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Electronic tuning of site-selectivity

Abstract

Site-selective functionalizations of complex small molecules can generate targeted derivatives with exceptional step efficiency, but general strategies for maximizing selectivity in this context are rare. Here, we report that site-selectivity can be tuned by simply modifying the electronic nature of the reagents. A Hammett analysis is consistent with linking this phenomenon to the Hammond postulate: electronic tuning to a more product-like transition state amplifies site-discriminating interactions between a reagent and its substrate. This strategy transformed a minimally site-selective acylation reaction into a highly selective and thus preparatively useful one. Electronic tuning of both an acylpyridinium donor and its carboxylate counterion further promoted site-divergent functionalizations. With these advances, we achieve a range of modifications to just one of the many hydroxyl groups appended to the ion channel-forming natural product amphotericin B. Thus, electronic tuning of reagents represents an effective strategy for discovering and optimizing site-selective functionalization reactions.

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Figure 1: Overview of an approach to functionalizing AmB to probe a possible interaction with ergosterol.
Figure 2: C2′ selectivity of acylation reactions.
Figure 3: Analysis of acylation reactions with para-substituted benzoyl chlorides.
Figure 4: Site-divergent acylation enabled by electronic tuning of the acylpyridinium ion and its carboxylate counterion.
Figure 5: Selective functionalizations at the C2′ position of AmB.

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References

  1. Lewis, C. A. & Miller, S. J. Site-selective derivatization and remodeling of erythromycin A by using simple peptide-based chiral catalysts. Angew. Chem. Int. Ed. 45, 5616–5619 (2006).

    Article  CAS  Google Scholar 

  2. Chen, M. S. & White, M. C. A predictably selective aliphatic C–H oxidation reaction for complex molecule synthesis. Science 318, 783–787 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Wender, P. A., Hilinski, M. K. & Mayweg, A. V. W. Late-stage intermolecular C–H activation for lead diversification: a highly chemoselective oxyfunctionalization of the C-9 position of potent bryostatin analogues. Org. Lett. 7, 79–82 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Peddibhotla, S., Dang, Y., Liu, J. O. & Romo, D. Simultaneous arming and structure/activity studies of natural products employing O–H insertions: an expedient and versatile strategy for natural products-based chemical genetics. J. Am. Chem. Soc. 129, 12222–12231 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Snyder, S. A., Gollner, A. & Chiriac, M. I. Regioselective reactions for programmable resveratrol oligomer synthesis. Nature 474, 461–466 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pathak, T. P. & Miller, S. J. Site-selective bromination of vancomycin. J. Am. Chem. Soc. 134, 6120–6123 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Afagh, N. A. & Yudin, A. K. Chemoselectivity and the curious reactivity preferences of functional groups. Angew. Chem. Int. Ed. 49, 262–310 (2010).

    Article  CAS  Google Scholar 

  8. Griswold, K. S. & Miller, S. J. A peptide-based catalyst approach to regioselective functionalization of carbohydrates. Tetrahedron 59, 8869–8875 (2003).

    Article  CAS  Google Scholar 

  9. Sanchez-Rosello, M., Puchlopek, A. L., Morgan, A. J. & Miller, S. J. Site-selective cataylsis of phenyl thionoformate transfer as a tool for regioselective deoxygenation of polyols. J. Org. Chem. 73, 1774–1782 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lewis, C. A., Merkel, J. & Miller, S. J. Catalytic site-selective synthesis and evaluation of a series of erythromycin analogs. Bioorg. Med. Chem. Lett. 18, 6007–6011 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lewis, C. A., Longcore, K. E., Miller, S. J. & Wender, P. A. An approach to the site-selective diversification of apoptolidin A with peptide-based catalysts. J. Nat. Prod. 72, 1864–1869 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kurahashi, T., Mizutani, T. & Yoshida, J. Functionalized DMAP catalysts for regioselective acetylation of carbohydrates. Tetrahedron 58, 8669–8677 (2002).

    Article  CAS  Google Scholar 

  13. Kawabata, T. & Furuta, T. Nonenzymatic regioselective acylation of carbohydrates. Chem. Lett. 38, 640–647 (2009).

    Article  CAS  Google Scholar 

  14. Kurahashi, T., Mizutani, T. & Yoshida, J. Effect of intramolecular hydrogen-bonding network on the relative reactivities of carbohydrate OH groups. J. Chem. Soc. Perkin Trans. I 465–473 (1999).

  15. Luning, U. et al. Concave pyridines for selective acylations of polyols. Eur. J. Org. Chem. 1077–1084 (1998).

    Article  Google Scholar 

  16. Katting, E. & Albert, M. Counterion-directed regioselective acetylation of octyl β-D-glucopyranoside. Org. Lett. 6, 945–948 (2004).

    Article  CAS  Google Scholar 

  17. Gu, J., Ruppen, M. E. & Cai, P. Lipase-catalyzed regioselective esterification of rapamycin: synthesis of temsirolimus (CCI-779). Org. Lett. 7, 3945–3948 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Park, H. G., Do, J. H. & Chang, H. N. Regioselective enzymatic acylation of multi-hydroxyl compounds in organic synthesis. Biotechnol. Bioprocess Eng. 8, 1–8 (2003).

    Article  CAS  Google Scholar 

  19. Hammond, G. S. A correlation of reaction rates. J. Am. Chem. Soc. 77, 334–338 (1955).

    Article  CAS  Google Scholar 

  20. Leffler, J. E. & Grunwald, E. Rates and Equilibria of Organic Reactions (Wiley, 1963).

  21. Jacobsen, E. N., Zhang, W. & Guler, M. L. Electronic tuning of asymmetric catalysts. J. Am. Chem. Soc. 113, 6703–6704 (1991).

    Article  CAS  Google Scholar 

  22. Palucki, M. et al. The mechanistic basis for electronic effects on enantioselectivity in the (salen)Mn(III)-catalyzed epoxidation reaction. J. Am. Chem. Soc. 120, 948–954 (1998).

    Article  CAS  Google Scholar 

  23. RajanBabu, T. V. & Casalnuovo, A. L. Role of electronic asymmetry in the design of new ligands: the asymmetric hydrocyanation reaction. J. Am. Chem. Soc. 118, 6325–6326 (1996).

    Article  CAS  Google Scholar 

  24. Harper, K. C. & Sigman, M. S. Three-dimensional correlation of steric and electronic free energy relationships guides asymmetric propargylation. Science 333, 1875–1878 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Xu, S. et al. The DMAP-catalyzed acetylation of alcohols — a mechanistic study. Chem. Eur. J. 11, 4751–4757 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Lutz, V. et al. Structural analyses of N-acylated 4-(dimethylamino)pyridine (DMAP) salts. Chem. Eur. J. 15, 8548–8557 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Cheong, P. H., Legault, C. Y., Um, J. M., Celebi-Olcum, N. & Houk, K. N. Quantum mechanical investigations of organocataysis: mechanisms, reactivities, and selectivities. Chem. Rev. 111, 5042–5137 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Palacios, D. S., Anderson, T. M. & Burke, M. D. A post-PKS oxidation of the amphotericin B skeleton predicted to be critical for channel formation is not required for potent antifungal activity. J. Am. Chem. Soc. 129, 13804–13805 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Palacios, D. S., Dailey, I., Siebert, D. M., Wilcock, B. C. & Burke, M. D. Synthesis-enabled functional group deletions reveal key underpinnings of amphotericin B ion channel and antifungal activities. Proc. Natl Acad. Sci. USA 108, 6733–6738 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Gray, K. C. et al. Amphotericin primarily kills yeast by simply binding ergosterol. Proc. Natl Acad. Sci. USA 109, 2234–2239 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Silberstein, A. Conformational analysis of amphotericin B-cholesterol channel complex. J. Membr. Biol. 162, 117–126 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Baran, M. & Mazerski, M. Molecular modelling of amphotericin B–ergosterol primary complex in water. Biophys. Chem. 95, 125–133 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Neumann, A., Czub, J. & Baginski, M. On the possibility of the amphotericin B–sterol complex formation in cholesterol- and ergosterol-containing lipid bilayers: a molecular dynamics study. J. Phys. Chem. B 113, 15875–15885 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Croatt, M. P. & Carreira, E. M. Probing the role of the mycosamine C2′-OH on the activity of amphotericin B. Org. Lett. 13, 1390–1393 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Matsumori, N., Sawada, Y. & Murata, M. Mycosamine orientation of amphotericin B controlling interaction with ergosterol: sterol-dependent activity of conformation-restricted derivatives with an amino-carbonyl bridge. J. Am. Chem. Soc. 127, 10667–10675 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. De Kruijff, B., Gerritsen, W. J., Oerlemans, A., Demel, R. A. & van Deenen, L. L. M. Polyene antibiotic–sterol interactions in membranes of Acholeplasma laidlawii cells and lecthin liposomes. III. Molecular structure of the polyene antibiotic–cholesterol complexes. Biochim. Biophys. Acta 339, 57–70 (1974).

    Article  CAS  PubMed  Google Scholar 

  37. Murata, M. et al. Ion channel complex of antibiotics as viewed by NMR. Pure Appl. Chem. 81, 1123–1129 (2009).

    Article  CAS  Google Scholar 

  38. Volmer, A. A., Szpilman, A. M. & Carreira, E. M. Synthesis and biological evaluation of amphotericin B derivatives. Nat. Prod. Rep. 27, 1329–1349 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Pandey, R. C. & Rinehart, K. L. Polyene antibiotics. IX. An improved method for the preparation of methyl esters of polyene antibiotics. J. Antibiot. 30, 158–162 (1977).

    Article  CAS  Google Scholar 

  40. Taylor, A. W., Costello, B. J., Hunter, P. A., MacLachlan, W. S. & Shanks, C. T. Synthesis and antifungal selectivity of new derivatives of amphotericin B modified at the C-13 position. J. Antibiot. 46, 486–493 (1993).

    Article  CAS  Google Scholar 

  41. Matsushita, N. et al. Synthesis of 25-13C-amphotericin B methyl ester: a molecular probe for solid-state NMR measurements. Chem. Lett. 38, 114–115 (2009).

    Article  CAS  Google Scholar 

  42. Jiang, L. & Chan, T. Regioselective acylation of hexopyranosides with pivaloyl chloride. J. Org. Chem. 63, 6035–6038 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. Nicolaou, K. C. & Webber, S. E. Stereocontrolled total synthesis of lipoxins B. Synthesis 453–461 (1986).

  44. Philippe, M. et al. New fatty monoesters of erythromycin A. Chem. Pharm. Bull. 38, 1672–1674 (1990).

    Article  CAS  Google Scholar 

  45. Hammett, L. P. Some relations between reaction rates and equilibrium constants. Chem. Rev. 17, 125–136 (1935).

    Article  CAS  Google Scholar 

  46. Garegg, P. & Samuelsson, B. Novel reagent system for converting a hydroxy-group into an iodo-group in carbohydrates with inversion of configuration. J. Chem. Soc. Perkin Trans. I 2866–2869 (1980).

  47. Hutchins, R. et al. Nucleophilic borohydride: selective reductive displacement of halides, sulfonate esters, tertiary amines, and N,N-disulfonimides with borohydride reagents in polar aprotic solvents. J. Org. Chem. 43, 2259–2267 (1977).

    Article  Google Scholar 

  48. Matsumori, N. et al. An amphotericin B-ergosterol covalent conjugate with powerful membrane permeabilizing activity. Chem. Biol. 11, 673–679 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Mayr, H. & Ofial, A. R. The reactivity-selectivity principle: an imperishable myth in organic chemistry. Angew. Chem. Int. Ed. 45, 1844–1854 (2006).

    Article  CAS  Google Scholar 

  50. Fiori, K. W., Puchlopek, A. L. A. & Miller, S. J. Enantioselective sulfonylation reactions mediated by a tetrapeptide catalyst. Nature Chem. 1, 630–634 (2009).

    Article  CAS  Google Scholar 

  51. Jordan, P. A., Kayser-Bricker, K. J. & Miller, S. J. Asymmetric phosphorylation through catalytic P(III) phosphoramidite transfer: enantioselective synthesis of D-myo-inositol-6-phosphate. Proc. Natl Acad. Sci. USA 107, 20620–20624 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank M.C. White for helpful discussions and P. Beak for a thoughtful review of the manuscript. The authors acknowledge Bristol-Myers Squibb for the gift of AmB, and the National Institutes of Health (GM080436) for financial support. M.D.B. is an HHMI Early Career Scientist.

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B.C.W., B.E.U. and M.D.B. designed experiments. B.C.W. performed acylation experiments. B.C.W., B.E.U., G.L.B., M.J.C. and T.M.A. contributed to the synthesis of intermediates and derivatives. B.C.W., B.E.U. and M.D.B. wrote the paper.

Corresponding author

Correspondence to Martin D. Burke.

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The authors declare no competing financial interests.

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Wilcock, B., Uno, B., Bromann, G. et al. Electronic tuning of site-selectivity. Nature Chem 4, 996–1003 (2012). https://doi.org/10.1038/nchem.1495

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