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.
This work has been performed in collaboration of Prof. John F. Hartwig (University of California) and Dr. Marc Garcia-Borràs of the DIMOCAT group of the Institute of Computational Chemistry and Catalysis (IQCC) of the University of Girona.
It has been recently published open access in Journal of the American Chemical Society:
B. J. Bloomer, I. A. Joyner, M. Garcia-Borràs, D. B. Hu, M. Garçon, A. Quest, C. Ugarte Montero, I. F. Yu, D. S. Clark, and J. F. Hartwig*
“Enantio- and Diastereodivergent Cyclopropanation of Allenes by Directed Evolution of an Iridium-Containing Cytochrome“
J. Am. Chem. Soc., 2024, 146, 1819-1824
DOI: 10.1021/jacs.3c13011
Girona, January 31, 2024
For more info: ges.iqcc@udg.edu