Targeted Discovery of a Natural -Quinone Methide Precursor and Green Generation of Its Oligomers.

-Quinone methides (-QMs) are a class of highly reactive intermediates that serve as important nonisolable building blocks (NBBs) in organic synthesis and small-molecule library construction. Because of their instability and nonisolability, most reported -QMs are generated through chemical synthesis, and only a few natural -QMs have been reported due to the lack of directed discovery strategies. Herein, a new natural -QM precursor (trichophenol A, ) was identified from the fungal strain of sp. AT0167 through genome mining, which was generated by (nonreducing polyketide synthase) and (2-oxoglutarate dependent dioxygenase). Combinatorial biosynthesis via two other known NRPKS genes with and was performed, leading to the generation of five new trichophenol -QM oligomers (trichophenols D-H, -). The strategy combining genome mining with combinatorial biosynthesis not only targetedly uncovered a new natural -QM precursor but also produced various new molecules through oligomerization of the new -QM and its designated -QM acceptors without chemical synthesis and isolation of intermediates, which was named NBB genome mining-combinatorial biosynthesis strategy for -QM molecule library construction. This study provides a new strategy for the targeted discovery of natural -QMs and small-molecule library construction with natural -QMs.