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Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

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

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  1. 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

  2. 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

  3. 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

  4. Quinine & Quinidine

  5. Initial Approach

  6. Initial Approach

  7. Fragment A Synthesis: Honer-Wadsworth-Emmons (HWE) Reversible reaction allows Thermodynamically Stable, (E) product

  8. Fragment A Synthesis: Catalyzed Michael Addition

  9. 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

  10. Fragment A Synthesis:Wittig Olefination

  11. Fragment A Synthesis:Alkylation

  12. Fragment B Synthesis

  13. Suzuki Coupling of A & B Ligand Gift from Buchwald

  14. Suzuki Cross-Coupling

  15. Sharpless Asymmetric Dihydroxylation ADmix-Beta = DHQD Admix-Alpha = DHQ

  16. Epoxidation

  17. CBz Removal / Intramolecular Sn2

  18. Conclusion • 5% total yield • Longest linear step is 13 • Quinine remains a target for total synthesis

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