Grainger and Welsh. ACIEE, 2007, Early View. DOI: 10.1002/anie.200701055.
I’ll apologise immediately for overlooking this paper; last week was a little busy – I’ve been teaching myself the art of the Evans Aldol. I guess another reason I didn’t blog this paper is the deceptive simplicity of the target. Only two stereocentre; how difficult can that be. Look closer, and you notice the quaternary centre and the stereodefined tertiary amine, and it starts getting a bit more complex…
So how did they start? With a little induction of stereochemistry from Ellman’s sulfinamide auxiliary to set the amine centre, using a Grignard attack into the imine. An explanation for this result comes directly from Ellman’s model, something I hadn’t previously considered. They then methylated the amine, did a particularly nice RCM with Grubbs II, and removed the auxiluary to leave the desired enantiomer of the amino cyclohexene derivative in high e.e. and yield.
Now for the most interesting reaction (IMHO) – a sweet 5-exo-trig cyclisation to generate the quaternary sterocenter from a dithiocarbamates (reminicent of Barton’s seminal work in this area). The regiochemistry of this reaction is explained nicely in a model in the actual paper (but suffice to say that 6-endo-trig cyclisations are considerably less favourable). Neatly, the cleaved dithiocarbamate then trapped to provide a third stereocentre, which was ultimately binned to introduce the phenolic ring.
This portion of the synthesis involved a couple of old-school reactions that I was happlily reacquainted with – a bit of Dale Boger’s chemistry to introduce the pyrone ring, and then an IED DA reaction dimethoxyethylene ketal followed by loss of CO2 and MeOH to give the phenol. Nice work (and cred to Boger where it’s due…). This then led them to an advance intermediate and a formal synthesis of a tricky little target, using some smart chemistry.