A KetoREDuctase (KRED) engineered via directed evolution technologies catalyzed the asymmetric reduction of (E)-methyl 2-(3-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-oxopropyl)benzoate to the corresponding (S)-alcohol, a key intermediate in the synthesis of montelukast sodium (Singulair). Through synergistic efforts in process chemistry, molecular biology, bioinformatics and high throughput screening, a KRED with very high enantioselectivity (>99.9% ee) was developed for an economical and simple process that takes advantage of the physical properties of the substrate and product. The evolved KRED is an efficient and robust enzyme for catalyzing the reaction of an essentially water insoluble substrate (c log P ≈ 7) at a 100 g/L loading in the presence of ∼70% organic solvents at 45 °C. The biocatalytic process currently runs at >200 kg scale.

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Lactone 24 was converted to demethyl-14 (72%; mp 111-112 °C) via the same reaction sequence used to convert 13 to 14. (23) Preliminary experiments have shown that the radicals derived from 15 and re(-(lS,5S,8S)-l-(3-buten-l-yl)-8-iodo-6-oxabicyclo[3.2.1]oct-2-en-7-one display endo-exo partitioning similar to that observed for 4.

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