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. 2016 Dec 23;55(52):16110-16114.
doi: 10.1002/anie.201608680. Epub 2016 Nov 25.

Gram-Scale Synthesis of Chiral Cyclopropane-Containing Drugs and Drug Precursors with Engineered Myoglobin Catalysts Featuring Complementary Stereoselectivity

Priyanka Bajaj  1 , Gopeekrishnan Sreenilayam  1 , Vikas Tyagi  1 , Rudi Fasan  1
Affiliations

Gram-Scale Synthesis of Chiral Cyclopropane-Containing Drugs and Drug Precursors with Engineered Myoglobin Catalysts Featuring Complementary Stereoselectivity

Priyanka Bajaj et al. Angew Chem Int Ed Engl. .

Abstract

Engineered hemoproteins have recently emerged as promising systems for promoting asymmetric cyclopropanations, but variants featuring predictable, complementary stereoselectivity in these reactions have remained elusive. In this study, a rationally driven strategy was implemented and applied to engineer myoglobin variants capable of providing access to 1-carboxy-2-aryl-cyclopropanes with high trans-(1R,2R) selectivity and catalytic activity. The stereoselectivity of these cyclopropanation biocatalysts complements that of trans-(1S,2S)-selective variants developed here and previously. In combination with whole-cell biotransformations, these stereocomplementary biocatalysts enabled the multigram synthesis of the chiral cyclopropane core of four drugs (Tranylcypromine, Tasimelteon, Ticagrelor, and a TRPV1 inhibitor) in high yield and with excellent diastereo- and enantioselectivity (98-99.9% de; 96-99.9% ee). These biocatalytic strategies outperform currently available methods to produce these drugs.

Keywords: asymmetric cyclopropanation; biocatalysis; carbenoids; myoglobin; protein engineering.

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Figures

Figure 1
Figure 1
Structure-reactivity guided design of Mb cyclopropanation biocatalysts with complementary stereoselectivity. The path in grey is described in ref. [4].
Scheme 1
Scheme 1
Total and formal synthesis of (a) levo- and dextrorotatory enantiomer of tranylcypromine, (b) Tasimelteon, (c) TRPV1 inhibitor 24, and (d) Ticagrelor, via myoglobin-catalyzed cyclopropanation in whole cells. See SI for details on synthetic steps. DPPA = diphenylphosphoryl azide, PTSA = para-toluenesulfonic acid, T3P = propane phosphonic acid anhydride, TFA = trifluoroacetic acid.
See this image and copyright information in PMC

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