A metalloenzyme platform for catalytic asymmetric radical dearomatization

Area of Science:

• Biocatalysis
• Organic Chemistry
• Enzyme Engineering

Background:

• Catalytic asymmetric dearomatization transforms planar aromatic molecules into complex 3D scaffolds.
• Radical mechanisms in dearomatization have been challenging for small-molecule catalysts.
• Biocatalysis offers a promising alternative for complex chemical transformations.

Purpose of the Study:

• To develop a novel enzymatic strategy for catalytic asymmetric dearomatization using a radical mechanism.
• To engineer new-to-nature metalloredox biocatalysts capable of efficient dearomatization.
• To explore the potential of directed evolution in creating novel enzymatic activities.

Main Methods:

• Directed evolution was employed to engineer new radical dearomatase enzymes (P450rad1-P450rad5).
• A broad range of aromatic substrates, including indoles, pyrroles, and phenols, were tested.
• Computational studies were used to investigate enzyme-substrate interactions and reaction mechanisms.
• The effect of designer non-ionic surfactants on biotransformation rates was evaluated.

Main Results:

• Engineered P450rad1-P450rad5 enzymes facilitated asymmetric dearomatization of diverse aromatic substrates.
• Both enantioconvergent and enantiodivergent radical dearomatization reactions were achieved with high enzymatic control.
• Computational analysis highlighted the role of hydrogen bonding in enhancing enzyme activity and enantioselectivity.
• Non-ionic surfactants significantly accelerated the biotransformation process.

Conclusions:

• A new-to-nature metalloenzyme platform enables challenging catalytic asymmetric dearomatization via radical pathways.
• The engineered enzymes provide excellent control over stereochemistry in dearomatization reactions.
• This work expands the toolkit for synthesizing complex 3D molecular architectures from aromatic precursors.
• The developed platform offers new possibilities for advancing biocatalysis in organic synthesis.