Unified enantiospecific synthesis of drimane meroterpenoids enabled by enzyme catalysis and transition metal catalysis

Merging the advantages of biocatalysis and chemocatalysis in retrosynthetic analysis can significantly improve the efficiency and selectivity of natural product synthesis. Here, we describe a unified approach for the synthesis of drimane meroterpenoids by combining heterologous biosynthesis, enzymatic hydroxylation, and transition metal catalysis. In phase one, drimenol was produced by engineering a biosynthetic pathway in Escherichia coli. Cytochrome P450BM3 from Bacillus megaterium was engineered to catalyze the C-3 hydroxylation of drimenol. By means of nickel-catalyzed reductive coupling, six drimane meroterpenoids (+)-hongoquercins A and B, (+)-ent-chromazonarol, 8-epi-puupehenol, (-)-pelorol, and (-)-mycoleptodiscin A were synthesized in a concise and enantiospecific manner. This strategy offers facile access to the congeners of the drimane meroterpenoid family and lays the foundation for activity optimization.