Complanadine A part I
Sarpong, Fischer. JACS, 2010, 132, 5926 DOI: 10.1021/ja101893b.
It’s quite hard to explain the phenomenon of simultaneous publication to people outside of chemistry, ’cause it simply isn’t easy to rationalise. This is now twice in as many months, as Englerin A took my fancy in this month’s Chemistry World. I’ve never been in the situation of working on a target with rival groups bearing down on me, but it must be quite punishing (I took the slightly easier option of working on a target that 1. had been made >30 times and 2. had it’s first synthesis in the 1960s…). The Sarpong and Siegel groups made it to JACS within days of each other, but the ribbon goes to the Sarpong group, so I’m covering their efforts first. Both syntheses show some similarity – the dimeric nature of the target almost requires this – but this aside, the routes are rather different. Lets see how the hold-up together…
Sarpong starts with the good stuff; a pretty remarkable cascade, starting with perchloric acid (thanks for the correction!), which hydrolyses the enamine-type system to provide a ketone which reacts as its enol tautomer. They then add a protected cyclohexenone (6 step literature synthesis), which is deprotected in-situ, forming the corresponding imine which goes on to react with the enol. A further reaction with the imine follows, with the cascade finally terminating with an enamide formation, completing two rings and the bulk of the Complanidine monomer, N-desmethyl ?-obscurine.
The dimerisation of this molecule is rather neat. Treatment of the 3,4-dihydropyridinone with lead acetate results in an oxidation to the pyridinone; a new reaction to me, but not particularly surprising. I wonder if one could substituted that nasty lead for a bit of hypervalent iodine – perhaps a little BAIB could do that oxidation. Anyway, it gets them to the next step in good yield, ready for triflation of the amide. This provides a neat handle for palladium chemistry, but they need a partner for that reaction. This was done easily – by reducing half of their material to the pyridine, and borylating in the 3-position using a little iridium catalysis and boron pinicolate (67% over two steps).
Coupling of the two halves was no problem – including the final deprotection, the finished the synthesis in a 42% yield. Very well executed.