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  1. New Inter- and Intramolecular Pauson-Khand Reactions Ahmad Farid Samin

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. Strained Alkenes in the Intermolecular PKR Marchueta et al. Org. Lett. 2001, 3, 3193-3196.

  12. Proposed Mechanism for the Intermolecular PKR Magnus and Principe Tetrahedron Lett. 1985, 26, 4851-4854.

  13. Proposed Mechanism Continued Magnus and Principe Tetrahedron Lett. 1985, 26, 4851-4854.

  14. The PKR Mechanism: Regiochemistry Schore et al. Org. React.1991, 40, 1-90.

  15. Effect of Pyridylsilyl on Ru-Catalyzed PKR Itami et al. J. Am. Chem. Soc. 2004, 126, 11058–11066.

  16. Effect of Pyridylsilyl on Ru-Catalyzed PKR Itami et al. J. Am. Chem. Soc. 2004, 126, 11058–11066.

  17. Directing Group Effect Itami et al. Angew. Chem. Int. Ed. 2002, 41, 3481-3484.

  18. 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.

  19. Effect of Temperature and Solvents on Conjugated Dienes Wender et al. Angew. Chem. Int. Ed. 2004, 43, 3076–3079.

  20. Effect of Temperature and Solvents on Conjugated Dienes Wender et al. Angew. Chem. Int. Ed. 2004, 43, 3076–3079.

  21. 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.

  22. PK Reactions Involving Allenes Añorbe et al. Tetrahedron Lett. 2004, 45, 4441-4444.

  23. 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.

  24. 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.

  25. Synthesis of Asperparalines Tanimori et al. Tetrahedron2005, 61, 2481-2492.

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

  27. Use of Thiourea Ligands in PKR Tang et al. Org. Lett. 2005, 7, 593-595.

  28. Use of Thiourea Ligands in PKR Tang et al. Org. Lett. 2005, 7, 1657-1659.

  29. CO-Free Intramolecular PKR Fuji et al. Tetrahedron2004, 45, 9163-9166.

  30. 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

  31. Thanks