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Unravelling mechanistic features of organocatalysis with in situ modifications at the secondary sphere


Secondary-sphere interactions serve a fundamental role in controlling the reactivity and selectivity of organometallic and enzymatic catalysts. However, there is a dearth of studies that explicitly incorporate secondary-sphere modifiers into organocatalytic systems. In this work, we introduce an approach for the in situ systematic modification of organocatalysts in their secondary sphere through dynamic covalent binding under the reaction conditions. As a proof-of-concept, we applied boronic acids as secondary-sphere modifiers of N-heterocyclic carbenes that contained a hydroxy handle. The bound system formed in the reaction mixture catalysed the enantioselective benzoin condensations of a challenging substrate class that contains electron-withdrawing groups. Linear regression coupled with data visualization served to pinpoint the divergent origins of enantioselectivity for different substrates and decision tree algorithms served to formulate selection criteria for the appropriate secondary-sphere modifiers. The combination of this highly modular catalytic approach with machine-learning techniques provided mechanistic insights and guided the streamlined optimization process of a gram-scale reaction at low organocatalyst loading.

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All data generated or analysed during this study are available in this published article and its Supplementary Information files, or from the corresponding author upon request. Experimental procedures, results, characterization data, spreadsheets of parameters used in the models and MATLAB scripts used for model identification are accessible online as Supplementary Information.

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  1. 1.

    Warren, J. J., Lancaster, K. M., Richards, J. H. & Gray, H. B. Inner- and outer-sphere metal coordination in blue copper proteins. J. Inorg. Biochem. 115, 119–126 (2012).

  2. 2.

    Werner, A. Zur kenntnis des asymmetrischen kobaltatoms. Ber. Dtschn Chem. Ges. 45, 121–130 (1912).

  3. 3.

    Werner, A. Über die raumisomeren kobaltverbindungen. Justus Liebig’s Ann. Chem. 386, 1–272 (1912).

  4. 4.

    Cook, S. A. & Borovik, A. S. Molecular designs for controlling the local environments around metal ions. Acc. Chem. Res. 48, 2407–2414 (2015).

  5. 5.

    Reedijk, J. Coordination chemistry beyond Werner: interplay between hydrogen bonding and coordination. Chem. Soc. Rev. 42, 1776–1783 (2013).

  6. 6.

    Shook, R. L. & Borovik, A. S. Role of the secondary coordination sphere in metal-mediated dioxygen activation. Inorg. Chem. 49, 3646–3660 (2010).

  7. 7.

    Baschieri, A., Bernardi, L., Ricci, A., Suresh, S. & Adamo, M. F. Catalytic asymmetric conjugate addition of nitroalkanes to 4-nitro-5-styrylisoxazoles. Angew. Chem. Int. Ed. 48, 9342–9345 (2009).

  8. 8.

    Kawai, H., Kusuda, A., Nakamura, S., Shiro, M. & Shibata, N. Catalytic enantioselective trifluoromethylation of azomethine imines with trimethyl(trifluoromethyl)silane. Angew. Chem. Int. Ed. 48, 6324–6327 (2009).

  9. 9.

    Nicolaou, K. C., Liu, G., Beabout, K., McCurry, M. D. & Shamoo, Y. Asymmetric alkylation of anthrones, enantioselective total synthesis of (−)- and (+)-viridicatumtoxins B and analogues thereof: absolute configuration and potent antibacterial agents. J. Am. Chem. Soc. 139, 3736–3746 (2017).

  10. 10.

    Sahu, S. et al. Secondary coordination sphere influence on the reactivity of nonheme iron(ii) complexes: an experimental and DFT approach. J. Am. Chem. Soc. 135, 10590–10593 (2013).

  11. 11.

    Ward, T. R. et al. Exploiting the second coordination sphere: proteins as host for enantioselective catalysis. Chimia 57, 586–588 (2003).

  12. 12.

    Uraguchi, D., Ueki, Y. & Ooi, T. Chiral organic ion pair catalysts assembled through a hydrogen-bonding network. Science 326, 120–123 (2009).

  13. 13.

    Meeuwissen, J. & Reek, J. N. H. Supramolecular catalysis beyond enzyme mimics. Nat. Chem. 2, 615–621 (2010).

  14. 14.

    Leenders, S. H. A. M., Gramage-Doria, R., de Bruin, B. & Reek, J. N. H. Transition metal catalysis in confined spaces. Chem. Soc. Rev. 44, 433–448 (2014).

  15. 15.

    Rowan, S. J., Cantrill, S. J. & Cousins, G. R. L. Dynamic covalent chemistry. Angew. Chem. Int. Ed. 41, 898–952 (2002).

  16. 16.

    Bapat, A. P., Roy, D., Ray, J. G., Savin, D. A. & Sumerlin, B. S. Dynamic-covalent macromolecular stars with boronic ester linkages. J. Am. Chem. Soc. 133, 19832–19838 (2011).

  17. 17.

    Bull, S. D. et al. Exploiting the reversible covalent bonding of boronic acids: recognition, sensing, and assembly. Acc. Chem. Res. 46, 312–326 (2013).

  18. 18.

    Wilson, A., Gasparini, G. & Matile, S. Functional systems with orthogonal dynamic covalent bonds. Chem. Soc. Rev. 43, 1948–1962 (2014).

  19. 19.

    Schaufelberger, F. & Ramström, O. Dynamic covalent organocatalysts discovered from catalytic systems through rapid deconvolution screening. Chem. Eur. J. 21, 12735–12740 (2015).

  20. 20.

    Lascano, S. et al. The third orthogonal dynamic covalent bond. Chem. Sci. 7, 4720–4724 (2016).

  21. 21.

    Seifert, H. M., Ramirez Trejo, K. & Anslyn, E. V. Four simultaneously dynamic covalent reactions. Experimental proof of orthogonality. J. Am. Chem. Soc 138, 10916–10924 (2016).

  22. 22.

    Zhou, Y., Li, L., Ye, H., Zhang, L. & You, L. Quantitative reactivity scales for dynamic covalent and systems chemistry. J. Am. Chem. Soc. 138, 381–389 (2016).

  23. 23.

    Akgun, B. & Hall, D. G. Fast and tight boronate formation for click bioorthogonal conjugation. Angew. Chem. Int. Ed. 55, 3909–3913 (2016).

  24. 24.

    Moulin, E., Cormos, G. & Giuseppone, N. Dynamic combinatorial chemistry as a tool for the design of functional materials and devices. Chem. Soc. Rev. 41, 1031–1049 (2012).

  25. 25.

    Teichert, J. F., Mazunin, D. & Bode, J. W. Chemical sensing of polyols with shapeshifting boronic acids as a self-contained sensor array. J. Am. Chem. Soc. 135, 11314–11321 (2013).

  26. 26.

    Wong, C.-H. & Zimmerman, S. C. Orthogonality in organic, polymer, and supramolecular chemistry: from Merrifield to click chemistry. Chem. Commun. 49, 1679–1695 (2013).

  27. 27.

    Wiskur, S. L. & Anslyn, E. V. Using a synthetic receptor to create an optical-sensing ensemble for a class of analytes: a colorimetric assay for the aging of scotch. J. Am. Chem. Soc. 123, 10109–10110 (2001).

  28. 28.

    Baragwanath, L., Rose, C. A., Zeitler, K. & Connon, S. J. Highly enantioselective benzoin condensation reactions involving a bifunctional protic pentafluorophenyl-substituted triazolium precatalyst. J. Org. Chem. 74, 9214–9217 (2009).

  29. 29.

    O’Toole, S. E. & Connon, S. J. The enantioselective benzoin condensation promoted by chiral triazolium precatalysts: stereochemical control via hydrogen bonding. Org. Biomol. Chem. 7, 3584–3593 (2009).

  30. 30.

    Langdon, S. M., Legault, C. Y. & Gravel, M. Origin of chemoselectivity in N-heterocyclic carbene catalyzed cross-benzoin reactions: DFT and experimental insights. J. Org. Chem. 80, 3597–3610 (2015).

  31. 31.

    Maji, R. & Wheeler, S. E. in Aromatic interactions: Frontiers in Knowledge and Application (eds Darren W Johnson, D. W. & Hof, F.) 18–38 (The Royal Society of Chemistry, Cambridge, 2017).

  32. 32.

    Paul, M., Breugst, M., Neudorfl, J. M., Sunoj, R. B. & Berkessel, A. Keto-enol thermodynamics of Breslow intermediates. J. Am. Chem. Soc. 138, 5044–5051 (2016).

  33. 33.

    Flanigan, D. M., Romanov-Michailidis, F., White, N. A. & Rovis, T. Organocatalytic reactions enabled by N-heterocyclic carbenes. Chem. Rev. 115, 9307–9387 (2015).

  34. 34.

    Hansch, C., Leo, A. & Taft, R. W. A survey of Hammett substituent constants and resonance and field parameters. Chem. Rev. 91, 165–195 (1991).

  35. 35.

    Verloop, A., Hoogenstraaten, W. & Tipker, J. in Drug Design Vol 7 (ed. Ariens, E. J.) 165–207 (Academic, 1976).

  36. 36.

    Milo, A., Bess, E. N. & Sigman, M. S. Interrogating selectivity in catalysis using molecular vibrations. Nature 507, 210–214 (2014).

  37. 37.

    Glendening, E. D., Landis, C. R. & Weinhold, F. Natural bond orbital methods. WIREs Comput. Mol. Sci. 2, 1–42 (2011).

  38. 38.

    Maji, R. & Wheeler, S. E. Importance of electrostatic effects in the stereoselectivity of NHC-catalyzed kinetic resolutions. J. Am. Chem. Soc. 139, 12441–12449 (2017).

  39. 39.

    Massey, R. S., Collett, C. J., Lindsay, A. G., Smith, A. D. & O’Donoghue, A. C. Proton transfer reactions of triazol-3-ylidenes: kinetic acidities and carbon acid pKa values for twenty triazolium salts in aqueous solution. J. Am. Chem. Soc. 134, 20421–20432 (2012).

  40. 40.

    Niu, Y. et al. Experimental and computational gas phase acidities of conjugate acids of triazolylidene carbenes: rationalizing subtle electronic effects. J. Am. Chem. Soc. 139, 14917–14930 (2017).

  41. 41.

    Companyó, X. & Burés, J. Distribution of catalytic species as an indicator to overcome reproducibility problems. J. Am. Chem. Soc. 139, 8432–8435 (2017).

  42. 42.

    Enders, D. & Henseler, A. A direct intermolecular cross-benzoin type reaction: N-heterocyclic carbene-catalyzed coupling of aromatic aldehydes with trifluoromethyl ketones. Adv. Synth. Catal. 351, 1749–1752 (2009).

  43. 43.

    Enders, D. N-heterocyclic carbene catalysed asymmetric cross-benzoin reactions of heteroaromatic aldehydes with trifluoromethyl ketones. Chem. Commun. 46, 6282–6284 (2010).

  44. 44.

    Enders, D., Niemeier, O. & Henseler, A. Organocatalysis by N-heterocyclic carbenes. Chem. Rev. 107, 5606–5655 (2007).

  45. 45.

    Renny, J. S., Tomasevich, L. L., Tallmadge, E. H. & Collum, D. B. Method of continuous variations: applications of Job plots to the study of molecular associations in organometallic chemistry. Angew. Chem. Int. Ed. 52, 11998–12013 (2013).

  46. 46.

    Thordarson, P. Determining association constants from titration experiments in supramolecular chemistry. Chem. Soc. Rev. 40, 1305–1323 (2011).

  47. 47.

    Neel, A. J., Milo, A., Sigman, M. S. & Toste, F. D. Enantiodivergent fluorination of allylic alcohols: data set design reveals structural interplay between achiral directing group and chiral anion. J. Am. Chem. Soc. 138, 3863–3875 (2016).

  48. 48.

    Hall, D. G. Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials 1–133 (Wiley, Weinheim, 2011).

  49. 49.

    Martínez-Aguirre, M. A. & Yatsimirsky, A. K. Brønsted versus Lewis acid type anion recognition by arylboronic acids. J. Org. Chem. 80, 4985–4993 (2015).

  50. 50.

    Collett, C. J. et al. Rate and equilibrium constants for the addition of N-heterocyclic carbenes into benzaldehydes: a remarkable 2-substituent effect. Angew. Chem. Int. Ed. 127, 6991–6996 (2015).

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This research was supported by the Israel Science Foundation (Grant no. 1193/17). We thank M. Sigman, D. Toste, A. Neel and D. Pappo for fruitful discussions. D.V. acknowledges the PBC for a postdoctoral fellowship. S.C.G. acknowledges the Kreitman Graduate School for a postdoctoral fellowship. Z.A. acknowledges the Kreitman Graduate School for the chemo-tech scholarship. Mass spectra measurements were performed with the help of M. Shema-Mizrachi and M. M. Karpasas.

Author information

All the authors designed and performed the experiments and analysed the data. The Supplementary Information was compiled by S.C.G. and D.V., the product distribution by HPLC was performed by Z.A. and mathematical modelling was performed by A.M.

Competing interests

The authors declare no competing interests.

Correspondence to Anat Milo.

Supplementary information

Supplementary information

Supplementary experimental details and compound characterization data.

Supplementary data

Excel spreadsheet listing parameters used in combination with MATLAB scripts for model development.

MATLAB scripts

A compressed directory of all the scripts used for model development.

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Fig. 1: The influence of secondary-sphere modulation of NHCs on the benzoin reaction.
Fig. 2: Multivariate model of the enantioselectivity for 6 hour reactions across a set of electron-withdrawing aldehydes.
Fig. 3: Disentangling the effect of racemization.
Fig. 4: Binding studies of BA to NHC in THF.
Fig. 5: Cross-over experiments between the benzoin product and an additional aldehyde.