Nucleophilic Heterocyclic Carbene Catalysis Nathan Werner Denmark Group Meeting September 22 th, 2009
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:
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, 249-282 Lapworth, A. J. Chem. Soc. 1903, 995 Ugai, T.; et al. J. Pharm. Soc. Jpn. 1943, 269
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, 3719-3726
The Catalytically Active Species? Wanzlick, H.W.; Angew. Chem. Int. Ed. 1962, 75-80 Lemal, D. M.; J. Am. Chem. Soc. 1964, 2518-2519 Castells, J.; J. Org. Chem. 1988, 4433-4436
NHC Catalyzed Asymmetric Benzoin 1966 1974 1996 1998 2002 Sheehan 61:39 er Sheehan 76:24 er Sheehan, J.; et al. J. Am. Chem. Soc. 1966, 3666-3667 Sheehan, J.; et al. J. Org. Chem. 1974, 1196-1199 Enders, D.; et al. Helv. Chim. Acta 1996, 1217-1221 Enders 76:24 er Leeper 90:10 er Enders 95:5 er Leeper, F. J.; et al. J. Chem. Soc., Perkin Trans. 1 1998, 1891-1893 Enders, D.; et al. Angew. Chem. Int. Ed. 2002, 1743-1745
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, 5770-5775 Enders, D.; et al. Acc. Chem. Res. 2004, 534-541
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, 1899-1902 For additional examples see: Rovis, T.; et al. Synlett 2009, 1189-1207
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: 10.1021/ja906361
Quaternary Stereogenic Centers Mechanistic Proposal: Glorius, F.; et al. J. Am. Chem. Soc. ASAP, DOI: 10.1021/ja906361
b-carbon Activation Umpolung and Conjugate Umpolung Glorius, F.; et al. Angew. Chem. Int. Ed. 2004, 6205-6208
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, 14370-14371 Glorius, F.; et al. Angew. Chem. Int. Ed. 2004, 6205-6208
Proposed Mechanism Bode, J.; et al. J. Am. Chem. Soc. 2004, 14370-14371 Glorius, F.; et al. Angew. Chem. Int. Ed. 2004, 6205-6208
NHC Homoenolate Chemistry Nolan, S. P.; et al. Angew. Chem. Int. Ed. 2007, 2988-3000
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, 3520-3521 Bode, J. W.; et al. J. Am. Chem. Soc. 2008, 418-419 Nair, V.; et al. J. Am. Chem. Soc. 2006, 8736-8737
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, 8714-8718
The Hypothesis Bode, J. W.; et al. J. Am. Chem. Soc. 2009, 8714-8718
Synthetic Examples Similar yields and selectivities are obtained Bode, J. W.; et al. J. Am. Chem. Soc. 2009, 8714-8718
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, 8714-8718
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, 8714-8718
NHC Activation of (pin)b B(pin) Hoveyda, A. H. et al. J. Am. Chem. Soc. 2009, 7253-7255
b-borylations of Cyclic Enones Ph 3 PO slowly catalyzes the rxn Hoveyda, A. H. et al. J. Am. Chem. Soc. 2009, 7253-7255
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, 7253-7255
Boron Enolate in situ Trap Reaction occurs at the more hindered enolate face Hoveyda, A. H. et al. J. Am. Chem. Soc. 2009, 7253-7255
Summary of NHC Reactivity Glorius, F.; et al. Ernst Schering Foundation Symposium Proceedings 2009, 159-181
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, 5606-5655 Nair, V.; et al. Chem. Soc. Rev. 2008, 2691-2698 Nolan, S. P.; et al. Angew. Chem. Int. Ed. 2007, 2988-3000 Enders, D.; et al. Acc. Chem. Res. 2004, 534-541