Reisman, Cha, Yeoman. J. Am. Chem. Soc, 2011, ASAP. DOI: 10.1021/ja2073356
A busy couple of weeks in the Reisman lab, it appears – really nice syntheses of the Cepharatines and 8-Demethoxyrunanine in Angewandte (doi: 10.1002/anie.201104487), but I decided to blog this tasty synthesis of Maoecrystal Z. Of course, this isn’t the first member of that family that I’e blogged – the seminal synthesis of Maoecrystal V made my December 2010 column in Chemistry World. I remember when I wrote that piece that the pseudo-3D structure used to represent the target annoyed me – in far too many papers, the author uses such a structure when a normal 2D sketch would do. However, trying to ‘flatten’ Maoecrystal Z or it’s family members is an exercise in mental self-harm – the best I could do is shown below, and is frankly ugly.
So what’ll do is stick to Reisman’s figures and hope that you can follow along…
The synthesis starts with γ-cyclogeraniol, initially TBS protecting the primary alcohol, and then epoxidising the exo-cyclic alkene using mCPBA. This takes them to the substrate for a rather ‘witches-brew’ type reaction, coupling the epoxide with methyl acrylate. The conditions were inherited from Gansauer, first published in his 1998 paper on reductive epoxide couplings (look at the hyperlink to see a reminder that Wiley used to be crap with DOI codes!), requiring the zinc as the terminal reductant. Unfortunately, the initial results were relatively poor – only a 28% yield was possible. However, by moving to 2,2,2-trifluoroethylacrylate rather than methyl acrylate, and adjusting the rate of addition of catalyst, the group were able to boost this to a very respectable 74%. Especially nice when you consider how direct this reaction is!
Working directly from the product of that reaction, the group coupled on a sidechain by alkylation, and added a pair of stereocenters. One came with the sidechain, and was it’s self constructed using a pseudo-ephidrine controlled alkylation (and I’ve got a feeling I’ve made this substrate myself, many years ago…). The other wasn’t controlled, and was later removed by oxidation of the lactone to an α,β-unsaturated lactone using the tried-and-tested phenyl-selenation and oxidising elimination.
After this, it was time to move to the pièce de résistance, a samarium (II) iodide mediated radical coupling. Treating the advanced intermediate with SmI2 initially resulted in disappointment, as only trace quantities of the product were identified. However, utilising lithium chloride and tert-butanol as additives saved the day, allowing the group a very reasonable 45% yield, with cracking stereoselectivity.
Bouyed with this success, the group then went made a similar substrate, but this time with an aldehyde instead of the protected primary alcohol. When this substrate was treated in the same manner, not only did a further ring formation occur, but the yield was improved to an even more impressive 54%.
More importantly, though – this pair of C-C bond formations and ring formations took the group remarkably close to the target in a single step. From here, the acetate group (actually, two…) was installed, followed by ozonolysis and treatment of the aldehyde with Eschenmoser’s salt and triethylamine to get to an enal. They the (slightly) selectively removed the erroneous actetate, completing the target in twelve steps.
Has to be strong candidate for synthesis of the year!