Total Synthesis and Complete Stereostructure of a Marine Macrolide Glycoside, (-)-Lyngbyaloside†B.

We have described in detail the total synthesis of both the proposed and correct structures of (-)-lyngbyaloside B, which facilitated the elucidation of the complete stereostructure of this natural product. Our study began with the total synthesis of 13-demethyllyngbyaloside B, in which an esterification/ring-closing metathesis (RCM) strategy was successfully used for the efficient construction of the macrocycle. We also established reliable methods for the introduction of the conjugated diene side chain and the l-rhamnose residue onto the macrocyclic framework. However, the esterification/RCM strategy proved ineffective for the parent natural product because of the difficulties in acylating the sterically encumbered C-13 tertiary alcohol; macrolactionization of a seco-acid was also extensively investigated under various conditions without success. We finally completed the total synthesis of the proposed structure of (-)-lyngbyaloside B by means of a macrolactonization that involves an acyl ketene as the reactive species. However, the NMR spectroscopic data of our synthetic material did not match those of the authentic material, which indicated that the proposed structure must be re-examined. Inspection of the NMR spectroscopic data of the natural product and molecular mechanics calculations led us to postulate that the configuration of the C-10, C-11, and C-13 stereogenic centers had been incorrectly assigned in the proposed structure. Finally, our revised structure of (-)-lyngbyaloside B was unambiguously verified through total synthesis.

Total synthesis, stereochemical reassignment, and biological evaluation of (-)-lyngbyaloside B.

(-)-Lyngbyaloside B is a 14-membered macrolide glycoside isolated from the marine cyanobacterium Lyngbya sp. as a cytotoxic substance by Moore and co-workers. The first total synthesis of (-)-lyngbyaloside B and the reassignment of its stereostructure is described. The synthesis features an Abiko-Masamune aldol reaction, a vinylogous Mukaiyama aldol reaction, and a macrocyclization involving an acyl ketene intermediate for the construction of the macrocyclic backbone, which contains an acylated tertiary alcohol. The antiproliferative activity of selected compounds against a small panel of human cancer cell lines is also reported.

Total synthesis of 13-demethyllyngbyaloside B.

Total synthesis of 13-demethyllyngbyaloside B, an unnatural analogue of a marine macrolide glycoside lyngbyaloside B, has been achieved. The 14-membered macrocyclic backbone was constructed in a convergent manner via esterification and ring-closing metathesis. The bromodiene side chain was introduced by means of a Stille-type reaction and a subsequent bromodesilylation. Finally, the rhamnopyranose unit was stereoselectively introduced by glycosylation under Schmidt conditions.