An efficient strategy to synthesize the western part of phainanoids is reported. The benzofuranone-based 4,5-spirocyclic motif is constructed diastereoselectively via a palladium-catalyzed intramolecular alkenylation. The computational study suggests that the remarkably high diastereoselectivity is attributed to the stabilizing interaction between the 2' carbonyl moiety and the palladium catalyst in the favored transition state.

The stereoselective construction of the CDEFGH ring system of lancifodilactone G is described. The key steps in this synthesis are (i) ring-closing metathesis for formation of the oxa-bridged eight-membered ring; (ii) an intramolecular Pauson-Khand reaction for construction of the sterically congested F ring; and (iii) sequential cross-metathesis, hydrogenation, and lactonization reactions for installation of the anomerically stabilized bis-spiro ketal fragment of lancifodilactone G.

Here we report the total synthesis of phainanoid A, a unique dammarane-type triterpenoid (DTT), using an unusual bidirectional synthetic strategy. It features two transition-metal-mediated highly diastereoselective transformations to access the two challenging strained ring systems that branch toward opposite directions from the tricyclic core. This work also highlights the strategic use of ketones (or enol triflates) as versatile handles for rapid growth of molecular complexity in all key transformations, which paves the way for efficient preparations of complex and biologically significant DTTs.

Here, we report our detailed efforts toward the synthesis of phainanoids, a novel class of dammarane-type triterpenoids with potent immunosuppressive activities and unique structural features. Systematic model studies have been carried out, and efficient approaches have been established to construct the benzofuranone-based 4,5-spirocycle, the D/E/F tricyclic core, the [4.3.1] propellane, and the 5,5-oxaspirolactone moieties. The asymmetric synthesis of (+)-phainanoid A has been achieved through kinetic resolution of the tricyclic core followed by diastereoselective installation of the A/B/C and G/H rings and fragment coupling with the enantioenriched I/J rings. In addition, novel estrone-derived phainanoid analogues have been prepared. The immunosuppressive and cell survival assays revealed that (+)-phainanoid A and some of its synthetic analogues can specifically inhibit stimulation-induced lymphocyte proliferation but not cell survival at their effective concentrations. Preliminary structure–activity relationship information has been obtained, which could inspire future design of immunosuppressive phainanoid analogues.