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Umpolung Reactivity of Functional Groups : The Stetter and The Benzoin Reactions

Umpolung Reactivity of Functional Groups : The Stetter and The Benzoin Reactions. Pierre-André Fournier Collins Group. What’s an Umpolung?. Any process by which the normal nucleophile and electrophile are interchanged. Classical example : the use of dithianes.

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Umpolung Reactivity of Functional Groups : The Stetter and The Benzoin Reactions

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  1. Umpolung Reactivity of Functional Groups : The Stetter and The Benzoin Reactions Pierre-André Fournier Collins Group

  2. What’s an Umpolung? Any process by which the normal nucleophile and electrophile are interchanged. Classical example : the use of dithianes • Additional protection/deprotection steps. • Stoichiometric amount of reagents. • Highly basic conditions.

  3. Benzoin and Stetter Reactions. Can we functionalize the aldehyde in one step? Catalyst : cyanide, phosphite or heterocyclic carbene. Benzoin reaction : Addition of an acyl anion equivalent to a carbonyl. Stetter reaction : Addition of an acyl anion equivalent to an activated olefin.

  4. Benzoin and Stetter Reactions : New Synthetic Tools? Total synthesis of (±)-Hirsutic Acid C (Trost, 1979) • Rough conditions (50 eq. of Et3N) • Low yields • Very specific Trost, B.M.; Shuey, C.D.; DiNinno, F.Jr.; MeElvain, S.S.. J. Am. Chem. Soc..1979, 101,1284-1285.

  5. The Cross Benzoin Reaction. No control of the chemioselectivity. Suzuki, K.; Bode, J.W.; Hachisu, Y. Adv. Synth Catal.2004, 346,1097-1100.

  6. Mechanism of the Benzoin Reaction.

  7. Asymmetric Benzoin Condensation. Enders, D.; Kallfass, U. Angew. Chem. Int. Ed..2002, 41, 1743-1745.

  8. Jeffrey S. Johnson Intermolecular Benzoin Reaction B.Sc. : University of Kansas (1994) Ph.D. : Harvard University (1999) (David A. Evans) PDF : University of California (1999-2001) (Robert Bergman) Assistant Professor : University of North Carolina (2001 – present)

  9. Controlling the Reaction : The Use of Acylsilanes. Need to prepare the acylsilanes… Aryl Alkyl Linghu, X.;Johnson, J.S.Angew. Chem. Int. Ed. 2003, 42, 2534-2536.

  10. Silyl Cross Benzoin Reaction : Mechanism. Linghu, X.;Johnson, J.S.Angew. Chem. Int. Ed. 2003, 42, 2534-2536.

  11. Silyl Benzoin Reaction : Scope and Limitations. Limitation : R1and R2 must be aryls to prevent aldol reaction. Linghu, X.;Johnson, J.S.Angew. Chem. Int. Ed. 2003, 42, 2534-2536. Linghu, X.; Bausch, C.C.; Johnson, J.S.J. Am. Chem. Soc. 2005, 127, 1833-1840.

  12. Other Synthetic Methods to Make a-Hydroxy Ketones. • Needs to form the enolate. • Lack of stereocontrol.

  13. Chiral Metallophosphites for Enantioselective Silyl Benzoin Reaction. Limitation : R1and R2 must be aryls to prevent aldol reaction. Linghu, X.; Potnick, J.R.; Johnson, J.S.J. Am. Chem. Soc. 2004, 126, 3070-3071.

  14. Jeffrey W. Bode Intramolecular Benzoin Reaction – Catalytic Homoenolate Generation B.Sc. : Trinity University (San Antonio) (1996) Ph.D. : ETH Zürich (2001) (Erick M. Carreira) PDF : Tokyo Institute of Technology (2001-2003) (Keisuke Suzuki) Assistant Professor : University of California (2003 – present)

  15. Aldehyde-Ketone Benzoin Cyclization. Suzuki, K.; Bode, J.W.; Hachisu, Y. Adv. Synth Catal.2004, 346,1097-1100. Takikawa, H.; Hachisu, Y.; Bode, J.W.; Suzuki, K. Angew. Chem. Int. Ed.2006, 45, 3492-3494.

  16. Catalytic Homoenolate Generation : Synthesis of g-Butyrolactones. Sohn, S.S.; Rosen, E.L.; Bode, J.W.J. Am. Chem. Soc. 2004, 126, 14370-14371.

  17. Catalytic Homoenolates Generation : Synthesis of g-lactames. Average yields, but low diastereoselectivities. He, M.; Bode, J.W.Org. Lett. 2005, 7, 3131-3134.

  18. Intermolecular Stetter Reaction in Total Synthesis. Tius’ synthesis of the macrocyclic core of Roseophilin. Harrington, P.E.; Tius, M.A.Org. Lett. 1999, 1, 649-651.

  19. Intermolecular Stetter Reaction. Lack of selectivity. Scheidt’s Methodology : Modification of the substrate.

  20. Karl A. Scheidt Intermolecular Stetter Reaction – Acylsilanes Chemistry B.S. : University of Notre-Dame (1994) Ph.D. : Indiana University / University of Michigan (1999) (William R. Roush) PDF : Harvard University (1999-2002) (David A. Evans) Assistant Professor : Northwestern University (2002 – present)

  21. Biomimetic Conjugate Addition of Acyl Anion. Nature‘s approach to acyl anions. Biomimetic approach to acyl anions. Myers, M.C.; Bharadwaj, A.R.; Milgram, B.C.; Scheidt, K.A.J. Am. Chem. Soc. 2005, 127, 14675-14680.

  22. Pyruvate as a Source of Acyl Anion Equivalent : Mecanism.

  23. Pyruvate as a Source of Acyl Anion Equivalent. Organic conditions: Aqueous conditions:

  24. Pyruvate as a Source of Acyl Anion Equivalent. Imidazole easily transformed to an amide or an ester .

  25. Addition of Acylsilanes. Lots of solvents, bases and catalysts screened. Mattson, A.E.; Bharadwaj, A.R.; Zuhl, A.M.; Scheidt, K.A.J. org. Chem. 2006, 71, 5715-5724.

  26. Addition of Acylsilanes. Effective preparation of 1,4-diketone.

  27. Synthesis of Pyrroles and Furanes by Sila-Stetter/Paal-Knorr Sequence. Furans: Pyrroles: Good yields for a one-pot synthesis of this type of molecule. Bharadwaj, A.R.; Scheidt, K.A.Org. Lett. 2004, 6, 2465-2468.

  28. Tomislav Rovis. Intramolecular Asymmetric Stetter Reaction – NHC Design B.Sc. : University of Toronto (1990) Ph.D. : University of Toronto (1993-1998) (Mark Lautens) PDF : Harvard University (1998-2000) (David A. Evans) Assistant Professor : Colorado State University (2000 – present)

  29. Asymmetric Intramolecular Stetter Reaction : First Screening. Catalyst Screening . Effect of the Electronic Properties of the Catalyst. Possible EWG : Ketones, Esters, Nitriles. Kerr, M.S.; de Alaniz, J.R.; Rovis, T.J. Am. Chem. Soc. 2002, 124, 10298-10299.

  30. Asymmetric Intramolecular Stetter Reaction : a-Substituted Cycloketones. Epimerization observed only in rare cases.

  31. Formation of Quaternary Stereocenters via Stetter Reaction. Highly selective methods for the formation of quaternary centers. Kerr, M.S.; Rovis, T.J. Am. Chem. Soc. 2004, 126, 8876-8877.

  32. Formation of Contiguous Stereocenters via Stetter Reaction. HMDS and the carbene can epimerize the stereocentres. No epimerization observed with a less basic carbene (p-CF3Ph)

  33. Formation of Contiguous Stereocenters via Stetter Reaction.

  34. Source of The Diastereoselectivity. Reactions with E and Z olefins shows that bond rotation is slower than protonation.

  35. Synthesis of Hydrobenzofuranones via Desymmetrization. Liu, Q.; Rovis, T.J. Am. Chem. Soc. 2006, 128, 2552-2553.

  36. Stetter and Benzoin Reaction. Intermolecular Benzoin Reaction: • Acylsilanes are required. • Alkyls are problematic. • Reaction works well with aryls. Intramolecular Benzoin Reaction: • No substrate modifications required. • Works with alkyl and aryl. • Promising asymmetric version. Intermolecular Stetter Reaction: • Acylsilanes or pyruvates are required. • Limited to aryls. • Effective synthesis of pyrroles and furanes. Intermolecular Stetter Reaction: • No substrate modifications required. • Works with alkyl and aryl. • Synthesis of multiple stereocenters in one step. J.S. Johnson J.W. Bode K.A. Scheidt T. Rovis

  37. --. Bode – Opening of epoxides.

  38. --. Bode - Opening of cyclopropanes.

  39. Applications of Ru-Based Chiral Metathesis Catalysts. Jeff Bode – Cross Stetter, intramolecular benzoin, intramolecular benzoin on ketones Johnson – Sylil benzoin (racemic and chiral) Enders - ? Karl Scheidt – Biomimetic Stetter, « esterification » of aldehydes, Sila-Stetter (+ Paal-Knorr one-pot) Tom Rovis – Asymmetric Stetter Tius, Trost,

  40. Sylil Benzoin Reaction : Scope and Limitations. Limitation : R1and R2 must be aryls.

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