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Totally Synthetic by Paul H. Docherty, 4 May 2010

Total Synthesis of Complanadine A


D. F. Fischer, R. Sarpong, J. Am. Chem. Soc. 2010, 132, 5926-5927.

DOI: 10.1021/ja101893b

It’s quite hard to explain the phenomenon of simultaneous publication to people outside of chemistry, because it simply isn’t easy to rationalise. 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. Let's see how they hold-up together…

Sarpong starts with an interesting and remarkable cascade, starting with perchloric acid, 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 then reacts 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 α-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. I wonder if one could substitute lead for a hypervalent iodine - perhaps BAIB could perform 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 an iridium catalyst and boron pinacolate (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.