Recently, we have introduced a concept to determine enantiomeric excess (ee) with synthetic multifunctional pores (Tanaka and Matile, Chirality 2008;20:307-312). The reported approach is, however, limited to macromolecules and not applicable to small molecules. The problem is that the ability of synthetic pores to respond to chemical stimulation decreases with the size and the charge of the analyte. Here we demonstrate that this problem can be overcome with reactive signal amplifiers that covalently capture elusive analytes for sensitive recognition by the pore. For proof of principle, we use L-lactate and D-lactate as representative pair of enantiomers, L-lactate oxidase as stereospecific signal generator, and cascade blue hydrazide as reactive signal amplifier to capture the produced pyruvate. After stereospecific signal generation and reactive signal amplification, L-lactate was detectable quantitatively and without further optimization in the presence of at least 99% ee of D-lactate. Attempts to sense the traces of impurity in commercial samples of D-lactate gave values in the expected range (99.6% ee expected, 99.3 +/- 0.1% ee found).