catalytic asymmetric total syntheses of quinine and quinidine izzat t. raheem, steven n. goodman,...

Catalytic Asymmetric Total Syntheses of Quinine and

QuinidineIzzat T. Raheem, Steven N. Goodman, and Eric N. Jacobsen

J. Am. Chem. Soc. 2004, 126, 3, 706

Presented by Michael Elbaum

Dr. Eric N. JacobsenBorn 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 Cii. 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