Combining ChemicalCatalysis with Enzymatic Stepsfor the Synthesis of the Artemisinin Precursor DihydroartemisinicAcid

The supply of artemisinin, the primary antimalarial drug recommended by the World Health Organization (WHO), is limited due to synthesis cost and supply constraints. This study explores novel chemo-enzymatic pathways for the efficient synthesis of dihydroartemisinic acid (DHAA), the penultimate precursor to artemisinin. The key concept here is to leverage the seamless integration of chemical and enzymatic steps for more thoroughly exploring synthesis alternatives. Using novoStoic, a biosynthetic pathway design tool, we identified previously unexplored carbon- and energy-balanced pathways for converting amorpha-4,11-diene (AMPD) to DHAA. For some of the enzymatically catalyzed steps lacking efficient enzymes, chemical catalysis alternatives were proposed and implemented, leading to a hybrid chemo-enzymatic pathway design. The proposed pathway converts AMPD directly to DHAA without going through artemisinic acid (AA), making it a shorter pathway compared with the existing synthesis routes for artemisinin. This effort paves the way for the systematic design of chemo-enzymatic pathways and provides insight into decision strategies between chemical synthesis and enzymatic synthesis steps. It serves as an example of how synthesis pathway design tools can be integrated with human intuition for accelerating retrosynthesis and how AI-based tools can identify and replace human intuitions to automate the decision processes. This can help reduce human-machine interventions and improve the development of future tools for synthesis planning.