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Totally Synthetic by Paul H. Docherty, 20 May 2009

Total Synthesis of 5-epi-Vibsanin E

Davies, Williams

D. D. Schwartz, J. R. Denton, Y. Lian, H. M. L. Davies, C. M. Williams, J. Am. Chem. Soc. 2009, 131, 8329-8332.

DOI: 10.1021/ja9019484

The substituted ring of 5-epi-Vibsanin E has been constructed by Huw Davies and Craig Williams as a collaborative effort. Davies provided some smart chemistry for building seven membered rings. However, another challenge is the heavy substitution, which has bothered several other groups (including individual efforts) already.

The total synthesis starts with the formation of the cycloheptadiene, using a vinyldiazoester and a triene (derived from Geraniol) to form a cyclopropane first. This was done enantio- and diastereoselectivly using Davies rhodium chemistry, and a catalyst containing a very bulky ligand (Ad = adamantyl). However, diasteroselectivity was unnecessary, as that cyclopropane was opened in [4+3] cycloaddition followed by Cope rearragement to generate the required ring and a quaternary centre in high e.e. and good yield. Considering the complexity of the system, that’s quite a success.

With one ring firmly in place, the next two followed very quickly by completing a Lewis-acid promoted hetero-Diels-Alder reaction. One new stereocenter followed, along with both rings, in excellent yield. Things started to get a bit more difficult here, as functionalising the ring isn’t particularly easy. Medium rings like this, often have unique conformations, which can interfere with stereoselective reactions. Davies and Williams approach was using a Claisen rearrangement to impart one of the more tricky stereocenters, but this was problematic, as they first had to generate an enolate with the correct regiochemistry. Silylation, followed by allylation of the ketone was quite effective though, and microwave assisted rearrangement gave the desired product in a reasonable yield and d.r..

Completion of the total synthesis required only a few more steps: deprotection, oxidation and olefination of the primary hydroxyl group using an Anders-Ga▀ner modification of the Wittig reaction performed by the Williams group. Although this olefination doesn’t look particularly traumatic, the trans-vinylacetate moiety seems to be particularly difficult to install.

This is a nice total synthesis, showcasing research of both groups, making a pretty recalcitrant molecule.