Biocompatible chemistry enables the interfacing of non-enzymatic catalysis with engineered microbial metabolism. Although various aldehydes can be produced by Escherichia coli, aldehyde derivatization in living systems is unexplored. Here we show that butanal produced from glucose by engineered E. coli undergoes α-methylenation in the presence of formaldehyde and various biocompatible organocatalysts. There is no known enzyme capable of aldehyde α-methylenation, and there are few examples of catalytic routes. Intriguingly, E. coli cells catalyze in situ C=C reduction of the methylenation product 2-ethylpropenal to form 2-methylbutanal. This formal α-methylation has no known enzymatic equivalent. Our results demonstrate that a metabolic pathway can be interfaced with biocompatible organocatalysis. Further metabolic engineering to produce other aldehydes could enable formal α-alkylation, a transformation that remains elusive in green chemistry.

α-Methylenation of metabolic aldehydes via a biocompatible aldol condensation

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ACS Fall 2022

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