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Highly Stereoselective Biocatalytic Synthesis of Key Cyclopropane Intermediate to Ticagrelor

Hernandez, Kari E. and Renata, Hans and Lewis, Russell D. and Kan, S. B. Jennifer and Zhang, Chen and Forte, Jared and Rozzell, David and McIntosh, John A. and Arnold, Frances H. (2016) Highly Stereoselective Biocatalytic Synthesis of Key Cyclopropane Intermediate to Ticagrelor. ACS Catalysis, 6 (11). pp. 7810-7813. ISSN 2155-5435. PMCID PMC5340201. http://resolver.caltech.edu/CaltechAUTHORS:20161024-123654794

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/acscatal.6b02550DOIArticle
http://pubs.acs.org/doi/abs/10.1021/acscatal.6b02550PublisherArticle
http://pubs.acs.org/doi/suppl/10.1021/acscatal.6b02550PublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340201PubMed CentralArticle
ORCID:
AuthorORCID
Lewis, Russell D.0000-0002-5776-7347
Kan, S. B. Jennifer0000-0001-6371-8042
Arnold, Frances H.0000-0002-4027-364X
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.
Funders:
Funding AgencyGrant Number
NSFCBET-1403077
Defense Advanced Research Projects Agency (DARPA)HR0011–15-C-0093
NSFIIP-1549855
NIH Predoctoral Fellowship5 T32 GM07616
Subject Keywords:biocatalysis, directed evolution, ticagrelor, cyclopropanation, Bacillus subtilis, truncated globin
PubMed Central ID:PMC5340201
Record Number:CaltechAUTHORS:20161024-123654794
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20161024-123654794
Official Citation:Highly Stereoselective Biocatalytic Synthesis of Key Cyclopropane Intermediate to Ticagrelor Kari E. Hernandez, Hans Renata, Russell D. Lewis, S. B. Jennifer Kan, Chen Zhang, Jared Forte, David Rozzell, John A. McIntosh, and Frances H. Arnold ACS Catalysis 2016 6 (11), 7810-7813 DOI: 10.1021/acscatal.6b02550
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:71390
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:24 Oct 2016 19:58
Last Modified:20 Aug 2018 23:25

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