Totally Synthetic by Paul H. Docherty, 14 May 2007
Total Synthesis of Biyouyanagin A
K. C. Nicolaou, D. Sarlah, D. M. Shaw, Angew. Chem. Int. Ed. 2007, 46, 4708-4711.
One glance at the palladium cascade in this paper and I had 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 µg) with a TI (teratogenic index) of about 31.3. Not stunning, but interesting none the less. On with the retroanalysis:
Perhaps the [2+2] photocycloaddition is a quite 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 aldol reactions 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 catalysed allylation, and extrusion of 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. An amazing total synthesis!