Total Synthesis of Ingenol

1
Total Synthesis of Ingenol

• Andrew Nickel, Toru Maruyama, Haifeng Tang,
  Prescott D. Murphy, Blake Greene, Naeem Yusuff,
  and John L. Wood

Sterling Chemistry Laboratory, Department of
Chemistry, Yale University, New Haven, Connecticut
J. Am. Chem. Soc. 2004, 126, 16300-16301
2
Total Synthesis of Ingenol

• 1.Introduction
• a. isolation
• b. bioactivity
• c. structure
• 2.Past synthesis of ingenol
• 3.Result and Discussion
• 4.Conclusion

3
Introduction of Ingenol

• 1.Isolation
• isolated by Hecker
• group in 1968 from
• the genus Euphorbia.

Figure.1 Spurges family (Euphorbia spp.)
4
Introduction of Ingenol

• 2.bioactivity
• a. activation of protein kinase C (PKC)
• b. tumour-promoting
• c. anticancer
• d. anti-HIV properties

5
Introduction of Ingenol
3.Structure inside-outside bridged BC ring
system
6
In/Out Isomerism
7
Past Synthesis of Ingenol
Jeffrey D. Winkler was the first total synthesis
of Ingenol in 2002.
J. Am. Chem. Soc. 2002, 124, 9726-9728
8
Past Synthesis of Ingenol

• intramolecular de Mayo reaction constructed
  inside-outside bridged BC ring system.

J. Am. Chem. Soc. 2002, 124, 9726-9728
9
Past Synthesis of Ingenol

• Isao Kuwajima reported total synthesis of ingenol
  in 2003 by employing tandem cyclization-rearrange
  ment

J. Am. Chem. Soc. 2003, 125, 1498-1500
10
Retrosynthesis of Ingenol
11
Construction of Ingenane Tetracycle
John L. Wood. Org. Lett. 2001, 3, 1563-1566
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Synthesis of Precursory Norborane
John L. Wood. Org. Lett. 2001, 3, 1563-1566
13
Construction of Ingenane Tetracycle
John L. Wood. Org. Lett. 2001, 3, 1563-1566
14
Construction of Ingenane Tetracycle
J. Am. Chem. Soc. 2004, 126, 16300-16301
15
Synthesis of Allylic Alcohol 8
16
Synthesis of a-Hydroxy Ketone 10
17
Gained Undesired anti products 12,13
18
Inerted Ene Reaction to Singlet Oxygen
19
Synthesis of Mesylate 19
20
Isomerized to Allylic Sulfone 23
21
Synthesis of Ingenol 1
22
Conclusion

• 1.a ring-closing metathesis approach has
  effectively employed in construction of
  inside-outside bridged BC ring system.
• 2.an efficient total synthesis delivers the
  biologically important diterpene ingenol in 32
  overall steps from 2