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

• Published in: Journal of the American Chemical Society Vol. 146; no. 3; pp. 1819 - 1824
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.01.2024; Amer Chemical Soc
• Subjects: Alkadienes; Alkenes - chemistry; Catalysis; Chemistry; Chemistry, Multidisciplinary; Iridium; Physical Sciences; Science & Technology
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.3c13011

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.