Design, Synthesis, and Applications of Stereodynamic Chirality Probes

Abstract

Novel stereodynamic chirality probes were developed for enantioselective sensing of chiral compounds, utilizing the concepts of dynamic covalent chemistry and metal-ligand coordination. Upon interaction with a chiral substrate, the probes generate strong circular dichroism (CD) responses due to asymmetric transformation of the first kind. Analysis of the magnitude and sign of the CD output was used for determination of the absolute configuration and enantiomeric excess (ee) of the analytes tested. Changes in the fluorescent readouts of several sensors were used for substrate concentration analysis.

Three new chirality probes were synthesized for the analysis of chiral amino compounds. These sensors consisted of an axially chiral salicylaldehyde moiety and a cofacial aromatic fluorescence reporter unit bound to a rigid naphthalene scaffold. Imine formation between the chiral analyte and the salicylaldehyde unit generates a CD response that can be correlated to the absolute configuration and enantiomeric excess of the substrates. Optimization of the sensor structure led to a fluorophore unit that is capable of intramolecular hydrogen bonding. Substrate binding was most efficient with the N-oxide of 1-(3’-Formyl-4’-hydroxyphenyl)-8-(4’-pyridyl)naphthalene, and this sensor proved to be a highly versatile probe that transforms a binding event into an enantioselective CD signal and a nonenantioselective fluorescence response.

1,1’-Dihydroxy-2,2’-binaphthalene was developed for absolute configuration and ee analysis of many diverse substrates. This ligand forms stereolabile zinc and boron complexes that undergo asymmetric transformation of the first kind upon substrate coordination. Strong CD signals were observed at high wavelength and with minute amounts of sample. The concept of chirality sensing with stereodynamic metal complexes was further developed and a new binaphthol ketone probe was introduced for the assignment of absolute configuration, enantiomeric excess, and concentration of a wide variety of chiral analytes. The ligand was used for the generation of stereodynamic zinc and aluminum complexes for enantioselective sensing of a large variety of chiral substrates. The use of this probe with Ti(OiPr)4 expanded the substrate scope to chiral 1,2-, 1,3- and 1,4-diols. The practicality of this approach and the potential for high-throughput screening was demonstrated with the analysis of crude reaction mixtures obtained by the Sharpless asymmetric dihydroxylation of stilbene.