Wang, Yang, Li, Gao, Tang, Dai, Wang. Org. Lett., 2008, ASAP. DOI: 10.1021/ol800977n.
Another top paper in from somewhere in China (there’s quite a few insitutions mentioned… and I got lost yet again trying to find a homepage… help?), 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, the herpes simplex, and vesicular stomatitis viruses’ – a pretty diverse CV. Hopefully you’ve all notice one intriguing structural feature – C2 symmertry. 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. Retro:
So with the molecule bisected, the two main transformations to be considered were a Diels-Alder to build the 1,4-naphthoquinone, and an impressive bit of Pd-juggling to build the 6,5-fused pyran system. On with the forward:
Now that’s what I like! I’ve always had a thing about lactonisations (I think you know why) – and that’s some pretty hot stuff. It’s quite a witch’s brew, though, so let’s look at the ingredients and rationale. Perhaps the most important additive was that of a thiourea ligand; normally, sulfur ligands eat Pd catalysts for breakfast, but in this case it was required to mediate the Lewis acidity of palladium acetate. This stemmed from a concern that by itself, the Pd(OAc)2 would chew-up the benzylic ether.
The copper chloride is there to aid catalytic turn-over of the palladium (used as 10 mol%), but in their screening, presented a complication, as the free chloride had an annoying habit of attacking the pi-allyl palladium complex. This is where the propylene oxide steps in; five equivalents were sacrificed to mop-up the chloride. Finally, the ammonium acetate was there for the carbonylation step – I quote ‘Our earlier work suggested acetates to be 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. Excellent stuff.
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 the sulfur ligands! However, this bad-boy wasn’t developed in-house – rather it’s the work of one Kristin Bowman-James. (Or at least the authors reckon it is, but it’s not actually in the cited paper…) The yield for the dimerisation is great, but a little confusing – y’see the authors claim that it’s an ‘87% yield over two steps’, but the previous step also has a yield attached to is – 76%. This kills the maths (so to speak) – what gives?! (The SI also states 87% over two steps and excises any mention of a yield for the borylation)
Anyway, dodgy maths aside, this is a cracking synthesis demonstrating exquisite control of those Pd atoms.
Li, Z., Gao, Y., Tang, Y., Dai, M., Wang, G., Wang, Z., Yang, Z. (2008). Total Synthesis of Crisamicin A. Organic Letters DOI: 10.1021/ol800977n