One-Pot Sequential Two-Step Photo-Biocatalytic Deracemization of sec-Alcohols Combining Photocatalytic Oxidation and Bioreduction

Abstract

Chiral alcohols are versatile building blocks and are of particular interest in the asymmetric synthesis of nonracemic active pharmaceutical ingredients, agrochemicals, fragrances, flavors, natural products, etc. Herein, we report on a “one-pot sequential two-step” concurrent oxidation-reduction photobiocatalytic process to synthesize enantiomerically enriched alcohols. In this regard, an efficient photocatalytic system based on irradiation with 440 nm blue LEDs in the presence of 9-fluorenone as a metal-free photocatalyst and molecular oxygen as the terminal oxidant in dry DMSO as the hydrogen peroxide-neutralizing agent was used to oxidize a broad range of racemic (hetero)benzylic alcohols into prochiral ketones quantitively (>99% conv.). The in situ formed carbonyl compounds were subsequently converted into the corresponding chiral alcohols via a sequential biocatalytic transhydrogenation catalyzed by lyophilized E. coli cells overexpressing highly stereoselective and stereocomplementary recombinant alcohol dehydrogenases (ADHs) originated from Rhodococcus ruber (E. coli/ADH-A) or Rhodococcus erythropolis (E. coli/ReADH) to obtain (S)-alcohols and Lactobacillus kefir (E. coli/Lk-ADH) or KRED-110 to obtain (R)-alcohols, respectively. Overall, the elaborated photobiocatalytic deracemization of racemic alcohols using a 9-fluorenone-O2-blue LED-DMSO-E. coli/ADH system carried out on a semipreparative scale (0.25 mmol; 63 mM final conc. in 4 mL) at room temperature yielded nonracemic aryl alcohols with 82-99.9% conv., in up to 92% isolated yield, with 97-99.9% ee and complementary chirality.