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.
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