Atropisomeric meroterpenoids with rare triketone-phloroglucinol-terpene hybrids from Baeckea frutescens

Abstract

Baefrutones A–F (1–6), six new meroterpenoids with rare triketone-phloroglucinol-monoterpene/sesquiterpene frameworks, together with their biosynthetically related intermediate (±)-baeckenon B (7), were isolated from the aerial part of Baeckea frutescens under the guidance of HPLC-Q/TOF-MS² investigation. Compounds 1–4 represent the first examples of natural meroterpenoids existing as four pairs of inseparable diastereomeric atropisomers (2 : 1, ¹H NMR integration) caused by the restricted rotation around the C-6–C-7–C-1′ bonds arising from the intramolecular hydrogen bond between C-1 carbonyl and 2′-OH. The discovery of these architectures not only largely enriched the chemodiversity of the meroterpenoid and atropisomer library, but also might be exciting and challenging for asymmetric organic synthesis. Their structures and absolute configurations were established by extensive spectroscopic analysis, X-ray diffraction, and ECD calculations. Compounds 5 and 6 were biomimetically synthesized from 7 and β-caryophyllene via a regioselective oxidative hetero-Diels–Alder reaction, thus providing access to the construction of the 6/6/9/4 tetracyclic ring system. The anti-inflammatory activities of these meroterpenoids were also discussed.