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Combinatorial evolution of site- and enantioselective catalysts for polyene epoxidation Guillaume Pelletier Literature meeting - November 20 th 2012. Lichtor, P. A.; Miller, S. J. Nature Chem. 2012 , ASAP. Analysis of biosynthetic patways reveals functional group selectivity.

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Lichtor p a miller s j nature chem 2012 asap

Combinatorial evolution of site- and enantioselective catalysts for polyene epoxidationGuillaume Pelletier Literature meeting - November 20th 2012

Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.


Analysis of biosynthetic patways reveals functional group selectivity

Analysis of biosynthetic patways reveals functional group selectivity

For a review, see: Clardy, J.; Walsh, C. Nature 2004, 432, 829-837.

Walker, K.; Croteau, R. Phytochemistry2001, 58, 1-7.

Mendoza, A.; Ishihara, Y.; Baran, P. S. Nature Chem. 2012, 4, 21-25.


Lichtor p a miller s j nature chem 2012 asap

Analysis of biosyntheticpatwaysrevealsfunctional group selectivity

For a review, see: Clardy, J.; Walsh, C. Nature 2004, 432, 829-837.

Novak, B. H.; Hudlicky, T.; Reed, J. W.; Mulzer, J.; Trauner, D. Curr. Org. Chem. 2000, 4, 343-362.

Calderon, S. N. et al. J. Med. Chem. 1997, 40, 695.


Lichtor p a miller s j nature chem 2012 asap

Analysis of biosyntheticpatwaysrevealsfunctional group selectivity

For a review, see: Clardy, J.; Walsh, C. Nature 2004, 432, 829-837.

Novak, B. H.; Hudlicky, T.; Reed, J. W.; Mulzer, J.; Trauner, D. Curr. Org. Chem. 2000, 4, 343-362.

Calderon, S. N. et al. J. Med. Chem. 1997, 40, 695.


Lichtor p a miller s j nature chem 2012 asap

Enzyme-mediatedoxidationdoesprecludegenerality…

Van Tamelen, E. E.; Heys, R. J. J. Am. Chem. Soc. 1975, 97, 1252-1253.


Lichtor p a miller s j nature chem 2012 asap

Small syntheticmoleculesmeetssome of these challenges

Zhang, W.; Basak, A.; Kosugi, Y.; Hoshino, Y.; Yamamoto, H. Angew. Chem., Int. Ed. 2005, 44, 4389-4391.

Egami, H.; Oguma, T.; Katsuki, T. J. Am. Chem. Soc. 2010, 132, 5886-5895.


Lichtor p a miller s j nature chem 2012 asap

Small syntheticmoleculesmeetssome of these challenges

Zhang, W.; Basak, A.; Kosugi, Y.; Hoshino, Y.; Yamamoto, H. Angew. Chem., Int. Ed. 2005, 44, 4389-4391.

Egami, H.; Oguma, T.; Katsuki, T. J. Am. Chem. Soc. 2010, 132, 5886-5895.


Lichtor p a miller s j nature chem 2012 asap

Small syntheticmoleculesmeetssome of these challenges

Barlan, A. U.; Basak, A.; Yamamoto, H. Angew. Chem., Int. Ed. 2006, 45, 5849-5852.

Chang, S.; Lee, N. H.; Jacobsen, E. N. J. Org. Chem. 1993, 58, 6939-6941.


Lichtor p a miller s j nature chem 2012 asap

Small syntheticmoleculesmeetssome of these challenges

Barlan, A. U.; Basak, A.; Yamamoto, H. Angew. Chem., Int. Ed. 2006, 45, 5849-5852.

Chang, S.; Lee, N. H.; Jacobsen, E. N. J. Org. Chem. 1993, 58, 6939-6941.


Lichtor p a miller s j nature chem 2012 asap

Template-directedinternalepoxidation of polyenes

Gnanadesikan, V.; Corey, E. J. J. Am. Chem. Soc. 2008, 130, 8089-8093.


The goal of the present study

The goal of the present study

Sharpless Epoxidation

Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.


Literature precedents on small peptide mediated epoxidation

Literature precedents on small peptide mediated epoxidation

Peris, G.; Jakobsche, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 8710-8711.

Kolundzic, F.; Noshi, M. N.; Tjandra, M.; Movassaghi, M.; Miller, S. J. J. Am. Chem. Soc. 2011, 133, 9104-9111.


Lichtor p a miller s j nature chem 2012 asap

Proposedcatalytic cycle for the asymmetricepoxidation

Peris, G.; Jakobsche, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 8710-8711.

Kolundzic, F.; Noshi, M. N.; Tjandra, M.; Movassaghi, M.; Miller, S. J. J. Am. Chem. Soc. 2011, 133, 9104-9111.


Lichtor p a miller s j nature chem 2012 asap

First screening of catalysts

  • With initial peptide catalyst screening, the authors chose to run the reactions at low

  • conversions in order to allow a preleminary assessment of catalyst krel

Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.


Methodology employed for catalyst design

Methodology employed for catalyst design

  • The one-bead-one-compound concept is based on the fact that combinatorial beads

  • beads prepared from the « split-pool synthesis » contain single beads displaying one

  • type of compounds although there may be 1013 copies on a 100 μm bead

Lam, K. S.; Lebl, M.; Krchňák, V. Chem. Rev. 1997, 97, 411-448.

Furka, A.; Sebestyen, F.; Asgedom. M.; Dibo, G. Int. J. Pept. Protein Res. 1991, 37, 487-493.


Lichtor p a miller s j nature chem 2012 asap

One-bead-one-compound and split-pool synthesis

Lam, K. S.; Salmon, S. E.; Hersh, E. M.; Hruby, V. J.; Kazmierski, W. M.; Knapp, R. J. Nature1991, 354, 82-84.


Lichtor p a miller s j nature chem 2012 asap

One-bead-one-compound and split-pool synthesis

Lam, K. S.; Salmon, S. E.; Hersh, E. M.; Hruby, V. J.; Kazmierski, W. M.; Knapp, R. J. Nature1991, 354, 82-84.


Lichtor p a miller s j nature chem 2012 asap

Initial screening (withparallel peptide synthesis)

Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.


Lichtor p a miller s j nature chem 2012 asap

Initial screening (withparallel peptide synthesis)

Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.

Lichtor, P. A.; Miller, S. J. ACS Comb. Sci. 2011, 13, 321-326.


Lichtor p a miller s j nature chem 2012 asap

Split-pool optimization and synthesis of a large OBOC library (iterativeapproach)

  • The resulting library possess a theorical size of about 3000 unique peptide sequences

  • (for the first directed library)

Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.

Lichtor, P. A.; Miller, S. J. ACS Comb. Sci. 2011, 13, 321-326.


Lichtor p a miller s j nature chem 2012 asap

OBOC libraryresultstowardsepoxidation of farnesol

Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.


Lichtor p a miller s j nature chem 2012 asap

Identification of peptides via sequencing and HPLC/MALDI-QToFanalysis

Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.


Lichtor p a miller s j nature chem 2012 asap

Resynthesis and « in solution » trials with hits

Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.


Lichtor p a miller s j nature chem 2012 asap

Resynthesis and « in solution » trials with hits

Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.


Lichtor p a miller s j nature chem 2012 asap

Substrate scope withoptimized9bcatalyst

Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.


Lichtor p a miller s j nature chem 2012 asap

Biased 2nd OBOC directedat 6,7-selectiveepoxidation

Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.


Lichtor p a miller s j nature chem 2012 asap

Resynthesis and « in solution » trials with hits

Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.


Lichtor p a miller s j nature chem 2012 asap

2,3-Selectivity and 6,7-Selectivityishydroxydriven in epoxidation

Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.


Lichtor p a miller s j nature chem 2012 asap

Validation of both9b and 12dcatalystwithgeranylgeraniol in solution

Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.


Lichtor p a miller s j nature chem 2012 asap

Conclusions

  • Enzymes mediated approches are most often not general to a series of substrates.

  • The application of diversity-based approaches may prove fruitful and may also offer analogy to the directed evolution of strategies employed by natural an bioengineered enzymatic systems.

  • Peptide 9b and 12d found by one-bead-one-compound library screening are operating via a hydroxyl-mediated mechanism.

  • They offer comparable selectivity to the well-known Sharpless epoxidation conditions and are amenable to new selectivity pattern.

Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.


Lichtor p a miller s j nature chem 2012 asap

Future aspects of peptide site-selectivity

Fowler, B. S.; Laemmerhold, K. M.; Miller, S. J. J. Am. Chem. Soc. 2012, 134, 9755-9761.

Pathak, T. P.; Miller, S. J. J. Am. Chem. Soc. 2012, 134, 6120-6123.


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