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New Inter - and Intramolecular Pauson - Khand Reactions Ahmad Farid Samin Outline Introduction What is the Pauson - Khand Reaction Brief History of Pauson - Khand Reaction Biological Significance of Some Cyclopentenone Derivatives Intermolecular PKR

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outline
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
what is the pauson khand reaction
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, 11058–11066.

brief history of pkr
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.

biological significance of some cyclopentenone derivatives
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.

anticancer activities of cyclopentenone
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.

antiviral activities of cyclopentenones
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.

bodybuilding drugs
Masterbolan

Muscle hardener and strength increaser

Subdermal water levels may drop

Paper thin appearance of muscle

Bodybuilding Drugs

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

intermolecular pkr
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, 11058–11066.

Martín et al. Chem. Eur. J. 2005, 11, 2716-2729.

reactivity of the alkenes in the intermolecular pkr
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.

strained alkenes in the intermolecular pkr
Strained Alkenes in the Intermolecular PKR

Marchueta et al. Org. Lett. 2001, 3, 3193-3196.

proposed mechanism for the intermolecular pkr
Proposed Mechanism for the Intermolecular PKR

Magnus and Principe Tetrahedron Lett. 1985, 26, 4851-4854.

proposed mechanism continued
Proposed Mechanism Continued

Magnus and Principe Tetrahedron Lett. 1985, 26, 4851-4854.

the pkr mechanism regiochemistry
The PKR Mechanism: Regiochemistry

Schore et al. Org. React.1991, 40, 1-90.

effect of pyridylsilyl on ru catalyzed pkr
Effect of Pyridylsilyl on Ru-Catalyzed PKR

Itami et al. J. Am. Chem. Soc. 2004, 126, 11058–11066.

effect of pyridylsilyl on ru catalyzed pkr16
Effect of Pyridylsilyl on Ru-Catalyzed PKR

Itami et al. J. Am. Chem. Soc. 2004, 126, 11058–11066.

directing group effect
Directing Group Effect

Itami et al. Angew. Chem. Int. Ed. 2002, 41, 3481-3484.

conjugated alkenes in the intermolecular pkr
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.

slide19

Effect of Temperature and Solvents on Conjugated Dienes

Wender et al. Angew. Chem. Int. Ed. 2004, 43, 3076–3079.

effect of temperature and solvents on conjugated dienes
Effect of Temperature and Solvents on Conjugated Dienes

Wender et al. Angew. Chem. Int. Ed. 2004, 43, 3076–3079.

pk reactions involving allenes
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.

pk reactions involving allenes22
PK Reactions Involving Allenes

Añorbe et al. Tetrahedron Lett. 2004, 45, 4441-4444.

intramolecular pkr
In 1981, Schore reported the first examples

Strained alkenes are not required

The first CO-free intramolecular PKR

Intramolecular PKR

Pérez-Serrano et al. J. Org. Chem. 2004, 69, 5413-5418.

Itami et al. J. Am. Chem. Soc. 2004, 126, 11058–11066.

synthesis of indolidine and its derivatives
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. Tetrahedron2005, 61, 2481-2492.

synthesis of asperparalines
Synthesis of Asperparalines

Tanimori et al. Tetrahedron2005, 61, 2481-2492.

tetracyclicindole derivatives
Tetracyclicindole Derivatives

Pérez-Serrano et al. J. Org. Chem. 2004, 69, 5413-5418.

use of thiourea ligands in pkr
Use of Thiourea Ligands in PKR

Tang et al. Org. Lett. 2005, 7, 593-595.

use of thiourea ligands in pkr28
Use of Thiourea Ligands in PKR

Tang et al. Org. Lett. 2005, 7, 1657-1659.

co free intramolecular pkr
CO-Free Intramolecular PKR

Fuji et al. Tetrahedron2004, 45, 9163-9166.

conclusion
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