The leaves of the rare littoral plant, Stemodia maritima L. (fam. Scrophulariaceae), from Jamaica have long been used as a folk medicine for the treatment of venereal disease in the Caribbean Islands.1) Attracted by the reported medicinal properties, Manchand and others isolated and characterized structurally unique tetracyclic diterpenes, stemodin 1 and stemodinone 2 (Fig. 1).2-7) Aphidicolin (3), 8,9) which has a highly related tetracyclic ring system to stemodanes 1 and 2, was isolated from Cephalalosporium aphidicola by Hesp and co-workers and later found to occur in Nigrosporum sphaerica. The fusion of the five-membered C ring to B in stemodanes 1 and 2 is cis in contrast to the trans fusion in aphidicolin 3. Aphidicolin is known as a potent antitumor (inhibits DNA replication and growth of several human and neoplastic cells) [10][11][12] and antiviral agent (promising activity against Herpes simplex).13-15) Stemodanes, with a similar structure to aphidicolanes, is expected to have related pharmacological activities.Their important medicinal properties as well as the presence of more than six stereocenters and four quaternary carbons, especially the two adjacent quaternary carbons at C-9 and C-10, make these natural products a worthy synthetic challenge.16) Although there are several reports on the synthesis of stemodinone, [17][18][19][20] other stemodanes, [21][22][23][24][25][26][27][28][29][30][31][32][33] and aphidicolanes [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] in a racemic form, asymmetric synthesis of this class of compounds is relatively rare.54-58) The asymmetric total synthesis of aphidicolin was first achieved by Holton and co-workers in 1987. 54) After that, formal synthesis of (ϩ)-aphidicolin was reported by Tanis 55) and Fukumoto.56) Recently, total synthesis of aphidicolanes using transannular Diels-Alder reaction was achieved by Deslongchamps and co-workers.57,58) These synthetic routes are extremely important in that the complex tetracyclic skeleton was constructed in an enantioenriched form; however, they are limited to the synthesis of a single aphidicolane or stemodane diterpene. Synthesis of other natural products or their analogs is not easily accessible by these routes because in many cases the A-ring having oxygen functionalities was constructed at the earlier stage of the synthetic routes. Therefore, development of a systematic synthetic route leading to various kinds of aphidicolanes, stemodanes, and their analogs in an enantiomerically pure form is desirable.We then planned a novel flexible synthetic route which can be applied to the synthesis of a variety of aphidicolanes and stemodanes, based on the asymmetric construction of the B/C/D ring system followed by formation of the highly-functionalized A-ring. A tricyclic enone 4 is considered as the key intermediate, which would lead to either natural or nonnatural aphidicolanes and stemodanes by stereoselective hydrogenation of the double bond as shown in Chart 1. In this paper, we descri...
