The Quest for Quinine - Northwestern University

[Pages:35]The Quest for Quinine

OMe N

3 4

8N

9

OH H

Literature Seminar March 7, 2005

References: Kaufman, T.; Ruvedo, E. Angew. Chem. Int. Ed. 2005, 44, 854-885. Nicolaou, K. Synder, S. Classics in Total Synthesis II; Wiley-VCH: Germany, 2003. Raheem, I.; Goodman, S.; Jacobsen, E. J. Am. Chem. Soc. 2004, 126, 706-707. Igarashi, J.; Katsukawa, M.; Wang, Y.; Acharya, H.; Kobayashi, Y. Tetrahedron Lett. 2004, 45, 3783-3786.

Quinine: The Facts

OMe

N

OH H N

1g/$3.61

? Isolated from the bark of cinchona trees ? A cinchona alkaloid

Synthetic Uses:

? Chiral Ligand ? Chiral Auxiliaries ? Phase Transfer Catalysis ? Asymmetric Catalyst ? Chiral Resolving Agent ? Enantioselective Transformations

? Sharpless Asymmetric Dihydroxylation ? Diels-Alder ? Hydrocyanations ? [2+2] Cycloadditions ? Michael Additions ? SmI2 Mediated Reductions ? Dehydrohalogenations

? Properties and Uses:

? Anti-malarial ? Analgesic ? Anaesthetic ? Antibacterial ? Anti-microbial ? Anti-parasitic ? Antiseptic ? Astringent ? Febrifuge ? Muscle-relaxant ? Bactericide ? Contraceptive ? Insecticide ? Insect-repellant ? Stomachic ? Tonic

Quinine: The History

A really really long time ago. . . Cinchona Tree Bark used Treat Fevers by Natives

1640: Cinchona Bark introduced to European Medicine: Countess of Chinchon cured from Malaria.

1681: Universally accepted as an Antimalarial Substance

1820: Authentic Sample of Quinine Isolated: Pelletier and Caventou

1854: Molecular Formula of Quinine Determined: Strecker

Quinine: Key Points in Synthetic History

1st attempted Synthesis: Perkin Correct Molecular Connectivities Reported: Rabe Rabe's Reconstruction of Quinine from Quinotoxine Woodward/Doering Formal Total Synthesis Hoffmann-La Roche Total Synthesis, Gates Total Synthesis Taylor Total Synthesis Stork Total Synthesis Jacobsen and Kobayashi Total Syntheses

1856 1908 1918 1944 1970 1972 2001 2004

Quinine: Key Points in Synthetic History

1897: Mass Spectrometry 1903: Chromatography 1912: X-Ray Crystallography 1945: NMR

First Attempted Synthesis of Quinine

1856: Perkin's "mathematical approach"

Me

H N

Me

H N

+

C10H13N

C10H13N

+ 3O

--[H2O]

OMe N

N

OH H

C20H24N2O2

R

Me

N

H2N

N

NH

Me

Mauvine

Quinine: Determination of Structure

Quintenine HO2C

OMe

OMe

OHC

1908: Rabe suggests correct connectivity of quinine

Br Br OMe

N

OH H N

OMe N

OAc N

OMe N

O N

Quinone

N

N

OH H N

[O]

Br2

OH

H N

HO2C HN

Meroquinene [O]

O3

Dilute Acid

Acylation [O]

OMe N

N

OH H

Acid

OMe HN

O

N

Quinotoxine

H2O, !

[O] (HNO3, H2CrO4)

KOH fusion

MeO

N

6-Methoxyquinoline

Me

MeO

CO2H

MeO

N

N

Quinic Acid

6-Methoxyepidine

Rabe's Partial Synthesis of Quinine

Reconstruction of Quinine from Quinotoxine

1853: Louis Pasteur observed quinine forms quinotoxine in aqueous sulfuric acid

OMe N

N

OH H

1918: Paul Rabe effects partial synthesis from quinotoxine

OMe HN

O N

NaOBr

OMe N

N Br

O

H2SO4

OMe HN

O N

Quinotoxine

NaOEt,

OMe

EtOH

N

Br

O

N

OMe N

N

OH H

OMe

Aluminum powder

N

N

Solvent

H O

OMe

H

N

O N

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