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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