This work describes the synthesis of phloroglucinol meroterpenoids Cleistocaltones A and B which have been isolated from Cleistocalyx operculatus by YE, WANG, and coworkers in 2019 and displayed excellent antiviral activity against respiratory syncytial virus (RSV). A convergent and a linear route have been developed for Cleistocaltone A starting from 2-acetyl phloroglucinol and geranyl acetate. Both routes include a TSUJI-TROST coupling, that tethers the phloroglucinol core to the terpene moiety and an intramolecular DIELS-ALDER cycloaddition (IMDA), that furnishes the 10-membered macrocycle and the cyclohexene moiety, as the keysteps. The convergent route was performed with a longest linear sequence of 6 steps with an overall yield of 1.7%. The linear route was performed in 8 steps with an overall yield of 2.2%. Additionally, the linear route was scaled up to a gram-scale. At the last step of the synthesis, an interesting side product was isolated that features a unique tetracyclic ring system with an eightmembered cyclic ether. It was suspected that this side product was a natural product from C. operculatus as well. However, all isolation attempts were unsuccessful. The synthesis of Cleistocaltone B was performed with a TSUJI-TROST coupling as the key-step with a subsequent one-pot aldol condensation. Cleistocaltone B was isolated as an inseparable 1:6 (Z/E) mixture with its undesired E-isomer. The antiviral activity of synthetic Cleistocaltone A was tested in a collaboration with MARTIN LUDLOW and SOPHIE KOLBE against a contemporary recombinant RSV-A strain. Synthetic Cleistocaltone A displayed a modestly higher IC50 than the isolated material from YE, WANG, and coworkers.
