Aplysiatoxin (1a) and debromoaplysiatoxin (1b) isolated from the digestive grand of sea hare, Stylocailous longicauda, are active tumor promoter and are structurally characterized by spiroacetal, large diolide ring, and four consecutive asymmetric centers. Although many synthetic efforts have been directed toward 1, the total synthesis of 1 was achieved only by Kishi et al. Now we would like to report here a formal total synthesis of 1 that was achieved by the convergent synthesis of Kishi's intermediate 2 because 2 contained all eight asymmetric centers required for the synthesis of 1 and had been reported to be convertible to 1 by further 6 steps. In a retrosynthetic analysis, 1 could be divided into four fragments, B, C, D and E as shown in Fig. 1. These fragments were synthetically corresponding to 9 (Scheme 1), 14 (Scheme 2), 24 (Scheme 3 and 4) and 30 (Scheme 5) which were prepared by using asymmetric epoxidation as a key reaction. With these fragments in hand, the construction of 2 was commenced by a coupling of 14 and 24 (Scheme 6). The desired coupling product 31 was converted to terminal epoxide 19 which was coupled with 30 to afford 2 after esterification with 9 by using Yamaguchi method (Scheme 7).
