New Inter- and Intramolecular Pauson-Khand Reactions

1
New Inter- and Intramolecular Pauson-Khand
Reactions

• Ahmad Farid Samin

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Outline

• Introduction
• What is the Pauson-Khand Reaction
• Brief History of Pauson-Khand Reaction
• Biological Significance of Some Cyclopentenone
  Derivatives
• Intermolecular PKR
• Proposed Mechanism for the Intermolecular PKR
• The PKR Mechanism Regiochemistry
• Effect of Pyridylsilyl on Ru-Catalyzed PKR
• Conjugated Alkenes in the Intermolecular PKR
• PKR Involving Allenes
• Intramolecular PKR
• Synthesis of Indolidine and its Derivatives
• Use of Thiourea Ligands in PKR
• CO-Free PKR
• Conclusion

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What is the Pauson-Khand Reaction?
Gibson and Stevenazzi Angew. Chem. Int. Ed. 2003,
42, 1800-1810. Itami et al. J. Am. Chem. Soc.
2004, 126, 1105811066.
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Brief History of PKR

• Discovered in 1973 by Peter Pauson and Ihsan
  Khand
• Initially catalyzed by Co2(CO)8
• High pressure/temperature
• Low yield
• In 1990s the PKR improved
• Ti, Zr, Mo, W, Fe, Pd, Ni, Ru, and Rh
• In 2004, CO-free PKR

Blanco-Urgoitti et al. Chem. Soc. Rev. 2004, 33,
32-42.
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Biological Significance of Some Cyclopentenone
Derivatives

• Useful building blocks for complex structures
• Prostacyclin (PGI2), major vasodilator and
  inhibitor
• Cyclopentenone prostanoids
• a. Interalia b. Anti-inflammatory c.
  Anti-viral pharmaceuticals
• Activities of larger organic molecules
• Anticancer
• Antiviral
• Body building drugs

Blanco-Urgoitti et al. Chem. Soc. Rev. 2004, 33,
32-42.
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Anticancer Activities of Cyclopentenone

• Prostaglandins (PGs), play vital role in human
  body
• PGs have exhibited important anti-tumor activities

Ishikawa et al. J. Org. Chem. 2004, 69, 8133-8135.
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Antiviral Activities of Cyclopentenones

• PG-Js, inhibit various viruses
• Delaying the onset of labor
• Preventing the continuation of labor

Gibson et al. J. Organomet. Chem. 2004, 689,
3873-3890.
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Bodybuilding Drugs

• Masterbolan
• Muscle hardener and strength increaser
• Subdermal water levels may drop
• Paper thin appearance of muscle

http//www.musclemg.com/119.htm. Accessed
10/01/05.
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Intermolecular PKR

• Three carbon-carbon bonds and two stereocenters
• Limited to strained olefins
• Norbornene and norbornadiene dominate

Itami et al. J. Am. Chem. Soc. 2004, 126,
1105811066. Martín et al. Chem. Eur. J. 2005,
11, 2716-2729.
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Reactivity of the Alkenes in the Intermolecular
PKR

• Related to back donation
• The greater the back donation, the higher the
  reactivity
• The smaller the angle, the lower the LUMO
• The lower the LUMO, the lower the energy barrier

Milet et al. J. Org. Chem. 2004, 69,
1075-1080. http//www.ch.ic.ac.uk/vchemlib/course/
mo_theory/main.html. Accessed 10/25/05.
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Strained Alkenes in the Intermolecular PKR
Marchueta et al. Org. Lett. 2001, 3, 3193-3196.
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Proposed Mechanism for the Intermolecular PKR
Magnus and Principe Tetrahedron Lett. 1985, 26,
4851-4854.
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Proposed Mechanism Continued
Magnus and Principe Tetrahedron Lett. 1985, 26,
4851-4854.
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The PKR Mechanism Regiochemistry
Schore et al. Org. React. 1991, 40, 1-90.
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Effect of Pyridylsilyl on Ru-Catalyzed PKR
Itami et al. J. Am. Chem. Soc. 2004, 126,
1105811066.
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Effect of Pyridylsilyl on Ru-Catalyzed PKR
Itami et al. J. Am. Chem. Soc. 2004, 126,
1105811066.
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Directing Group Effect
Itami et al. Angew. Chem. Int. Ed. 2002, 41,
3481-3484.
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Conjugated Alkenes in the Intermolecular PKR

• Conjugated dienes have low-lying LUMO
• More reactive than normal alkenes
• Cyclopentadiene is more reactive than
  cyclopentene

Gibson and Mainolfi Angew. Chem. Int. Ed. 2005,
44, 3022-3037.
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Effect of Temperature and Solvents on Conjugated
Dienes
Wender et al. Angew. Chem. Int. Ed. 2004, 43,
30763079.
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Effect of Temperature and Solvents on Conjugated
Dienes
Wender et al. Angew. Chem. Int. Ed. 2004, 43,
30763079.
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PK Reactions Involving Allenes

• Important substrate for PKR
• In 1985 Pauson reported for the first time
• Several reports on the use of allenes in
  intramolecular PKR
• Intermolecular PKR is not extensively explored

Hashmi Angew. Chem. Int. Ed. 2000, 112, 3737-3740.
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PK Reactions Involving Allenes
Añorbe et al. Tetrahedron Lett. 2004, 45,
4441-4444.
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Intramolecular PKR

• In 1981, Schore reported the first examples
• Strained alkenes are not required
• The first CO-free intramolecular PKR

Pérez-Serrano et al. J. Org. Chem. 2004, 69,
5413-5418. Itami et al. J. Am. Chem. Soc. 2004,
126, 1105811066.
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Synthesis of Indolidine and its Derivatives

• Indole alkaloids, occur widely nature
• Play a vital role in human body
• Ergotamine
• Mitomycin
• In 2000, Hayashi discovered asperparalines
• Recently, Tanimori synthesized it, via
  intramolecular PKR

Pérez-Serrano et al. J. Org. Chem. 2004, 69,
5413-5418. Tanimori et al. Tetrahedron 2005, 61,
2481-2492.
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Synthesis of Asperparalines
Tanimori et al. Tetrahedron 2005, 61, 2481-2492.
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Tetracyclicindole Derivatives
Pérez-Serrano et al. J. Org. Chem. 2004, 69,
5413-5418.
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Use of Thiourea Ligands in PKR
Tang et al. Org. Lett. 2005, 7, 593-595.
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Use of Thiourea Ligands in PKR
Tang et al. Org. Lett. 2005, 7, 1657-1659.
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CO-Free Intramolecular PKR
Fuji et al. Tetrahedron 2004, 45, 9163-9166.
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Conclusion

• Many improvements have been made on the
  Pauson-Khand reaction since its discovery in 1973
  
• The process yields cyclopentenones, which can be
  easily transformed into different cyclopentenones
  
• The intramolecular PKR is well established
• Formaldehyde can satisfactorily replace
  conventional methods that use carbon monoxide
• Intermolecular version is still quite limited to
  strained olefins
• Instead of the usual alkene, allenes are also
  attractive substrates in the PKR
• The Pauson-Khand reaction will continue to be a
  powerful synthetic process

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• Thanks