Nucleophilic Heterocyclic Carbene Catalysis. Nathan Werner Denmark Group Meeting September 22 th, 2009

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1 Nucleophilic Heterocyclic Carbene Catalysis Nathan Werner Denmark Group Meeting September 22 th, 2009

2 Thiamine Thiamine Vitamin B 1 The first water-soluble vitamin described Is naturally synthesized by bacteria, fungi, and plants Deficiency in animals results in the beriberi disease, and can be fatal Important as a coenzyme in a number of biochemical reactions Pyruvic acid decarboxylation: Acetoin synthesis:

3 The Benzoin Reaction The dimerization of aromatic aldehydes to produce a-hydroxy ketones is known as the benzoin reaction In 1903, Arthur Lapworth proposed the mechanism of the cyanide catalyzed benzoin reaction Later, Ugai found Thiamine in the presence of base catalyzed the benzoin reaction Wohler, F.; Liebig, J. Ann. Pharm. 1832, Lapworth, A. J. Chem. Soc. 1903, 995 Ugai, T.; et al. J. Pharm. Soc. Jpn. 1943, 269

4 Breslow s Intermediate Recognizing the similarities in reactivity of thiamine and cyanide in the benzoin reaction, Breslow implicated a stabilized carbene as responsible for the reactivity of thiamine. This work constitutes the first mechanistic description of NHC catalysis Breslow, R.; J. Am. Chem. Soc. 1958,

5 The Catalytically Active Species? Wanzlick, H.W.; Angew. Chem. Int. Ed. 1962, Lemal, D. M.; J. Am. Chem. Soc. 1964, Castells, J.; J. Org. Chem. 1988,

6 NHC Catalyzed Asymmetric Benzoin Sheehan 61:39 er Sheehan 76:24 er Sheehan, J.; et al. J. Am. Chem. Soc. 1966, Sheehan, J.; et al. J. Org. Chem. 1974, Enders, D.; et al. Helv. Chim. Acta 1996, Enders 76:24 er Leeper 90:10 er Enders 95:5 er Leeper, F. J.; et al. J. Chem. Soc., Perkin Trans , Enders, D.; et al. Angew. Chem. Int. Ed. 2002,

7 Asymmetric Benzoin TS Model DG rel =0, obs. 95:5 er (S) DG rel =2.8 DG rel =2.9 Houk, K. N.; et al. Proc. Natl. Acad. Sci. U. S. A. 2004, Enders, D.; et al. Acc. Chem. Res. 2004,

8 The Stetter Reaction Originally described with NaCN: First Asymmetric Stetter Reaction: NHC catalysis has allowed for an asymmetric Stetter reaction and reaction of aliphatic aldehydes Stetter, H.; Schreckenberg, M. Angew. Chem. Int. Ed. 1973, 81 Enders, D.; et al. Helv. Chim. Acta 1996, For additional examples see: Rovis, T.; et al. Synlett 2009,

9 Stetter with Unactivated Olefins 18 NHC s, KCN & Ph 3 P screened (SI) Substitution of the terminal carbon diminishes reactivity Glorius, F.; et al. J. Am. Chem. Soc. ASAP, DOI: /ja906361

10 Quaternary Stereogenic Centers Mechanistic Proposal: Glorius, F.; et al. J. Am. Chem. Soc. ASAP, DOI: /ja906361

11 b-carbon Activation Umpolung and Conjugate Umpolung Glorius, F.; et al. Angew. Chem. Int. Ed. 2004,

12 Synthesis of g-butyrolactones Bode s Conditions: 1 equiv enal 2 equiv aldehyde 8 mol % cat 7 mol % dbu 10:1 THF/tBuOH 25 C, 15 h 79%, 4:1 cis/trans Glorius Conditions: 1 equiv enal 1 equiv aldehyde 5 mol % cat 10 mol % KOtBu THF rt, 16 h 49%, 4:1 cis/trans Bode, J.; et al. J. Am. Chem. Soc. 2004, Glorius, F.; et al. Angew. Chem. Int. Ed. 2004,

13 Proposed Mechanism Bode, J.; et al. J. Am. Chem. Soc. 2004, Glorius, F.; et al. Angew. Chem. Int. Ed. 2004,

14 NHC Homoenolate Chemistry Nolan, S. P.; et al. Angew. Chem. Int. Ed. 2007,

15 Propose a Mechanism R 1 =Me, Ar 2 =Ar 2 =Ph Only 1 diastereomer 94%, >99:1 er R 1 =R 2 =Ph 78%, 11:1 cis/trans >99:1 er Only 1 diastereomer 90% Bode, J. W.; et al. J. Am. Chem. Soc. 2007, Bode, J. W.; et al. J. Am. Chem. Soc. 2008, Nair, V.; et al. J. Am. Chem. Soc. 2006,

16 Cinnamaldehyde Derivative Surrogates Relatively few cinnamaldehyde derivatives are commerically available and most are expensive (~$20 / g, Aldrich) Many NHC catalyzed reactions use cinnamaldehyde derivatives as substrates Aryl substituted a -hydroxyenones are stable solids that are easily prepared from aldol condensation of an aromatic aldehyde and commerically available 3-hydroxy-3-methylbutanone ($5.70 / g, Aldrich) Can these a -hydroxyenones be used as surrogates of cinnamaldehyde? Bode, J. W.; et al. J. Am. Chem. Soc. 2009,

17 The Hypothesis Bode, J. W.; et al. J. Am. Chem. Soc. 2009,

18 Synthetic Examples Similar yields and selectivities are obtained Bode, J. W.; et al. J. Am. Chem. Soc. 2009,

19 a -Hydroxyenone / Enal Comparison Competition Experiments: The diminished reactivity of the a -hydroxyenone is attributed to increased steric demand and decreased electrophilicity, and not a slow retro-benzoin reaction Bode, J. W. et al. J. Am. Chem. Soc. 2009,

20 Chiral NHC w/ a -Hydroxyenones Promotes both retro-benzoin and annulation Most chiral NHCs are too sterically hindered to react with a -hydroxyenones Promotes retrobenzoin but not annulation Bode, J. W. et al. J. Am. Chem. Soc. 2009,

21 NHC Activation of (pin)b B(pin) Hoveyda, A. H. et al. J. Am. Chem. Soc. 2009,

22 b-borylations of Cyclic Enones Ph 3 PO slowly catalyzes the rxn Hoveyda, A. H. et al. J. Am. Chem. Soc. 2009,

23 b-borylation Scope n=1, 97% n=2, 98% 90% 7.1:1 dr 95% 69% 92% 70% 7.2:1 dr Hoveyda, A. H. et al. J. Am. Chem. Soc. 2009,

24 Boron Enolate in situ Trap Reaction occurs at the more hindered enolate face Hoveyda, A. H. et al. J. Am. Chem. Soc. 2009,

25 Summary of NHC Reactivity Glorius, F.; et al. Ernst Schering Foundation Symposium Proceedings 2009,

26 Conclusions NHC catalysis has been extensively used to generate Umpolung reactivity with aldehydes and their a,b-unsaturated derivatives Acyl anions (aldehydes) Bezoin Reaction Stetter Reaction Homoenolate equivalents (enals) Formation of substituted: g-lactones g-lactams Cyclopentenes Dihydropyridinones Spiro g-butyrolactones Recent work by Hoveyda expands the scope of activated groups to include B B bonds For additional references: Enders, D.; et al. Chem. Rev. 2007, Nair, V.; et al. Chem. Soc. Rev. 2008, Nolan, S. P.; et al. Angew. Chem. Int. Ed. 2007, Enders, D.; et al. Acc. Chem. Res. 2004,