Catalytic combinatorial libraries substrates

We screened our libraries for the site-selective epoxidation of famesol (120) [182]. Either the peracid reagent /mCPBA, or catalytic n-alkyl acids, provided a benchmark for the intrinsic and poorly selective product distribution of monoepoxides (see Fig. 13b inset for schematic of famesol nomenclature). Hits from the initial libraries, however, showed selectivity toward 2,3-epoxide 121 and 6,7-epoxide 122, inspiring the development of biased combinatorial libraries to select further for these oxidation sites (Fig. 13b). Further optimization of the sequences after additional library sequences yielded peptide 123, which provided 2,3-epoxy famesol 121 with 1 1 >100 site selectivity (10,11 6,7 2,3) in 81% yield and 86% ee. These values are comparable to those provided for this substrate by the venerable Sharpless asymmetric epoxidation [187]. Optimization of the 6,7-biased sequence led to peptide 124, which provided 6,7-epoxy famesol 122 in 1.2 8.0 1.0 site selectivity (10,11 6,7 2,3) in 43% yield and 10% ee. Despite the modest ee of 122, we note that, to our knowledge, no existing catalytic epoxidation method is capable of providing 122 directly in reasonable purity. 

In addition, their ease of synthesis and modular nature allows for a simple tuning of the catalytic activity through the synthesis of combinatorial libraries of catalysts, thus allowing optimization of their structure with respect to the substrate and reaction under investigation. 

Larsson, R. Ramstrom, O. Dynamic combinatorial thiolester libraries for efficient catalytic self-screening of hydrolase substrates. Ear. J. Org. Chem. 

The fca(t estimated for the amide hydrolysis by 11 or 19 was much greater than either 0.1 h"1 at pH 8.5 and 50°Cor0.2h 1 at pH 8 and 50 °C. This fccal may be compared with the 0.18 h 1 for hydrolysis of an amide substrate (at the optimum pH of 9 and 25 °C) observed with a catalytic antibody [54] that had been elicited by a joint hybridoma and combinatorial antibody library approach. 

Larsson R, Pei Z, Ramstrom O (2004) Catalytic self-screening of cholinesterase substrates from a dynamic combinatorial thioester library. Angew Chem hit Ed 43 3716-3718... 

Apo(Sal)3PEI is the first organic artificial proteinase based on synthetic materials. Organic artificial proteinases based on biotic materials have been obtained with catalytic antibodies. As discussed above, the best antibody catalyst for amide hydrolysis reported to date has been elicited recently by a joint hybridoma and combinatorial antibody library approach. The measured with a primary amide substrate at pH 9 and 25 °C was 5x10" s . This corresponds to a half-life of 4 h when the substrate is fully complexed to the active site. The half-lives for the amide hydrolysis catalyzed by the antibodies may be compared with that (ca. 1 h at pH 7 and 50 °C when the substrate is only partially complexed to the active site) by apo(Sal)3PEI. 

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