A Three‐Step Chemoenzymatic Cascade Synthesis of Miconazole Analogues Based on the Asymmetric Synthesis of β‐Heteroaryl Amino Alcohols via Ketoreductases

Abstract

AbstractChiral β‐heteroaryl amino alcohols play a crucial role as intermediates in the synthesis of numerous bioactive pharmaceuticals, including cenobamate, oteseconazole, and miconazole. Nevertheless, there is a lack of literature documenting the establishment of a versatile approach for the synthesis of β‐heteroaryl amino alcohols and the aforementioned drugs. In this study, we successfully asymmetrically synthesized 50 pairs of chiral β‐heteroaryl amino alcohols using two engineered ketoreductases (KREDs) with opposite stereopreference. Based on this achievement, we developed a three‐step chemoenzymatic cascade route for synthesizing of chiral miconazole analogues from commercially available 2‐bromoacetophenone derivatives. By optimizing the solvent for the synthesis of α‐imidazolyl ketones in the first step, followed by the reduction of α‐imidazolyl ketones using KREDs in the second step and etherification in the third step, we obtained 20 chiral miconazole analogues with promising yields (26–84%) and impressive stereoselectivities (up to >99% ee). Notably, this route eliminates the need for the isolation of ketone and alcohol intermediates, and avoids the use of metal catalysts in the synthesis of chiral miconazole analogues. Furthermore, we successfully scaled up the preparation of (S)‐miconazole, achieving a 30% isolated yield and >99% ee. This method presents a novel synthetic approach for production chiral ether drugs and chiral β‐heteroaryl amino alcohols, offering new possibilities in pharmaceutical synthesis.