Totally Synthetic by Paul H. Docherty, 18 June 2007
Total Synthesis of Aphanorphine
R. S. Grainger, E. J. Welsh, Angew. Chem. Int. Ed. 2007, 46, 5377-5380.
I guess another reason I have not described this paper earlier, is the deceptive simplicity of the target. Only two stereocenter; 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 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 - a 5-exo-trig cyclisation to generate the quaternary sterocenter from a dithiocarbamates. 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 stereocenter, which was ultimately removed to introduce the phenolic ring.
This portion of the synthesis involved a couple of well known reactions that I was happily reacquainted with - a bit of Dale Boger’s chemistry to introduce the pyrone ring, and then an inverse electron-demand Diels-Alder reaction of dimethoxyethylene ketal followed by loss of CO2 and MeOH to give the phenol. Nice work! This then led them to an advanced intermediate and a formal synthesis of a tricky little target, using some smart chemistry.