A Photoenzyme for Challenging Lactam Radical Cyclizations

Area of Science:

• Organic synthesis
• Biocatalysis
• Medicinal chemistry

Background:

• Reductive radical cyclizations are essential for synthesizing complex organic molecules.
• Synthesizing N-heterocyclic motifs, such as lactams, via radical cyclization of haloamides is challenging due to slow amide bond rotation, leading to undesired acyclic products.
• Existing methods for lactam synthesis via radical cyclization often suffer from low selectivity.

Purpose of the Study:

• To compare four distinct methods for synthesizing alpha-, beta-, gamma-, and zeta-lactams using radical cyclization.
• To identify the most effective method for selective lactam formation.
• To elucidate the mechanism behind improved selectivity in the optimal method.

Main Methods:

• Comparison of four different reductive radical cyclization strategies for lactam synthesis.
• Utilized a photoenzymatic approach employing flavin-dependent 'ene'-reductases.
• Analyzed product selectivity and yield for each method.

Main Results:

• The photoenzymatic method demonstrated superior product selectivity compared to the other three methods.
• This enzymatic approach effectively favored the formation of the desired lactam products.
• The observed selectivity is attributed to the enzyme's preferential binding of the cis amide isomer.

Conclusions:

• Photoenzymatic reductive radical cyclization using flavin-dependent 'ene'-reductases is a highly selective method for synthesizing diverse lactams.
• Enzyme-mediated substrate preorganization, specifically binding the cis amide isomer, is key to enhancing cyclization efficiency and preventing premature radical termination.
• This approach offers a significant advancement in the synthesis of N-heterocyclic compounds.