catalytic asymmetric total syntheses of quinine and quinidine izzat t. raheem, steven n. goodman,...
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Catalytic Asymmetric Total Syntheses of Quinine and
QuinidineIzzat T. Raheem, Steven N. Goodman, and Eric N. Jacobsen
J. Am. Chem. Soc. 2004, 126, 3, 706
Presented by Michael Elbaum
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Dr. Eric N. JacobsenBorn February 22, 1960
B.S. New York University (1982)
Ph.D. UCLA Berkeley (1986)
Postdoctoral Fellow MIT, Barry K. Sharpless
Associate Professor University of Illinois
Currently Sheldon Emery Professor of Chemistry, Harvard
Development of new methods for organic synthesis with an emphasis on asymmetric catalysis
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Quinine & Quinidine Cinchona alkaloids have long been known for their medicinal properties; Antipyretic, antimalarial, analgesic and anti-inflammatory
Naturally occurs in the bark of cinchona trees
Correct connectivity was discovered by Rabe in 1907
First synthesis of quinine from quinotoxine by Rabe and Kindler in 1918
Woodward and Doering synthesizes quinotoxine in 1944
First stereoselective approach used by Uskokovic and Gutzwiller in 1978
First entirely stereoselective total synthesis of quinine by Stork in 2000
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Quinine & Quinidine
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Initial Approach
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Initial Approach
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Fragment A Synthesis: Honer-Wadsworth-Emmons (HWE)
Reversible reaction allows Thermodynamically Stable, (E) product
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Fragment A Synthesis: Catalyzed Michael Addition
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Fragment A Synthesis:Hydrogenation / Lactamization
Cis/Trans 1:1.7 converted to 3:1 with:
i. LDA, THF, -78o Cii. H2O/THF (5%), -78o C
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Fragment A Synthesis:Wittig Olefination
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Fragment A Synthesis:Alkylation
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Fragment B Synthesis
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Suzuki Coupling of A & B
Ligand Gift from Buchwald
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Suzuki Cross-Coupling
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Sharpless Asymmetric Dihydroxylation
ADmix-Beta = DHQD Admix-Alpha = DHQ
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Epoxidation
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CBz Removal / Intramolecular Sn2
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Conclusion
5% total yield
Longest linear step is 13
Quinine remains a target for total synthesis