Totally Synthetic by Paul H. Docherty, 18 June 2008

Total Synthesis of Crisamicin A

Wang, Yang

Z. Li, Y. Gao, Y. Zang, M. Dai, G. Wang, Z. Wang, Z. Yang, Org. Lett. 2008, 10, 3017-3020.

Another top paper from China. This is certainly a different class of natural product, and one with quite a biological clout. To quote the paper, we’re talking about ‘activity against B16 murine melanoma cells, herpes simplex, and vesicular stomatitis viruses’ - a pretty diverse CV. Hopefully you’ve all notice one intriguing structural feature - C₂ symmetry. Generally there are two ways to take advantage of that facet: two directional synthesis, or dimerisation. In this case, the symmetry was centred on a biaryl linkage, so they made the more logical dimerisation disconnection. Retrosynthesis:

So with the molecule bisected, the two main transformations to be considered were a Diels-Alder reaction to build the 1,4-naphthoquinone, and an impressive construction of the 6,5-fused pyran system using Pd catalysis. On with the forward synthesis:

Now that’s what I like! That’s a pretty interesting lactonisation! It’s quite strange, though, so let’s look at the ingredients and rationale. Perhaps the most important additive was that of a thiourea ligand. In this case, it was required to mediate the Lewis acidity of palladium acetate so the benzylic ether remains intact.

The copper chloride improves the catalytic turnover of the palladium (used as 10 mol%), but in their screening the free chloride had the annoying habit of attacking the π-allyl palladium complex. This is where the propylene oxide steps in; five equivalents should scavange the chloride. Finally, the ammonium acetate is "a beneficial additive in the Pd-catalyzed carbonylations". In effect, it seems to boost the d.r. of the ring fusion to completely cis, rising from a 6.5:1 d.r. in it’s absence. An excellent work!

After doing a rather nice Diels Alder / oxidation sequence to provide the naphthoquinone core, a triflation and Pd-mediated borylation provided the substrate for the dimerisation. Again with sulfur ligands! This is a very interesting total synthesis demonstrating exquisite control of Pd catalysis.