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Axinellamines Pt. II   

20 August 2011 12,455 views 28 Comments

Baran, Su, Rodriguez. J. Am. Chem. Soc, 2011, ASAP. DOI: 10.1021/ja206191g Article PDF Supporting Information Group Website

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!

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  • BRSM says:

    Hey, nice post – must be handy to have the old chemdraw files to use as these things are a pain to draw! Also, thanks alot for adding me to your list of blogs!

    With regards to that unusual chlorination, I think they say that they get no spectroscopic change mixing the TfNH2 and starting material (or t-BuOCl, but they do when they mix it with the product. I’m not even sure what that implies. There are an awful lot of steps here that aren’t really understood, aren’t there?

  • gippgig says:

    The key intermediate needs a Cl & a couple more H in the introduction & final figure respectively.
    The x-ray structure in the SI of the product (19) of the Barbier reaction shows the OH with the opposite configuration.

    • Tot. Syn. says:

      You’re right about the chlorine and missing protons, so thanks for that. However, I’m fairly sure that you’re wrong about the Barbier reaction product. It’s been rotated through 180 degrees relative to the 2D sketch – just try to bend your mind around it.

      • gippgig says:

        I’m holding a model of the x-ray structure right now. The OH points up and when I rotate it counterclockwise about a quarter turn so the orientation of the OH-bearing carbon is the same as the 2D sketch (the ring is flipped over but that doesn’t matter, it’s just rotation about a single bond) the OH still points up rather than down. Try making a model.

      • gippgig says:

        The last structure is still missing one hydrogen.

  • Heiko says:

    Nice post, thx for that. It is always impressive to see the baran group in action. Especially these strange reactions they discover throughout their endevour. But I was wondering if they tried to run the Pauson-Khand reaction in an asymmetric fashion?

    • Tot. Syn. says:

      Good thought- perhaps not the most efficient or modern of methods, but perhaps the could stick a chiral auxiliary on to the propargyl amine? Rather than Boc protecting it…

      • antiaromatic says:

        Something a bit more modern could be the use of a chiral diol, depending on the role it plays in the reaction. I think if they do find it to be critical in the RDS, a slap of a chiral diol may well induce enantioselectivity.

  • Jostein says:

    “However, getting the [Pauson–Khand 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.”

    I have no ideas about the ethylene glycol, but NMO and other tertiary amine oxides are often used to oxidize off a molecule of CO from the metal (18-electron rule), thereby “making room” for coordination and getting the reaction going.

  • THF extractor says:

    If you are having trouble getting really polar molecules out of the aqueous layer try a THF extraction. It is miscible with water but a little bit of added brine and it will salt right out. Use a centrifuge for really slow layer separation. Works like a charm and saved my PhD

  • Jostein says:

    Isopropanol and chloroform mixtures is also a classic.

  • j says:

    awesome use of protecting groups……good to see they are sticking to their principles

  • simpson says:

    Well I dare anyone to go from butane diol to these compounds in around 10 steps with so much nitrogen and without using at least some PG chemistry. Whats amazing is that the end-game proceeds without any protection, which is the opposite to all other approaches that have appeared.

    In fact, if you have seen the other groups work on these systems its a PG-orgy. So baran group is sticking to principles by minimizing their use as much as possible.

  • Mao's Pride and Joy says:

    Who needs Ian Seiple when you have Shun Su?

  • ZZZZZ says:


    They open themselves up to legitimate criticism (cynicism), given the ‘hype’ they published on the topic of protecting groups.

    In any case, nice chemistry.


  • milkshake says:

    The slow LAH reduction of the propargyl alcohol: RedAl would work better/faster, the bitch is removing the methoxyethanol from the product though.

    • Tot. Syn. says:

      I tried that too – found the reaction less messy and generally less dangerous, but it didn’t return a better yield, so I went back to lashings of LAH solution. I tried working with the powder as well, but whilst the results could be Sally good, they could also be really crap. I never got to the bottom of the variability in batches of LAH, but I found the same thing in many reactions. We used to lable the cans of LAH with things like “Shane’s Ninja Lith-Al” and “Frankie’s woosy LAH”…

      • antiaromatic says:

        Not sure if this would work or if this is what they did, but since they wanted it silyl protected anyway, they could probably just do bis-protection of butynediol followed by Na or Li reduction of the alkyne to the trans-alkene. Seems like that would obviate the difficulties you guys are mentioning.

  • ninja says:

    the title compound is Axinellamine B (OH,H = beta) not A

    • gippgig says:

      The structure shown here agrees with the structure shown for axinellamine A (the opposite enantiomer is shown but the absolute configuration was not yet known) in the supplementary information from the paper (JOC 64 731) reporting the isolation of the axinellamines .

  • Matallochem says:

    I am a organometallic chemist and today I saw an example of a rather “difficult” reaction. This made me investigate further and here is what I saw. I am talking about the total synthesis of echinopines in organic letters today (DOI: 10.1021/ol202053m).
    13C NMR of the aldehyde product 17 is from an earlier paper published by the same group in 2010 (DOI: 10.1021/ja9093988, check the SI and compare the baseline…its spot to spot!!!).
    The product NMR’s from Echinipine A and B are all from the earlier paper again totally similar (print out the 1 H NMR from page 65 of the 2010 JACS and compare it with the NMR from this org lett. paper on page 56 ). Amazing isn’t it!
    Is it common in total synthesis to use spectra’s from previous work? In any case, I have a few strong comments on the shown cyclopropanation reaction but I need to do a few experiments before I bring that up. What do you guys think about it?

  • Cascade says:

    Wow….what a catch. I agree That the spectras make the work look fishy… to say the least.