears in an attem,t to mas uinine@s eAceedin&l" bitter taste. %ere the

:ritish ,roved es,eciall" success+ul* -hen u,on their conuest o+ ndia the" be&an su,,l"in& uinine doses

dissolved in -ater* to -hich -as added &in and lemon. 8he resultin& tonic -as re&arded as a &eneral#,ur,ose

restorer and stren&thenin& a&ent roborant4* thus becomin& the ,recursor o+ a still -idel" ,o,ular coctail*

the &in and tonic.

3onic 9atern 'erman"* the idea o+ tonic wateris ineAtricabl" lined -ith the name Sch-e,,es. )round 17I0* the-atchmaer Dohann Dacob Sch-e,,e 17M091I214 develo,ed a ,rocess +or addin& carbon dioAide to -ater* and

then bottlin& the resultant liuid. %e soon ,atented the ,rocedure* and shortl" therea+ter established* in 'eneva*

the ver" +irst +acilit" +or ,re,arin& soda -ater carbonated -ater4 on a commercial scale. n 17L2* to&ether -ith

,artners* he established a second bottlin& ,lant in ;ondonN 7chweppes. Dohann Sch-e,,e himsel+ le+t thecom,an" in 1I02* but the name ,ersisted B51.

%is successors +urther develo,ed soda -ater in En&land* and a+ter ca. 1I30 made available a -ater -ith+lavorin&*Indian :onic &ater. :ritish colonial o++icials stationed in ndia are said to have reacted -ithenthusiasm to carbonated -ater containin& uinine* re&ardin& it as a ,leasanter -a" o+ consumin& the dru&.

!hether that ,articular ndian 8onic !ater ,rovided an" ,ro,h"laAis or curative ,o-ers -ith res,ect to

malaria -ould seem uestionable* ho-ever.

8oda"@s 7chweppes Indian :onic &atercontains 6I m& o+ uinine ,er liter. 8o in&est the e++ective oral dose o+uinine o+ 2 & ,er da"* +or a 70 &?15M lb?man* it -ould be necessar" to drin 30 liters nearl" I &allons=4 o+

Sch-e,,es ndian 8onic !ater ever" da" B52. 8hat -ould* o+ course* be almost im,ossible* even -ithout?let

alone with?&in B53.

8onic -ater is a so+t drin* and not a ,articularl" lo-#calorie eAam,le. ne liter o+ 7chweppes Indian :onic&aterre,resents 3I0 cal ---.sch-e,,es.de4* or L0 cal ,er I +luid ounce servin& ---.sch-e,,esus.com4.n other -ords* one dail" dose o+ 30 ;* corres,ondin& to the reuired amount o+ uinine e++ective a&ainst

malaria* -ould be euivalent to 11*M00 calories cal4= Even in one o+ the mountain sta&es o+ the :our de"rance* a ,ro+essional c"clist burns u, onl" about I*000 cal.

ot onl" Sch-e,,es* but also various Jrench entre,reneurs too advanta&e o+ the ,ossibilit" o+ introducin&

uinine to add a bitter note to their ,roducts. )n" number o+ varieties o+ bitters -ere once +lavored -ithcinchona bar* their names t",icall" ,ointin& clearl" to-ard their alle&ed e++icacious ,o-ers. :ut onl" ;uinquina 'ubonnettoda" sim,l"'ubonnet?and9ina @illettoda"@illet Blanc4 have survived* and are stillconsumed toda".

8he basis +or uinuina Oubonnet is -ine* to -hich alcoholic eAtracts o+ cinchona bar and other herbs are

added. 8he Jrenchman Dose,h Oubonnet develo,ed this a,eriti+ in 1IM6. n the basis o+ its uinine content it

-as su,,osed to +unction as a malaria ,ro,h"laAis +or Jrench Jorei&n ;e&ionaires in )+rica.

Cocktail No. 1: Queen Mums a!orite "rink, cl 'ubonnet2 cl gin.

i32 and serve with a slice of lemon and two ice cubes


25/26

;illet :lanc ,reviousl" no-n as Kina ;illet4 is an a,eriti+ based on -hite -ine* to -hich has been added

alcoholic eAtracts o+ citrus +ruit and cinchona bar. )s -ith Oubonnet* Kina ;illet and related a,eriti+s a,,eared

in the conteAt o+ the Jrench conuest o+ orth )+rica* intended to su,,l" uinine to the ;e&ionaires in a more

a&reeable +orm.

;illet :lanc became ,o,ular a&ain in 2006 as a result o+ the Dames :ond +ilm Casino Ro"al* in -hich the star

Oaniel Crai& orders a $es,er


26/26

Ackno9led#ementsn our becomin& +amiliar -ith this eAtensive and scienti+icall" demandin& +ield* and in ,re,aration o+ our

manuscri,t* numerous collea&ues have stood b" to assist us. S,ecial thans &o to nur Ksal* %arr"@s e-

Vor :ar in the 'rand %otel Es,lanade* :erlin Or. 'abriele radel* R!8% )achen Or. Robert $o&t*

:otanical niversit\t :erlin and Or. . !inchester* also o+ the Jreie >niversit\t :erlin.

8he startin& ,oint +or our article -as a visit to the Chinin+abri uinine Jactor"4 :uchlerin :raunsch-ei&.

!e -ish to eA,ress our s,ecial &ratitude to 8. !. :uchler* Or. R. :hm* ). errin* and Or. C. von Riesen +or

their hos,italit" and su,,ort.

Re+erences

BM6 O. D. Sullivan Dr.* inBiopolymers). SteinbZchel* niversit" o+ :erlin* 'erman"* and

,ermanent author o+ this series.

Ri&htN Pro%( Dr( abine treller* -ith a stirred $es,er

bark conquer the world

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