A practical synthesis of glucokinase activator 1 as a drug candidate for type 2 diabetes treatment is presented. Structural feature of 1 is cis-difluorinated cyclopentane moiety conjugated with double bond in its main structure. An efficient and practical synthetic route for 1 has been established with one-pot difluorination via diastereoselective epoxidation and modified Julia olefination followed by isomerization. Whereas the original medicinal chemistry route has drawbacks such as the use of dangerous and expensive reagents (LiAlH4, OsO4, and Deoxo-Fluor) and low efficiency (&lt;4% overall yield, 20 steps), the developed method achieved safer and more effective results (15% overall yield, 12 steps).

Practical and scalable synthesis of a glucokinase activator using modified Julia olefination and one-pot difluorination

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