1. Pierre-André Fournier
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 , 101,

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

6. Mechanism of the Benzoin Reaction.

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

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 ( ) (Robert Bergman)
Assistant Professor : University of North Carolina (2001 – present)

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

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

11. Silyl Benzoin Reaction : Scope and Limitations.
Limitation : R1 and R2 must be aryls to prevent aldol reaction.
Linghu, X.;Johnson, J.S. Angew. Chem. Int. Ed. 2003, 42,
Linghu, X.; Bausch, C.C.; Johnson, J.S. J. Am. Chem. Soc. 2005, 127,

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 : R1 and R2 must be aryls to prevent aldol reaction.
Linghu, X.; Potnick, J.R.; Johnson, J.S. J. Am. Chem. Soc. 2004, 126,

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 ( ) (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,
Takikawa, H.; Hachisu, Y.; Bode, J.W.; Suzuki, K. Angew. Chem. Int. Ed. 2006, 45,

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

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

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,

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 ( ) (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,

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,

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,

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

29. Asymmetric Intramolecular Stetter Reaction : First Screening.
Catalyst Screening .
R1/R2 X
Yield (%)
ee (%)
H/Bn
BF4 85 90
H/t-Bu -
H/i-Pr Cl 27 79
H/Ph 48 80
Indanyl 58 95
Effect of the Electronic Properties of the Catalyst. X
Yield (%)
ee (%) H 58 95 Cl 60 91
OMe 94
Possible EWG : Ketones, Esters, Nitriles.
Kerr, M.S.; de Alaniz, J.R.; Rovis, T. J. Am. Chem. Soc. 2002, 124,

30. Epimerization observed only in rare cases.
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,

32. Formation of Contiguous Stereocenters via Stetter Reaction.Ar
Base
Yield (%)
ee (%)
dr (%) Ph
KHMDS 85 90
3:1 to 12:1
--- 88
15:1
p-CF3Ph 94 95
30:1
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.Ar
Yield (%)
ee (%)
dr (%)
4-MeOPh 90 88
>95:5 Ph 75 80
C6F5 92 31
Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128,

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.
Synthesis of multiple stereocenters in one step.
J.S. Johnson
J.W. Bode
K.A. Scheidt
T. Rovis

37. Bode – Opening of epoxides.
--.
Bode – Opening of epoxides.

38. Bode - Opening of cyclopropanes.
--.
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 : R1 and R2 must be aryls.