Reaction microarrays and small-molecule printing

The development of reaction microarrays, a new technique for the parallel enantiomeric excess measurement of tens-of-thousands of samples, and extensions of this methodology are presented in this thesis. Inspiration for this work came from a desire to blend the high-throughput experimentation of combinatorial catalysis with the high-throughput analysis of DNA microarrays. We sought to adapt the high-throughput analytical format of DNA microarray technology to the measurement of the enantiomeric composition of solutions of small molecules that were envisioned to arise from catalytic, enantioselective reactions.; Amino acid derivatives were contact printed via DNA microarrayers and covalently attached to derivatized glass microscope slides. Two pseudoenantiomeric fluorescent chiral probes, Cy3-(R)-proline and Cy5-(S)-proline, were observed to provide enantiomeric discrimination of these immobilized amino acids under amide coupling conditions. Kinetic resolution in this amide coupling step provided a ratio of fluorophores at each printed spot that was proportional to the enantiomeric ratio of amino acid at that spot. Laser scanning of the glass slides yielded a fluorescence intensity ratio of fluorophores at each printed spot that was used to calculate the enantiomeric excess of the original sample solutions. The applicability of the reaction microarray method for high-throughput analysis was demonstrated by rapid identification of two >99% ee samples of proline out of 15,552 total samples.; A general strategy for the immobilization of organic small molecules to a glass surface was also developed. Substrates were printed onto sulfonyl azide-derivatized glass slides, which were then photolyzed using a handheld 365 nm UV lamp. Arrayed substrates were found to be covalently attached to the surface via a presumed reactive nitrene intermediate. Biologically relevant small molecules, including those not possessing reactive functional groups, were immobilized on a glass surface using this photolytic sulfonyl azide decomposition strategy. These arrays were used to detect the binding of small molecules by proteins.