Divergent synthesis of Haplomitrium diterpenoids via a late-stage biomimetic skeletal reorganization approach.

Abstract

Labdane-type terpenoids, the large super-family of diterpenoids, exhibit diverse biological significance. Labdane-derived hapmnioide-type diterpenoids, which have been identified as chemical markers for Haplomitrium liverwort, show potent anti-inflammatory and allelopathic activities. Biosynthetically, their structural complexity and diverse carbon skeletons arise from cascade ring mutations. We describe total synthesis of seven typical Haplomitrium diterpenoids through late-stage biomimetic skeletal reorganization, featuring 1,2-acyl migration, tandem C5-isomerization/aldol/retro-Claisen reactions, and light-initiated [2 + 2] cyclization. A diastereoselective intramolecular Diels-Alder reaction is employed to rapidly assemble the common labdane core skeleton. The 1,2-migration of the labdane intermediate is developed to synthesize hapmnioide A and haploide O. Furthermore, the tandem C5-isomerization/aldol/retro-Claisen reactions and light-initiated [2 + 2] cyclization of the common labdane intermediate enables the reconstruction of haploide C and haplomitrins A/C, respectively. The synthetic work provides mechanistic insights into the biosynthesis of hapmnioide-type diterpenoids. Further investigations of the 1,2-acyl migration of other terpenoids demonstrate the general and potential applicability of such late-stage rearrangements for the synthesis of homologous molecules.