Isolation and bioinspired synthesis of lauenones A and B, skeleton-rearranged diterpenoids with antiadipogenic activity from Croton laui

Skeleton-rearranged diterpenoids have attracted burgeoning interest. Chemical investigation into an ethnomedicinal plant, Croton laui, resulted in the isolation of two highly rearranged labdane diterpenoids, lauenones A (1) and B (2), featuring an unprecedented carbon skeleton with six contiguous stereogenic centers. To validate the proposed biosynthetic origin and obtain sufficient materials for biological studies, chemical syntheses of lauenones A and B were achieved without using any protecting groups in 10 and 11 steps, respectively. The key features of the current synthesis include a semipinacol rearrangement to construct the contracted B-ring and a substrate-controlled one-pot reaction cascade involving photooxidation and aldol condensation to forge the sterically congested 4-hydroxy-2-cyclopentenone moiety. Our synthetic attempts suggested that the semipinacol rearrangement step likely occurred prior to the aldol condensation step in the biosynthetic pathway. This study underscores the importance of arranging the sequence of crucial reactions in achieving a successful synthesis process. Furthermore, both lauenones A and B exhibited antiadipogenic effects in 3T3-L1 adipocytes by downregulating the differentiation factors (PPARγ and C/EBPα) and liposynthesis enzymes (FASN and ACC) at both mRNA transcription and protein expression levels.