categories: catalyst screening, asymmetric synthesis, solid supported chemistry, peptides
Screening Rhodium Metallopeptide Libraries “On Bead”: Asymmetric Cyclopropanation and a Solution to the Enantiomer Problem
Ramya Sambasivan and Zachary Ball*
Rice University Department of Chemistry
Angewandte Chemie, International Edition 2012, 51, 8568-8572, doi: 10.1002/anie.201202512
Highlight by: Dr. Thomas O. Painter, University of Kansas Center for Chemical Methodologies and Library Development
- In this article, the authors confront the well known “enantiomer problem” that results when naturally occurring compounds are used for asymmetric induction, i.e. one product enantiomer is easily accessible, but the other is not. The article details a method for quickly generating libraries of peptide-based rhodium(II)-metallopeptides to identify catalysts of a cyclopropanation between simple alkenes and a-diazoesters.
To begin, the authors cite their prior work to develop a Rh(II)-metallopeptide catalyst consisting of the metal and two nonapeptide ligands. This catalyst provides Re selectivity in the cyclopropanation reaction and served as the starting point for the study. To obtain Si products, peptide ligands derived from D-amino acids could be used, however this strategy is expensive. In the present paper, the authors took an alternative approach whereby a high-throughput ligand/catalyst screen was carried out. The screen surveyed the efficacy of a rhodium catalyst featuring a single nonopeptide “on bead” as a faster alternative to solution-phase screening of bis-peptide catalysts, which cannot be assembled on solid support. Because the monopeptide-derived catalysts are known to give lower enantioselectivities than bis-peptide-derived catalysts, the best ligands found in the screen would be further used in a bis-peptide format to provide optimal selectivity. The screened nonapeptides consisted of natural amino acid residues and featured carboxyl groups in the i and i+4 positions, which would induce helicity upon metal binding.
Two rounds of iterative library screening identified monopeptide catalysts that provided Si selectivity in ca. 45% ee. The best peptide ligands were then used in bis-peptide catalysts to produce Si cyclopropanation products in up to 97% ee. Finally, a series of reactions was performed to compare the original ligand that provides the “normal” Re addition products to the newly discovered ligand that provides “opposite” Si enantiomers.
The most interesting aspect of this study is the difference in residues found in the two catalyst ligands. The ligand that provides Re selectivity consists mostly of bulkier residues such as leucine, isoleucine, and phenylalanine at the i-1 and i+3 positions. In contrast, the ligand that provides good Si selectivity contains residues possessing polar side chains such as glutamine and asparagine in the same positions. The authors suggest that each catalyst system is operating through a different mechanism of asymmetric induction.
The power of high-throughput techniques coupled with modular design is showcased well in this article. An elegant method for tackling the “enantiomer problem” has been demonstrated without recourse to peptides derived from rare D-amino acids.
- Recent coverage on peptide synthesis: Amino Acids, Peptides and Proteins in Organic Chemistry, Volume 3: Building Blocks, Catalysis and Coupling Chemistry; Hughes, A. B., WILEY-VCH Verlag & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany, 2011.
- Selected articles on high-throughput catalyst screening: (a) “Evolutionary Catalyst Screening: Iridium-Catalyzed Imine Hydrogenation” Kluwer, A. M.; Detz, R. J.; Abiri, Z.; van der Burg, A. M.; Reek, J. N. H., Adv. Synth. Catal. 2012, 354, 89-95. (b) “From High-Throughput Catalyst Screening to Reaction Optimization: Detailed Investigation of Regioselective Suzuki Coupling of 1,6-Naphthyridone Dichloride” Cai, C.; Chung, J. Y. L.; McWilliams, J. C.; Sun, Y.; Shultz, C. S.; Palucki, M., Org. Proc. Res. Dev. 2007, 11, 328-335. (c) “New Catalysts and Conditions for a C-H Insertion Reaction Identified by High Throughput Catalyst Screening” Burgess, K.; Lim, H. -J.; Porte, A. M.; Sulikowski, G. A., Angew. Chem., Int. Ed. Engl. 1996, 35, 220-222.
-An instructive review on the asymmetric cyclopropanation reaction using rhodium(II)-catalysis: Davies, H. M. L.; Walji, A. M. “Rhodium(II)-Stabilized Carbenoids Containing Both Donor and Acceptor Substituents.” In Modern Rhodium-Catalyzed Organic Reactions, Evans, P. A., Ed.; WILEY-VCH Verlag & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany, 2005; pp 301-340.