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 For a review, see: Clardy, J.; Walsh, C. Nature 2004, 432, Walker, K.; Croteau, R. Phytochemistry 2001, 58, 1-7. Mendoza, A.; Ishihara, Y.; Baran, P. S. Nature Chem. 2012, 4,

Analysis of biosynthetic patways reveals functional group selectivity For a review, see: Clardy, J.; Walsh, C. Nature 2004, 432, Novak, B. H.; Hudlicky, T.; Reed, J. W.; Mulzer, J.; Trauner, D. Curr. Org. Chem. 2000, 4, Calderon, S. N. et al. J. Med. Chem. 1997, 40, 695.

Analysis of biosynthetic patways reveals functional group selectivity For a review, see: Clardy, J.; Walsh, C. Nature 2004, 432, Novak, B. H.; Hudlicky, T.; Reed, J. W.; Mulzer, J.; Trauner, D. Curr. Org. Chem. 2000, 4, Calderon, S. N. et al. J. Med. Chem. 1997, 40, 695.

Enzyme-mediated oxidation does preclude generality… Van Tamelen, E. E.; Heys, R. J. J. Am. Chem. Soc. 1975, 97,

Small synthetic molecules meets some of these challenges Zhang, W.; Basak, A.; Kosugi, Y.; Hoshino, Y.; Yamamoto, H. Angew. Chem., Int. Ed. 2005, 44, Egami, H.; Oguma, T.; Katsuki, T. J. Am. Chem. Soc. 2010, 132,

Small synthetic molecules meets some of these challenges Zhang, W.; Basak, A.; Kosugi, Y.; Hoshino, Y.; Yamamoto, H. Angew. Chem., Int. Ed. 2005, 44, Egami, H.; Oguma, T.; Katsuki, T. J. Am. Chem. Soc. 2010, 132,

Small synthetic molecules meets some of these challenges Barlan, A. U.; Basak, A.; Yamamoto, H. Angew. Chem., Int. Ed. 2006, 45, Chang, S.; Lee, N. H.; Jacobsen, E. N. J. Org. Chem. 1993, 58,

Small synthetic molecules meets some of these challenges Barlan, A. U.; Basak, A.; Yamamoto, H. Angew. Chem., Int. Ed. 2006, 45, Chang, S.; Lee, N. H.; Jacobsen, E. N. J. Org. Chem. 1993, 58,

Template-directed internal epoxidation of polyenes Gnanadesikan, V.; Corey, E. J. J. Am. Chem. Soc. 2008, 130,

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 Peris, G.; Jakobsche, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, Kolundzic, F.; Noshi, M. N.; Tjandra, M.; Movassaghi, M.; Miller, S. J. J. Am. Chem. Soc. 2011, 133,

Proposed catalytic cycle for the asymmetric epoxidation Peris, G.; Jakobsche, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, Kolundzic, F.; Noshi, M. N.; Tjandra, M.; Movassaghi, M.; Miller, S. J. J. Am. Chem. Soc. 2011, 133,

First screening of catalysts Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP. With initial peptide catalyst screening, the authors chose to run the reactions at low conversions in order to allow a preleminary assessment of catalyst k rel

Methodology employed for catalyst design Lam, K. S.; Lebl, M.; Krchň á k, V. Chem. Rev. 1997, 97, Furka, A.; Sebestyen, F.; Asgedom. M.; Dibo, G. Int. J. Pept. Protein Res. 1991, 37, 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 copies on a 100 μm bead

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. Nature 1991, 354,

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. Nature 1991, 354,

Initial screening (with parallel peptide synthesis) Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.

Initial screening (with parallel peptide synthesis) Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP. Lichtor, P. A.; Miller, S. J. ACS Comb. Sci. 2011, 13,

Split-pool optimization and synthesis of a large OBOC library (iterative approach) Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP. Lichtor, P. A.; Miller, S. J. ACS Comb. Sci. 2011, 13, The resulting library possess a theorical size of about 3000 unique peptide sequences (for the first directed library)

OBOC library results towards epoxidation of farnesol Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.

Identification of peptides via sequencing and HPLC/MALDI-QToF analysis 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.

Resynthesis and « in solution » trials with hits Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.

Substrate scope with optimized 9b catalyst Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.

Biased 2 nd OBOC directed at 6,7-selective epoxidation 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.

2,3-Selectivity and 6,7-Selectivity is hydroxy driven in epoxidation Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.

Validation of both 9b and 12d catalyst with geranylgeraniol in solution Lichtor, P. A.; Miller, S. J. Nature Chem. 2012, ASAP.

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. Conclusions 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, Pathak, T. P.; Miller, S. J. J. Am. Chem. Soc. 2012, 134,