Recent Research Developments

Total Synthesis and Structural Assignment of Spongidepsin via a Stereodivergent RCM Strategy¹

Jiehao Chen and Craig J. Forsyth


While sponges are considered to be the most primitive of multicellular animals, they continue to be a rich source of complex, biologically active organic molecules. Spongidepsin (1) is a remarkable recent example isolated from a Spongia sp sponge collected off of the Vanuatu Islands, Australia, by Riccio and co-workers in Italy.² Its cytotoxic and antiproliferative activities against cancer cell lines are accompanied by an unprecedented structure that combines amino acid and unprecedented ketide motifs within a 13-membered macrocycle. The ketide domain is comprised of a 9-hydroxy-2,4,7-trimethyltetradeca-14-ynoic acid, while the amino acid has been established as (S)-N-methylphenylalanine. The dimethyl substitution at C2 and C4 was originally determined to be syn, but the absolute configuration was not established. Neither the relative, nor the absolute stereochemistry of the two remaining stereogenic centers at C7 and C9 were originally assigned. Hence, the actual structure of 1 could have been one of eight possible stereoisomers
[(2S,4S) or (2R,4R) + (7R /S,9R/S)].

Collected in Australia, and isolated in Italy, the complete structure of 1 was fully established in Minnesota. For this, a stereodivergent total synthesis strategy that features macrocycle formation via ring closing metathesis (RCM) as the key step was employed. The stereochemical determination strategy relied upon the preparation of all eight possible diastereoisomers of the macrolide-containing portion of spongidepsin incorporating (S)-N-methylphenylalanine. These include both (2S,4S)- and (2R,4R)-enantiomers of the syn-2,4-dimethyl moiety conjoined with the four diastereomeric combinations of (R,S)-isomers at C7 and C9. Comparison of the spectral data of each of the diastereomeric probes with those of natural spongidepsin indicated that a specific isomer was to be selectively advanced to the total synthesis of 1. The 13-membered macrolides were prepared by RCM of dienes 2 and subsequent alkene hydrogenation. The RCM substrates 2, in turn, were derived from syn-2,4-dimethyl and C7,C9-containing fragments representing C1-C5 (4) and C6-C11 (3) of 1, respectively. The two enantiomers of syn-2,4-dimethyl carboxylic acid 4 are derivable from acetate-alcohol 6, which was provided by Jianyan Xu, via alternative manipulations of the terminal functional groups. Each of the four stereoisomers of 3 originated from the known L-malate-derived epoxide 5 bearing a C9 stereogenic center.

¹HNMR spectrum of synthetic (2R,4R,7R,9R,16S)-1.

      Synthetic (2R,4R,7R,9R,16S)-1 prepared in this fashion matched natural spongidepsin by ¹H and ¹³C NMR spectroscopy, HRMS spectrometry and specific rotation. This work highlighted the convergence of synthetic design, methodology, and spectroscopic analyses to fully define the structure and provide an alternative source of the antiproliferative natural product spongidepsin. It also reflects the involvement of Minnesota chemists in successful global scientific alliances.

1)    J. Chen and C. J. Forsyth Angew. Chem. Int. Ed. Engl. 2004, in press.

2) A. Grassia, I. Bruno, C. Debitus, S. Marzocco, A. Pinto, L. Gomez-Paloma, R. Riccio, Tetrahedron, 2001, 57, 6257. We thank Prof. Riccio and co-workers for providing comparative spectroscopic data.

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