Highly Stereoselective Biocatalytic Synthesis of Key Cyclopropane Intermediate to Ticagrelor

• Published in: ACS catalysis Vol. 6; no. 11; pp. 7810 - 7813
• Main Authors: Hernandez, Kari E, Renata, Hans, Lewis, Russell D, Kan, S. B. Jennifer, Zhang, Chen, Forte, Jared, Rozzell, David, McIntosh, John A, Arnold, Frances H
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 04.11.2016
• Subjects: truncated globin; ticagrelor; cyclopropanation; Bacillus subtilis; biocatalysis; directed evolution
• ISSN: 2155-5435; 2155-5435
• DOI: 10.1021/acscatal.6b02550

Extending the scope of biocatalysis to important non-natural reactions such as olefin cyclopropanation will open new opportunities for replacing multistep chemical syntheses of pharmaceutical intermediates with efficient, clean, and highly selective enzyme-catalyzed processes. In this work, we engineered the truncated globin of Bacillus subtilis for the synthesis of a cyclopropane precursor to the antithrombotic agent ticagrelor. The engineered enzyme catalyzes the cyclopropanation of 3,4-difluorostyrene with ethyl diazoacetate on a preparative scale to give ethyl-(1R, 2R)-2-(3,4-difluorophenyl)-cyclopropanecarboxylate in 79% yield, with very high diastereoselectivity (>99% dr) and enantioselectivity (98% ee), enabling a single-step biocatalytic route to this pharmaceutical intermediate.