catalytic asymmetric total syntheses of quinine and quinidine

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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

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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) - PowerPoint PPT Presentation

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Page 1: Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

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

Page 2: Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

Dr. Eric N. JacobsenBorn February 22, 1960B.S. New York University (1982)Ph.D. UCLA Berkeley (1986)Postdoctoral Fellow MIT, Barry K. SharplessAssociate Professor University of IllinoisCurrently Sheldon Emery Professor of Chemistry,

HarvardDevelopment of new methods for organic synthesis

with an emphasis on asymmetric catalysis

Page 3: Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

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

Page 4: Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

Quinine & Quinidine

Page 5: Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

Initial Approach

Page 6: Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

Initial Approach

Page 7: Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

Fragment A Synthesis: Honer-Wadsworth-Emmons (HWE)

Reversible reaction allows Thermodynamically Stable, (E) product

Page 8: Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

Fragment A Synthesis: Catalyzed Michael Addition

Page 9: Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

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

Page 10: Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

Fragment A Synthesis:Wittig Olefination

Page 11: Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

Fragment A Synthesis:Alkylation

Page 12: Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

Fragment B Synthesis

Page 13: Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

Suzuki Coupling of A & B

Ligand Gift from Buchwald

Page 14: Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

Suzuki Cross-Coupling

Page 15: Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

Sharpless Asymmetric Dihydroxylation

ADmix-Beta = DHQD Admix-Alpha = DHQ

Page 16: Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

Epoxidation

Page 17: Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

CBz Removal / Intramolecular Sn2

Page 18: Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

Conclusion

5% total yieldLongest linear step is 13Quinine remains a target for total synthesis