Activation modes in biocatalytic radical cyclization reactions

Abstract

Radical cyclizations are essential reactions in the biosynthesis of secondary metabolites and the chemical synthesis of societally valuable molecules. In this review, we highlight the general mechanisms utilized in biocatalytic radical cyclizations. We specifically highlight cytochrome P450 monooxygenases (P450s) involved in the biosynthesis of mycocyclosin and vancomycin, non-heme iron- and α-ketoglutarate-dependent dioxygenases (Fe/αKGDs) used in the biosynthesis of kainic acid, scopolamine, and isopenicillin N, and radical S-adenosylmethionine (SAM) enzymes that facilitate the biosynthesis of oxetanocin A, menaquinone, and F420. Beyond natural mechanisms, we also examine repurposed flavin-dependent ‘ene’-reductases (ERED) for non-natural radical cyclization. Overall, these general mechanisms underscore the opportunity for enzymes to augment and enhance the synthesis of complex molecules using radical mechanisms.

Improved broad-spectrum antibiotics against Gram-negative pathogens via darobactin biosynthetic pathway engineering

“… 20 Furthermore, alkyl–arylic couplings like the ones observed for darobactin are usually formed in radical reactions catalysed by radical-SAM-type enzymes or Cytochrome P450 enzymes, which supports the previous hypothesis. 29 As no further genes are located within the BGC, we assume the involvement of other genes in the cyclization reactions to be unlikely since those genes would need to be located elsewhere in the genomes of both the native and heterologous producer strains.…”

Biocatalytic Alkylation Chemistry: Building Molecular Complexity with High Selectivity

“…Natural enzymes perform radical chemistry with high activity and precision, as demonstrated in countless biosynthetic pathways of complex natural products [81] . However, radical chemistry of natural enzymes depends on activation modes that differ from those in synthetic organic chemistry [82] . A reliable method for radical generation is dehalogenation of readily available haloalkanes, which is widely used in chemistry but uncommon in biology [83] .…”

Using Enzymes to Tame Nitrogen-Centered Radicals for Enantioselective Hydroamination

“…Moreover, it remains difficult to design catalysts capable of harnessing NCRs for enantioselective transformations 16 . Given the precedent for enzymatic control of highly reactive intermediates, such as Compound I in P450s 19 and carbon radicals generated by radical Sadenosyl-L-methionine (SAM) enzymes 20 , we hypothesized that enzymes could also be used to control NCRs in synthetically useful reactions 21 . However, to the best of our knowledge, no enzymes utilize NCRs in their natural setting.…”

“…Both enantiomers of a variety of 5-phenylpiperidin-2-one derivatives with para-, meta-, and orthosubstituents on the aromatic ring were efficiently prepared in high yields and with good levels of enantioselectivity (8 to 20), and furan (21), thiophene (22), and pyridine (23) heterocycles were also accessible. In addition to 5-phenylpiperidin-2-ones, the reaction afforded 5-methyl piperidine-2-one (24) in good yield, albeit with a low level of enantioselectivity.…”