One-Pot, Two-Module Three-Step Cascade To Transform Phenol Derivatives to Enantiomerically Pure (R)- or (S)-p-Hydroxyphenyl Lactic Acids

Readily available phenol derivatives were substituted in para -position via a C–C bond formation to give enantiomerically pure ( R )- or ( S )-3-( para -hydroxyphenyl) lactic acids. The transformation was achieved by designing a biocatalytic cascade consisting of three linear steps, namely, (i) the C–C coupling of the phenol and pyruvate in the presence of ammonia to afford the corresponding l -tyrosine derivative, followed by (ii) oxidative deamination and (iii) enantioselective reduction. Compatibility analysis showed that the reaction rate of the first step is slowed in the presence of the product of the third step; consequently, the three-step cascade was subdivided in two modules (module 1 = step 1; module 2 = steps 2 and 3), which were run in one pot sequentially. Because of the exquisite selectivity achieved in the C–C coupling step, para -isomers were obtained exclusively. By choosing the appropriate alcohol dehydrogenase, the ( R )- as well as the ( S )-isomer were isolated in enantiopure form. Preparative transformations of 2-, 3-, and 2,3-disubstituted phenols (23–96 mM) afforded the corresponding ( R )- and ( S )- para -hydroxyphenyl lactic acids in high yield (58%–85%) and enantiopure form ( ee > 97%).