Combinatorial evolution of site- and enantioselective
catalysts for polyene epoxidation
Guillaume Pelletier Literature meeting - November
20th 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, 829-837.
Walker, K.; Croteau, R. Phytochemistry 2001, 58, 1-7.
Mendoza, A.; Ishihara, Y.; Baran, P. S. Nature Chem. 2012, 4, 21-25.
Analysis of biosynthetic patways reveals
functional 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.
Analysis of biosynthetic patways reveals
functional 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.
Enzyme-mediated oxidation does preclude
generality…
Van Tamelen, E. E.; Heys, R. J. J. Am. Chem. Soc. 1975, 97, 1252-1253.
Small synthetic molecules meets some 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.
Small synthetic molecules meets some 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.
Small synthetic molecules meets some 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.
Small synthetic molecules meets some 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.
Template-directed internal epoxidation of
polyenes
Gnanadesikan, V.; Corey, E. J. J. Am. Chem. Soc. 2008, 130, 8089-8093.
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, 8710-8711.
Kolundzic, F.; Noshi, M. N.; Tjandra, M.; Movassaghi, M.; Miller, S. J. J. Am. Chem. Soc. 2011, 133, 9104-9111.
Proposed catalytic cycle for the asymmetric
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.
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
• 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.
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, 82-84.
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, 82-84.
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, 321-326.
Split-pool optimization and synthesis of a large
OBOC library (iterative approach)
• 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.
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 2nd 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.
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.
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.