Formaldehyde‐Enabled Enzymatic Hydroxymethylation for the Synthesis of High Value‐Added Multifunctional Compounds

Abstract Given the importance of multifunctional compounds and the versatile reactivity of one‐carbon (C1) molecule formaldehyde, the synthesis of value‐added multifunctional compounds from formaldehyde and other simple molecules via C─C bond formation has been the focus of intensive investigations. In view of the uncontrollable reactivity of formaldehyde, the employment of formaldehyde in the C─C bond formation is considered as one of the most challenging tasks in organic synthesis. Aldolases and thiamine pyrophosphate (ThDP)‐dependent enzymes have been regarded as the most potential biocatalytic tools for carbon–carbon (C─C) bond formation. In the present review, aldolases and ThDP‐dependent enzymes are shown to be the simplest and powerful biocatalytic platforms for controlling the reactivity of formaldehyde to effectively produce multifunctional compounds. The recent advances in the construction of multienzymatic cascade reactions for the synthesis of complex multifunctional compounds from formaldehyde via C─C bond formation have also been presented.