Throughout history, natural products have consistently proven to be invaluable sources of solutions for humanity, particularly regarding the development of treatments for diseases. If only small molecules are taken into consideration, almost half of the approved anti-cancer drugs since mid-last century are either natural products or compounds related to them in some way. Among the natural products that have gained increasing interest in recent decades are cannabinoids and related meroterpenoids.
The cis-fused tetrahydro-6H-benzo[c]chromene structural arrangement, found in the minor cannabinoid cis-THC, is widely distributed in nature, and has been found in natural products isolated from both marine and terrestrial sources. Studies of these compounds highlight the importance of the heterocyclic system, which has demonstrated potential biological activities, including antiproliferative effects.
This work introduces a methodology to access cis-enriched octahydro-6H-benzo[c]chromenes using FeCl₃ as catalyst under environmentally friendly conditions, including the use of ethyl acetate as solvent. The approach demonstrates versatility across multiple starting materials and achieves gram-scale reproducibility. In addition, preliminary studies on oxidation conditions for cyclohexenone ring aromatization have shown promising progress toward the synthesis of cis-cannabinoids.