Discovery and Total Synthesis of a New Class of Minor Immunosuppressive Plant Sesterterpenoids

Abstract

Plant sesterterpenoids are an extremely rare family of natural products that generally possess novel chemical structures and diverse biological activities. Here, we report the discovery of an unprecedented group of minor plant sesterterpenoids, gracilisoids B-E (2-5), which feature two types of highly functionalized bicyclo[3.2.0]heptane carbon skeletons, along with their biogenetically-related precursor gracilisoid A (1), from a Lamiaceae ethnomedicinal plant, Eurysolen gracilis. To confirm their structures and obtain adequate materials for biological research, the asymmetric total syntheses of gracilisoids A-E (1-5) and four new biogenetically-related congeners gracilisoids F-I (6-9) were achieved from commercially available (−)-citronellal via a bioinspired approach that involves a Norrish-Yang photocyclization/α-hydroxy ketone rearrangement tandem reaction and a late-stage biomimetic photo-oxidation as key steps. Biological investigations revealed that gracilisoids A-I (1-9) significantly inhibited IFN-γ production and/or T cell proliferation probably via inhibition of the STAT pathway. The findings herald the potential of these gracilisoids as novel immunosuppressive agents, and the efficient synthetic approaches will facilitate a comprehensive evaluation of their value in future drug development.