2D NMR-based MatchNat Dereplication Strategy Enables Explosive Discovery of Novel Diterpenoid Alkaloids†

Comprehensive Summary The tribe Delphineae, comprising two genera, Aconitum L. and Delphinium L., is the richest source of bioactive diterpenoid alkaloids (DAs), while their highly similar chemical structures create a major challenge for dereplication from complex mixture. To solve the inefficient discovery process of natural DAs, a novel dereplication strategy based on pattern recognition of specific heteronuclear multiple bond correlation (HMBC) signals has been established in this study. This strategy utilized the diagnostic signals in the HMBC spectra of C-19-DAs, which could indicate the structural categories. The newly designed software MatchNat allowed in silico recognition of C-19-DA types. The developed dereplication system was demonstrated to be a practical strategy to dereplicate a variety of natural products from two Delphineae plants, including Aconitum vilmorinianum Kom. and Delphinium pachycentrum Hemsl. Known compounds could be rapidly recognized from the mixture, and novel DAs were found with the aid of MatchNat. Consequently, targeted isolation led to the explosive discovery of a series of novel DAs. This dereplication system has the potential to be adopted for dereplication of any other class of natural products and has shown promising application as a complementary tool in the nuclear magnetic resonance analysis of traditional Chinese medicines.