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The Hetero-Ene Reaction: Development and Synthetic Utility

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  1. The Hetero-Ene Reaction: Development and Synthetic Utility October 13, 2005 Laura Wysocki Burke Group

  2. Outline • History and Reaction Description • Hetero-Ene Reactions and Synthetic Applications • Carbonyl-Ene • Thio-Ene • Imino-Ene • Oxo-Ene (Schenck Reaction) • Aza-Ene • Retro-Ene • All-Carbon Ene • Tandem Reactions in Synthesis • Conclusion

  3. Discovery: Alder’s “Substituting Addition” Alder, K.; Pascher, F.; Schmitz, A. Ber. Dtsch. Chem. Ges.1943, 76, 27 Nobel Lectures. Chemistry. 1942-1962. Elsevier: Amsterdam. 1964, 253

  4. Discovery: Tandem Substituting Addition and Diene Synthesis Alder, K.; Münz, F. Ann. Chem.1949, 565, 126 Nobel Lectures. Chemistry. 1942-1962. Elsevier: Amsterdam. 1964 pp. 253

  5. Ene and Diels-Alder • “Enophile” rather than “Dienophile” • Good dienophile usually good enophile • Ene often side reaction of Diels-Alder • Some catalysts are effective for both reactions

  6. Ene and Diels-Alder • Endo and exo transition states can be described, like Diels-Alder • Slight endo preference is sensitive to steric effects • Ene has higher activation energy than Diels-Alder, leading to the necessity of higher temperatures • Ene favored by electron withdrawing groups on enophile, strain in ene, and geometric alignment

  7. Mechanism: Concerted or Stepwise? • Continuum of possible reaction mechanisms • Placement of reaction on continuum depends on system and conditions: • Thermal, all carbon, low strain - asynchronous concerted • Strained systems unable to achieve geometry - biradical • Lewis acid catalyzed - close to zwitterionic

  8. Intramolecular Ene Reaction • Intramolecular lower activation energy than intermolecular because of entropic advantage • Useful regio- and stereoselectivity • Classified into three major types Oppolzer, W.; Snieckus, V. Angew. Chem., Int. Ed. Engl.1978, 17, 476

  9. Outline • History and Reaction Description • Hetero-Ene Reactions and Synthetic Applications • Carbonyl-Ene • Thio-Ene • Imino-Ene • Oxo-Ene (Schenck Reaction) • Aza-Ene • Retro-Ene • All-Carbon Ene • Tandem Reactions in Synthesis • Conclusion

  10. Carbonyl-Ene

  11. Carbonyl-Ene: Thermal vs. Lewis Acid • Thermal Ene: Steric accessibility of double bond and allylic hydrogen are primary concern • Lewis Acid-Promoted Ene: Positive charge develops at the ene component so trisubstituted alkene more reactive than monosubstituted Mikami, K.; Shimizu, M. Chem. Rev.1992, 92, 1021

  12. Carbonyl-Ene: Thermal vs. Lewis Acid syn/anti selectivity is reversed with the use of a Lewis Acid Mikami, K.; Shimizu, M. Chem. Rev.1992, 92, 1021

  13. Transition State Geometry Thermal Reaction “Envelope” Early Transition State Lewis Acid Catalyzed “Chair-like” Late Transition State Loncharich, R. J.; Houk, K. N. J. Am. Chem. Soc.1987, 109, 6947 Mikami, K.; Loh, T.-P.; Nakai, T. Tetrahedron Lett.1988, 29, 6305

  14. Thermal Transition State syn anti Benner, J. P.; Gill, G. B.; Parrott, S. J.; Wallace, B.; Begley, M. J. J. Chem. Soc. Perkin Trans. I1984, 315

  15. Lewis Acid Transition State syn anti Mikami, K.; Shimizu, M. Chem. Rev.1992, 92, 1021

  16. Carbonyl-Ene: Asymmetric Reaction si face addition Whitesell, J. K. Acc. Chem. Res.1985, 18, 280

  17. Carbonyl-Ene: Asymmetric Reaction Maruoka, K.; Hoshino, Y.; Shirasaka, T.; Yamamoto, H. Tetrahedron Lett.1988, 29, 3967

  18. Carbonyl-Ene: Asymmetric Reaction With BINOL 33% ee, product in 91.4% yield and 92% ee Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc.1990, 112, 3949

  19. Carbonyl-Ene: Positive Non-Linear Effect Mikami, K.; Shimizu, M. Chem. Rev.1992, 92, 1021

  20. Carbonyl-Ene: Proposed Transition State Mikami, K.; Narisawa, S.; Shimizu,M.; Terada, M. J. Am. Chem. Soc.1992, 114, 6566 Corey, E. J.; Barnes-Seeman, D.; Lee, T. W.; Goodman, S. N. Tetrahedron Lett.1997, 38, 6513

  21. Carbonyl-Ene: Asymmetric Reaction Johnson, J. S.; Evans, D. A. Acc. Chem. Res.2000, 33, 325

  22. Carbonyl-Ene: Reversal of Stereochemistry X-Ray crystal structures Geometry distortion from planarity Evans, D. A.; Johnson, J. S.; Burgey, C. S.; Campos, K. R. Tetrahedron Lett.1999, 40, 2879

  23. Carbonyl-Ene: Transition State Square planar Cu(II) Nucleophilic attack from si face endo transition state anti selective Johnson, J. S.; Evans, D. A. Acc. Chem. Res.2000, 33, 325 Evans, D. A.; Tregay, S. W.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T. J. Am. Chem. Soc.2000, 122, 7936

  24. Carbonyl-Ene: Asymmetric Reaction exo transition state syn selectivity Evans, D.A.; Wu, J. J. Am. Chem. Soc.2005, 127, 8006

  25. Carbonyl-Ene: Desymmetrization Whitesell, J. K., Allen, D. E. J. Org. Chem.1985, 50, 3025 Whitesell, J. K.; Allen, D. E. J. Am. Chem. Soc.1988, 110, 3585

  26. Carbonyl-Ene in Synthesis Takagaso Process for production of menthol Nakatani, Y.; Kawashima, K. Synthesis1978, 147

  27. Carbonyl-Ene in Synthesis Shortened synthesis of this piece by 13 steps Pitts, M. R.; Mulzer, J. Tetrahedron Lett.2002, 43, 8471

  28. Oxonium-Ene in Synthesis Overman, L. E.; Thompson, A. S. J. Am. Chem. Soc.1988, 110, 2248

  29. Oxonium-Ene in Synthesis kH/kD = 1.65 Blumenkopf, T. A.; Look, G. C.; Overman, L. E. J. Am. Chem. Soc.1990, 112, 4399

  30. Thio-Ene

  31. Thio-Ene: Regioselectivity Bachrach, S. M.; Jiang, S. J. Org. Chem.1997, 62, 8319

  32. Thio-Ene: Regioselectivity To alcohol Ea= 31.12 Erxn= -7.97 To thiol Ea= 20.15 Erxn= -18.75 To ether Ea= 44.73 Erxn= -1.04 To sulfide Ea= 21.44 Erxn= -19.70 All numbers in kcal/mol Bachrach, S. M.; Jiang, S. J. Org. Chem.1997, 62, 8319

  33. Imino-Ene Borzilleri, R. M.; Weinreb, S. M. Synthesis1995, 347

  34. Imino-Ene: Asymmetric Reaction Ferraris, D.; Young, B.; Cox, C.; Dudding, T.; Drury, W. J. III; Ryzhkov, L.; Taggi, A. E.; Lectka, T. L. J. Am. Chem. Soc.2002, 124, 67

  35. Imino-Ene: Synthesis Borzilleri, R. M.; Weinreb, S. M.; Parvez, M. J. Am. Chem. Soc.1995, 117, 10905

  36. Imino-Ene: Synthesis Elder, A. M.; Rich, D. H. Org. Lett.1999, 1, 1443

  37. Oxo-Ene (Schenck Reaction) Schenck, G. O.; Schulte-Elte, K. Liebigs Ann. Chem.1958, 618, 185

  38. Schenck Reaction: Transition State CASSCF/6-31G* Houk used potential energy surfaces to conclude a highly asynchronous concerted mechanism takes place UB3LYP/6-31G* RB3LYP/6-31 Leach, A. G.; Houk, K. N. Chem. Commun.2002, 1243

  39. Schenck Reaction: Regioselectivity ‘cis effect’: the more substituted side of the double bond is the most reactive - also seen with allylic alcohols, styrene-type molecules, and trisubstituted enol ethers Hydrogen next to bulky group is usually more reactive Stratakis, M.; Orfanopoulos, M. Tetrahedron2000, 56, 1595

  40. Schenck Reaction: Synthesis Dussault, P. H.; Woller, K. R. J. Am. Chem. Soc.1997, 119, 3824

  41. Aza-Ene Hoffman, H. M. R. Angew. Chem., Int. Ed. Engl.1969, 8, 556

  42. Aza-Ene: Transition State Stepwise Ene reactions proceed through diradical intermediates, which have high rotational barriers about the single bonds. Leach, A. G.; Houk, K. N. Chem. Commun.2002, 1243

  43. Aza-Ene: Indole Protection Using Methyl Triazolinedione (MTAD) Baran, P. S.; Guerrero, C. A.; Corey, E. J. Org. Lett.2003, 5, 1999

  44. Aza-Ene: Synthesis Baran, P. S.; Guerrero, C. A.; Corey, E. J. J. Am. Chem. Soc.2003, 125, 5628

  45. Retro-Ene • Higher temperatures required for retro-ene (Flash Vacuum Thermolysis) • Like Ene reaction, the mechanism of Retro-ene can be anywhere from concerted to stepwise radical or polar, depending on the ene-adduct • Hetero-retro-ene reactions are widespread with heteroatoms in any of the 5 centers involved • Retro-ene can be used to generate reactive species Ripoll, J.-L.; Vallée, Y. Synthesis1993, 659

  46. Retro-Ene: Synthesis Touré, B. B.; Hall, D. G. J. Org. Chem.2004, 69, 8429

  47. Outline • History and Reaction Description • Hetero-Ene Reactions and Synthetic Applications • Carbonyl-Ene • Thio-Ene • Imino-Ene • Oxo-Ene (Schenck Reaction) • Aza-Ene • Retro-Ene • All-Carbon Ene • Tandem Reactions in Synthesis • Conclusion

  48. All-Carbon Ene • Carbon-carbon bond forming with atom economy • Can proceed with high levels of selectivity • Thermal reaction still suffers from high temperatures • Alkyne enophiles proceed more easily than alkene enophiles • Recent advances in transition metal catalyzed all-carbon ene reactions have greatly improved their synthetic utility • Trost’s Ru catalyst for alkene-alkyne coupling

  49. All-Carbon Ene: Stereoselectivity Mikami, K.; Takahashi, K.; Nakai, T. Synlett1989, 45

  50. All-Carbon Ene: Ru Catalyst Trost, B. M.; Toste, F. D. Tetrahedron Lett.1999, 40, 7739 Trost, B. M.; Pinkerton, A. B.; Toste, F. D.; Sperrle, M. J. Am. Chem. Soc.2001, 123, 12504