Engineering Dirhodium Artificial Metalloenzymes for Diazo Coupling Cascade Reactions*

Area of Science:

• Biocatalysis
• Organometallic Chemistry
• Synthetic Chemistry

Background:

• Artificial metalloenzymes (ArMs) are crucial for controlling stereoselectivity in catalysis.
• Achieving chemoselectivity in ArM-catalyzed reactions remains a significant challenge.
• Cascade reactions offer efficient synthetic routes but require precise control over multiple steps.

Purpose of the Study:

• To engineer a dirhodium ArM capable of catalyzing diazo cross-coupling and subsequent reduction in a one-pot cascade.
• To enhance the stereoselectivity and chemoselectivity of the ArM for diverse substrates.
• To investigate the impact of reaction conditions and ArM variants on cascade efficiency.

Main Methods:

• Engineering of a dirhodium artificial metalloenzyme for diazo cross-coupling.
• Development of a one-pot cascade reaction involving alkene formation and reduction by an alkene reductase.
• Directed evolution of the ArM to optimize catalytic performance.
• Molecular dynamics (MD) simulations to elucidate cofactor-protein interactions and conformational dynamics.

Main Results:

• The engineered ArM successfully catalyzed diazo cross-coupling to form alkenes with high enantioselectivity (>99% ee) in a cascade reaction.
• The cascade reaction proceeded efficiently despite the presence of various protein and small molecule components.
• Directed evolution improved ArM yields and E/Z selectivities, leading to enhanced cascade reaction yields.
• MD simulations provided insights into the structural basis for the ArM's conformational dynamics and catalytic activity.

Conclusions:

• Artificial metalloenzymes can be engineered to control both stereoselectivity and chemoselectivity in complex catalytic processes.
• The developed one-pot cascade reaction enables efficient synthesis in challenging media by minimizing undesired side reactions.
• This work demonstrates the potential of ArMs for enabling sophisticated chemical transformations with high precision.