Stereodivergent atom-transfer radical cyclization by engineered cytochromes P450

Abstract

Radical cyclization made easy Metalloenzymes contain metal cofactors that can sometimes be exploited to catalyze reactions distinct from their natural function. Drawing on inspiration from heme-based radical polymerizations, Zhou et al . screened a panel of metalloproteins for candidates that could catalyze an atom-transfer radical cyclization, producing a lactam from an amide substrate bearing bromoalkyl and alkene functional groups (see the Perspective by Zhang and Dydio). Cytochrome P-450 derivatives were effective catalysts, and a series of enzyme variants were generated by directed evolution to access the full range of enantiomer and diastereomer products for model substrates. Such biocatalysts are valuable additions to the synthetic chemistry toolkit and reiterate the potential of metalloenzymes in catalyzing useful unnatural reactions. —MAF

Probing the Free Energy Landscape of Organophotoredox-Catalyzed Anti-Markovnikov Hydrofunctionalization of Alkenes

“…It must be noted that SET can occur from different combinations of photoexcited states of the catalyst as long as the average redox potential is ∼1.83 V (see the Supporting Information for detailed discussion). Finally, we applied Marcus theory to estimate the barrier for electron transfer from 1 to Mes-Acr* + to generate the radical cation 1 •+ . − The four-point approximation was used to calculate the inner sphere reorganization energies, and a modified two sphere model was applied to the outer sphere reorganization energies. From this analysis, we found that TS-SET is ∼0.2 kcal/mol uphill from 1 + Mes-Acr *+ (∼13.9 kcal/mol relative to 1 •+ + Mes-Acr• , the arbitrary zero in Figure ).…”

Enzyme Catalysis for Reversible Deactivation Radical Polymerization

“…The fact that no stereoselectivity is observed in Enz‐ATRP suggests that polymerization mainly occurs in solution, and not in the enzyme cavity. Although, exciting enantioselectivity has been reported for radical reactions catalyzed by photoenzymes and metalloproteins, [33a,c, 60] stereoselectivity remains elusive, to date, and a grand challenge in Enz‐RDRP.…”

Redesigning Enzymes for Biocatalysis: Exploiting Structural Understanding for Improved Selectivity

“…In addition, the chemistry, using a diazoacetate to generate the Fe-bound carbene, does not have a known analog in biological chemistry (Liu and Arnold, 2021). This result has been built on in recent examples, including engineered cytochrome P450 catalyzed atom transfer radical cyclization (ATRC), where a new C-C bond and a new C-Halogen bond are formed (Zhou et al, 2021). In a further recent development from the Arnold lab, they report the P450 catalyzed enantioselective ring expansion of aziridines to azetidines (Miller et al, 2022).…”