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Enantio- and Diastereodivergent Cyclopropanation of Allenes by Directed Evolution of an Iridium-Containing Cytochrome.
Bloomer, Brandon J; Joyner, Isaac A; Garcia-Borràs, Marc; Hu, Derek B; Garçon, Martí; Quest, Andrew; Ugarte Montero, Consuelo; Yu, Isaac F; Clark, Douglas S; Hartwig, John F.
Afiliação
  • Bloomer BJ; Department of Chemistry, University of California, Berkeley, California 94720, United States.
  • Joyner IA; Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States.
  • Garcia-Borràs M; Department of Chemistry, University of California, Berkeley, California 94720, United States.
  • Hu DB; Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States.
  • Garçon M; Institut de Química Computacional i Catàlisi (IQCC) and Departament de Química, Universitat de Girona, Girona 17003, Spain.
  • 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; Division of Chemical Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States.
  • Clark DS; Department of Chemistry, University of California, Berkeley, California 94720, United States.
  • Hartwig JF; Department of Chemistry, University of California, Berkeley, California 94720, United States.
J Am Chem Soc ; 146(3): 1819-1824, 2024 01 24.
Article em En | MEDLINE | ID: mdl-38190322
ABSTRACT
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 >991 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 2872 E/Z ratio. Computational studies show that the orientation of the carbene unit dictated by the mutated positions accounts for the stereoselectivity.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Alcadienos / Irídio Idioma: En Revista: J Am Chem Soc Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Alcadienos / Irídio Idioma: En Revista: J Am Chem Soc Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos