Organic Chemistry Portal
Reactions >> Total Syntheses

Totally Synthetic by Paul H. Docherty, 9 July 2008

Total Synthesis of Cyanthiwigin F


J. A. Enquist, B. M. Stoltz, Nature 2008, 453, 1228-1231.

DOI: 10.1038/nature07046

The cyanthiwigins offer a pretty interesting range of biological activities, including antimicrobial and antineoplastic, along with nerve growth factor stimulation; Cyanthiwigin F has some moderate cytoxicity versus human primary tumour cells. 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 centrosymmetry in the molecule, with the cyclohexanone moiety at its core. Focus on the quaternary stereocenters, and the position of the double bond, and one can recognise that there’s something to work with there. Stoltz went one further, and realised that both stereocenters could be imparted using the same reagent-controlled asymmetric alkylation. First, they had to make the substrate:

A Dieckmann condensation dimerised the 1,4-diallyl esters to give the required 1,4-cyclohexanedione functionality very quickly - a nice use of an old school reaction. This was then bis-methylated in the thermodynamic manner to give the substrate for Pd catalysis. I must stress that at this point we have both (R,R), (S,S) and the meso compound as a statistical mixture.

The first step is an unselective deallylative decaboxylalion to lose one stereocenter. This gives an enolate, and a remaining stereocenter, which may be either S or R, so we’ve got a racemic mixture of enantiomers. Next up, the enolate center is alkylated using the enantiomerically enriched Pd catalyst to give mostly the R configuration at the center. So now we’ve got a mixture of diastereoisomers, R,R and R,S. However, the remaining allyl ester is then decarboxylated to give the respective enolate - but now we only have one stereocenter, and it is mostly R. Lastly, the freshly installed enolate is alkylated, again attaining R configuration to give a predominance of the desired (R,R) product.

Now, to complete the target. A desymmetrization established a triflate from one of the carbonyl groups, and allowed a Negishi coupling with an unsaturated partner. RCM completed the medium ring, followed by hydroboration and oxidation of the remaining terminal olefin to an aldehyde. The aldehyde was then cyclised using a bit of radical chemistry, completing the final ring.

Lastly, Stoltz did a further triflation and a Pd catalysed coupling reaction with an i-Pr-organocuprate. This is very similar to Negishi chemistry, but they describe it as being ‘difficult’, and there’s no reference cited… An interesting reaction, although details are unknown!

Fantastic total synthesis - and I’ve not even mentioned the lack of protecting groups until now!