B.R.S.M. To strive, to seek, to find and not to give a yield


(+/-)-axinellamines A and B

Update 20/08/11 - Tot. Syn. covers the same paper. Also, check out Tot. Syn. coverage of Baran's original route.

Scalable, Stereocontrolled Total Syntheses of (±)-Axinellamines A and B

Baran et al., J. Am. Chem. Soc., 2011, ASAP; [PDF][SI][GROUP]

DOI: 10.1021/ja206191g

Okay, so this isn't a new synthesis per se as Baran finished his impressive first generation synthesis of these two natural products back in 2008. At the time, this was a real tour de force as they hadn't been made, and are a total pain to draw and handle, let alone actually synthesise. However, as in his cortistatin work, Phil wasn't content to stop at just a first total synthesis, and has apparently spent some time since cleaning up and optimising the route to allow production of decent amounts of material for biological testing. And what a job the group has done! Shown below is the key intermediate used for the axinellamines (as well as previous Baran syntheses of the massadines and palau'amine), which, being a cyclopentane bearing 5 contiguous stereocentres, previously took them 20 steps to make. This paper reports a new pared down route of just 8 steps, all which can be performed on gram scale, which is an amazing achievement for a fragment of this complexity, and presumably will also allow access to larger quantities of the other natural products as well.

Some of the optimised conditions used are fantastically original, betokening the amount of work put into trimming down the route; Zinc mediated Barbier coupling low yielding? Just chuck in some indium! Tricky Pauson-Khand? Add ethylene glycol! Capricious chlorination? Needs more TfNH2! Read on to see how they came up with some of this stuff...

The route began with the Pauson-Khand reaction between the propargyl carbamate and the bis(allylic trimethyl silyl ether) shown. In the presence of the usual additives (various amine N-oxides) yields remained unacceptably low, but after what could only have been extensive experimentation, the group found that a combination of NMO, 4Å molecular sieves and ethylene glycol gave a much improved yield of the desired product. They're not exactly sure how this combination helps and apparently we can look forward to more work being done on this in the future. Luche reduction of the enone carbonyl and Appel-type chlorination of the resulting alcohol gave the allylic chloride required for the planned Barbier reaction as an inseparable (but inconsequential) 2:1 mixture of diastereomers.


Unfortunately, the Barbier step proved to be non-trivial, and after trying various metals under anhydrous conditions without success, the group discovered that the use of zinc dust (16.5 equiv.) and indium powder (1.87 equiv.) in a mixture of THF and aq. NH4Cl (6%) gave a good yield of the desired alcohol. I'd only be guessing, but I don't think those are the first conditions they tried. This combination appeared to be synergistic as neither Zn, In, or even InCl3 were able to effect the same transformation under the above conditions. Cunningly, this step destroyed the allylic stereocentre, creating a C2 symmetric intermediate which then reacted with the 2,2,2-trifluoro-N-(2-oxoethyl)-acetamide (which was actually there from the start, this being a Barbier reaction).  Displacement of the two remaining chlorides with azide in DMF, and Boc deprotection proceeded uneventfully under fairly normal conditions. The guanidine fragment was then introduced by reacting the newly exposed amine with known  N,N’-bis(Boc)-N’’-triflylguanidine in the presence of triethylamine. Impressively, up to this intermediate only three chromatographic purifications were required and all the steps were conducted on at least 4 grams!

It was now time to set the final two stereocentres around the cyclopentane ring, which was done via a chloronium mediated cyclisation of the guanidine onto the nearby olefin employing t-butyl hypochlorite. The group's first generation approach to the key intermediate at the beginning of this post produced the C-7 quaternary centre (set during the guanidine cyclisation) without any stereocontrol (i.e. as a 1:1 mixture of diastereomers), but it was anticipated that steric shielding by the nearby methylene azide group in this system would favour the desired diastereomer. This did turn out to be the case, and a single diastereomer was obtained, but the reaction was found to be extremely fickle and the yield obtained varied wildly. After much head scratching it was determined that small amounts of trifluoromethylsulfonamide left over from the previous step were affecting the reaction, but not in any easily explainable way. In the presence of no TfNH2 or one or more equivalents, only complex mixtures were obtained; the optimal amount was found to be 25 mol%. Again, as with the role of ethylene glycol in the modified Pauson-Khand conditions, the group were unable to determine the role of this crucial additive - no change in the 19F NMR was observed when the additive was mixed with t-BuOCl (ruling out a TfNHCl type reagent) or the starting material (ruling out the formation of some more reactive species). Bizarrely, addition of the additive to the cyclic guanidine product did result in a dramatic change to the spectrum, but it was not obvious what was going on (the before and after spectra are in the free SI if you'd like to take a guess...). Concentration, followed by oxidation and deprotection (all in the same flask) gave the key spiro aminoketone intermediate to the axinellamines, massadines and palau'amine in a sequence less than half the length of that previously reported by the group, in more than ten times greater yield. Nice work!


From here it was only 5 steps to complete the axinellamines (and only 4-6 to the others using previously reported chemistry). The second guanidine was installed though the use of cyanamide in basic brine (how do they come up with this stuff? do organic compounds even dissolve in brine?). Oxidation with DMDO, followed by dehydrative cyclisation using TFA gave the redoubtable looking tetracyclic system as a mixture of diastereoisomers that wasn't isolated at this point. Instead, direct exposure of the mixture to silver(II) picolinate, an oxidant used a number of times previously by the group, effected stereoselective installation of the final alcohol onto the carbon skeleton. At this point the two diastereomers (at the new ring junction) were separated chromatographically and carried forwards separately to the two natural products. Thus, the azide groups were finally reduced to the corresponding amines, which were then coupled with 2,3-dibromo-5-trichloroacetylpyrrole to give the axinellamines A and B.[1]

These natural products are truly terrifying to behold, but Baran handles them so deftly here you can almost forget all the hard work done and think it was easy. This is a great example of what synthetic organic chemistry should be - a large scale, practical synthesis of interesting and biologically important molecules where the problems met have forced the development of new synthetic methods! Great!


1. The corresponding acid chloride presumably isn't very stable.




Comments (10) Trackbacks (1)
  1. Anyone who’s worked with pyrroles can tell you how frustrating they can be to work with due to nucleophilicity, acid sensitivity, etc.. Here they’re brominated, so less electron-rich, but doing coupling reactions with trichloroacetates instead of the acid chlorides is the usual workaround.

  2. Most synthesis papers make it look easy. Readers who aren’t familiar with lab work (me) should read the supplementary information for at least one synthesis paper (this one is a good choice) to better understand how complicated these reactions are (but this still doesn’t include the trial and error to figure out the right reactions to use).

    Speaking of these compounds being a total pain to draw, you’ve got one of the amides backwards, and the supplementary information for the paper has the configuration of the newly formed hydroxyl on structure 19 (right after the protected aminoacetaldehyde was added) opposite to the x-ray structure also shown.
    According to the SI the azides were added at 85 rather than 80 C.
    Any idea why the silver picolinate was such a selective and mild oxidant? I’d expect divalent silver to completely destroy the intermediate on contact.

  3. James: No I’ve never had the joy of pyrrole chemistry. Did a lot of work with furans as a masters student, trying to oxidise them to enediones without breaking them but I’m sure pyrroles are much worse. I was only guessing about the acid chloride – it just doesn’t look like a thing which should exist or would be much fun.

    Gippgig – No, unfortunately (sometimes, at least), authors generally don’t share a lot of the details of what didn’t work, which is often as instructive as what did. When I said they were a pain to draw I wasn’t talking about the amides so much, but that’s fixed now (gah, I was wrong in 3/4 of the images, thanks to copy and pasting). The way 19 and subsequent structures are drawn in the paper does indeed appear to contradict the crystal structure, which is a bit odd. Not sure what’s happened there or which to use.

    Regarding the silver(ii) picolinate – in short, no I’m not sure why it’s so good at this transformation. I saw Baran give a talk on this work back in 2009 and he said they tried something like a hundred oxidants before they found this compound, most of them just giving a black sticky mess. Apparently, at the time, the use of this compound as an oxidant for organic substrates was almost unknown – they had to dredge the prep for it out of an ancient paper and make it specially (which I guess says something about how desperate they were). I’m not even sure if it’s a one or two electron oxidant here (they use an excess). I’ll try and do some digging when I next have access to a real internet connection – I currently have my computer connected up to my smartphone, which is very slow, and not conducive to quick research or browsing the literature.

  4. The quaternary center is equidistant from two methylene azide groups that point in opposite directions so what is the mechanism for stereocontrol?

    • The new quat. centre at C-7 is, as you say, equidistant from the methylene azides. However, it’s important to realise that the mechanism for forming the C-N bond here is by opening of a chloronium ion formed from the double bond and the t-BuOCl. Like the opening of epoxides, the opening of halonium intermediates is stereospecific (i.e. with inversion, unless neighbouring groups are getting involved). Therefore, it’s the stereochemistry of the chloronium ion which determines the C-7 sterochem. The double bond where the chloronium is going to form is closer to the bottom left (as drawn) methylene azide. This group points down, blocking the bottom face and forcing chloronium formation on the top face. This means that the guanidine must attack the bottom face, giving the sterochemistry shown. Or something like that.

  5. I would not speak of a large-scale synthesis. Baran sould have synthesized 100g of axinellamine then one can talk about a scalable synthesis.
    The chemistry is of course nice and I like the fact that yields are not always >95%+. This makes it more honest.

  6. I wonder if it would be possible to start with a protected propargylguanidine instead of propargylamine to eliminate the deprotection/guanidinylation steps.
    Speaking of guanidine, would protecting it with a carbonyloxycarbonyl (OCOCO, forming a nice 6-membered ring) work?

    • Good idea, but Baran tried it and it didn’t work. The original plan was to use the bis(azide) in place of the bis(TMSoxy) compound and have the propargylguarnidine in place of the propargylamine. However, the former, wasn’t very stable, and the later ‘showed only marginal reactivity’. Regarding your idea for a protecting group, I’ve never seen it done. I suspect the answer is probably but I don’t know how easy that’d be to make, or how robust it would be…

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