Diversity-Oriented Enzymatic Synthesis of Cyclopropane Building Blocks

Area of Science:

• Biocatalysis and Drug Discovery
• Protein Engineering
• Organic Synthesis

Background:

• Biocatalysis is gaining traction in drug development but is underutilized in early discovery phases.
• Enzyme engineering offers a pathway to create novel chemical entities for drug pipelines.
• Chiral building blocks are essential for synthesizing stereochemically pure drug candidates.

Purpose of the Study:

• To engineer a biocatalyst for generating diverse, stereopure cyclopropane building blocks.
• To demonstrate the utility of engineered enzymes in early drug discovery.
• To create cyclopropane motifs with functional handles for further derivatization.

Main Methods:

• Engineering of two variants of Rhodothermus marinus nitric oxide dioxygenase (RmaNOD).
• Catalysis of the formation of cis- and trans- diastereomers of a pinacolboronate-substituted cyclopropane.
• Derivatization of the cyclopropane products to yield diverse stereopure building blocks.

Main Results:

• Successful engineering of RmaNOD variants for cyclopropane formation.
• Production of both cis- and trans- diastereomers with high stereochemical purity.
• Demonstration of the versatility of the generated building blocks through derivatization.

Conclusions:

• Engineered biocatalysts can efficiently produce valuable cyclopropane building blocks for drug discovery.
• This approach expands the toolkit for generating molecular diversity in early-stage research.
• Biocatalysis presents a promising strategy for accessing complex chiral motifs in medicinal chemistry.