Nicolaou, Chen, Ding, Richard. JACS, 2010, ASAP. DOI: 10.1021/ja9093988.
As I twittered the earlier today, redrawing KC’s crayonisation of Echinopine A took quite a while – but I think one needs to see both representations to get a feeling for the complexity here. The unique [188.8.131.52] carbon skeleton is pretty special – apparently enough that no biological rationale is given for this work. Perhaps I spend too much time looking a biological assay results these days…
So with nothing else for me to witter-on about, I’ll get into the synthesis. The first few steps are actually kinda neat – KC does a CBS reduction (second step in the synthesis…) of a cyclohexenone to get an enatiomerically enriched cychexenol. This was then ozonolysed to get a di-aldehyde, which was treated with base to get the aldol product – a cyclopentene. The remaining aldehyde was reduced to the primary alcohol, perfectly set for one of my favourite reactions – a Johnson-Claisen.
This neat little rearrangement provided a moderate level of diastereoselectivity in the creation of a tertiary center, and left a pair of useful functional handles. Clearly dissatisfied with this result, the group tried an alternative sequence from the same alcohol, appending a conspicuous looking stannane. When treated with base, this did a 2,3-Wittig rearrangement to give a similar product as before, but in a far reduced yield. Importantly, though, was the increase in diastereoselectivity, boosted to a more useful 7:1.
It has to said that elaboration to the diazo compound shown in my next scheme was kinda steppy, requiring six steps from the alcohol. Howeverl the JC product only needed two steps, so it’s tough to say which I’d go with. I guess it’d come-down to the ease of chromtography. Anyway, any step I show with a diazo-group is inevitably followed by a pinch of rhodium, and KC doesn’t dissaapoint. Carbene formation and insertion into the exo-cyclic alkene results in a neat formation of both a cyclopentene and a cyclopropane, and as a single diastereoisomer. Quite a neat route to the desired 5,5,3-system.
A few functional group transformations brought the group to a homoallylic alcohol, which when reduced presents a system recognisably similar to that of the target. Selectivity again went in their favour, with new stereocenter generated entirely in the desired configuration. As close as this product seems to the natural product, there was actually quite a lot of work to do, as they needed to add quite a lot of carbon to finish the medium ring.
This started with a olefination to extend the C-7 sidehain. Reduction of an ester and the new olefin was done simultaneously using LiEt3BH, providing a terminal alcohol. A pair of oxidations then gave the group a C-1 ketone, along with an aldehyde – perfectly set for a samarium-mediated coupling. This rather powerful reaction provided the carbon-carbon bond in a rather reasonable yield (given the complexity of the system), and generated a pair of stereocenters. As it happens, both hydroxyl groups were removed shortly after this reaction, but that only describes the wealth of hydroxyl chemistry at our disposal. Unfortunately, the group had to use that ever-so-nasty HMPA, but that seems awfully common when working with samarium diiodide.
As I said, the group had to loose reduce-off the C1 hydroxyl, oxidise and then methylenate the other, and finally one-carbon homologate the sidechain – all accomplished with some efficiency in terms of yield, but again rather steppy. And that concludes this synthesis rather aptly, as there are simply too many steps for me to be stunned. Coupled with the alternative routes in this paper, you can tell that this was a battle, and one in which the ultimately succeed. However, I expect we’ll see a second generation synthesis in the future, as I can’t imagine KC’s done with this target.