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

Highly Stereoselective Biocatalytic Synthesis of Key Cyclopropane Intermediate to Ticagrelor

Creators

  • 1. ROR icon California Institute of Technology
  • 2. ROR icon Provivi (United States)

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.

Attached Files

Accepted Version - nihms830234.pdf

Supplemental Material - cs6b02550_si_001.pdf

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cs6b02550_si_001.pdf

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Additional details

Identifiers

PMCID
PMC5340201
Eprint ID
71390
Resolver ID
CaltechAUTHORS:20161024-123654794

Funding

NSF
CBET-1403077
Defense Advanced Research Projects Agency (DARPA)
HR0011–15-C-0093
NSF
IIP-1549855
NIH Predoctoral Fellowship
5 T32 GM07616

Dates

Created
2016-10-24
Created from EPrint's datestamp field
Updated
2022-04-11
Created from EPrint's last_modified field