Stoltz and Enquist. Nature, 2008, 453, 1228. DOI: 10.1038/nature07046.
We’re going high-concept again, here… but before it all gets complex, let’s examine the why before the how.Â The cyanthiwigins are pretty diverse biological agents, with antimicrobial and antineoplastic activities, along with nerve growth factor stimulation; this particular beastie has some moderate cytoxicity versus human primary tumour cells. However, there’s another 29 with their own particular efficacies.Â Indeed, as Stoltz mentions, it’s surprising that they’ve only been the product of two syntheses (Andrew Phillips and Jagadeeswar Reddy).
Key to Stoltz’s approach is a recognition of an element of centro-symmetry in the molecule, with the cyclohexanone moiety at it’s core.Â Focus on the quaternary stereocentres, and the position of the double bond, and one can recognise that there’s something to work with there.Â Stoltz went one-further, and realised that both stereocenters could be imparted using the same reagent-controlled asymmetric alkylation.Â First, they had to make the substrate:
A bit of Dieckmann condensation action dimerised the 1,4-diallyl esters to give the required 1,4-cyclohexane-dione functionality very quickly – a nice use of an old-school reaction (and a nice reminder of Mini Dickmanns… mmm…).Â This was then bis-methylated in the thermodynamic manner to give the substrate for the Pd-wizardry – in the form of a racemic mixture.Â I must stress that at this point we have both (R,R), (S,S) and the meso compound as a statitisical mixture.
Now lets take this slowly.Â I found the diagram in the original paper over-complicated, so I’ve simplified for the chemically aware (god-damned biologists…).Â The first step is an unselective deallylative decaboxyaltion to lose one stereocenter.Â This gives an enolate, and a remaining stereocenter, which may be either S or R, so we’ve got a racemic mixture of enantiomers.Â Next up, the enolate center is alkylated using the enantiomerically enriched Pd catalyst to give only (mostly) the R configuration at the center. So now we’ve got a mixture of diastereoisomers, R,R and R,S.Â However, the remaining allyl ester is then decarboxylated to give the respective enolate – but now we only have one stereocenter, and it is exclusively (mostly) R.Â Lastly, the freshly installed enolate is alkylated, again attaining R configuration to give a predominance of the desired (R,R) product.Â Phew…Â Bloody awesome stuff, too…
Now, to complete the target.Â A desymmeterisation established a triflate from one of the carbonyl groups, and allowed a Negishi coupling with an unsaturated partner.Â RCM completed the medium ring, at the same time (quite impressively) hydroborating and oxidising the remaining terminal olefin to an aldehyde.Â (I would have added this scheme too, but that would’ve been the whole paper…).Â The aldehyde was then cyclised using a bit or radical chemistry, completing the final ring.
Lastly, Stoltz did a further triflation and a Pd-catalysed coupling reaction with an i-Pr-organocuprate.Â I can see that this is very similar to Negishi chemistry, but they describe it as being ‘difficult’, and there’s no reference cited… interesting stuff – just wish I knew more about what was going on.
Fantastic synthesis – and I’ve not even mentioned the lack of protecting groups until now!
Enquist Jr, J.A., Stoltz, B.M. (2008). The total synthesis of (-)-cyanthiwigin F by means of double catalytic enantioselective alkylation. Nature, 453(7199), 1228-1231. DOI: 10.1038/nature07046