Nanomole-Scale Assignment and One-Use Kits for Determining the Absolute Configuration of Secondary Alcohols.

Abstract

Two different protocols were developed and optimized to address the need for (1) high sensitivity or (2) convenient utilization in the determination of the absolute configuration of secondary alcohols. The first protocol uses the competing enantioselective conversion (CEC) method to determine configuration on nanomole scale. Reactions were conducted with 145 nmol of the substrate using a 50 μL microsyringe as the reaction vessel, and the absolute configuration was assigned via qualitative determination of the fast reaction by thin-layer chromatography. This protocol resulted in a 50-fold reduction in material required from previous CEC method studies. The approach was evaluated with benzylic and β-aryl systems. The second protocol was optimized to address the needs of practicing medicinal chemists. A one-use CEC kit was developed, where the fast reaction was identified by (1)H NMR spectroscopy and thin-layer chromatography. The CEC reaction conditions developed for the microsyringe protocol and the one-use kit both displayed data consistent with pseudo-first-order kinetics in substrate. Therefore, the lower limit of sensitivity for the substrate is limited only by the ability to effectively detect the reaction conversions between alcohol substrate and ester product.