Asymmetric Total Synthesis of (+)-Phainanoid A and Biological Evaluation of the Natural Product and Its Synthetic Analogues
Jiaxin Xie, Zhong Zheng, Xin Liu, Nan Zhang, Shinyoung Choi, Chuan He, Guangbin Dong
Abstract
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.