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Totally Synthetic by Paul H. Docherty, 20 August 2011

Total Synthesis of Axinellamine A & B


S. Su, R. A. Rodriguez, P. S. Baran, J. Am. Chem. Soc. 2011, 133, 13922-13925.

DOI: 10.1021/ja206191g

Baran’s work in the area of pyrrole-imidazole alkaloids is still facinating, even though I’ve written about it more than a few times! What we’re looking at here, though, isn’t quite newly conquered territory; rather, it's an efficient smoothing-over of some the bumps along the way to Baran's previous total synthesis of the Axinellamines.

Have a look back at my previous post on the Axinellamines, and perhaps the post on Palau'amine. Although the chemistry is pretty amazing, too many steps are involved. The key precursor in these syntheses is a spriocycle, produced with no control of stereochemistry at that central position. The initial work, which can be followed in my post from 2009, or in more detail in this 2010 J. Org. Chem. paper, takes twenty steps to get to that intermediate, and not without a lot of chromatography.

So, in other words, the group were set the reasonable challenge of improving upon that situation. In the latest paper, the synthetic action begins with a rather neat Pauson - Khand cycloaddition of a bis-allylic TMS ether and Boc-protected propargylamine. Except I don’t think you can buy 2-Butene-1,4-diol bis(trimethylsilyl) ether - I think one would have to make it. And since trans-2-Butene-1,4-diol is really expensive, I expect that they had to make it from the corresponding acetylene. Now, this might not look like an issue, but this reduction is a really problematic reaction as far as I can remember. Basically, there isn’t a good solvent for this reaction - the chemistry only happens to the small portion of the SM that goes into the THF and runs over the weekend. Getting the product out of the aqueous layer was very difficult - even after drying out the reaction.

Anyhow, I survived, and the Baran group have got their 2-butene-1,4-diol bis(trimethylsilyl) ether from somewhere. What’s important is that the Pauson - Khand they do is really nice, setting up that trans-bis-ethanol type system required of their target intermediate. However, getting this reaction to behave took quite a bit of effort, as both ethylene glycol and NMO were required to get a sensible yield. My reading of the paper suggests that the group aren’t entirely sure of why these conditions are so effective, but based on past efforts from the team, I expect they’ll publish a neat explanation at some point.

Next up, they did a Luche reduction, which also removed the TMS protecting groups, giving them a triol. This was then treated with N-chlorosuccinimide and a triphenylphosphine to effect a substitution of all three alcohols with chloride. The group then planned a desymmetrizing Barbier coupling of an aldehyde to install a sidechain, but again came unstuck. Using typical conditions, only a very modest yield could be achieved, but moving a slightly bizzare combination of Zinc and Indium with ammonium chloride gave them the goods in great yield. They’ve done all the right control experiments - it’s not indium chloride, and they do need both metals - but they’re again still figuring this one out in the lab. Impressive result, though - setting two stereocenters and working very directly.

Treating the bis-chloride with sodium azide did the expected displacement, followed by deprotection of the Boc group with TFA and guanidine installation. This took the group to the pivotal spirocycle formation - which went without stereocontrol in their previous route. However, they then stumbled upon yet another interesting set of conditions, as the chlorination reaction was strongly encouraged by trace trifluoromethanesulfonamide remaining from the previous reaction. Thus, employing TfNH2 as catalyst, and tert-butyl hypochlorite as the chlorinating agent, the spirocycle formed in excellent yield, and crucially, as a single diastereoisomer. NMR studies performed by the group suggest that the trifluoromethanesulfonamide isn’t acting on the t-butyl hypochlorite, but on the substrate…

Oxidation of the initial spirocyclic intermediate, and a little more TFA, took the team to the key intermediate targeted at the outset, but this time in eight steps from the starting materials described. Not only was the yield increased markedly, the amount of chromatography required was significantly reduced. Neat. The paper then describes the remaining steps to get to the natural products (see that earlier post), but from what I read, nothing has changed significantly (not that it needed to).

Great work - anyone looking for a couple of great process chemists should call the chemists above!