Nicolaou, Sarlah and Shaw. ACIEE, 2007, Early View. DOI: 10.1002/anie.200701552.
I wasn’t planning on putting this synthesis up today; in fact, I’ve got a tasty number from Steve Ley to put up. However, one glance at the palladium cascade in this paper left me with my jaw on the floor, and I’d started transcribing the structures before I knew it! So, a quick look at the biological activity would be in order: selective inhibitory activity against HIV replication in H9 lymphocytes (EC50=0.798 Î¼g) with a TI of about 31.3, along with lipopolysaccharide (LPS)-induced cytokine production (but less potent). Not stunning, but interesting none the less. On with the retro:
Perhaps the photo [2+2] is a quite an obvious disconnection, but using palladium to build the spiro bis-lactone is interesting… So we split the molecule into two fragments – the bis-lactone and the cyclohexene. The cyclohexene was built quite simply, using a pair of aldols on methyl-vinyl-ketone to build a cyclohexenone. The initial aldol used a proline-derivative, giving decent diastereomeric control.
However, it’s the other fragment that interested me: to me it seems to be a carbonylative Sonogashira coupling, followed by carbonate formation and attack into the acetylene. Then, palladium does it’s Ï€-allyl thing, and extrudes carbon dioxide as a top leaving group. Then, rearrangement of the palladium-enolate type species gives a palladacycle which eliminates to give the spiro bis-lactone.
How did they see that as a disconnection?!
So, with the fragments complete, it was time to do the photocyclisation, which went reasonably well, giving the natural product directly. I wonder if what happened to the mass-balance? Anyway, amazing stuff!