Abstract
The development of general catalytic methods for the regio- and stereoselective construction of chiral N-heterocycles in a diversity-oriented fashion remains a formidable challenge in organic synthesis. N-heterocyclic carbene (NHC) catalysis has been shown to produce a variety of outcomes, but control of the reactivity has rarely been demonstrated. Here we report a switchable catalytic activation of enals with aromatic azomethine imines that provides high selectivity using NHC organocatalysts. The original selectivity corresponds to the acidity of the base used in the reaction. The catalytically generated chiral homoenolate or enol intermediate undergoes enantioselective annulation with electrophiles such as N-iminoquinolinium ylides, N-iminoisoquinolinium ylides and β-N-iminocarboline ylides. The good-to-high overall yields, high regioselectivities and excellent enantioselectivities observed are controlled by the catalyst and reaction conditions.
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References
Enders, D. & Balensiefer, T. Nucleophilic carbenes in asymmetric organocatalysis. Acc. Chem. Res. 37, 534–541 (2004).
Enders, D., Niemeier, O. & Henseler, A. Organocatalysis by N-heterocyclic carbenes. Chem. Rev. 107, 5606–5655 (2007).
Marion, N., Díez-González, S. & Nolan, S. P. N-Heterocyclic carbenes as organocatalysts. Angew. Chem. Int. Ed. 46, 2988–3000 (2007).
Cohen, D. T. & Scheidt, K. A. Cooperative Lewis acid/N-heterocyclic carbene catalysis. Chem. Sci. 3, 53–57 (2012).
Izquierdo, J., Hutson, G. E., Cohen, D. T. & Scheidt, K. A. A continuum of progress: applications of N-hetereocyclic carbene catalysis in total synthesis. Angew. Chem. Int. Ed. 51, 11686–11698 (2012).
Vora, H. U., Wheeler, P. & Rovis, T. Exploiting acyl and enol azolium intermediates via N-heterocyclic carbene-catalyzed reactions of α-reducible aldehydes. Adv. Synth. Catal. 354, 1617–1639 (2012).
Bugaut, X. & Glorius, F. Organocatalytic umpolung: N-heterocyclic carbenes and beyond. Chem. Soc. Rev. 41, 3511–3522 (2012).
Ryan, S. J., Candish, L. & Lupton, D. W. Acyl anion free N-heterocyclic carbene organocatalysis. Chem. Soc. Rev. 42, 4906–4917 (2013).
Hopkinson, M. N., Richter, C., Schedler, M. & Glorius, F. An overview of N-heterocyclic carbenes. Nature 510, 485–496 (2014).
Vora, H. U. & Rovis, T. Asymmetric N-heterocyclic carbene (NHC) catalyzed acyl anion reactivity. Aldrichim. Acta 44, 3–11 (2011).
DiRocco, D. A. & Rovis, T. Catalytic asymmetric intermolecular Stetter reaction of enals with nitroalkenes: enhancement of catalytic efficiency through bifunctional additives. J. Am. Chem. Soc. 133, 10402–10405 (2011).
Fang, X. Q., Chen, X. K., Lv, H. & Chi, Y. R. Enantioselective Stetter reactions of enals and modified chalcones catalyzed by N-heterocyclic carbenes. Angew. Chem. Int. Ed. 50, 11782–11785 (2011).
Sun, L.-H., Liang, Z.-Q., Jia, W.-Q. & Ye, S. Enantioselective N-heterocyclic carbene catalyzed aza-benzoin reaction of enals with activated ketimines. Angew. Chem. Int. Ed. 52, 5803–5806 (2013).
Xu, J., Mou, C., Zhu, T., Song, B.-A. & Chi, Y. R. N-Heterocyclic carbene-catalyzed chemoselective cross-aza-benzoin reaction of enals with isatin-derived ketimines: access to chiral quaternary aminooxindoles. Org. Lett. 16, 3272–3275 (2014).
Burstein, C. & Glorius, F. Organocatalyzed conjugate umpolung of α,β-unsaturated aldehydes for the synthesis of γ-butyrolactones. Angew. Chem. Int. Ed. 43, 6205–6208 (2004).
Sohn, S. S., Rosen, E. L. & Bode, J. W. N-Heterocyclic carbene-catalyzed generation of homoenolates: γ-butyrolactones by direct annulations of enals and aldehydes. J. Am. Chem. Soc. 126, 14370–14371 (2004).
Chan, A. & Scheidt, K. A. Highly stereoselective formal [3+3] cycloaddition of enals and azomethine imines catalyzed by N-heterocyclic carbenes. J. Am. Chem. Soc. 129, 5334–5335 (2007).
Phillips, E. M., Reynolds, T. E. & Scheidt, K. A. Highly diastereo- and enantioselective additions of homoenolates to nitrones catalyzed by N-heterocyclic carbenes. J. Am. Chem. Soc. 130, 2416–2417 (2008).
Rommel, M., Fukuzumi, T. & Bode, J. W. Cyclic ketimines as superior electrophiles for NHC-catalyzed homoenolate additions with broad scope and low catalyst loadings. J. Am. Chem. Soc. 130, 17266–17267 (2008).
Raup, D. E. A., Cardinal-David, B., Holte, D. & Scheidt, K. A. Cooperative catalysis by carbenes and Lewis acids in a highly stereoselective route to γ-lactams. Nature Chem. 2, 766–771 (2010).
Zhao, X., DiRocco, D. A. & Rovis, T. N-Heterocyclic carbene and Brønsted acid cooperative catalysis: asymmetric synthesis of trans-γ-lactams. J. Am. Chem. Soc. 133, 12466–12469 (2011).
Fu, Z., Xu, J., Zhu, T., Leong, W. W. Y. & Chi, Y. R. β-Carbon activation of saturated carboxylic esters through N-heterocyclic carbene organocatalysis. Nature Chem. 5, 835–839 (2013).
Izquierdo, J., Orue, A. & Scheidt, K. A. A dual Lewis base activation strategy for enantioselective carbene-catalyzed annulations. J. Am. Chem. Soc. 135, 10634–10637 (2013).
Lv, H., Jia, W.-Q., Sun, L.-H. & Ye, S. N-Heterocyclic carbene catalyzed [4+3] annulation of enals and o-quinone methides: highly enantioselective synthesis of benzo-ε-lactones. Angew. Chem. Int. Ed. 52, 8607–8610 (2013).
Reynolds, N. T. & Rovis, T. Enantioselective protonation of catalytically generated chiral enolates as an approach to the synthesis of α-chloroesters. J. Am. Chem. Soc. 127, 16406–16407 (2005).
He, M., Struble, J. R. & Bode, J. W. Highly enantioselective azadiene Diels–Alder reactions catalyzed by chiral N-heterocyclic carbenes. J. Am. Chem. Soc. 128, 8418–8420 (2006).
Kaeobamrung, J., Kozlowski, M. C. & Bode, J. W. Chiral N-heterocyclic carbene-catalyzed generation of ester enolate equivalents from α,β-unsaturated aldehydes for enantioselective Diels–Alder reactions. Proc. Natl Acad. Sci. USA 107, 20661–20665 (2010).
Fang, X. Q., Jiang, K., Xing, C., Hao, L. & Chi, Y. R. A highly regio- and stereoselective cascade annulation of enals and benzodi(enone)s catalyzed by N-heterocyclic carbenes. Angew. Chem. Int. Ed. 50, 1910–1913 (2011).
McCusker, E. O. & Scheidt, K. A. Enantioselective N-heterocyclic carbene catalyzed annulation reaction with imidazolidinones. Angew. Chem. Int. Ed. 52, 13616–13620 (2013).
Fu, Z. et al. Controlled β-protonation and [4+2] cycloaddition of enals and chalcones via N-heterocyclic carbene/acid catalysis: toward substrate independent reaction control. Chem. Commun. 49, 261–263 (2013).
Boger, D. L., McKie, J. A., Nishi, T. & Ogiku, T. Total synthesis of (+)-duocarmycin A, epi-(+)-duocarmycin A and their unnatural enantiomers: assessment of chemical and biological properties. J. Am. Chem. Soc. 119, 311–325 (1997).
Maruoka, K., Murase, N., Bureau, R., Ooi, T. & Yamamoto, H. Lewis acid-promoted selective rearrangement of trisubstituted epoxides to aldehydes or ketones. Tetrahedron 50, 3663–3672 (1994).
Deng, X.-M. et al. Enantioselective synthesis of vinylcyclopropanes and vinylepoxides mediated by camphor-derived sulfur ylides: rationale of enantioselectivity, scope, and limitation. J. Am. Chem. Soc. 128, 9730–9740 (2006).
Wang, Q.-G. et al. Tandem Michael addition/ylide epoxidation for the synthesis of highly functionalized cyclohexadiene epoxide derivatives. J. Am. Chem. Soc. 130, 5408–5409 (2008).
Schreiber, S. L. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 287, 1964–1969 (2000).
Tan, D. S. Diversity-oriented synthesis: exploring the intersections between chemistry and biology. Nature Chem. Biol. 1, 74–84 (2005).
White, N. A., DiRocco, D. A. & Rovis, T. Asymmetric N-heterocyclic carbene catalyzed addition of enals to nitroalkenes: controlling stereochemistry via the homoenolate reactivity pathway to access δ-lactams. J. Am. Chem. Soc. 135, 8504–8507 (2013).
Guo, C., Sahoo, B., Daniliuc, C. G. & Glorius, F. N-Heterocyclic carbene catalyzed switchable reactions of enals with azoalkenes: formal [4+3] and [4+1] annulations for the synthesis of 1,2-diazepines and pyrazoles. J. Am. Chem. Soc. 136, 17402–17405 (2014).
Michael, J. P. Indolizidine and quinolizidine alkaloids. Nat. Prod. Rep. 25, 139–165 (2008).
Xiang, L. et al. Alkaloids from Portulaca oleracea L. Phytochemistry 66, 2595–2601 (2005).
Daly, J. W., Witkop, B., Tokuyama, T., Nishikawa, T. & Karle, I. L. Gephyrotoxins, histrionicotoxins and pumiliotoxins from the neotropical frog Dendrobates histrionicus. Helv. Chim. Acta 60, 1128–1140 (1977).
Zhou, Y. et al. Highly enantioselective [3+3] cycloaddition of aromatic azomethine imines with cyclopropanes directed by π–π stacking interactions. Angew. Chem. Int. Ed. 52, 1452–1456 (2013).
Xu, X., Zavalij, P. Y. & Doyle, M. P. Highly enantioselective dearomatizing formal [3+3] cycloaddition reactions of N-acyliminopyridinium ylides with electrophilic enol carbene intermediates. Angew. Chem. Int. Ed. 52, 12664–12668 (2013).
MacMillan, D. W. C. The advent and development of organocatalysis. Nature 455, 304–308 (2008).
Grondal, C., Jeanty, M. & Enders, D. Organocatalytic cascade reactions as a new tool in total synthesis. Nature Chem. 2, 167–178 (2010).
Legault, C. & Charette, A. B. Highly efficient synthesis of o-(2,4-dinitrophenyl)hydroxylamine. Application to the synthesis of substituted N-benzoyliminopyridinium ylides. J. Org. Chem. 68, 7119–7122 (2003).
Chen, Z., Yu, X. & Wu, J. Silver triflate and N-heterocyclic carbene co-catalyzed reaction of N′-(2-alkynylbenzylidene)hydrazine, methanol with α,β-unsaturated aldehyde. Chem. Commun. 46, 6356–6358 (2010).
Ni, Q. et al. Asymmetric synthesis of pyrroloindolones by N-heterocyclic carbene catalyzed [2+3] annulation of α-chloroaldehydes with nitrovinylindoles. Angew. Chem. Int. Ed. 52, 13562–12566 (2013).
Breslow, R. On the mechanism of thiamine action. IV. Evidence from studies on model systems. J. Am. Chem. Soc. 80, 3719–3726 (1958).
Berkessel, A. et al. Umpolung by N-heterocyclic carbenes: generation and reactivity of the elusive 2,2-diamino enols (Breslow intermediates). Angew. Chem. Int. Ed. 51, 12370–12374 (2012).
Acknowledgements
The authors acknowledge financial support from the Alexander von Humboldt Foundation (C.G.), the Deutsche Forschungsgemeinschaft IRTG 2027 (M.F.) and the Deutsche Forschungsgemeinschaft (SPP 1179, Leibniz award; F.G.). The authors also thank M.N. Hopkinson, K. Chepiga and J. Neugebauer for discussions and corrections during the preparation of the manuscript. This work is dedicated to the memory of C. Djerassi.
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C.G. and F.G. conceived and designed the study, and co-wrote the paper. C.G. and M.F. performed the experiments and analysed the data. C.G., M.F. and D.J.-M. performed the mechanism study. C.G.D. performed the crystallographic studies. All the authors discussed the results and commented on the manuscript.
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Crystallographic data for compound 3k. (CIF 330 kb)
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Structure factors for compound 3k. (CIF 203 kb)
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Crystallographic data for compound 3l. (CIF 35 kb)
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Structure factors for compound 3l. (CIF 421 kb)
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Guo, C., Fleige, M., Janssen-Müller, D. et al. Switchable selectivity in an NHC-catalysed dearomatizing annulation reaction. Nature Chem 7, 842–847 (2015). https://doi.org/10.1038/nchem.2337
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DOI: https://doi.org/10.1038/nchem.2337
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