v. Vanderwalled, Vanderwalling, Vanderwals
v. tr. To complete an impossibly short, but racemic, synthesis of a popular target e.g.
A Synthesis of Echinopine B
Since their isolation in 2008 the echinopine sesquiterpenes have proved quite popular targets for total synthesis, probably thanks to their unusual and compact molecular architectures. Johann Mulzer, one of my favourite living synthetic chemists, succeeded in a beautiful first total synthesis just a year after their isolation, asymmetrically synthesising both natural products (starting from cyclooctadiene!) and assigning their absolute configurations in an excellent paper that somehow ended up in Organic Letters. The year 2010 saw rather a lengthy synthesis by Nicolaou as well as a paper by Chen outlining studies that developed into a total synthesis last year, which I commented on at the time. Until a couple of weeks ago, Mulzer led the pack needing a mere 20 steps from commercial materials, with Chen a close second at 24, and KCN's ponderous 39 step route languishing at the back. At the time it came out, I didn’t think Mulzer was doing too badly, given the dearth of oxygen in the target and the lack of obvious disconnections. However, the synthetic bar has just been raised by Vanderwal and co-workers, who recently reported a nifty 12 step, albeit racemic, total synthesis that I think should stay at the top for a little while.
The route began with the construction of a guaiane-type precursor from a cheap commercial ketoester. The seven-membered ring was formed first, by conversion of the ketone to the corresponding TMS enol ether, followed by cyclopropanation and treatment with ferric chloride to effect ring expansion to the enone. Cuprate addition then gave a good yield of a mixture of diastereomers, which, although separable, were carried through the following sequence together. The TBS protected alcohol was converted to the corresponding tosylate, and formation of the five-membered ring by intramolecular alkylation then gave the required cis-bicyclo[5.3.0]decan-8-one. Next, Wittig olefination began the process of removing unwanted oxygen functionality from the molecule, and this was continued by conversion of the ester to the aldehyde and thence the alkyne through use of the handy Ohira-Bestmann reagent.
With the guaiane-type precursor in hand, it was time to test the last few bond forming steps to contruct the final two rings. I notice that the group refer to the approach they take as ‘bioinspired’, presumably in reference to the order of bond construction rather than the reagents and conditions used. After functionalisation of the alkyne with suitable substituents for later development into the ester, a rather nifty platinum catalysed cycloisomerisation reaction was used to simultaneously form both remaining rings. In fact, the group developed two very similar approaches, depending on which ester equivalent was used. The higher yielding option found to be a methoxymethyl group, introduced by alkylation of the alkyne with MOMCl. When this substrate was heated platinum(II) chloride in toluene, the cycloisomerisation cascade gave the enol ether shown, which could then be oxidised directed to the methyl ester using a little PCC. Alternatively, a slightly more direct (but lower yielding) route using trimethyl orthoformate in place of MOMCl was also described. Exposure of the resulting dimethyl acetal to the same conditions temporarily gave the dimethyl ketene acetal, which upon work-up to directly yielded the target molecule.
A great piece of work, admirably concise from the title of the paper right through to the final step!
1. Totally Synthetic covered the Nicolaou synthesis, which I wasn’t particularly impressed with, so I’ll just put the graphical abstract up here, to serve as inspiration for the on-going Colouring Competition.
The fact that KCN's 39 step route to these targets got into JACS when Mulzer's 20 step one, which was also the first, ended up in Org. Lett. seems like a bit of an injustice to me.
2. Due to the conformational flexibility of the system, the relative configuration of the two centres could not be readily determined using NMR methods, even after formation of the second ring.
3. The yield obtained for the intramolecular alkylation is a little on the low side, but was accompanied by recovery of some 30% of the starting materials. Due to the lack of a strong cis/trans preference in these types of systems, prolonged reaction times were often accompanied by epimerisation so the reaction had to be stopped at quite low conversion. In fact, these 5-7 systems can be pretty tricky to work with when the opportunity to epimerisation is open to them:
From T. Hudlicky et al., Synlett, 2005, 2911-2914
4. I'm loathe to try and draw a mechanism for this, as the last two times I've proposed mechanisms for reactions on this blog I've been wrong. Oh, go on then... you guys can correct me in the comments:
Update 30/06/12: See Arr Oh's suggested mechanism: