Enantio- and Diastereodivergent Cyclopropanation of Allenes by Directed Evolution of an Iridium-Containing Cytochrome.

Autor:	Bloomer BJ; Department of Chemistry, University of California, Berkeley, California 94720, United States.; Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States., Joyner IA; Department of Chemistry, University of California, Berkeley, California 94720, United States.; Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States., Garcia-Borràs M; Institut de Química Computacional i Catàlisi (IQCC) and Departament de Química, Universitat de Girona, Girona 17003, Spain., Hu DB; Department of Chemistry, University of California, Berkeley, California 94720, United States., Garçon M; Department of Chemistry, University of California, Berkeley, California 94720, United States.; Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States., Quest A; Department of Chemistry, University of California, Berkeley, California 94720, United States., Ugarte Montero C; Department of Chemistry, University of California, Berkeley, California 94720, United States., Yu IF; Department of Chemistry, University of California, Berkeley, California 94720, United States., Clark DS; Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States.; Department of Chemical and Biomolecular Engineering, University of California, Berkeley, California 94720, United States., Hartwig JF; Department of Chemistry, University of California, Berkeley, California 94720, United States.; Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States.
Jazyk:	angličtina
Zdroj:	Journal of the American Chemical Society [J Am Chem Soc] 2024 Jan 24; Vol. 146 (3), pp. 1819-1824. Date of Electronic Publication: 2024 Jan 08.
DOI:	10.1021/jacs.3c13011
Abstrakt:	Alkylidene cyclopropanes (ACPs) are valuable synthetic intermediates because of their constrained structure and opportunities for further diversification. Although routes to ACPs are known, preparations of ACPs with control of both the configuration of the cyclopropyl ( R vs S ) group and the geometry of the alkene ( E vs Z ) are unknown. We describe enzymatic cyclopropanation of allenes with ethyl diazoacetate (EDA) catalyzed by an iridium-containing cytochrome (Ir(Me)-CYP119) that controls both stereochemical elements. Two mutants of Ir(Me)-CYP119 identified by 6-codon (6c, VILAFG) saturation mutagenesis catalyze the formation of ( E )-ACPs with -93% to >99% ee and >99:1 E / Z ratio with just three rounds of 96 mutants. By four additional rounds of mutagenesis, an enzyme variant was identified that forms ( Z )-ACPs with up to 94% ee and a 28:72 E/Z ratio. Computational studies show that the orientation of the carbene unit dictated by the mutated positions accounts for the stereoselectivity.
Databáze:	MEDLINE
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