Activation modes in biocatalytic radical cyclization reactions

Area of Science:

• Biochemistry
• Organic Chemistry
• Enzymology

Background:

• Radical cyclizations are crucial in natural product biosynthesis and chemical synthesis.
• Understanding enzymatic mechanisms is key to developing novel synthetic strategies.

Purpose of the Study:

• To review general mechanisms of biocatalytic radical cyclizations.
• To highlight specific enzyme classes involved in these reactions.
• To explore the potential of enzymes in synthesizing complex molecules via radical pathways.

Main Methods:

• Review of literature on biocatalytic radical cyclizations.
• Focus on specific enzyme families: cytochrome P450 monooxygenases (P450s), nonheme iron- and α-ketoglutarate-dependent dioxygenases (Fe/αKGDs), and radical S-adenosylmethionine (SAM) enzymes.
• Examination of flavin-dependent "ene"-reductases (EREDs) for non-natural reactions.

Main Results:

• Detailed mechanisms of P450s in mycocyclosin and vancomycin biosynthesis.
• Mechanisms of Fe/αKGDs in kainic acid, scopolamine, and isopenicillin N biosynthesis.
• Mechanisms of radical SAM enzymes in oxetanocin A, menaquinone, and F420 biosynthesis.
• Demonstration of EREDs for novel radical cyclizations.

Conclusions:

• Enzymes provide versatile mechanisms for radical cyclizations.
• Natural biocatalytic radical cyclization pathways offer blueprints for synthetic chemistry.
• Enzymes can be leveraged to enhance the synthesis of complex molecules through radical mechanisms.