Synthesis Towards Biologically Active Natural Products

In 2005 two research groups independently reported the isolation of a series of structurally intriguing C-19 terpenolides from the plants Thapsia transtagana and Thapsia garganica. The compounds were shown to be potent inhibitors of the sarco/endoplasmic reticulum Ca2+-ATPases. The interesting biological properties and the unique structural characteristics of the transtaganolides/basiliolides (the names transtaganolides/basiliolides were suggested in parallel in 2005) led to a great response from the synthetic community, with four groups presenting synthetic strategies towards this novel class of natural products. Herein, an approach towards transtaganolides C and D, utilizing an Ireland-Claisen rearrangement/Diels-Alder cycloaddition reaction sequence from an achiral 5-halo-activated prenylated pyran-2-one, is presented. In addition, the biomimetic total synthesis of transtaganolides E and F, synthesized via an Ireland-Claisen/high-pressure Diels-Alder reaction sequence from an unactivated geranylated pyran-2-one reported from T. transtagana, and efforts in transforming these into transtaganolides C and D are disclosed. Furthermore, a protocol for the synthesis of C-1 indolyl substituted tetrahydroisoquinolines (THIQs) via the classical Pictet-Spengler reaction has been developed. This protocol has been used for the synthesis of several diketopiperazine fused C-1 indolyl substituted THIQs which have been assayed for their inhibitory activity on hormone-independent and metastatic PC-3 prostate cancer cell lines. The inhibitory effects of the assayed compounds were compared to that of etoposide and several of the assayed compounds showed comparable or even better inhibitory effect at higher concentrations