5-epi-vibsanin E

Davies, Williams, Schwartz, Denton, Lian. JACS, 2009, ASAP. DOI: 10.1021/ja9019484. 

Now that’s a substituted ring…  done and dusted by Huw Davies and Craig Williams as a collaborative effort (I’d quite like to know how this worked, as the two groups are quite removed), with Davies weighing in with some smart chemistry for building seven-membered rings.  This clearly critical to the synthesis of such a molecule, but the challenge is the heavy substitution, which has thwarted several groups (includingindividual efforts).  Whilst this paper doesn’t complete the parent molecule, vibsanin E, the C-5 epimer is also a natural product, so they get the badge for this impressive work.

It’s that neat cycloheptadiene-forming chemistry that kicks this synthesis off, using a vinyldiazoester and a triene (derived from Geraniol) to form a cyclopropane.  This was done enantio- and diastereoselectivly using Davies rhodium chemistry, and a catalyst containing a very bulky ligand (that Ad is adamantyl).  However, diasteroselectivity was unnecessary, as that cyclopropane snapped-open in a [4+3] to generate the requred seven-ring, and a quaternary centre in cracking e.e. and decent yield.  Considering the complexity of the system, that’s quite a success – but it took a bit of optimisation, which I’ll leave in the paper.

With one ring firmly in-place, the next two followed very quickly by completing a Lewis-acid promoted hetero-Diels-Alder.  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 bad-boy, often have unique conformations, which can play-havoc with stereoselective reactions.  Davies and Williams approach was use 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 (developing the correct regiochemistry) was quite effective though, and microwave assisted rearrangement gave the desired product in a reasonable yield and decent d.r. (again, considering the system).

Completion of the synthesis required only a few more steps – deprotection, oxidation and olefination of the primary hydroxyl using Williams chemistry (an Anders–Gaßner modification).  Although this olefination doesn’t look particularly traumatic, the trans-vinylacetate moiety seems to be particularly difficult to install.

This is a nice piece of work, showcasing work gleened from both groups, making a pretty recalcitrant molecule.