DeprÃ©s and Carret. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200702031.
Isolated from the plant colloquially known as the “vomiting bush”, Geigerin is a member of the guaianolide family, represented in the 5,7,5 tricyclic structure. No further mention of the biological activity is noted in this paper, but they do point out that this isn’t the first synthesis of this family, referencing Lee and Bartons works.
The synthesis starts with a bit of chemistry quite familiar to the group, doing a regioselective [2+2] cycloaddition with
diphosgene 2,2,2-trichloroacetyl chloride and 7-methylcycloheptatriene. In their previous papers, they had to use a metal to take diphosgene to dichloroketene, but in this case, a bit of ultrasound worked rather well. They then ring-expanded to give the 5,7 motif required.
A few steps further along, they used DMDO to generate the hydroxyl group with good substrate control, which formed the lactone under acid conditions. To reuse a phrase I type a lot – not new chemistry, but nice!
The lactone product was then subjected to a rather tricky sp2-sp3 Suzuki coupling; the vinyl chloride SM can’t be the best nucleophilic partner, and the methyl boronic acid is also a less than ideal partner. However, using rather standard conditions, they achieved the coupling with a reasonable yield. I’ve only seen one other example of this type of methylation (though I be there are many in the literature), but Evans used the methyl boronate trimer in his synthesis of the FR compounds.
My jaw is left fully in place, but I did like this approach to the target, and the use of some smart literature reactions.