This one looks, at least from the JACS communication, to be short piece of work over only two pages, 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.Â Although this synthesis is racemic, that isn’t actually an important issue, as the natural product may be racemic itself.Â The lack of certainty seems a bit odd to me, as it doesn’t take much material to get a quick alpha-dee, but at least we know the relative stereochemistry for sure, from an x-ray.
The starting material for the chemistry I’m going to ramble about was made in seven steps, from simple precursors, splitting about the ever-attractive amide bond.Â Treatment of the functionalised imidazole with triflic anhydride resulted in a Pummerer reaction (remember that from the first time you tried to do a Swern oxidation), which could proceed in either of the two mechanisms below.Â Postulate a is a vinylogous Pummerer, where a sulfonium ion is firstly formed along with an iminium ion.Â Something about this intermediate (i.e. the two charges) makes me a bit uncomfortable…Â The other option is a more standard Pummerer, where the amide nitrogen attacks (hmm…) 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.Â To do this, they simple dropped the SM into a bit of NCS, which led to a cracking yield of the target.Â 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.Â Elination of chloride (and overall oxidation) proceeds via sulfonium ion formation (and another dication), which can be attacked by the imidazole to form the desired ring system.Â The iminium ion can then be quenched by attack of the chloride ion (which has been hanging around…).
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.Â Any thoughts on what is going on there?