High-Throughput Assay for Enantiomeric Excess Determination in 1,2- and 1,3-Diols and Direct Asymmetric Reaction Screening

4 years ago

High-Throughput Assay for Enantiomeric Excess Determination in 1,2- and 1,3-Diols and Direct Asymmetric Reaction Screening

Pavel Anzenbacher, Elena G. Shcherbakova, Tony D. James, Vincent M. Lynch, Valentina Brega

A simple and efficient method for determination of the yield, enantiomeric/diasteriomeric excess (ee/de), and absolute configuration of crude chiral diols without the need of work-up and product isolation in a high throughput setting is described. This approach utilizes a self-assembled iminoboronate ester formed as a product by dynamic covalent self-assembly of a chiral diol with an enantiopure fluorescent amine such as tryptophan methyl ester or tryptophanol and 2-formylphenylboronic acid. The resulting diastereomeric boronates display different photophysical properties and allow for fluorescence-based ee determination of molecules containing a 1,2- or 1,3-diol moiety. This method has been utilized for the screening of ee in a number of chiral diols including atorvastatin, a statin used for the treatment of hypercholesterolemia. Noyori asymmetric hydrogenation of benzil was performed in a highly parallel fashion with errors <1 % ee confirming the feasibility of the systematic examination of crude products from the parallel asymmetric synthesis in real time and in a high-throughput screening (HTS) fashion. Gathered in the spotlight: Self-assembled fluorescent probes incorporating chiral diols, allowing for simultaneous determination of ee, de, and product yields in a complicated matrix with only 10–20 ng/well of the substrate. Fluorescence is directly proportional to the absolute configuration and concentration of the diols. The applicability of this simple approach, demonstrated on the products of Noyori asymmetric hydrogenation of benzil and lipid-lowering drug atorvastatin in a highly parallel fashion with errors <1 % ee confirming the feasibility of assaying crude products in real time, without any work up, as required for high-throughput screening.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/chem.201701923