The development and application of a selection-based approach to reaction discovery

Researchers traditionally search for new reactions only in areas of chemical reactivity predicted to be productive. The ability to evaluate the reactivity of many substrate combinations in a single experiment may enable a much more extensive exploration of chemical reactivity. Here we describe a selection-based approach to reaction discovery wherein >100 combinations of substrates are evaluated for bond-forming reactivity in a single experiment. We use DNA-templated synthesis to organize a complex mixture of substrates into discrete pairs of substrates that can react independently and separate reactive substrate pairs from non-reactive pairs using a simple biotin-streptavidin affinity selection. PCR amplification followed by DNA microarray analysis efficiently identifies the reactive substrate pairs. Using this approach, we discover an efficient Pd(II)-mediated reaction between an alkyne and an alkene to form an enone. This result suggests that selections may identify many productive areas of chemical reactivity that have been overlooked. To expand the reaction conditions that can be evaluated with selections, we explore the possibility of performing selections in non-aqueous solutions. By organizing and encoding substrate combinations with single DNA strands, we are able to select for bond-formation in solutions that are 90% organic solvent.