Cross-acyloin condensation of aldehydes catalysed by transketolase variants for the synthesis of aliphatic α-hydroxyketones

Abstract

We demonstrate that transketolase variants from Geobacillus stearothermophilus catalyse an acyloin condensation reaction involving two hydroxylated or not aliphatic aldehydes. This promiscuous TK-catalysed reaction offers an attractive alternative to the ketol transfer from α-ketoacids used as donor substrates in the usual TK mechanism, adding atom economy by avoiding carbon dioxide release. Transketolase variants H102L/L118I/H474G(S) showed a de novo activity towards the self-condensation of propanal, and to a lesser extent of ethanal, and a remarkable ability to control the selectivity of the more challenging cross-acyloin condensation reaction with propanal or iso-butanal used as nucleophiles, and different hydroxylated aldehydes (C2–C4) as electrophiles. The synthesis of seven aliphatic symmetrical and unsymmetrical α-hydroxyketones was performed from stoichiometric amounts of aldehydes, giving yields similar to those obtained with the common TK reaction based on α-ketoacid decarboxylation. This novel enzymatic cross-acyloin condensation reaction extends the toolbox for the synthesis of unsymmetrical aliphatic α-hydroxyketones while improving mass metrics of previous enzymatic and chemical strategies.