Towards the Total Synthesis of Tedanolide

 

Markus Kalesse, Jorma Hassfeld, Gunnar Ehrlich, Ulrike Eggert

 

Institut für Organische Chemie, Universität Hannover, Germany

 

 


 

 

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.

 

 

  1. F.J. Schmitz, S.P. Gunasekera, G. Yalamanchili, M. B. Hossain, D. van der Helm, J. Am. Chem. Soc. 1984, 106, 7251.
  2. Isolated from Mycale adhaerens: N. Fusetani, T. Sugawara, S. Matsunaga, H. Hirota, J. Org. Chem. 1991, 56, 4971.  
  3. A. B. Smith III., C. M. Adams, S. A. Lodise, A. Barbosa, P. Degnan, J. Am. Chem. Soc. 2003, 125, 350.
  4. J. Hassfeld, M. Kalesse, Synlett 2002, 2007.