Andrastins are meroterpenes isolated from Penicillium sp. FO-3929 that display highly potent inhibitory activities toward protein farnesyltransferase. Structurally, they possess a unique steroidal tetracyclic skeleton (the ABCD-ring) with three contiguous quaternary stereocenters on the C-ring. Herein, we describe our nitrile cyclization-based approach to the stereoselective construction of the BCD-ring system of andrastins, which contains three contiguous quaternary stereocenters on the C-ring and the correct oxidation states of the D-ring.