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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)
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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 Uskokovicand Gutzwillerin 1978 • First entirely stereoselective total synthesis of quinine by Stork in 2000
Fragment A Synthesis: Honer-Wadsworth-Emmons (HWE) Reversible reaction allows Thermodynamically Stable, (E) product
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
Suzuki Coupling of A & B Ligand Gift from Buchwald
Sharpless Asymmetric Dihydroxylation ADmix-Beta = DHQD Admix-Alpha = DHQ
Conclusion • 5% total yield • Longest linear step is 13 • Quinine remains a target for total synthesis