Totally Synthetic by Paul H. Docherty, 16 March 2010

Total Synthesis of Echinopine A

Nicolaou, Chen

K. C. Nicolaou, H. Ding, J.-A. Richard, D. Y.-K. Chen, J. Am. Chem. Soc. 2010, 132, 3815-3818.

The unique [3.5.5.7] carbon skeleton is pretty special - apparently enough that no biological rationale is given for this work.

So I’ll get into the synthesis. The first few steps are actually very neat - KC does a CBS reduction (second step in the synthesis…) of a cyclohexenone to get an enatiomerically enriched cyclohexenol. This was then ozonolysed to get a dialdehyde, 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 rearrangement.

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 underwent 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 be said that elaboration to the diazo compound shown in the next scheme was fairly slow work, requiring six steps from the alcohol. However the product of the Johnson-Claisen rearrangement only needed two steps. Anyway, rhodium-catalyzed 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 a 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 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 carcinogenic HMPA, but that seems awfully common when working with samarium diiodide.

As I said, the group had to remove the C1 hydroxyl, oxidise and then methylenate the other, and finally perform a one-carbon homologation of the sidechain - all accomplished with some efficiency in terms of yield, but again a long sequence. Coupled with the alternative routes in this paper, you can tell that this was a battle, and one in which they 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.