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Published November 4, 2016 | Accepted Version + Supplemental Material
Journal Article Open

Highly Stereoselective Biocatalytic Synthesis of Key Cyclopropane Intermediate to Ticagrelor

Abstract

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.

Additional Information

© 2016 American Chemical Society. Received: September 6, 2016. Revised: October 7, 2016. Publication Date (Web): October 17, 2016. We thank Dr. S. Virgil and the Center for Catalysis and Chemical Synthesis (3CS) at Caltech for assistance with the SFC. This work was supported in part by the National Science Foundation, Office of Chemical, Bioengineering, Environmental and Transport Systems SusChEM Initiative (grant CBET-1403077) and the Defense Advanced Research Projects Agency Biological Robustness in Complex Settings Contract HR0011–15-C-0093. Funding for this work to Provivi, Inc. from the National Science Foundation under Phase 1 STTR Grant 1549855 is also gratefully acknowledged. R.D.L. is supported by NIH/NRSA training grant (5 T32 GM07616). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the funding organizations.

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Accepted Version - nihms830234.pdf

Supplemental Material - cs6b02550_si_001.pdf

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