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

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Presentation on theme: "1 Umpolung Reactivity of Functional Groups : The Stetter and The Benzoin Reactions Pierre-André Fournier Collins Group."— Presentation transcript:

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

2 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 3 Benzoin and Stetter Reactions. Can we functionalize the aldehyde in one step? Benzoin reaction : Addition of an acyl anion equivalent to a carbonyl. Stetter reaction : Addition of an acyl anion equivalent to an activated olefin. Catalyst : cyanide, phosphite or heterocyclic carbene.

4 4 Benzoin and Stetter Reactions : New Synthetic Tools? Total synthesis of (±)-Hirsutic Acid C (Trost, 1979)  Rough conditions (50 eq. of Et 3 N)  Low yields  Very specific Trost, B.M.; Shuey, C.D.; DiNinno, F.Jr.; MeElvain, S.S.. J. Am. Chem. Soc , 101,

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

6 6 Mechanism of the Benzoin Reaction.

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

8 8 Jeffrey S. Johnson 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) Intermolecular Benzoin Reaction

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

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

11 11 Silyl Benzoin Reaction : Scope and Limitations. 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, Limitation : R 1 and R 2 must be aryls to prevent aldol reaction.

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

13 13 Chiral Metallophosphites for Enantioselective Silyl Benzoin Reaction. Limitation : R 1 and R 2 must be aryls to prevent aldol reaction. Linghu, X.; Potnick, J.R.; Johnson, J.S. J. Am. Chem. Soc. 2004, 126,

14 14 Jeffrey W. Bode 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) Intramolecular Benzoin Reaction – Catalytic Homoenolate Generation

15 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 16 Catalytic Homoenolate Generation : Synthesis of  -Butyrolactones. Sohn, S.S.; Rosen, E.L.; Bode, J.W. J. Am. Chem. Soc. 2004, 126,

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

18 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 19 Intermolecular Stetter Reaction. Lack of selectivity. Scheidt’s Methodology : Modification of the substrate.

20 20 Karl A. Scheidt 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) Intermolecular Stetter Reaction – Acylsilanes Chemistry

21 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 22 Pyruvate as a Source of Acyl Anion Equivalent : Mecanism.

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

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

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

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

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

28 28 Tomislav Rovis. 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) Intramolecular Asymmetric Stetter Reaction – NHC Design

29 29 Asymmetric Intramolecular Stetter Reaction : First Screening. Kerr, M.S.; de Alaniz, J.R.; Rovis, T. J. Am. Chem. Soc. 2002, 124, R 1 /R 2 XYield (%)ee (%) H/BnBF H/t-BuBF 4 0- H/i-PrCl2779 H/PhCl4880 IndanylBF XYield (%)ee (%) H5895 Cl6091 OMe94 Catalyst Screening. Effect of the Electronic Properties of the Catalyst. Possible EWG : Ketones, Esters, Nitriles.

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

31 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 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-CF 3 Ph) ArBaseYield (%)ee (%)dr (%) PhKHMDS85903:1 to 12:1 Ph :1 p-CF 3 Ph :1

33 33 Formation of Contiguous Stereocenters via Stetter Reaction.

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

35 35 Synthesis of Hydrobenzofuranones via Desymmetrization. ArYield (%)ee (%)dr (%) 4-MeOPh9088>95:5 Ph7580>95:5 C6F5C6F5 9231>95:5 Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128,

36 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 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 40 Sylil Benzoin Reaction : Scope and Limitations. Limitation : R 1 and R 2 must be aryls.


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