Pseudolaric Acid B
Trost, Waser and Meyer, JACS, 2007, EarlyView. DOI: 10.1021/ja076165q.
I think this natural product can be considered different enough from the Amphidinolides that were the subject of the last synthesis, manifesting in some pretty exotic key steps. But let’s not get too far ahead of ourselves, as this isn’t a particularly well known beast. Antifungal, antifertility, cytotoxic and activity against multidrug resistant cancer cell lines sums up the biological activity in what appears to be a potent little target; appealing enough for lots of work towards it’s synthesis. Only one synthesis so far, though, and that’s of Pseudolaric Acid A, the slightly less complex analogue.
Trost’s approach was to use the [5+2] metal-mediated cyclisation he’s pioneered with Wender to build the 5,7-ring system. The key cyclisation substrate was produced using some pretty cool chemistry, involving a Noyori reduction and a Charette cyclopropanation. But it’s the cyclisation that we’re here for! They tried it first with a ruthenium catalyst, [CpRu(CH3CN)3]+PF6-, but with only a modest yield. They attribute this to insertion of the catalyst into the bis-allylic C-H bond (the one with the proton indicated), and shut-down of the catalytic cycle. Boo. However, a change of metal did the job – and delivered a decent yield of the product.
Manipulation of the product from this reaction (including an interesting TBAF-mediated isomeristion) led to the next cyclisation substrate, ready for a bit of radical action.Â You’ll notice that they’ve used VASO in this case – for the uninitiated, it’s a surrogate for AIBN, which is now quite hard to get hold of. I like this cyclisation a lot – it’s not often you see such an interesting radical being generated, and with such success. This completed the polycyclic ring system, and set them up nicely for the appendage of the sidechain.
Not a long paper, but a nice synthesis.