Combinatorial evolution of site- and enantioselective catalysts for polyene epoxidation

Journal name:
Nature Chemistry
Volume:
4,
Pages:
990–995
Year published:
DOI:
doi:10.1038/nchem.1469
Received
Accepted
Published online
Corrected online

Abstract

Selectivity in the catalytic functionalization of complex molecules is a major challenge in chemical synthesis. The problem is magnified when there are several possible stereochemical outcomes and when similar functional groups occur repeatedly within the same molecule. Selective polyene oxidation provides an archetypical example of this challenge. Historically, enzymatic catalysis has provided the only precedents. Although non-enzymatic catalysts that meet some of these challenges became known, a comprehensive solution has remained elusive. Here, we describe low molecular weight peptide-based catalysts, discovered through a combinatorial synthesis and screening protocol, that exhibit site- and enantioselective oxidation of certain positions of various isoprenols. This diversity-based approach, which exhibits features reminiscent of the directed evolution of enzymes, delivers catalysts that compare favourably to the state-of-the-art for the asymmetric oxidation of these compounds. Moreover, the approach culminated in catalysts that exhibit alternative-site selectivity in comparison to oxidation catalysts previously described.

At a glance

Figures

  1. Precedent and goal of catalytic oxidation of farnesol.
    Figure 1: Precedent and goal of catalytic oxidation of farnesol.

    a, Catalytic cycle of aspartic acid-mediated epoxidations. b, Site selectivity of m-CPBA and epoxidation based on propionic acid. c, Precedent of the Sharpless epoxidation of 1. d, The goal of the present study. *Entry 1, 10 mol% acid, HOBt (10 mol%), DMAP (10 mol%), 1.0 equiv. DIC, 2.0 equiv. H2O2. Entry 2, 1.0 equiv. m-CPBA, Na2HPO4 (2.0 equiv.), DCM, H2O. Determined by uncalibrated GC integrations (see Supplementary Information for details).

  2. Catalyst library design by split-and-pool synthesis via the OBOC library method.
    Figure 2: Catalyst library design by split-and-pool synthesis via the OBOC library method.

    a, Design of the first directed library. b, Histogram of theoretical library composition.

  3. Results and raw data for the site-selective oxidation of farnesol and geranylgeraniol with m-CPBA, 2,3-selective catalyst 9b and 6,7-selective catalyst 12d.
    Figure 3: Results and raw data for the site-selective oxidation of farnesol and geranylgeraniol with m-CPBA, 2,3-selective catalyst 9b and 6,7-selective catalyst 12d.

    a, Optimized oxidation conditions with 12d. b,c, Comparison of product ratios and GC spectra from crude reaction mixtures with m-CPBA, catalyst 9b and catalyst 12d, with the relevant area of GC spectra for farnesol (b) and geranylgeraniol (c). *The peak has a shoulder that is integrated and so the area is overestimated. Conditions for m-CPBA reactions are given in Fig. 1b, for reactions with catalyst 9b in Table 2 and for reactions with catalyst 12d in (a).

Compounds

13 compounds View all compounds
  1. Farnesol
    Compound 1 Farnesol
  2. Propionic acid
    Compound 2 Propionic acid
  3. (2S,3S)-2,3-Epoxyfarnesol
    Compound 3 (2S,3S)-2,3-Epoxyfarnesol
  4. 6,7-Epoxyfarnesol
    Compound 4 6,7-Epoxyfarnesol
  5. 10,11-Epoxyfarnesol
    Compound 5 10,11-Epoxyfarnesol
  6. (S)-4-((S)-2-(((5S,8S,11R,14S)-11-Benzyl-8-((R)-1-(benzyloxy)ethyl)-5-(methoxycarbonyl)-3,7,10,13,16-pentaoxo-1,1,1,18,18,18-hexaphenyl-2,6,9,12,17-pentaazaoctadecan-14-yl)carbamoyl)pyrrolidin-1-yl)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid
    Compound 8b (S)-4-((S)-2-(((5S,8S,11R,14S)-11-Benzyl-8-((R)-1-(benzyloxy)ethyl)-5-(methoxycarbonyl)-3,7,10,13,16-pentaoxo-1,1,1,18,18,18-hexaphenyl-2,6,9,12,17-pentaazaoctadecan-14-yl)carbamoyl)pyrrolidin-1-yl)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid
  7. (S)-3-((tert-Butoxycarbonyl)amino)-4-((S)-2-(((S)-1-(((R)-1-((S)-2-(((S)-1-methoxy-1,4-dioxo-4-(tritylamino)butan-2-yl)carbamoyl)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1,4-dioxo-4-(tritylamino)butan-2-yl)carbamoyl)pyrrolidin-1-yl)-4-oxobutanoic acid
    Compound 9b (S)-3-((tert-Butoxycarbonyl)amino)-4-((S)-2-(((S)-1-(((R)-1-((S)-2-(((S)-1-methoxy-1,4-dioxo-4-(tritylamino)butan-2-yl)carbamoyl)pyrrolidin-1-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1,4-dioxo-4-(tritylamino)butan-2-yl)carbamoyl)pyrrolidin-1-yl)-4-oxobutanoic acid
  8. (S)-4-((R)-2-(((4S,7S,10S,11R)-4-(4-(tert-Butoxy)benzyl)-11-methyl-3,6,9-trioxo-7-(2-oxo-2-(tritylamino)ethyl)-13-phenyl-2,12-dioxa-5,8-diazatridecan-10-yl)carbamoyl)pyrrolidin-1-yl)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid
    Compound 12b (S)-4-((R)-2-(((4S,7S,10S,11R)-4-(4-(tert-Butoxy)benzyl)-11-methyl-3,6,9-trioxo-7-(2-oxo-2-(tritylamino)ethyl)-13-phenyl-2,12-dioxa-5,8-diazatridecan-10-yl)carbamoyl)pyrrolidin-1-yl)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid
  9. (S)-4-((R)-2-(((3R,4S,7S,10S)-10-(4-(tert-Butoxy)benzyl)-3-methyl-5,8,11-trioxo-7-(2-oxo-2-(tritylamino)ethyl)-1-phenyl-2-oxa-6,9,12-triazahexadecan-4-yl)carbamoyl)pyrrolidin-1-yl)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid
    Compound 12c (S)-4-((R)-2-(((3R,4S,7S,10S)-10-(4-(tert-Butoxy)benzyl)-3-methyl-5,8,11-trioxo-7-(2-oxo-2-(tritylamino)ethyl)-1-phenyl-2-oxa-6,9,12-triazahexadecan-4-yl)carbamoyl)pyrrolidin-1-yl)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid
  10. (3R,4S,7S,10S)-10-(4-(tert-Butoxy)benzyl)-4-((R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-carboxypropanoyl)pyrrolidine-2-carboxamido)-3-methyl-5,8,11-trioxo-7-(2-oxo-2-(tritylamino)ethyl)-1-phenyl-2-oxa-6,9,12-triazatetradecan-14-oic acid
    Compound 12d (3R,4S,7S,10S)-10-(4-(tert-Butoxy)benzyl)-4-((R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-carboxypropanoyl)pyrrolidine-2-carboxamido)-3-methyl-5,8,11-trioxo-7-(2-oxo-2-(tritylamino)ethyl)-1-phenyl-2-oxa-6,9,12-triazatetradecan-14-oic acid
  11. Geranylgeraniol
    Compound 13 Geranylgeraniol
  12. (2S,3S)-2,3-Epoxygeranylgeraniol
    Compound 14 (2S,3S)-2,3-Epoxygeranylgeraniol
  13. 6,7-Epoxygeranylgeraniol
    Compound 15 6,7-Epoxygeranylgeraniol

Change history

Corrected online 20 November 2012
In the version of this Article originally published, the bottom right-hand structure of Table 1 appeared incorrectly. This has now been corrected in the HTML and PDF versions.

References

  1. van Tamelen, E. E. & Heys, J. R. Enzymic epoxidation of squalene variants. J. Am. Chem. Soc. 97, 12521253 (1974).
  2. Katsuki, T. & Martin, V. S. Asymmetric epoxidation of allylic alcohols: the Katsuki–Sharpless epoxidation reaction. Org. React. 48, 1299 (1996).
  3. Zhang, W., Basak, A., Kosugi, Y., Hoshino, Y. & Yamamoto, H. Enantioselective epoxidation of allylic alcohols by a chiral complex of vanadium: an effective controller system and a rational mechanistic model. Angew. Chem. Int. Ed. 44, 43894391 (2005).
  4. Malkov, A. V., Czemerys, L. & Malyshev, D. A. Vanadium-catalyzed asymmetric epoxidation of allylic alcohols in water. J.Org. Chem. 74, 33503355 (2009).
  5. Egami, H., Oguma, T. & Katsuki, T. Oxidation catalysis of Nb(salan) complexes: asymmetric epoxidation of allylic alcohols using aqueous hydrogen peroxide. J. Am. Chem. Soc. 132, 58865895 (2010).
  6. Barlan, A. U., Basak, A. & Yamamoto, H. Enantioselective oxidation of olefins catalyzed by a chiral bishydroxamic acid complex of molybdenum. Angew. Chem. Int. Ed. 45, 58495852 (2006).
  7. Corey, E. J. & Zhang, J. Highly effective transition structure designed catalyst for the enantio- and position-selective dihydroxylation of polyisoprenoids. Org. Lett. 3, 32113214 (2001).
  8. Chang, S., Lee, N. H. & Jacobsen, E. N. Regio- and enantioselective catalytic epoxidation of conjugated polyenes. Formal synthesis of LTA4 methyl ester. J.Org. Chem. 58, 69396941 (1993).
  9. Burke, C. P. & Shi, Y. Regio- and enantioselective epoxidation of dienes by a chiral dioxirane: synthesis of optically active vinyl cis-epoxides. Angew. Chem. Int. Ed. 45, 44754478 (2006).
  10. Breslow, R. & Maresca, L. M. Template-directed epoxidation of farnesol and geranylgeraniol as conformational probes. Tetrahedron Lett. 10, 887890 (1978).
  11. Saito, I., Mano, T., Nagata, R. & Matsuura, T. Inter- and intramolecular epoxidation utilizing silyl-protected peroxy esters and copper salt. Tetrahedron Lett. 28, 19091912 (1987).
  12. Gnanadesikan, V. & Corey, E. J. A strategy for position-selective epoxidation of polyprenols. J. Am. Chem. Soc. 130, 80898093 (2008).
  13. Colby Davie, E. A., Mennen, S. M., Xu, Y. & Miller, S. J. Asymmetric catalysis mediated by synthetic peptides. Chem. Rev. 107, 57595812 (2007).
  14. Wennemers, H. Asymmetric catalysis with peptides. Chem. Commun. 47, 1203612041 (2011).
  15. Francis, M. B., Jamison, T. F. & Jacobsen, E. N. Combinatorial libraries of transition-metal complexes, catalysts and materials. Curr. Opin. Chem. Biol. 2, 422428 (1998).
  16. Kuntz, K. W., Snapper, M. L. & Hoveyda, A. H. Combinatorial catalyst discovery. Curr. Opin. Chem. Biol. 3, 313319 (1999).
  17. Peris, G., Jakobsche, C. E. & Miller, S. J. Aspartate-catalyzed asymmetric epoxidation reactions. J. Am. Chem. Soc. 129, 87108711 (2007).
  18. Kolundzic, F., Noshi, M. N., Tjandra, M., Movassaghi, M. & Miller, S. J. Chemoselective and enantioselective oxidation of indoles employing aspartyl peptide catalysts. J. Am. Chem. Soc. 133, 91049111 (2011).
  19. Thibodeaux, C. J., Chang, W-C. & Liu, H-W. Enzymatic chemistry of cyclopropane, epoxide and aziridine biosynthesis. Chem. Rev. 112, 16811709 (2012).
  20. Sharpless, K. B. Searching for new reactivity (Nobel Lecture). Angew. Chem. Int. Ed. 41, 20242032 (2002).
  21. Kotaki, T., Shinada, T. & Kaihara, K. Structure determination of a new juvenile hormone from a Heteropteran insect. Org. Lett. 11, 52345237 (2009).
  22. Koohang, A. et al. Enantioselective inhibition of squalene synthase by aziridine analogues of presqualene diphosphate. J. Org. Chem. 75, 47694777 (2010).
  23. Tanuwidjaja, J., Ng, S-S. & Jamison, T. F. Total synthesis of ent-dioxepandehydrothyrsiferol via a bromonium-initiated epoxide-opening cascade. J. Am. Chem. Soc. 131, 1208412085 (2009).
  24. Uyanik, M., Ishibashi, H., Ishihara, K. & Yamamoto, H. Biomimetic synthesis of acid-sensitive (–)-caparrapi oxide and (+)-8-epicaparrapi oxide induced by artificial cyclases. Org. Lett. 7, 16011604 (2005).
  25. Marshall, J. A. & Hann, R. K. A cascade cyclization route to adjacent bistetrahydrofurans from chiral triepoxyfarnesyl bromides. J. Org. Chem. 73, 67536757 (2008).
  26. Dittmer, D. C. et al. A tellurium transposition route to allylic alcohols: overcoming some limitations of the Sharpless–Katsuki asymmetric epoxidation. J. Org. Chem. 58, 718731 (1993).
  27. Lichtor, P. A. & Miller, S. J. One-bead-one-catalyst approach to aspartic acid-based oxidation catalyst discovery. ACS Comb. Sci. 13, 321326 (2011).
  28. Lam, K. S., Lebl, M. & Krchnák, V. The ‘one-bead-one-compound’ combinatorial library method. Chem. Rev. 97, 411448 (1997).
  29. Furka, A., Sebestyen, F., Asgedom, M. & Dibo, G. General method for rapid synthesis of multicomponent peptide mixtures. Int. J. Pept. Protein Res. 37, 487493 (1991).
  30. Lam, K. S. et al. A new type of synthetic peptide library for identifying ligand-binding activity. Nature 354, 8284 (1991).
  31. Singh, J. et al. Application of genetic algorithms to combinatorial synthesis: a computational approach to lead identification and lead optimization. J. Am. Chem. Soc. 118, 16691676 (1996).
  32. Reetz, M. T. Laboratory evolution of stereoselective enzymes: a prolific source of catalysts for asymmetric reactions. Angew. Chem. Int. Ed. 50, 138174 (2011).
  33. Brustad, E. M. & Arnold, F. H. Optimizing non-natural protein function with directed evolution. Curr. Opin. Chem. Biol. 15, 201210 (2011).
  34. Copeland, G. T. & Miller, S. J. Selection of enantioselective acyl transfer catalysts from a pooled peptide library through a fluorescence-based activity assay: an approach to kinetic resolution of secondary alcohols of broad substrate scope. J. Am. Chem. Soc. 123, 64966502 (2001).
  35. Schreiber, S. L., Schreiber, T. S. & Smith, D. B. Reactions that proceed with a combination of enantiotopic group and diastereotopic face selectivity can deliver products with very high enantiomeric excess: experimental support of a mathematical model. J. Am. Chem. Soc. 109, 15251529 (1987).

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Affiliations

  1. Department of Chemistry, Yale University, PO Box 208107, New Haven, Connecticut 06520-8107, USA

    • Phillip A. Lichtor &
    • Scott J. Miller

Contributions

P.A.L. designed and performed the experiments and S.J.M. oversaw the project. Both authors analysed data and co-wrote the manuscript.

Competing financial interests

The authors declare no competing financial interests.

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