Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

Zhensheng DingJanuary 22 2004

Chinese New Year Day

1. Jacobsen, E., N. J. Am. Chem. Soc. 2004, ASAP

2. Stork, G.; Niu, D. J. Am. Chem. Soc. 2001, 123, 3239

3. Nicolaou, K., C. Classics in Total Synthesis II: More Targets,

Strategies, Methods, Wiley-VCH: Weinheim, Germany, 2003, Ch. 15

N

OMe

OH

N

Quinine

1

23

45

6

7

8

9N

OMe

N

Quinidine

1

23

45

6

7

89

OH

1

1 2

1

Pasteur’s Degradation Reaction of Quinine

N

OMe

OHH

NH2SO4

N

OMe

OHH

NH

H2ON

OMe

OH

HN

N

OMe

O

HN

quinine quinotoxine

3 4

5

Classics in Total Synthesis II, Wiley-VCH,Germany, 2003, Ch. 15

Louis Pasteur (1822 - 1895)

Chance favors only the prepared mind. —Louis Pasteur

5 6 7

8 1

Formal Synthesis of Quinine By Woodward and Doering

HNN

N

OMe

ON

MeOCO2Et

BzNO

OEtH

HN

OMe

OHH

Condensation

OH

CHO

AcN

H

H MeOAcN

MeOHN

MeOH

quinine quinotoxine

Rabe route

+

1 5 9 10

11121314

Woodward/Doering’ Retrosynthetic Analysis and Strategy

J. Am. Chem. Soc. 1945, 67, 860J. Am. Chem. Soc. 1944, 66, 849

14 15 16 16

171312

12

11

11

18 19 20

21 22

22 23 10

95

What we can learn from Woodward’s Synthesis

1. The formation, modification, and eventual cleavage of carbonframeworks in cyclic settings to generate acyclic stereochemicalelements

2. Rapid construction of the carbon framework in the targetmolecule

3. The application of nitrite ester cleavage protocol can preventepimerization, directly afford the requisite ester side chain, andmake it easy to make double bond

AcN

H

H MeOBzN

O

OEtH

H10 11

NOH

17N

vs. BzNO

OEtH

H10

The First Stereoselective Total Synthesis of Quinine By Stork

Gilbert Stork (Emeritus)Department of ChemistryColumbia UniversityBox 3118, Havemeyer HallNew York, NY 10027 (212) 854-2178gjs8@columbia.edu

Stork’s Retrosynthetic Analysis and Strategy

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

N

OMe

OHH

N O

N

OMeN

N

OMe

NOR

N

OMeN

OR

N

OMeN3

OR

O

N

OMeN3

OR

HO

Alkylation N

OMe

N

OMe

Me

N

OMe

NOR

H

H

NHOR

N3O

RO

1: quinine 24: deoxyquinine

8

+

Reduction and imine formation

Nucleophilicaddition

Selective hydridedelivery

2526

27 28 29 30

1 6

31 32 33

343530

29 30 28 26

25241

What we can learn from Stork’s Synthesis

1. Conformational analysis shows that the two pseudo-chair formsof the synthetic precursor are of similar energy, and makes the C-8non-stereoselective.

2. Follow the words of wisdom by Robert Ireland: “All too oftenthe most convenient way to draw a molecule on paper belies themost efficient synthetic approach.” This helps to construct the C-8stereocenter.

3. Install C-9 stereocenter by oxygenation which utilize the stericbulk of the bridgehead nitrogen in the quinuclidine ring.

N

OMeHN8

N

OMe

HNvs. 8

N

OMeN

OMe

NOR

H

H

NHOR

8 8

Catalytic Asymmetric Synthesis of Quinine and Quinidine By Jacobsen

Eric N. JacobsenSheldon Emery Professor of Chemistry

Harvard UniversityDepartment of Chemistry, 12 Oxford StreetCambridge, MA 02138(617) 496-3690 (Assistant)

J. Am. Chem. Soc. 2004, ASAP

Yesterday Once More: N1-C8 DisconnectionJacobsen’s Retrosynthetic Analysis and Strategy

N

OMe

OH

N

N

OMePNO

NH

CO2Me

OCOPh

CNPONH

Ph

O O

PO

N

OMe

PN

H

H

M

NP

N

OMe

X

quinine

IntramolecularSN2

Suzuki coupling

Enantioselectiveconjugate addition

Sharplessdihydroxylation

+

8 1

1 21 20

5 469

J. Am. Chem. Soc. 2004, ASAP

Jacobsen’s Total Synthesis of Quinine

J. Am. Chem. Soc. 2004, ASAP

Jacobsen’s Total Synthesis of Quinine

J. Am. Chem. Soc. 2004, ASAP

N

OMe

N

OH

2

Jacobsen’s Total Synthesis of Quinidine

What we can learn from Jacobsen’s Synthesis

1. Application of recently developed (salen)Al-Catalyzed conjugateaddition of methyl cyanoacetate to construct C4 stereocenterefficiently.

2. C8 & C9 chiral center can be formed by Sharplessdihydroxylation with high dr.

3. Yes, disconnection of N1-C8 bond provides a way to asymmetrictotal synthesis of quinine

Date Group Step Yield Reality Key Step2001 Stork 16 7% Stereoselective C8 High Stereospecific reduction set C82004 Jacobsen 16 5% Catalytic,

AsymmetricC4, C8 and C9 High, Sharpless

dihydroxylation

Comparison of the Two Steroselective Total Synthesis of Quinine

Large-Scale Synthesis of VANOL

Park, O. S, Jang, B. S. Archives of Phar.Research, 1995, 18, 277

Method IV to intermediate 20

Ph

OHO

OHPh

OEtO

OH

PhPh

O

CO2EtPh

O

Br CO2Et

2) Addition to ketone

Hydrolysis

+ + Zn

1) Reformatsky reaction

+ BnMgCl28 40

41 42

43

Ph

OMeO

Br CO2Et PhH Ph

OEtO

OHMeO

+Zn, I2,

96%

44 45

Ph

OBr CO2Et

PhH, Et2O, 4hPh

OEtO

OH+Zn, I2 ,

worked41 42 28

Ph

OHO

OH

28

Successful examples:

Synthesis of 20 from b-hydroxyester

Can this condition be used for my compound?

Large-Scale Synthesis of VANOL

Future Work: Synthesis of VANOL and Resolution

OHOHPh

Ph

OHPh

OOPh

Ph PO

OH

5 3

190oCair, 32h

1) POCl3

2) H2O1) (-)-brucine2) resolution3) reduction

(+) and (-)VANOL

33

N

O

N

O

MeO

MeO

H

H

H

H(-)-brucine

Key point: monomer 5 must be pure for oxidative coupling

Bao, J.; Wulff, W. D. et al J. Am. Chem. Soc., 1996, 118, 3392

Large-Scale Synthesis of VANOL

Conclusions

1) A new synthetic approach of VANOL was studied. This new method provides a cheap,efficient way for large scale synthesis of VANOL ligand.

2) Conditions for Michael addition, hydrolysis and Friedel-Crafts reaction wereoptimized.

3) Michael addition was scaled up successfully in high yields. More work is needed toscale up Friedel-Crafts reactions.

4) Dehydrogenation reaction was studied and optimization of the conditions is inprogress.

5) Some new methods have been briefly discussed.