Synthesis of AZD6738

Key words

AZD6738 - asymmetric sulfoxidation - sulfoximines - biocatalysis - rhodium catalysis

Significance

Workers at AstraZeneca recently reported a mol-scale synthesis of ATR inhibitor AZD6738 based on the use of chiral HPLC to access the chiral sulfoxide intermediate G (J. Med. Chem. 2018, 61, 9889). A plant scale synthesis of AZD6738 is now reported that features a biocatalytic asymmetric sulfoxidation reaction (F → G) and a cyclopropanation (J → L) in continuous stirred tank reactors.

Comment

The sulfoxidation reaction uses a ­Baeyer–Villiger monooxygenase in tandem with nicotinamide adenine dinucleotide phosphate ­(NADPH), which is oxidized to NADP⁺. NADPH is then regenerated through reduction of NADP⁺ by a ketoreductase (KRED) enzyme, which in turn oxidizes the co-solvent isopropanol to acetone. Efficient gas–liquid mass transfer of oxygen is key to obtaining a high yield.