the constipation was worth it - david a....

N

OH

N

MeO

H

H

H3

4

8

9

Quinine : From Rabe to Stork and those inbetween

The Constipation Was Worth It...

R. Verpoorte, The Cinchona Alkaloids. In The Monoterpene Indole AlkaloidsJ. E. Saxton, Ed.; John Wiley & Sons Ltd, 1994, Chapter 12, 647.

M. R. Uskokovic and G. Grethe. In The Chemistry of Heterocyclic compoundsJ. E. Saxton, Ed.; Wiley Interscience: NY, 1983, Vol. 23, Part 4, 279.

R. B. Turner and R. B. Woodward, The Chemistry of the Cinchona Alkaloids. In The Alkaloids R. H. F. Manske, Ed.; Academic Press: NY, 1953, Vol. 3, Chapter 16.

Dom Reynolds, 8th March 2002

Quin-01-Title 3/6/02 2:22 PM

Quinine : The Anti-Malaria Drug

1630

Quina bark administeredto the Countess of Chinchon

1679

Robert Talbot used ’Jesuit’s Powder’ to cure King Charles II

1850

The G&T’s of the Raj - a necessity

before a pleasure

1897

Sir Ronald Ross deducedthat the malaria parasite is

spread by mosquitoes

Quin-02-AntiMalaria 3/1/02 8:02 AM

Quinine : Early Investigations

N

OH

N

MeO

H

H

H3

4

8

9

1820 : P. J. Pelletier and J. B. Caventou identified Quinine as the active ingredient of Cinchona.

1852 : Initial stereochemical investigations undertaken by L. Pasteur, identifying Quinine as leavo-rotatory.

1854 : A. Strecker established the empirical formula of Quinine as C20H24N2O2. Later confirmed by Zd. Skraup.

1907 : The correct connectivity of the atoms was established - largely through the work of P. Rabe.

Ann. 1854, 91, 155

Ann. 1907, 40, 3655

Compt. Rend. 1853, 37, 110

Ann. Chim. Phys. 1820, 15, 291 and 337

Quin-03-Early Investigations 3/1/02 9:20 AM

N

OH

MeO

N

H

H

H

XMe NH

C20H24N2O2

Sir William H. Perkin

+ 3 O+ H2O

PotassiumChromate

"... it is obvious that napthalidine, differing only by the elements of twoequivalents of water might pass into [quinine] simply by an assumptionof water. We cannot of course, expect to induce the water to entermerely by placing it in contact, but a happy experiment may attain thisend by the discovery of an appropriate metamorphic process."

A. W. Hofmann, Report of the Royal College of Chemistry, 1849

Quinine : First Attempted Synthesis

C10H13N

Quin-04-First Synthesis 3/7/02 12:00 PM

Me NH2N

NMe Me

N

Me

Me

H

X-

Sir William H. Perkin : Easter,1856

Penny Red

PotassiumChromate +

Mauveine

Account presented in Hofmann Memorial LectureJ. Chem. Soc. 1896, 69, 596

Corrected Mauveine StructureJ. Chem. Soc., Perkin Trans. 1, 1994, 5

1857 : A dye factory set up to produce Mauveine, located just south of the Black Horse public House, in Greenford, West London. The Pub is still there.

1862 : At the Royal Exhibition, Queen Victoria made an appearance in a silk gown dyed with mauveine

1865 : The Perkin Process is patented and the ’Aniline Dye Industry’ goes on to spawn many of the world’s major pharmaceutical companies includingBASF, Hoechst, Ciba-Geigy and ICI

Actually a mixtureof ortho and para

Quin-05-Mauveine 3/7/02 8:33 AM

N

H

N

R

OHH

H

R = HR = OMe

CinchonidineQuinine

R = HR = OMe

CinchonineQuinidine

34

N

OH

N

R

H

H

H

34 34

3

4

8

9

6'

3

4

98

6'

NH

CO2H

NH

CO2H

CO2H

NH

CO2H

CO2H

Quinine : The Issue of Stereochemistry

+224+254

-111-158

αD αD

All 4 Compounds

DestructiveFusion

CausticPotash

Meroquinene

Oxidation

β−Cincholoiponic Acid

α−Cincholoiponic Acid

The Alkaloids, R. H. F. Mankse, Ed; Academic Press, NY, 1953, Vol. 3, Chap. 16, p. 25Quin-06-Stereochem 3/7/02 1:27 PM

334 4 34

343434

3

N

OH

N

MeO

H

H

H3

4

EtEt

Et

Me

Et

Et

BrBr

NH

Et

Et

EtO2C CO2Et

Et

Et

CO2H

NH

Et

Et

Et

NH

CO2H

Prelog : Confirmation C3/C4 Stereochemistry

Meroquinene

i. HBr

ii. Zn/ AcOH

Von-Braun Degradation

then NaOH

Relative

Optically Active

i. Ag Saltii. Br2

iii. Raney Nickel Absolute

Prelog manipulates meroquineneto establish C3/C4 cis -relationshipand the absolute stereochemistryof the quinuclidine portion.

1944 :

Helv. Chim. Acta, 1944, 27, 534 and 545

OH

Quin-07-C3/C4 Stereochem 3/6/02 2:29 PM

Quinine : Rationalisation of the C8 Stereochemistry

J. Kenner, Ann. Rep. Chem. Soc, 1922, 19, 157

N

H

N

R

OHH

R = HR = OMe

CinchonidineQuinine

R = HR = OMe

CinchonineQuinidine

N

OH

N

R

H

H

H

8

9

8N

H

N

R

OH

H

R = HR = OMe

CinchonineQuinidine

98

X

H

9

No Cyclisation

Cyclic Ether Formation

Therefore C8 = S

Conditions

3

3 3

Quin-08-C8 Stereochem 3/19/02 1:32 PM

NO

HR''

Ar

H

R

H

HR'

NO

HR''

H

R

HAr

HR'

N

OH

N

MeO

H

H

H

8

9

N

H

N

MeO

OH

H

H

8

9

Me

HO

NHMe

Me

HO

NHMe

Quinine : Rationalisation of the C9 Stereochemistry

The Alkaloids, R. H. F. Mankse, Ed; Academic Press, NY, 1953, Vol. 3, Chap. 16, p. 31

W. Leithe, Ber. 1932, 65, 660

Quinine epi-Quinine

Ephedrine γ−Ephedrine

Weaker bases Stronger bases

K. Freundenberg, J. Am. Chem. Soc, 1932, 54, 234

The involvement of a quasi - ring was proposed by Prelog

+ +

and and

Quin-09-C9 Stereochem 3/1/02 2:06 PM

N

OH

N

MeO

H

H

H

HN

N

MeO

H

O

N

H

HHO2C

CO2H

N

MeO

Quinine : The Situation at the Turn of the Century

The Alkaloids, R. H. F. Mankse, Ed; Academic Press, NY, 1953, Vol. 3, Chap. 16, p. 2

Quinine Quinotoxin Homomero-quinene

C8-N1 disconnection was adopted due to the degradation studies (Pasteur, 1852) which allowed isolable quantities of quinotoxin

81

Synthetic chemists started to publish routes to both the Quinoline and Quinuclidine portions from as early as 1882 (Weidel) and 1904 (Koenigs)

Quinic Acid

Pasteur Prelog

Quin-10-Situation 3/9/02 3:00 PM

N

OH

N

MeO

H

H

H

HN

N

MeO

H

O

N

N

MeO

H

H

O

N

N

MeO

H

OBr

HN

N

MeO

H

O

BrNaOEt

EtOH/NaOEt

HOBr

Quinine : 1918, the ’Rabe’ Synthesis

P. Rabe, Chem. Ber. 1918, 51, 466

Quinine

Quinotoxin

Quininone

Al Powder

12%

25%2 steps

P. Rabe, Chem. Ber. 1911, 44, 2088Quin-11-RabeSynthesis 3/2/02 3:27 PM

N

OH

N

MeO

H

H

H

HN

N

MeO

H

O

N

H

HHO2C

N

N

MeO

H

H

O

CO2H

N

MeO

Quinine : The First Synthesis ?

Quinine QuinotoxinHomomero-

quinene

"... [The method] ist noch nicht eingehend beschreiben worden."

P. Rabe, Ann. 1932, 492, 242

"[Rabe] simply did not sufficiently document what he reported having done that one could be sure to do the relevant chemical transform-ations exactly the way he did them."

Gilbert Stork, 2001

Quinic Acid

P. Rabe, Chem. Ber. 1918, 51, 466

Quin-12-RabeAnalysis 3/2/02 3:41 PM

N

OH

N

MeO

H

H

MeH

PN

N

MeOMe

H

O

EtO2C

N

MeH

COPhEtO2C

CO2Et

N

MeOMeO

NH2N

Et

Me

Rabe : Synthesis of Dihydroquinine

Dihydroquinine

N-Benzoylhomocin-choloipon Ethyl Ester

Ethyl Quinate

P. Rabe, Chem. Ber. 1931, 64, 2487

Claisen Condensation

β-Collidinep-Anisidine

Quin-13-Rabe Dihydroquinine 3/2/02 3:43 PM

CO2Et

N

MeO

Me

N

MeO

OH

Me

N

MeO

N

MeO

Ph

MeO

NH2

EtO

O O

ZnCl2

PhCHO

Rabe : Synthesis of Ethyl Quinate

Ethyl Quinate

P. Rabe, Chem. Ber. 1931, 64, 2487

p-Anisidine

90% H2SO4

i. PCl5/POCl3

~68%

ii. Al/AcOH

3 Steps

i. CaMnO4

ii. EtOH/H+

~80%3 Steps

Quin-14-Rabe Ethyl Quinate 3/6/02 2:32 PM

N

Me

EtO2C

PhO

i. Na/

NH

Et

CO2Et

N

Et

CO2H

EtOH

NaOH

N

Et

OH

CCl3

NH

Et

CO2Et

Cl3CCHO

PhCOCl

N

Et

Me

Rabe : Synthesis of Quinuclidine Precursor

N-Benzoylhomo-cincholoipon ethyl ester

P. Rabe, Chem. Ber. 1931, 64, 2487

β-Collidine

P. Rabe, Chem. Ber. 1919, 52, 1842E. Koenigs, Chem. Ber. 1921, 5254, 1343

BaOH/ZnCl2

67% 88%Amylalcohol

ii. EtOH/HCl88%

70-80%

d-tartrate

Potash100%

10-15%

~30g

As tartratesalt

Quin-15-Rabe Quinuclidine 3/2/02 3:54 PM

N

Me

EtO2C

PhO

CO2Et

N

MeO N

N

MeOMe

O

EtO2C

COPh

HN

N

MeOMe

O

N

N

MeOMe

O

N

N

MeOMe

OHH

Salzsäure

H2

NaOEt

EtOH

Rabe : Synthesis of Dihydroquinine

P. Rabe, Chem. Ber. 1931, 64, 2487

62.5%+ 64%

HOBrthen NaOEt

Pd (cat)

Dihydroquinine

?23%

"The outstanding contributions of Rabe to the study of the cinchona alkaloids were crowned by the total synthesis in 1931 of dihydroquinine"

R. B. Woodward, 1953

Quin-16-Rabe Dihydroquinine 3/2/02 3:36 PM

N

N

MeO

N

OH

COPh

N

N

MeO

OCOPh

EtO2C

PhO

NEtO2C

HN

N

MeO

O

CO2Et

N

MeO

ii. PhCOCl

HNHO2C

Prelog : Synthesis of Quinotoxin

Helv. Chim. Act. 1943, 26, 1965

i. EtOH/HCl70-80%

Potash100%

correctenantiomerQuinotoxin

Quin-17-Prelog Quinotoxin 3/6/02 2:33 PM

N

OH

N

MeO

H

H

H

HN

N

MeO

H

O

N

H

HHO2C

Quinine : Revised target

Quinine Quinotoxin

Homomero-quinene

P. Rabe V. Prelog

N

OH

Me

Woodward

Quin-18-WoodwardAnalysis 3/6/02 2:41 PM

N

HHO2C

OH

O

MeONH2

OMe

N

OH

Me

Ac

N

OH

Me

N

OH

NaOMeMeOH

N

OH

N

OH

N

N

OH

H2C=O

HN

Woodward : Synthesis of Homomeroquinene

J. Am. Chem. Soc. 1945, 67, 860

i.

ii. 80% H2SO4

J. Am. Chem. Soc. 1944, 66, 849

94% +Aq NaOH

then H+crystalise

60%

62%

220° 16h65%

3

4

[or 60%, 2 steps]

AcOHH2/PtO2

thenAc2O

95%

Quin-19-Homomeroquinene 3/6/02 2:52 PM

N

HHO2C

N

OH

Me

Ac

NH

H

Ac

O

MeH

N

OH

Me

Ac

H

H

N

Me

Ac

H

H

O

N

OH

Me

Ac

H

H AcOH

H2Cr2O7

N

O

Me

Ac

H

H

N

Me

Ac

H

H

OH

OH

Et2OH2O


J. Am. Chem. Soc. 1945, 67, 860

Raney NiH2/EtOH

150°, 3000psi

1:1, cis/transcrystalline

+

crystalline

benzene

28%

"...the system would assume, by facile inter-conversion through the enol, whatever

configuration was most stable."

Quin-20-Homomeroquinene2 3/6/02 2:56 PM

N

HHO2C

N

Me

Ac

H

H

O

N

Ac

H

H

O

N

MeOEt

O

N

Ac

H

H

O

N

Me O

EtO

N

N

Ac

H

H

CO2Et

Me

OH

H+

N

Ac

H

H

NMe O

OEt

O

N

NMe3I

Ac

H

H

CO2Et

Me


J. Am. Chem. Soc. 1945, 67, 860

NaOEt/EtOHEtO-N=O

68%

i. H2/PtO2

AcOH

ii. MeI K2CO3

90%, 2 Steps


N

HHO2C

CO2Et

N

MeO

HN

N

MeO

O

HN

N

MeO

O

N

NMe3I

Ac

H

H

CO2Et

Me

N

H

H

CO2H

NH2O

N

H

H

CO2Et

PhO


J. Am. Chem. Soc. 1945, 67, 860

c. NaOH, 180°

then KCNO

dil. HCl/EtOH

then PhCOCl,K2CO3

Prelog

i. NaOEt fusion

ii. 6N HCl

racemicQuinotoxin

50%

40% from oxime 96%

dibenzoyld-tartrate

d-Quinotoxin

Rabe

1.4g30 mg after 4 recrystalisations


HNHO2C

NEtO2C

PhON

OH

Me

Woodward Synthesis : Summary

15 Steps

By this route synthetic quinine estimated to cost $3000/lb. Natural quinine $16/lb.

"The duplication of the highly complicated chemical architecture of the quinine molecule, hailed by leading scientists at Harvard and other institutions as one of the greatest scientific achievements in a century."

W. M. Lawrence, The New York Times, 4th May, 1944

"[quinine’s] total laboratory synthesis in 1944 is one of the classical achievements of synthetic organic chemistry."

The Encyclopedia Britannica, 15th Ed. Chicago, 1997; Vol 9, p 862

racemicHomomero-

quinene

Quin-23-Summary 3/6/02 3:00 PM

Woodward : The Glamour

Quinine : Two Young Chemists End a Century’s Search by Making Drug Synthetically from Coal Tar

Quin-24-Life 3/7/02 4:59 PM

H

N

OH

N

MeO

H

H

C8-N

N

MeO

Y

HN

N

MeO

X

XC HN

H

Quinine

81

C8-N Disconnection

Meroquinine

Rabe

Quin-25-C8-N 3/5/02 11:27 AM

RhH2

N

O

COPh

H

H

N

O

COPh

NaN3

NaN3

PPA, 60°

N

COPh

NH

O

N

COPh

H

H

CO2H

N

COPh

O

O

H

H

N

COPh

NH

O

H

H

N2O4

N

O

O

COPh

NN

H

H

N

COPh

N

O

H

H

NO

RO2C N

H

Uskokovic : Meroquinine Synthesis

Meroquinine

J. Am. Chem. Soc. 1970, 92, 203

67%

16hRh/Al2O3

H2

Quant 125°

50% 30%

+

Resolved at this stage

>60% cis

2:1

J. Am. Chem. Soc. 1978, 100, 571

P

Quin-26-MeroQ Uskokovic1 3/6/02 3:14 PM

RO2C N

H

N

CO2Me

Cl

N

CO2Me

Cl

PhO

NH

CO2Me

TFA

HCl

N

CO2Me

PhO

N

CO2Me

N

Uskokovic : Meroquinine Synthesis

J. Am. Chem. Soc. 1971, 93, 5902

Meroquinine

β-Collidine

(MeO)2COLDA

88%

H2/Pt82%

d-Tartaric Acid

i. Hg Lamp200W

ii. PhCOCl84%

Löffler-FreytagReaction

i. MeOH/1N KOHii. tBuOK/DMSO

iii. CH2N2

NCSEt2O92%

N-benzoylmeroquinineMethyl Ester

87%

then

M. E. Wolff, Chem. Rev. 1963, 63, 55

J. Am. Chem. Soc. 1978,100, 571

NCO2Me

H

HH

HHH

+

via N-radical

Cl

P

Quin-27-MeroQ Uskokovic2 3/6/02 3:14 PM

RO2C N

H

OMeO2C

O-ββββGluH

H

MeO2C

NHMeO2C

H

H

MeO2C

OMeO2C

O-ββββGlu(Ac)4H

H

CHO

NH

CO2Me

Ac2O

OMeO2C

O-ββββGluH

H

CHO

Brown : Meroquinine Synthesis

Tet. Lett. 1978, 1605

Meroquinine

MeroquinineMethyl Ester

J. Chem. Soc. Chem. Commun. 1978, 725

Secologanin

i. Jones [O]ii. CH2N2

iii. MeONa

i. β-Glucosidase NH4OAc

ii. NaBH3CN

i. 1% HCl

ii. NaBH4

pH 6.5~60%

>95%

~60%

P

Quin-28-MeroQ Brown 3/6/02 3:15 PM

RO2C N

H

O

TBSO

NCOPh

TBSCl

N

CO2TBS

COPh

N

O

O

COPh

I-N Cl

Me

N

O

N2

COPh

N

OH

O OTHP

COPh

PhCO2Ag

Cl

OTHP

NaH

N

CO2Me

COPh

HN

OH

COPh

O

Funk : Meroquinine Synthesis

Meroquinine

J. Org. Chem. 1984, 49, 4319

N-BenzoylmeroquinineMethyl Ester

NEt3, MeOH

67%

i. PPTS MeOH

ii.

+

67%

LDA

93%

i. HFii. NaH/(ClOC)2

iii. CH2N2

76%77%

P

Quin-29-MeroQ Funk 3/7/02 1:27 PM

O

AcO

OAc

OAc

OAcO

O

tBuOOAc

Cu(CN)MgBr

N

CO2Me

Ph

BrOMe

O

OO

CO2Me

H

HPhCH2NH2

NaCNBH3

N

CO2Me

H.HCl

O

O

tBuO

H

CO2Me

H

OAc

OHO

H

CO2Me

H

OH

RO2C N

H

Hannesian : Meroquinine Synthesis

Meroquinine

Tetrahedron 1990, 46, 231

2

then,

3 Steps

6 Steps

34%

If you think this is bad see : S. Takano, J. Chem. Soc. Chem. Commun. 1979, 556

i. EtOCOClii. HCl

63%

61%

48%

73%75%

NaIO4

P

Quin-30-MeroQ Hannesian 3/6/02 3:15 PM

Ph NH

O

O

O

TMS

Cl

Ph N

O O

O

TMS

N

CO2Me

Bn

then KF

MeOHN

O

TMSH

H

O

Bn

N

O

O

TMSH

H

O

Bn

MeOHHCl

NEt3Ph N

O

TMS

Me

O

OTBS

TMSN

O

Bn

RO2C N

H

P

TBSOTfNEt3

Wilson : Meroquinine Synthesis

Meroquinine

J. Org. Chem. 1991, 56, 4767

94%

i. HCl/THF 95%

ii. Wittig

71%

mCPBA

86%71%

"Secondary orbital overlap and the steric requirments of the TMS group ... are critical to the high selectivity."

64%

O

N

CHO

Bn

i. LiAlH4

ii. Swern [O]

90%

Quin-31-MeroQ Wilson 3/9/02 3:08 PM

RO2C PN

H

No

No

No

Summary of Meroquinine Syntheses

Meroquinine

Uskokovic 1Uskokovic 2BrownFunkHannesianWilson

Woodward

Key StepSteps

3 to RCO2H9 to RCO2Me

8 to NH8 to RCO2Me14 to NH.HCl10 to NBn

OpticallyPure ?

ResolveResolve

Chiral SM

Chiral SM

17 to RCO2Et

2:1

HighN/AHighEpimeriseHigh

1:1

(Homomo-meroquinine)

Group Yield

30%24%

23%

32%24%

3%

<5%

Nitrosation/fragmentationLöffler-Freytag chlorinationSecoglanin manipulationClaisen RearrangmentGlucose manipulationDA/TMS directed Baeyer Villiger

Cis-hydrogenation to set C3/C4

Comment

Quin-32-MeroQ summary 3/9/02 3:16 PM

H

N

OH

N

MeO

H

H

C8-N

N

MeO

Y

HN

N

MeO

XC HN

H

Quinine

81

Quinine : C8-N Disconnection

Meroquinine

Rabe

Quin-33-C8-N vinyl 3/6/02 3:21 PM

N

N

MeO

COPh

O N

N

MeO

AcO

H

N

N

MeO

HN

HN

MeO

N

MeO

Me

MeO2C N

COPh

Uskokovic : Quinine Synthesis

J. Am. Chem. Soc. 1978, 100, 576

LDA, -78°

then,

78%

i. DiBAl-H85%

3:2

ii. AcOH BF3•OEt2

96%

AcONaAcOHBenzene79%

+

43 : 57

J. Am. Chem. Soc. 1970, 92, 204

Quin-34-VinylQ1 Uskokovic 3/6/02 2:05 PM

N

N

MeO

H

OHH

N

N

MeO

H

N

HN

MeO

N

HN

MeO

OHH

N

N

H

OMe

H

DMSO


J. Am. Chem. Soc. 1978, 100, 576

+

tBuOK/tBuOH

1O2

40%

+

Quinine

Quinidine

Deoxyquinine

Deoxyquinidine

"Preferred backside attack of theoxygen radical anion ... to avoid therepulsive force of the quinuclidino nitrogen free electron pair."

J. Am. Chem. Soc. 1970, 92, 204

Quin-35-VinylQ2 Uskokovic 3/6/02 3:22 PM

N

N

MeO

H

N

N

MeO

HN

N

MeO

H

N

MeO

PPh3

OHC N

COMe

N

COMePh3P

N

MeO

O

Gates and Taylor : Quinine Synthesis

Gates, J. Am. Chem. Soc. 1970, 92, 205

’mixture’

or

’mixture’

AcOHE-isomer

PhotolysisZ-isomer

Taylor, J. Am. Chem. Soc. 1974, 96, 8095

Taylor Gates

67%

Quin-36-Gates/Taylor VinylQ 3/6/02 10:40 AM

H

N

OH

N

MeO

H

H

C8-N

N

MeO

Y

HN

N

MeO

X

XC HN

H

Quinine

81

Uskokovic : C8-N Disconnection

Meroquinine

Rabe

Quin-37-C8-N epox 3/6/02 3:21 PM

N

N

MeO

COPh

O N

N

MeO

HO

H

H

N

N

MeO

OHH


J. Am. Chem. Soc. 1978, 100, 576

i. NBSii. NaBH4

40%iii. DiBAl-H

4 Diastereoisomers

TolueneEtOH

Reflux

Quinine 13%

+ epi-Quinine 18%+ Quinidine 24%+ epi-Quinidine 18%

63%

Quin-38-EpoxyQ Uskokovic 3/6/02 2:06 PM

00

00

0 000

00

00

00

00

00

0 0 0

00

00

00

00

00

00000

00000

00

N

N

MeO

COPh

O N

N

MeO

H

O

ClCl

N

N

MeO

OH

H

H

N

N

MeO

O

H

N

HN

MeO

O

Helv. Chim. Acta. 1973, 56, 1494

Si Face


J. Am. Chem. Soc. 1978, 100, 576

Helv. Chim. Acta. 1973, 56, 1485

i. 3N H2SO4

ii. iPr2NCl

iv. BaOH MeOH

34%

iii. NaBH4

+

DiBAl-H

33%

epimerizes oncrystalisation+ 39% Quinidine

Woodward, J. Am. Chem. Soc. 1945, 67, 1425Quin-39-DichlorQ Uskovic 3/6/02 2:52 PM

H

N

OH

N

MeO

H

H

C9-C10

N

MeO

Y N

H

XO

Quinine

910

Uskokovic : C9-C10 Disconnection

+

Quin-40-C9-C10 3/6/02 3:23 PM

N

CO2Me

PhO

N

PhO

CHCl2

OH

NEtO2C

HN

N

H

XO

Uskokovic : Quinuclidine Synthesis

J. Am. Chem. Soc. 1978, 100, 581

i. DiBAl-Hii. PhCOCl

iii. Cl2HCLi80%

74%

KOHBenzene

57%

i. AgNO2

ii. EtOH/H+

54%

J. Am. Chem. Soc. 1971,93, 5904

NOHC

Cl

O

Quin-41-Quinuclidine Uskokovic 3/6/02 3:27 PM

N

N

MeO

OHH

N

N

MeO

OHH

NOHC

N

MeO

Li

NEtO2C

N

MeO

Li

Et2O, -78°

Et2O, -78°


J. Am. Chem. Soc. 1978,100, 589

Quinine 13%

+ epi-Quinine 5%+ Quinidine 15%+ epi-Quinidine 5%

i.

ii. DiBAl-H30-40%

Quinine 33%69%

+ Quinidine 36%

Quin-42-Quinine Uskokovic 3/9/02 3:12 PM

H

N

OH

N

MeO

H

H

Quinine

81

Uskokovic : Summary

HN

N

MeO

X

Y

H

Quinuclidine formation by cyclisation onto a prochiral C8 or

functionalisation of SN2 quinuclidine cyclisation precursors

C8 Stereochemistry is problematic

Oxidation of deoxyquinine to quinine is highly stereoselective

Quin-43-Uskovic Summ 3/6/02 3:29 PM

H

N

OH

N

MeO

H

H

N

N

MeO

H

H

NH

N

MeO

H

H

X

[O]

N

N

OMeOH

[H]

HNX

N

MeO

H

N-C6

NH

N

OMe

X

Quinine

6

Stork : N-C6 Disconnection

1

Deoxyquinine

Quin-44-Stork N-C6 3/6/02 3:31 PM

OO

NH

OTBS

O

Ph

Me

O

EtOOH

KOHMeOH

NH

OTBS

O

Ph

Me

O

EtOOH

OO

HOOH

MeC(OEt)3

Taniguchi : Chiral γγγγ-lactone

Bull. Chem. Soc. Jpn. 1988, 61, 4361

+[3,3] 89%

26%

30%

+

thenTsOH58%

3

Chem. Lett. 1974, 741

PhCH2NH2

OO

3

AlMe3

OH

OH

heat

Quin-45-Stork sm 3/6/02 3:35 PM

OO

OTBDPS

Et2NOTBS

O

OTBDPS

IOTBDPS

OH

OTBDPS

MeO

Et2NOTBS

O

OTBDPS

O N3

OO

Stork : Quinine Synthesis

J. Am. Chem. Soc. 2001, 123, 3239

i. Et2NAlMe2

ii. TBSCl/imid

79%

LDA, -78°

79% >20:1

PPTS/EtOHthenXylene93%

i. DiBAl-H

ii. Ph3PCH(OMe)

75%

i. (PhO)2P(O)N3

Ph3P/DEAD

ii. 5N HCl

74%

3

4

Quin-46-Stork Quin 3/9/02 3:01 PM

N

N

MeO

H

H

N

MeO

OTBDPS

O N3

OTBDPS

N3OH

OTBDPS

NHH

N

OMe

OTBDPS

N

N

OMe


J. Am. Chem. Soc. 2001, 123, 3239

LDA, -78°

then,

70%

i. Swern [O]

ii. PPh3/THF

69%

NaBH4

THF/MeOH

91%

i. HF/MeCNii. MsCl/Pyr

iii. MeCN

65%Relux

Deoxyquinine

N

N

MeO

H

H

OHH

NaH/DMSO

then O2

78%, ~14:1

Quinine

N

OMe


OO

N

N

MeO

H

H

OHH


J. Am. Chem. Soc. 2001, 123, 3239

Quinine

Nature, 2001, 411, 429Chemistry in Britain, 2001, Vol 10

www.chemsoc.org/chembytes/ezine/2001/ball_oct01.htm

"An absolute classic ... [the work] has tremendous historical value."

"the Stork paper is written with an insight and historical perspective (as well as correcting some myths) rarely seen in the primary chemical literature, and should be required reading for all students of organic chemistry."

S. Weinreb, 2001

A. Smith, 2001

~7%16 Steps


C8 1:1

C8 1:1

Summary of Quinine Syntheses

Rabe

Woodward

Uskokovic

Gates

TaylorUskokovic

Stork

Key StepSteps

3a

23

14

15c

13c

15

Reality

C8/9 All 4

C8/9 All 4

C8 1:1

C8 1:1

16

1:1

1:1

C9 5:1

C9 5:1

C9 5:1C9 High

C8 High

Yield

3%

0.075%b

5%

5%

3%c

2%c

7%

GroupDate

1918

1944

1970

1970

19741978

2001

a : Starts from Quinotoxinb : Uses Rabe results to complete a formal synthesisc : Incorporated Uskokovic steps and yields for meroquinine

Original C8-N disconnection

Non-selective hydrogenation

Vinyl quinoline; C9 O2 oxidation

Wittig reagent from meroquinine

Quinoline derived phosphoraneAmino-chloroepoxide cyclisation

Stereospecific reduction set C8

C8 1:1Uskokovic 17 C9 High1%1978 Via quinuclidine electrophile

Stereo-selective

N

OH

N

MeO

H

H

H3

4

8

9

Quin-49-Quinine Summary 3/6/02 2:08 PM

the constipation was worth it - david a....

Documents