HUNDRED YEARS OF QUEST FOR SYNTHESIS OF POTENT MIRACLE ...students.orgchem.iisc.ernet.in/students/nagaraju/nagaraju graduate... · HUNDRED YEARS OF QUEST FOR SYNTHESIS OF POTENT MIRACLE

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HUNDRED YEARS OF QUEST FOR SYNTHESIS OF POTENT MIRACLE DRUG: QUININE

G. NAGARAJUDept. of Org.Chem

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INTRODUCTION

ONE FAILED ATTEMPT IN 1856 BY WILLIAM HENRY PERKIN

RABE-KINDLER PARTIAL SYNTHESIS OF QUININE

WOODWARD - DOERING’S FIRST FORMAL TOTAL SYNTHESIS

SYNTHESIS OF MEROQUINENE AND QUININE BY USKOKOVIC et al.

THE SUBSTANCE OF THE CONTROVERSY

THE FIRST STEREOSELECTIVE TOTAL SYNTHESIS OF QUININE BY GILBERT STORK

SOLUTIONS TO THE CONTROVERSIES

CONCLUSION

Outline…

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INTRODUCTION

Quinine is a cinchona alkaloid, found in cinchona bark.

Isolated from yellow bark of cinchona in 1820 by Pelletier and Caventou.

Molecular formula ( ) was established in 1854 by Adolf Strecker.

Rabe proposed correct structure of quinine in 1908.

Quinuclidine with 3 chiral centers is characteristic feature of cinchona alkaloids.

Quinine have 4 asymmetric carbons and so possible 16 isomers.

N

N

H

H

HOH

OMe

Quinine

3

45

6

78

9 1

C20H24N2O2

8 (S), 9 (R) quinine8 (R), 9 (S) quinidine8 (S), 9 (S) epi-quinine8 (R), 9 (R) epi-quinidine

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Why quinine occupied a central place among the many plantalkaloids which are used in medicine?

Quinine is an most potent antimalarial drug.

Quinine has shown antipyritic properties.

Around 1640’s, introduced cinchona bark into medical use to cure malaria.

Universally it was accepted as an antimalarial substance in 1681.

The drug to have relieved more human suffering than any other in the history.

It was the only effective remedy to malaria for centuries.

U.S. still imported over 68 tons of quinine and its salts in 1999.

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RUNNING TOWARDS SYNTHESIS…

In the middle of the 19th century, both the alkaloid as well as the cinchonabark were always in short supply, since they were the only effective knowntreatment against malaria.

So, the race for synthesis of quinine was heating up by mid. 19th century

Best evidence for demanding target structure elucidation and synthesis of quininewas, French Society of Pharmacy made a call to the chemists in the following way:

“… during a long time, there has been an important problem to find a Substitute for quinine with its same therapeutic effects…Therefore, wemake a call…offering the amount of 4000 francs to the … discoverer of the way to prepare synthetic quinine”.

Participants were notified of the January 1, 1851 deadline and the requirement of submitting at least half a pound of the synthetic substance. But no body claimed the prize.

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ONE FAILED ATTEMPT IN 1856 BY WILLIAM HENRY PERKIN

William H. Perkin attempted potassium dichromate mediated oxidativedimerization of N-allyltoluidine ( ). Since N-allyltoluidine is structurally nothing like half a quinine molecule ( ). But this attempt wasutterly futile and he did not succeed.

Me

NH

N-allyltoluidine

C20H24N2O2 + H2O+ 3 (O)2 C10H13N XQuinine

like a true Prince of Serendip—a prepared mind in search of unanticipated wonders - Perkin must have observed something in the noxious, black coal tar derivative formed,which spurred him into next trying to similarly oxidize “aniline”.

C10H13NC20H24N2O2

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Although Perkin did not produce quinine, he discovered to his amazement that after a series of clever manipulations his experiment produced a new dye known as mauveine.

This new dye was resistant to fade or run when subjected to washingor when exposed to sunlight.

The exact structure of the products resulting from the chemicaltransformations made by Perkin was studied more than one century later by employing modern high-field NMR techniques.

ONE FAILED ATTEMPT IN 1856 BY THE WILLIAM HENRY PERKIN

N

N

NH

Me

+

Me

H2N N

N

NH

Me

+

Me

H2N

Me

A B

In 1857 he opened his factory at Greenford Green, for commercialization of his discovery. Thus, young Perkin began work in the world’s first large-scaleorganic chemical factory.

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N

H

HO

Quinotoxine

N

H

BrO

N

OMe

N

H

H

O

Quinidinone

+N

H

O

H

Quininone

N

N

H

H

HOH

OMe

+

N

N

H

HOMe

HOH+

N

OMe

N

H

H OH

H+

N

OMe

N

H

H

OHH

epiquinidine QuinidinineQuinine epi-quinine

NaOEt, EtOH25%, overall

Al powderNaOEt/EtOH12%

N

OMe

N

OMe

N

OMeNaOBr, NaOHaq HCl, Et2O55% of crude product

H+

P. Rabe, K. Kindler, Ber. Dtsch. Chem. Ges. 1918, 51, 466.

Rabe provided the first steps and the Partial synthesis of quinine seems to become simpler

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Woodward Believed and Doering Believes in the Woodward–DoeringTotal Synthesis of Quinine…

N

H

HO

QuinotoxineN

N

H

H

HOH

OMe

QuinineN

OMe

NH

CH2CH2CO2HH

homomeroquinene

NHO

7-hydroxyisoquinoline

N

MeOCOOEt

Ethylquininate

+

Retrosynthetic analysis

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N

N

CH2N

NHO

CH3

HO

HOCH2O

piperidine, MeOH 62%

7-hydroxyisoquinoline

NHHO

CH3

NHO

CH3

COCH3

NHO

CH3

COCH3

NaOMe, MeOH

220°C

7-hydroxy,8-methylisoquinoline

H2, Pt.CH3COOH

7-hydroxy,8-methyl-1,2,3,4-tetrahydroisoquinoline

Ac2O, MeOH quant.

N

CH3

COCH3+

64%

(only 10% formed)N-acetyl-8-methyldecahydro isoquinoline

H2, Raney NickleEtOH, 150°C, 3000 poundsquant.NHO

CH3

COCH3

mixtue of stereoisomers

Pt, CH3 COOHH2


R. B.Woodward, W. E. Doering, J. Am. Chem. Soc. 1944, 66, 849.

NH

3

4

Homomeroquinene

COOH

11

(mixture of cis and trans) cis

N

O

CH2CH2CO2Et

NOHN

O

CH2CH2CO2Et

NH2

NaOEt-EtOHEtNO2

NHO

CH3

COCH3NO

CH3

COCH3 NO

CH3

COCH3

H

H

(mix. of stereo isomers)

H2CrO4 cis obtained as crystalline hydrate

68%

H2, Pt,CH3COOH, rt.

(mix. of isomers)

N-Acetyl-7-hydroxy-8-methyl- decahydroisoquinoline

9

10

CH3COOH

R. B. Woodward, W. E. Doering, J. Am. Chem. Soc. 1945, 67, 860


NH

3

4

Homomeroquinene

COOH

12

N

O

CH2CH2CO2Et

NH2 N

CH2CH2CO2Et

N (CH3)3 NH

CH2CH2CO2H

O

cis

MeI (excess)

N

CH2CH2CO2Et

+I -

(mix. of isomers) (mix. of isomers)

(alkaline hydrolysis)

(homomeroquinene)

ethyl ester of homomeroquinene hydrochloride salt

N-Acetyl-10-aminohomomeroquinene ethyl ester

K2CO3, EtOH

failed to isolate free acid

KCNO (excess)

CONH2N-uramidohomomeroquinene

/ 0.1N HCl

EtOH NH

CH2CH2CO2Et

+Cl-

42% (for 3 steps)


NH

3

4

Homomeroquinene

COOH

13

NH

CH2CH2CO2Et

N

CH2CH2CO2Et

Ph O

N

HNCH2CH2

O

H3CO

N

NCH2CH2

O

H3CO

CO2Et Ph

O

mixture

PhCOCl,K2CO3

dl-cis homomeroquinene ethyl ester

N

COOEtMeO

Ethyl Quninate

NaOEt (condensation)

keto ester, obtained as alkali soluble oil

boiling with 6N HCl50% (for 2 steps)

(dl-Quinitoxine)

96% (for 2 steps)

separated as its dibenzoyltartarate salts by crystalisation method

N

H

HO

N

OMe

N

N

H

H

HOH

OMe

Quinine

3

45

6

78

9 1Rabe and kindler partial synthesis

[α]D

d-quinotoxine (synthetic)

d-quinotoxine (natural)

+44° +43°

dibenzoyl d-tartarate (M.P.) 185.5-186 185.5-186


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Woodward-Doering’s synthetic route to quinine suffered from the lack of stereocontrol,produced the precursors of their homomeroquinene target as a mixture of cis and trans stereoisomers, in roughly equal amounts.

Yields of corresponding transformations in Woodward-Doering synthetic route are not clear

The difficult separations of the 4 isomers anticipated from the Rabe scheme for the conversion of quinotoxine to quinine because that half of the synthesiswas not stereoselective.

Woodward-Doering were succeeded in the formal synthesis of quinine, but its lack of value as commercial source of quinine.

There is no evidence, whether they repeated Rabe and Kindler conversion of quinotoxine to quinine.

Woodward – Doering synthesis of quinine suffering from…

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Birthday celebration: Woodward being carried in a sedan chairby members of his research group at Harvard, April 10, 1978.

QUININE! This single-word made the world turned to think aboutone of the greatest chemists ever to have lived, Robert Burns Woodward

Jeffry I Seeman* Angew. Chem. Int. Ed. 2007, 46, 1378.

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N

O

C6H5O

N

NH O

C6H5O

N

N

C6H5O

O H

+NaN3PPA

H

H

N-Benzoyloctahydroisoquinolone

N

O

C6H5O

N

N

C6H5O

O H

N

NH O

C6H5O

+

α, β−unsaturatedisoquinolone

NaN3PPA

(1 : 5)enamine lactam conjugated lactam

(desired lactam)

(desired lactam)(1 : 1)

H2 (1atm), Rh on Al2O3EtOH, 1.25h

UV: 245 nm UV: 222 nm

Synthesis of meroquinene …

J. Gutzwiller and M. R. Uskokovic*, J. Am. Chem. Soc. 1978, 92, 571.

NH

3

4

Meroquinene

COOH

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N

N

C6H5O

O H

N

N

C6H5O

O NO

N

C6H5O

COOC2H5

NH2

N

C6H5O

COOH

N2O4, CCl4,CH3COONa -70° C, quant.

desired lactam

H

H

H

H pyrolytic fragmentation 125° C, 1h +

N

C6H5O

COOCH3

OH

N-Benzoylmeroquinene 10%

5% EtOH.HClreflux, 100h, 65%

1) HCHO,HCOOH,100° C, 1h2) 30% H2O2, 0° C-rt, 16h N

C6H5O

COOC2H5

NMe2

O Pyrolysis90° C-125°C, 25min N

C6H5O

COOC2H5

N-Benzoylmeroquinene ethyl ester

overall yeild for 3 steps 85%

48%

Synthesis of meroquinene …

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N

Ph O

H

HCOOCH3

N

H3COCH3

N

O

N Ph

OH

H

H3CO

N

Ph O

H

HCHO

N

N Ph

OH

H

H3COOH

N

N HH

H

H3COOH

LDA, THF, -78° C 1.5h, 78%

6-methoxylepidine N-benzoyl ketone

DIBAL-H,toluene, -78° C, 3h49%

N

H3COCH2Li

-78° C - rt, 17 h, 55%

epimeric N-benzoyl alcohols

NaAlH4, THF rt, 90%

epimeric amino alcohols

+

N-benzoylmeroquinene methyl ester

NaAlH4, THF rt, 91%

Stereoselective total synthesis of quinine and quinidine…

J. Gutzwiller and M. R. Uskokovic*, J. Am. Chem. Soc. 1978, 92, 576.

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N

N HH

H

H3COOH

NH

N HH

H

H3CO

+

N

N

H

H3CO H

N

N

H

H3CO H

N

N

HHHO

H3CO H

Quinine

N

N

HOHH

H3CO H

+

CH3COOH, BF3OEt250° C, 18h, 96%

N

N HH

H

H3COOAc

epimericacetates (3:2)

vinylquinoline intermediate

5% CH3COOH, CH3COONa (excess)reflux ,

deoxyquinine deoxyquinidine

cyclization79%

(43 :57)

O2, DMSO : tBuOHtBuOK , (4 : 1)

O2, DMSO : tBuOHtBuOK , (4 : 1)

Quinidine

32% 40%

epimeric amino alcohols

Stereoselective total synthesis of quinine and quinidine…

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The Substance of the Controversy: Good or Bad Science? Poor Judgement? Fraud in Science? Scientific Incompetence?

Woodward and Doering did not claim to have confirmed Rabe’s 1918 report,in a few lines, that he had succeeded in converting quinotoxine to quinine nor is there any evidence that they produced any quinine in their own laboratories.

The lack of direct and complete experimental information has been the basis forthe current recent, public and widely held conclusion that the claim of a total synthesis of quinine by Woodward and Doering is, in fact, not complete and a myth, as stated by Stork.

“There has been some debate in the current literature concerning the validity ofRabe’s reconstitution of quinine from quinotoxine in regards to the final reduction using aluminum powder … This issue is clearly of consequence because if this reaction did not proceed as written, then the Woodward/Doering route would not constitute a formal synthesis of quinine, but merely a synthesis of quinotoxine sincethe Harvard researchers did not repeat Rabe’s chemistry.

T. S. Kaufman, E. A. Rfflveda, Angew. Chem. 2005, 117, 876.

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Rabe and Kindler never reported the full experimental details of their d-quinotoxine to quinine transformation is also clear and unambiguous.

Did Woodward and Doering use poor judgement by not repeating the d-quinotoxine to quinine transformation or developing one themselves? Perhaps the answer to that question depends on the answer to another question, namely,

Did Rabe and Kindler actually succeed in their claim to have completed this transformation?

If Rabe and Kindler did, in fact, convert d-quinotoxine into quinine, thenWoodward and Doering did, in fact, complete the first formal total synthesis of quinine. If Rabe and Kindler did not convert d-quinotoxine into quinine as they claimed, then either Rabe and Kindler committed scientific fraud by misrepresenting their experimental results, or they were experimentally incompetent and honestly thought that they had prepared “quinine” but in fact they did not.

The Substance of the Controversy: Good or Bad Science? Poor Judgement? Fraud in Science? Scientific Incompetence?

Jeffry I Seeman* Angew. Chem. Int. Ed. 2007, 46, 1378.

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N

N

OMe

N

N

X

MeO

N

HNX

OMe

N

NX

OMe

A

N

OMe

HOH

quinine deoxyquinine

OTBDPS

N3OHC+

N

CH3MeO

6-methoxy-4-methylquinoline

OO

(S)-4-Vinylbutyrolactone

The First Stereoselective Total Synthesis of Quinine, it’s a 55 years Quest by Gilbert Stork

Retrosynthetic plan

G. Stork et. al. J. Am. Chem. Soc. 2001, 123, 3239 – 3242.

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OO Et2NOTBS

O

Et2NOTBS

O

OTBDPSOO

OTBDPS

1) Et2NH, AlMe3

2) TBS-Cl, Imidazole DMF, 79%

ICH2CH2OTBDPS

PPTS(0.3eq), EtOH, 12h,xylenes, reflux, 8-10h

79%

93%

(S)-4-Vinyl butyrolactone

LDA, -78oC

The First Stereoselective Total Synthesis of Quinine…

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OTBDPS

MeOOH

OHC

OTBDPS

N3

1) DIBAL-H, -78oC

2) Ph3P=CHOMe

(PhO) 2P(O)N3

5N HClTHF/CH2Cl2

OTBDPS

MeON3

Ph3P, DEAD

OO

OTBDPS

azido aldehyde


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N

CH3MeO

N

OTBDPS

MeON3OH

N

OTBDPS

MeON3O

DMSO, (COCl)2Et3N, 85%

70%6-Methoxy-4-methylquinoline

LDA, THF, -78oC

OHC

OTBDPS

N3

Ph3P, THF, reflux

81%

N

N

OTBDPS

MeO


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N

N

OTBDPS

MeO

N

NH

OTBDPS

MeOHNaBH4

MeOH/THF91%

95%

N

NH

OH

MeOH

N

NH

OMs

MeOH

MsCl/PyCH2Cl2

HF,CH3CN

CH3CN, reflux

N

N

OMe

68% (for 2 steps)

6

1

6

3

58

deoxyquinine


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N

N

OMe

6

3

58

deoxyquinine

N

N

OMe

HOHO2

N

N

OMe

HOH+

(Quinine : Epiquinine) 14 : 1

NaH, DMSO


The moment when stork’s quest fulfilled…

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The First Stereoselective Total Synthesis of Quinine, it’s a 55 years Quest by Gilbert Stork

Overcoming the problems which were faced in the past syntheses……

It’s a completely stereoselective synthesis.

Yields are good.

Uses less catalytic reactions than the sequence developed by Woodward-Doering.

The key feature of his synthetic design was the observation that the C6 - Nstrategy generated a trisubstituted piperidine instead of C8 - N.

Controlled the stereochemistry by choosing trans vicinal substituents on a piperidene intermediate instead of cis-3,4 disubstitution like in previous syntheses.

Employed carbon–carbon bond forming reactions rather than chemical degradation for the synthesis of the alicyclic moiety.

Whole sequence extremely simple and efficient in its design.

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Solutions to the Controversies…Rabe Rest in Peace: Confirmation of the Rabe–Kindler Conversion ofd-Quinotoxine Into Quinine: Experimental Affirmation of theWoodward–Doering Formal Total Synthesis of Quinine

Aaron C. Smith and Robert M. Williams* Angew. Chem. Int. Ed. 2008, 47, 1736.

Heating quinine in H2O/acetic acid (13:1) at 100° C for 35 h provided between50–75% yield of pure d-quinotoxine. Williams et al. carefully examined the conversion described by Rabe – Kindler in 1918.

N

H

HO

Quinotoxine

N

H

BrO

N

OMe

N

H

H

O

Quinidinone

+N

H

O

H

Quininone

N

N

H

H

HOH

OMe

+N

OMe

N

H

H OH

H

Quinidinine Quinine

NaOEt, EtOH25%, overall

Al powderNaOEt/EtOH12%

N

OMe

N

OMe

N

OMeNaOBr, NaOHaq HCl, Et2O55% of crude product

N

N

H

H

HOH

OMe

Quinine

H2O : CH3COOH (13 : 1)

, 50-75%

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These results clearly establish that the “aluminum powder” reagent that isdeployed in these reductions must contain some Al III impurities to give significant conversion of the ketone substrates to the secondary-alcohol products.

The crucial Aluminium powder reduction step in rabe’s synthesiswas extensively studied .

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Solutions to the Controversies…

Owing to the low and variable yields of the final reduction step in our hands, which they concluded is a function of the quality of the aluminum powder used,in Rabe–Kindler conversion of d-quinotoxine into quinine

Williams et al. concluded that, Woodward and Doering had attempted to repeat theRabe–Kindler reduction protocol and experienced difficulties (i.e., because of the absence of sufficient AlIII impurities in their reagent), they could have reasonably turned to other reducing agents available in 1944.

The powerful tools were not available to Rabe and Kindler in 1918 and also not available to Woodward and Doering in 1944. It then remained for us to repeat theRabe–Kindler work under conditions and using techniques that would have been available in 1944 to reasonably validate the relay conversion of their syntheticd-quinotoxine into quinine, which Woodward and Doering chosen to do so.

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The entire three-step sequence originally reported by Rabe and Kindler in 1918was validated, from d-quinotoxine to quinine, without needing to purify anyintermediates nor resorting to any modern separation, purification or analytical technologies.This sequence was found to be consistently reproducible and was done underlaboratory conditions that existed in 1944.

The conclusions made by Seeman on the validity of the Rabe–Kindler work nowhave firm experimental support which vanquishes any resilient doubts initiallyraised by Stork in a letter to Woodward in 1944.

The Woodward and Doering paper concludes unambiguously: “In view of theestablished conversion of quinotoxine to quinine, with the synthesis ofquinotoxine (by M. Williams et al. in 2008) the total synthesis of quinine was complete.”

And finally stork’s first stereoselective synthesis of quinine is an absolute classic and a work of tremendous historical value

CONCLUSIONS

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Figure . Crystals of quinine tartrate obtained directly from quinotoxineaccording to the Rabe–Kindler protocol without the use of anymodern isolation,chromatographic or analytical techniques.

THANK

U

THANK

U

HUNDRED YEARS OF QUEST FOR SYNTHESIS OF POTENT MIRACLE ...students.orgchem.iisc.ernet.in/students/nagaraju/nagaraju graduate... · HUNDRED YEARS OF QUEST FOR SYNTHESIS OF POTENT MIRACLE

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