Combinatorial catalysis: The development of new screens and catalysts from split and mix libraries

Abstract

A new method is described for the detection of active catalysts from libraries generated by combinatorial synthesis. The technique was reliant on bifunctional substitution of a resin with a common substrate and a library of potential catalysts. Site proximity effects allowed the interaction between these two species such that catalysis could occur. The substrate was chosen such that under reaction conditions, catalytic activity brought about a visual change, and thus allowed the identification of beads which contained active catalysts. Selection of positive beads, followed by identification of the supported library compound led to the discovery of novel catalysts.

Using this technique a library of 1000 potential tripeptide catalysts were screened for Diels Alder catalytic activity. A strong sequence correlation was found in the active catalysts which led to the synthesis of six arginine based catalysts which were found to give up to four fold rate accelerations.

A new mass spectrometry based method of peptide sequencing, suitable for single bead applications has been developed, based on the software extraction of isotropically labelled fragments. A new mild acid labile amine protecting group is described.

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