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Totally Synthetic by Paul H. Docherty, 8 November 2007

Total Synthesis of Pseudolaric Acid B


B. M. Trost, J. Waser, A. Meyer, J. Am. Chem. Soc. 2007, 129, 14556-14557.

DOI: 10.1021/ja076165q

The total synthesis of this natural product features some pretty exotic key steps. 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 very interesting 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 wilkhth the proton indicated), and shut-down of the catalytic cycle. 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 isomerisation) led to the next cyclisation substrate, ready for a bit of radical action. You’ll notice that they’ve used VAZO in this case - 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 construction of the sidechain.

Not a long paper, but a nice total synthesis.