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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 multi-step 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.

SUBMITTER: Hernandez KE

PROVIDER: S-EPMC5340201 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Highly Stereoselective Biocatalytic Synthesis of Key Cyclopropane Intermediate to Ticagrelor.

Hernandez Kari E KE Renata Hans H Lewis Russell D RD Jennifer Kan S B SB Zhang Chen C Forte Jared J Rozzell David D McIntosh John A JA Arnold Frances H FH

ACS catalysis 20161017 11

Extending the scope of biocatalysis to important non-natural reactions such as olefin cyclopropanation will open new opportunities for replacing multi-step chemical syntheses of pharmaceutical intermediates with efficient, clean, and highly selective enzyme-catalyzed processes. In this work, we engineered the truncated globin of <i>Bacillus subtilis</i> for the synthesis of a cyclopropane precursor to the antithrombotic agent ticagrelor. The engineered enzyme catalyzes the cyclopropanation of 3, ...[more]

PMID: 28286694

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