# DERA-Catalyzed Chemoenzymatic Access to Nucleobase-Substituted Candidate Statin Precursors

## TL;DR

Researchers developed a new method using an enzyme to create statin precursors with nucleobase substitutions, opening up possibilities for new drug candidates.

## Contribution

A novel chemoenzymatic approach using a DERA variant to synthesize nucleobase-substituted statin precursors is introduced.

## Key findings

- A C49M variant of PaDERA catalyzed aldol additions with nucleobase aldehydes to form lactols.
- Nucleobase-derived aldehydes were accepted in DERA-catalyzed reactions for the first time.
- The method provides structurally novel statin side-chain precursors for drug development.

## Abstract

Aldolases are powerful biocatalysts for the stereoselective formation of carbon–carbon bonds and are widely used in the synthesis of chiral intermediates for pharmaceutical applications. Among them, 2-deoxyribose-5-phosphate aldolase (DERA) has been extensively exploited for the preparation of the conserved side chain of statins. In this work, we report a novel chemoenzymatic approach for the synthesis of nucleobase-substituted lactol products as potential precursors of new statin analogues. A C49M variant of DERA from Pectobacterium atrosepticum (PaDERA C49M) was employed to catalyze sequential aldol additions using aldehyde-functionalized nucleobases as non-natural electrophilic substrates. The formation of nucleobase-containing lactols was confirmed, demonstrating for the first time the acceptance of nucleobase-derived aldehydes in DERA-catalyzed aldol reactions. This strategy provides access to structurally novel statin side-chain precursors and expands the synthetic potential of DERA toward the generation of new classes of bioactive compounds.