Du Bois and Mulcahy. JACS, 2008, ASAP. DOI: 10.1021/ja805651g.
One quick inspection, and you know we’re looking at a dinoflagellate neurotoxin, with more guanidine groups and derivatives than you can shake a stick at.Â Unlike other large families of natural products with common functionalities, there doesn’t seem to be a universal strategy that (whilst ugly) could synthesise the majority of the family.Â This means we get to see a whole variety of strategies towards these targets (and ultimately, the daddy, palau’amine).
Du Bois’ approach starts with the use of L-serine as the starting material, and source of asymmetry.Â Smart choice, as in only four steps they had dihydropyrrolo[1,2]pyrimidin-1(2H)-one product shown below.Â It was the cyclisation step (as ever) that caught my eye, treating the aldehyde with allylamine to get the imine, and then Lewis acid mediated cyclisation.Â Great result; the yield is reasonable, but the d.r. is excellent.Â I thought I’d read a bit about the procedure, but I was disappointed to see that the SI is extremely sparse – there’s plenty of data, but no experimental procedures.Â Grrr…!
A few steps further into the synthesis comes another sweet cyclisation; this time using a rhodium catalyst to effect formation of the final 5-membered ring.Â Again, the yield was cracking, and the d.r. apparently complete.Â Mechanistic insights are somewhat less clear (as this is still a topic of some debate).Â Du Bois suggests initial formation of an aziridine, and then opening of the allylic aziridine with acetic acid to give the product.Â He then reduced out the O,N-acetal (which was causing them serious problems) using an interesting reagent combination: Et3SiH and BF3Â·OEt2.
With the ring-system complete, they attempted a ketohydroxylation, but as in their synthesis of saxitoxin, this proved problematic.Â Instead, they did a standard Upjohn Oxidation, protected the less hindered hydroxyl and then oxidised the remaining.Â The completion of the synthesis was quite sweet; deprotection of all protecting groups with a bit of hydrogen, acetic acid and then some ammonia resulted in a strange beast – the Î± hydroxy ketone hydrate.Â Then, addition of DMFÂ·SO3 resulted in selective sulfation of the C11 alcohol, and the target.Â Nice!