Asymmetric Synthesis of Florfenicol by Dynamic Reductive Kinetic Resolution with Ketoreductases

Abstract

A chemoenzymatic synthesis of the veterinary antibiotic florfenicol is described. The key step involves the dynamic reductive kinetic resolution (DYRKR) of a keto ester by using a ketoreductase‐02 (KRED‐02) to afford the two contiguous stereocenters of the (2S,3R)‐cis‐1,2‐amino alcohol intermediate in >99 % ee and a diastereomeric ratio (dr) of 99 %. This green biocatalysis is environmental friendly with high enantioselectivity and product yields. Two methods for the nucleophilic fluorination step involved the use of aziridines and cyclic sulfates to safely prepare fluoroamines with high regioselectivity. Additional studies have indicated that KRED‐02 can also be used to afford chiral alcohol (S)‐21 in good yields with high enantioselectivity. This study shows that the integration of biocatalysis into organic synthesis can be useful and provide industrial opportunities for applications of florfenicol.

Synthesis of Fluorine‐Containing Molecular Entities Through Fluoride Ring Opening of Oxiranes and Aziridines

“…Fluorine introduction was accomplished by regioselective aziridine ring opening of 299 (Scheme ). Notably, the use of more acidic reagents like pyridine/9HF and the HF complex of 1,3‐dimethyl‐3,4,5,6‐tetrahydro‐2(1 H )‐pyrimidinone (HF‐DMPU) led to no reaction …”

Stereoselective syntheses of 3-aminocyclooctanetriols and halocyclooctanetriols

“…For the synthesis of amino- and chlorocyclitols and their derivatives, we first selected endoperoxide 5 as the starting molecule, which was prepared using a procedure described in the literature [ 33 ] ( Scheme 1 ). Among the most relevant precursors for the synthesis of aminocyclitols are cyclic sulfates [ 36 – 37 39 – 40 ] and they have been also used in the synthesis of C8-aminocarbasugars [ 36 – 37 ] recently. We envisioned that aminotriol 12 could be prepared by the reaction with sodium azide of the corresponding cyclic sulfate intermediate 9 , which contains the only stereocentre.…”

Stereoselective syntheses of 3-aminocyclooctanetriols and halocyclooctanetriols

“…For the synthesis of amino-and chlorocyclitols and their derivatives, we first selected endoperoxide 5 as starting molecule, which was prepared using a procedure described in the literature [34] (Scheme 1). Among the most relevant precursors for the synthesis of aminocyclitols are cyclic sulphates [37,38,40,41] and they have been also used in the synthesis of C8-aminocarbasugars [37,38] recently. We envisioned that aminotriol (12) could be prepared by the reaction with sodium azide of the corresponding cyclic sulphate intermediate (9), which contains the only stereocentre.…”