Axinellamines Pt. II

Baran, Su, Rodriguez. J. Am. Chem. Soc, 2011, ASAP. DOI: 10.1021/ja206191g

When does a person or groups work in a particular area of total synthesis become pedestrian, or even dull? This may sound harsh (especially as he’s a really nice guy), but Paterson’s (at Cambridge) work on macrolides isn’t doing it for me any more. Conversely, Baran’s work in the area of pyrrole-imidazole alkaloids is still facinating, even though I’ve blogged 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 synthesis of the Axinellamines.

Have a look back at my previous post on the Axinellamines (can’t believe that was more than three years ago!!), and perhaps the post on Palau’amine. Although the chemistry is pretty amazing stuff, the step count definitely leans towards the arse-end of the alphabet. This has clearly stuck in the collective throat of the Baran group, and they address the their strategy towards a key intermediate in this paper. 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 pig of a reaction – I should know, as it was the starting point for a lot of the work I did in my DPhil. 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. I used start with about 30g of the SM, then syringe in three 100mL bottles of LAH in THF, and then heat the crap out of it over the weekend. Getting the product out of the aqueous layer was quite a battle, I remember, even after drying out the reaction.

However, (and if you’ll permit me to drone on like this), I do remember one weekend where I didn’t have to vac the reaction down at all. Y’see, I’d bunged up the three-necked flask I was using with septae, syringed in the LAH and set the heater stirrer, and then buggered off to the pub. When I came in on the Saturday, I couldn’t see into the flask… and on further examination, I realised that I’d left the damn septae in, which had swollen and then popped-off the flask. The THF, of course, was gone, leaving about 12g of still-quite-active LAH caked onto the sides of the flask. Not a fun day…

Any-ho, 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 stripped the TMS protecting groups, giving them a triol. This was then treated with N-chlorosuccinimide and a little 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 acheived, 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 (nasty!) did the expected displacement, whilst deboccing with a little TFA followed by guanidine installation. This took the group to the pivotal spirocycle formation – which went without stereocontrol in their previous route. However, they them 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 a little 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 blog 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!