Organic Chemistry Portal
Reactions >> Total Syntheses

Totally Synthetic by Paul H. Docherty, 21 October 2008

Total Synthesis of Dibromoagelaspongin


K. S. Feldman, M. D. Fodor, J. Am. Chem. Soc. 2008, 130, 14964-14965.

DOI: 10.1021/ja807020d

K. S. Feldman, A. P. Skoumbourdis, M. D. Fodor, J. Org. Chem. 2007, 72, 8076-8086.

DOI: 10.1021/jo701487j

The total synthesis of dibromoagelaspongin looks to be short piece of work, but it’s very reliant upon methodology and ideas presented in a JOC full-paper from back in 2007, so perhaps we be best to read that one first. Although this synthesis is racemic, that isn’t actually an important issue, as the natural product may be racemic itself. At least we know the relative stereochemistry for sure, from an x-ray.

The starting material for the chemistry described here was made in seven steps, from simple precursors. Treatment of the functionalised imidazole with triflic anhydride resulted in a Pummerer reaction, which could proceed in either of the two mechanisms below. Postulate a) is a vinylogous Pummerer, where a sulfonium ion is firstly formed along with an iminium ion. The two charges of the intermediate makes me feel bit uncomfortable… The other option is a more standard Pummerer, where the amide nitrogen attacks the imidazole directly, resulting in a spiro-fused intermediate that must do a 1,2 N-shift to give the 6,5-fused target.

Either way, the yield is fairly good for such a piece of chemistry!

Next up was a deprotection of the SEM group, which gave the intermediate required for the next cyclisation, which would complete the 5,5,6,5-ring system. They added the starting material to NCS, which led to a astonishingly high yield of the target. However, the mechanism for this reaction is again lacking clarity.

This time, though, the group were able to be a bit more proactive; repeating the reaction with other halide sources led them to conclude that a further Pummerer process was at play, probably beginning with chlorination of the sulfane. Elimination of chloride (and overall oxidation) proceeds via sulfonium ion formation, which can be attacked by the imidazole to form the desired ring system. The iminium ion can then be quenched by attack of the chloride ion.

A couple of deprotections, and formation of a guanidine left them with the natural product, but I did think that the displacement of the methyl sulfoxide by azide in the presence of zinc iodide was quite interesting.