Chemoenzymatic approach towards the synthesis of the antitumor and antileishmanial marine metabolite (+)-Harzialactone A via the stereoselective, biocatalyzed reduction of a prochiral ketone

The ocean hides molecules that fight cancer and leishmaniasis—now chemists are borrowing nature's own catalysts to build one of them, with stunning precision.

Marine natural products are a treasure trove of bioactive compounds, and (+)-Harzialactone A is one of its gems. This metabolite, isolated from marine organisms, has shown promising antitumor and antileishmanial activity, making it a hot target for synthetic chemists. But nature's complexity often makes such molecules difficult to produce in the lab. In this study, researchers turned to biocatalysis—using enzymes as nature's own catalysts—to streamline the synthesis. They designed a chemoenzymatic route that hinges on a key step: the stereoselective reduction of a prochiral ketone, 4-oxo-5-phenylpentanoic acid or its esters. A library of oxidoreductases, both wild-type and engineered, along with various microbial strains, was screened for efficiency. After fine-tuning co-solvents and co-substrates, two champions emerged: the yeast T. molischiana, working with a NADES (choline chloride-glucose), and the enzyme ADH442. These biocatalysts delivered the desired (S)-enantiomer with excellent enantiomeric excess (97% to >99%) and good to excellent conversion (88% to 80%, respectively). This work offers a new, greener path to synthesize (+)-Harzialactone A, potentially accelerating drug development from marine sources.

Key Points

• Marine metabolite (+)-Harzialactone A shows antitumor and antileishmanial activity.
• Chemoenzymatic synthesis via stereoselective biocatalyzed reduction of prochiral ketone.
• T. molischiana with NADES and ADH442 give 97-99% ee, 80-88% conversion.