Quinine

1
Quinine
June 14, 2005 Peter Siengalewicz
Illustration of Kinquina from Pierre Pomet,
Histoire generale des drogues. Paris Jean
Baptiste Loyson Augustin Pillon, 1694, p. 132.
2
Isolation Pharmaceutical Properties

• antipyretic, analgesic properties, use as
  flavoring agent in bitter drinks
• potent anti-malaria agent, known since 1681
• now replaced by quinacrine, chloroquine and
  primaquine
• malaria affects approx. 40 of the worlds
  population
• 300 500 million new cases each year
• 1.5 2.7 million casualties annually
• extracted from the yellow bark of the
  South-American Cinchona tree
• isolated and named in 1820 by Pelletier and
  Caventou
• name means bark of the barks in quechua
• elucidation of the molecular connectivity by P.
  Rabe in 1908
• stereochemically exact structure proven by V.
  Prelog in 1944

3
Structural Properties
4
Rabes Efforts to a Synthesis of Quinine (1918)
5
First Total Synthesis of Quinine by Woodward and
Doering (1944)
6
First Total Synthesis of Quinine by Woodward and
Doering (1944)
7
Synthesis of Quinine by Taylor and Gates (1974 /
1970)
8
C9 C4 Coupling Approach by Uskokovic (1978)
9
Synthesis of N-benzoylmeroquinene by Uskokovic
10
Synthesis of Meroquinene from a Pyridine
Derivative
3. BzCl, base
11
Retrosynthetic Approach to Quinine by Stork et
al. (2001) C6 N Bond Forming Strategy
12
Synthesis of Quinine by Stork by Use of
Taniguchis Lactone
13
Completion of the Synthesis
14
Retrosynthetic Analysis of Quinine by Jacobsen et
al. (2004) C8 N Bond Forming Strategy
15
Synthesis of Quinine by Jacobsen et Co-workers
16
Synthesis of Quinine by Jacobsen et Co-workers
17
Retrosynthetic Analysis of Quinine by Kobayashi
et al. (2004) C8 N Bond Forming Strategy
18
Synthesis of Quinine by Acharya and
Kobayashi Construction of the Meroquinene
Derivative
19
Synthesis of Quinine by Acharya and
Kobayashi Construction of the Aromatic Portion
20
Synthesis of Quinine by Acharya and
Kobayashi Completion of the Synthesis
21
Citations

• Kaufmann, T. S. and Rúveda E. A. Ang. Chem. Int.
  Ed. 2005, 44, 854
• Rabe, P. and Kindler, K. Ber. Dtsch. Chem. Ges.
  1918, 51, 466
• Woodward, R. B. and Doering, W. E. J. Am. Chem.
  Soc. 1944, 66, 849
• Taylor, E. C. and Martin, S. F. J. Am. Chem. Soc.
  1974, 96, 2874, 8095
• Gates, M. et al. J. Am. Chem. Soc. 1970, 92, 205
• Uskokovic M. R. et al. J. Am. Chem. Soc. 1978,
  100, 581, 589
• Stork, G. J. Am. Chem. Soc. 2001, 123, 3239
• Jacobsen, E. N. et al. J. Am. Chem. Soc. 2004,
  126, 706
• Kobayashi, Y. Tetrahedron Lett. 2004, 45, 3783