The rapid rise in resistance to known antimalarial drugs has prompted the need for further drug discovery and development. Isonitrile terpene kalihinol A was isolated in 1984, and was later found to be a potent antimalarial compound with an EC50 of 1.2 nM against Plasmodium falciparum and selective index of 317. It is proposed that the trans-decalin core of kalihinol A can be constructed in an efficient manner via an N-acylimminium ion initiated/propargylsilane terminated bicyclization. It is also hypothesized that the attached chlorinated pyran ring can be assembled via the development of a novel chloroetherification. A pharmacophore model of related isonitrile terpenes has recently been set forth and the compounds were found to target the parasite within its blood stage by inhibiting the formation of hemozoin. It is likely that kalihinol A binds to free heme in a similar manner and a direct synthetic route to kalihinol A will pave the way for the preparation of structurally modified compounds to identify the cellular target and potentially enhance the biological activity.