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 Uskokovic and Gutzwiller in 1978  First entirely stereoselective total synthesis of quinine by Stork in 2000

4. Quinine & Quinidine

5. 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, -78 o C ii. H 2 O/THF (5%), -78 o 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