Diaporthichalasin (1), isolated from an endophytic fungus Diaporthe sp., was reported by Pornpakakul and co-workers in 2007. This natural product exhibited significantly potent inhibition against the enzyme CYP3A4. Its gross structure and relative stereochemistry were established based on spectroscopic analysis. The structure of 1 is characterized by a pentacyclic core framework, which consists of a tetrahydroisoindolone and a decahydrocyclopentanaphthalene substructure. We have involved in a total synthesis of 1 by featuring a sequential Diels-Alder (IMDA) approach. We synthesized first the substrate 5 for an intramolecular Diels-Alder (IMDA) reaction for constructing the upper-half octahydronaphthalene substructure. The Suzuki-Miyaura cross-coupling of (E,E,E)-trienyl boronate 10, prepared from tiglic aldehyde, and (E)-alkenyl iodide 14, prepared from (S)-citronellol, provided an all-trans conjugated tetraenyl allylic alcohol 15 which was converted to unsatureated aldehyde 5. The BF_3-0Et_2-promoted IMDA reaction of 5 provided an endo-adduct 4 as a sole product. After unsuccessful results for installing a lower-half equivalent (a functionalized pyrrolidinone ring) into the bicyclic intermediate 4, we explored the Diels-Alder reaction of 20 derived from 4 and N-protected maleimide 18 for constructing the tetrahydroisoindolone substructure in 1. The DA reaction proceeded in the presence of Me_2A1C1 at -78 ℃ to produce a tetracyclic D-A adduct 21 as a sole product (its stereochemistry is tentatively assigned). Further synthetic endeavor toward the total synthesis of 1 is under exploration, and the results will be presented.
