Towards the Total Synthesis of Tedanolide
Markus Kalesse, Jorma Hassfeld, Gunnar Ehrlich, Ulrike Eggert
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Tedanolide (1), a highly cytotoxic 18-membered macrolide, was isolated from the Caribbean sponge Tedania ignis, also known as fire sponge, by Schmitz and co-workers in 1984.1 Its structure was unambiguously assigned by X-ray crystal structure analysis. Because of their significant antitumor activity in combination with their challenging structure, tedanolide and its 13-deoxy analogue2 have attracted considerable synthetic attention over the past decade. Very recently, Smith et al. published the first total synthesis of 13‑deoxytedanolide 23, while a total synthesis of macrolide 1 has not been accomplished yet.
Our retrosynthetic analysis proposes an aldol coupling between C12 and C13 with the a-methyl group of the methyl ketone in combination with the a- and b-stereocenters of the aldehyde affecting the stereochemical outcome of the reaction.
The connection between C4 and C5 is accomplished through a vinylogous Mukaiyama aldol reaction with subsequent dihydroxylation of the double bond. 4
The three ketone carbonyl groups in the natural product are sensitive to retro-aldol processes and were therefore carried through the synthesis as protected alcohols, which could be selectively liberated and oxidized at a later stage. After successful macrolactonisation, selective epoxidation of the allylic double bond is expected to complete the total synthesis of tedanolide.