Trost and Dong. Nature, 2008, 456, 485. DOI: 10.1038/nature07543.
Ah, back in to Nature for another nibble at organic synthesis for the biologists, and some slightly-odd looking structures. It took me rather a while to get used to COOMe rather than CO2Me… However, one thing guaranteed with chemistry in Nature is quality, and it certainly shows in Trost’s latest work.
The target is one he’s been working on for quite a while, but with good reason, as it’s quite a tasty number. To quote the paper, they speak of ‘exceptional biological activity’ and back this up with references to use of bryostatins in the clinic. However (and isn’t this always the stickler…) it’s not exactly bountiful in abundance – apparently only 18 grammes were isolated from 14 tonnes!! That’s quite a column…
Anyway, on with the synthesis – and the starting point, as usual, is assembly of the fragments. One of those was already discussed in a previous Trost paper on this molecule (last year), but a different, and shorter synthesis is used here. One step I found particularly interesting was a propargylation of an aldehyde using chemistry developed by Teck-Peng Loh a few years back. Interesting brew of reagents, but it’s a neat way to build this homo-propagylic alcohol. However, the result is still racemic, so an oxidation and CBS reduction was used to induce an enantiomeric excess.
For the coupling of this fragment with a (somewhat) related partner, Trost used his own funky ruthenium chemistry. In this case, the situation is complicated by the highly functionalised nature of the partners; ligation of the metal to the olefins in both SMs or the product is the reason given for the lowish yield. However, the starting materials were easily isolated, resubmitted and a decent amount brought through.
Transformation of the vinyl silane into a vinyl bromide was done with a bit of NBS – not a reaction I’d thought of as being so high yielding (98%) or selective in such a substrate. Next up was a rather sweet series of acid-mediated reactions in one pot, selectively removing the TBS group and performing a neat transesterification/ketalisation. Really, a very neat way to put in that ketal.
The vinyl bromide was carbonylated rather nicely using fairly traditional reagents to get a decent yield (83%). More traumatic to my eye was the required selective saponification of the beta-hydroxyl methyl ester. I’d probably be thinking about ways to use that hydroxyl to differentiate the esters, but no way would I have fell upon the reagent used by Trost. A bit of trimethyl tin hydroxide, and tickle with the bunsen did the job amazingly well, which Trost suggests is down to the lewis acidity of the reagent. This allowed it to be directed by the hydroxyl, and deliver the impressive selectivity. I’m again impressed with the robustness of the substrate, though – heating under (admittedly mildly) Lewis acidic conditions…
Last is a seriously impressive run of reactions – firstly, a palladium mediated coupling of the diyne, using Trost’s chemistry again. The selectivity, again, is hugely impressive, though as with most macrocyclisations, dilution was key to keeping the reactivity intramolecular. Quite an impressive example of a new means for macrocyclisation, though (even if the yield is only moderate). More impressive was the fact that they were now perfectly set up for the final cyclisation. After attempting this with a few different gold catalysts (a regioselectivity problem was apparent), they struck gold with the reagents shown (I should write the Angewandte captions…).
After that, all that remained was pivalation and deprotection; again done with apparent ease, rounding off an incredible synthesis, using impressive methodology in exactly the right way. A master class…