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

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