Non-enzymatic methylcyclization of alkenes.

Area of Science:

• Organic Chemistry
• Catalysis
• Enzymology

Background:

• Methyltransferases are enzymes catalyzing methyl group transfer.
• Bifunctional methyltransferase-cyclases uniquely perform both methylation and cyclization of alkenes.
• Existing synthetic methods for alkene methylation, like hydromethylation, lack the efficiency and scope of enzymatic processes.

Purpose of the Study:

• To develop a synthetic method for electrophilic methylcyclization that mimics the selectivity of bifunctional methyltransferase-cyclases.
• To create a versatile and synthetically viable method for methylcyclization reactions.
• To explore novel chemical structures inaccessible through conventional synthetic routes.

Main Methods:

• A silver(I)-mediated electrophilic methylcyclization reaction was developed.
• The method utilizes readily available commercial reagents.
• Computational studies were employed to elucidate the reaction mechanism.

Main Results:

• The developed method achieves selectivities comparable to enzymes in methylcyclization.
• The reaction is applicable to a broad range of substrates, including heterocycles.
• Unique and complex molecular structures were synthesized, which are challenging to obtain via traditional methods.
• Computational analysis supports a stepwise cationic pathway with rate-limiting methyltransfer.

Conclusions:

• The silver(I)-mediated methylcyclization offers a powerful and selective synthetic strategy.
• This method overcomes the substrate limitations inherent in natural methylcyclase enzymes.
• It provides access to novel chemical architectures for diverse applications in chemistry.