title: Gram-Scale Synthesis of Chiral Cyclopropane-Containing Drugs and Drug Precursors with Engineered Myoglobin Catalysts Featuring Complementary Stereoselectivity.
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.
authors.affiliation: Department of Chemistry, University of Rochester, 120 Trustee Road, Rochester, NY, 14627, USA.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Bajaj
authors.affiliation: Department of Chemistry, University of Rochester, 120 Trustee Road, Rochester, NY, 14627, USA.
authors.forename: Gopeekrishnan
authors.initials: G
authors.lastname: Sreenilayam
authors.affiliation: Department of Chemistry, University of Rochester, 120 Trustee Road, Rochester, NY, 14627, USA.
authors.forename: Vikas
authors.initials: V
authors.lastname: Tyagi
authors.affiliation: Department of Chemistry, University of Rochester, 120 Trustee Road, Rochester, NY, 14627, USA.
authors.forename: Rudi
authors.identifier: 0000-0003-4636-9578
authors.initials: R
authors.lastname: Fasan
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry; D001572:Benzofurans / Q000737:chemistry*; D002384:Catalysis; D003521:Cyclopropanes / Q000737:chemistry*; D004926:Escherichia coli / Q000166:cytology / Q000378:metabolism; D015394:Molecular Structure; D009211:Myoglobin / Q000737:chemistry* / Q000378:metabolism; D015202:Protein Engineering; D013237:Stereoisomerism; D000077486:Ticagrelor; D014191:Tranylcypromine / Q000737:chemistry*
chemical_list: D001572:Benzofurans; D003521:Cyclopropanes; D009211:Myoglobin; D014191:Tranylcypromine; C030797:cyclopropane; D000077486:Ticagrelor; D000241:Adenosine; C478745:tasimelteon
keywords: asymmetric cyclopropanation; biocatalysis; carbenoids; myoglobin; protein engineering