Biaryl coupling reactions catalyzed by cytochrome P450s

Biaryl coupling reactions are pivotal in the synthesis of complex therapeutic compounds, such as michelline B, vancomycin and arylomycin A2 derivatives. Synthesizing macrocycles, particularly the 2,2'-disubstituted biaryl-bridged peptide in arylomycin derivatives, present significant challenges, including low yields and the requirement for high transition metal loadings. Recent advances in DNA sequencing and enzyme engineering have facilitated the exploration of biocatalytic transformations. By leveraging enzyme engineering and substrate modifications, we report the development of a biocatalytic process using engineered cytochrome P450 enzymes for the oxidative carbon-carbon bond formation, yielding the biphenolic macrocycles present in arylomycin derivatives, at gram scale. This work underscores the transformative potential of P450 enzymes in synthetic organic chemistry, paving the way for novel pharmaceutical advancements.