Synthetic Studies on Tedanolide: Stereoselective Synthesis of the C1-C7 Fragment

Abstract

Tedanolide (1), an 18-membered macrolide, was isolated by Schmitz et al. 1a in 1984 from the Caribbean sponge Tedania ignis and structurally related 13-deoxytedanolide (2) was isolated from a Japanese sea sponge, Mycale adhaerens, by Fusetani et al. 1b in 1991. Both tedanolide (1) and 13-deoxytedanolide (2) exhibit very potent biological activities against certain tumor cell lines.1a Their complex structures and distinctive biological properties make them extremely attractive targets for synthetic chemists.2 Recently Kalesse 3a,b and Smith 3c have reported successful total syntheses of tedanolide (1).As shown in Scheme 1, our retrosynthetic strategy for tedanolide (1) was the disconnection to two subunits 4 and 5 via cleavage at ester C-O bond and the aldol condensation transformation. The subunit 5 was envisioned to be obtained from the coupling between precursors 6 and 7. Herein we disclose our efforts in the construction of the C1-C7 fragment 6 of tedanolide (1).At first stage, we have utilized the Roush protocol as a key methodology toward fragment 6. The synthesis began with the known aldehyde 9. 4 The Roush asymmetric crotylation upon 9 with 10 gave the desired product in 80% yield as a 92:8 mixture of two diastereomers, 5 which was methylated to the methyl ether 11 in good yield. Ozonolysis of 11 furnished aldehyde 12. The second Roush crotylation on 12 did not yield the desired product. Instead we obtained a mixture of diastereomers (Scheme 2).Because of the observed lability of aldehyde 12 during the second crotylation, we considered the modification of the synthetic pathway. As a replacing measurement for the second Roush crotylation, we devised the combined application of Sharpless asymmetric epoxidation 6 and Gilman cuprate reaction. 7As shown in Scheme 3, we established a highly stereoselective synthesis of precursor 6 via epoxide ring-opening and Mitsunobu reaction. 8 The oxidative cleavage of the terminal vinyl group of 11 followed by immediate Horner-