Catalytic Asymmetric Total
Syntheses of Quinine and
Quinidine
Izzat T. Raheem, Steven N. Goodman, and Eric N. Jacobsen
J. Am. Chem. Soc. 2004, 126, 3, 706
Presented by Michael Elbaum
Dr. Eric N. Jacobsen
 Born 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
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
Quinine & Quinidine
Initial Approach
Initial Approach
Fragment A Synthesis:
Honer-Wadsworth-Emmons
(HWE)
Reversible reaction allows Thermodynamically Stable,
(E) product
Fragment A Synthesis:
Catalyzed Michael Addition
Fragment A Synthesis:
Hydrogenation / Lactamization
Cis/Trans 1:1.7 converted to 3:1 with:
i. LDA, THF, -78o C
ii. H2O/THF (5%), -78o C
Fragment A Synthesis:
Wittig Olefination
Fragment A Synthesis:
Alkylation
Fragment B Synthesis
Suzuki Coupling of A & B
Ligand Gift from Buchwald
Suzuki Cross-Coupling
Sharpless Asymmetric
Dihydroxylation
ADmix-Beta = DHQD
Admix-Alpha = DHQ
Epoxidation
CBz Removal / Intramolecular
Sn2
Conclusion
 5% total yield
 Longest linear step is 13
 Quinine remains a target for total synthesis