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Fusarisetin A   

14 January 2012 20,669 views 33 Comments

Li, Deng, Zhu, Lu, Yu. JACS, 2011, ASAP. DOI: 10.1038/nchem.1196 Article PDF Supporting Information Group Website

Just take a quick look at that target and consider that the synthetic route I’m about to summarise took thirteen steps.  I’m fairly stunned – I read the top-line number in the abstract, and immediately thought that they must have started with an advanced intermediate or degredation product, but no – the synthetic action (like many natural product syntheses) begins with Citronellal.  Sure, only three of the rings are carbocyclic, but there’s a lot going on here, so lets get into it.

As I said, the synthetic starting material is a fairly large pot of tasty-smelling citronellal.  It’s not exactly cheap, (about £100 for 5g from S-A), there are more expensive entries to this terpenoid skeleton. They spend the first four steps (which they somewhat cheekily don’t count as it’s all known chemistry) mashing the isoprene group into a protected hydroxyl group, and then do a pair of Horner-Wadsworth-Emmons reactions to firstly build the triene system, and latterly bolt-on the 1,3-dicarbonyl moiety.  Interestingly, you’ll note the thioester group – this was to make the prior carbonyl chemistry a bit less dramatic, and make the subsequent chemistry very neat.

A little cooling and addition of everyone’s favourite Lewis acid with weird punctuation resulted in a very neat intramolecular Diels-Alder, building four stereocenters, three tertiary and one quaternary in a yield anyone would be happy with.

Whilst that is a very neat reaction, Diels-Alder cycloadditions are so 19th-century; what happens has to be at least early 20th century!  The 1,3-dicarbonyl moiety is, of course, quite acidic, so an allylic displacement reaction could be encouraged by addition of Ag[TFA] and a little base (transesterification conditions).  The reaction initially occurs by O-alkylation, forming a furan system, but the equilibrium of C-alkylation to O-alkylation could be transformed by treatment with Pd(OAc)2 and electron-rich ligand PBu3.  I’m guessing a little, but I suppose that formation of a Pd-[allyl] intermediate allows this facile interconversion to occur.

Okay, the three carbocyclic rings are in, but we’ve still got two heterocycles to build.  The teams next step towards that was formation of an amide by displacement of the fluorinated ester chain with a derivative of D-serine.  The remaining terminal olefin was oxidised (after a little experimentation) under Wacker conditions, and the carbonyl reduced with some selectivity to the secondary alcohol.  Lastly, this final intermediate was treated with sodium methoxide, promoting a Dieckmann condensation – the base again deprotonates the remaining proton on the 1,3-dicarbonyl, which attacks the methyl ester.  The immediate product is the cyclic keto-lactam, but the ketone is attacked by the proximal secondary alcohol, neatly forming the last ring and completing the target.

There was one catch, though – which you may have noticed.  The team unfortunately made the enantiomer of the target, but as the spectral data matched with opposing optical rotation, I think we should let them have their prize!

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  • Baran says:

    Nice work, but I think it’s actually 17 steps from cintronellal.

  • gippgig says:

    Did the OH-bearing carbon epimerize (as drawn, it’s S in the starting material, R in the product) in the last step?

  • Young Padawan says:

    You’re alive!!!

  • fengxueqing says:

    Too much stories, too many competitiers

  • nofilternate says:

    Not such an exciting synthesis as a majority of the chemistry was already precedented by the Ley group in a very similar natural product (Org. Biomol. Chem. 2005, 274-280)

    • KCs nephew says:

      Right, they put those papers in refs anyway. I don’t think it matters much how they make the decalin though. Seems the hard part came aferwards.

    • leo says:

      totally agree with you, only the endgame step-the Dieckmann-triggered cascade was interesting to me, of course the global strategy was also good and straightforward

      • nofilternate says:

        Ley did a similar Lacy Dieckmann, almost exact. The only difference was the added one level of oxidation introduced by the Wacker, and even then if you look carefully at the precedent there was little to no imagination with regards to the synthetic strategy employed.

        • leo says:

          nofilternate, sorry , you’re damn right, I didn’t spend much time comparing the structure of Fusarisetin A with equisetin, now I know in fact these two molecules belongs to the same family, then how could they mention nothing about equisetin in their introduction ? of course if they mentioned it, their paper would not be accepted by JACS…

          • nemesis says:

            A success of KC style: Use as many people as possible; Push material forward as much/fast as possible; Yield? Not important! You can write a XXX% for a YYY% if only the number of labor can beat the number of yield. Originality? Not important! 99% of the kids will not notice the existing precedents and simply be impressed by the words like “first total synthesis”. Fairness? Who cares! If you are not the pet of the boss, you should just suffer.

            Be a wolf or be a dwarf!

  • KCs sons says:

    KC offspring – no doubt

    “set the stage for a second H-W-E olefination…”
    “With 7 in hand, we turned our attention to…”
    “At this point, it became obvious that…”

    BTW, where do you get ENANTIOPURE citronellal (-ol) from at a reasonable price? The S-A- stuff is low nineties ee

  • KC says:

    Thanks for the dedication! Acutally this is the most exciting part of this synthesis for me ;)

  • nemesis says:

    6 people for this molecule…this group must have lots of resources. Typical KC style.

    • Young Padawan says:

      What is the most abundant ressource in China? Apart from rare earths which they don’t want to export any more, probably cheap labour is very abundant.

  • Can anyone help me with the mechanism of the reactions in Figure 3 that was published by garg group in JACS 2012 (http://pubs.acs.org/doi/pdf/10.1021/ja210837b)

    I can think of through the atmospheric oxygen (not sure), but I’d like to know the exact mechanism

    Thanks in advance

    • EC says:

      A reasonable mechanism for those kinds of reactions is something along the lines of formation of the corresponding oxindole enolate, which is then oxidised by air generating the corresponding radical. That might then be coupled with atmospheric oxygen to form a peroxy radical which can abstract H. (a hydrogen atom) from the solvent. The resulting imediate product would therefore be a peroxyde which might be reduced during the workup (if they employ some kind of reducing agent during the workup, something which I didn’t check).
      Any other ideas?

  • Grease Trouble says:

    Does anyone have any tips on removing grease from organic compounds? Or how to avoid grease contamination? (Not silicone grease; NMR at 1.26 and 0.88, so it’s not from greasing joints) It seems to be contaminating my products after column chromatography (not in the crude product).

    • Tot. Syn. says:

      How much gear have you been columning?

      And what was the solvent system in the column?

      • Grease Trouble says:

        About 50 mg. Hexanes, ethyl acetate (4:1) or hexanes, DCM (1:1). I had the same problem doing a prep TLC as well.

    • Flush the column with pentane first (it’ll remove grease) & then with ur eluent

    • beaker says:

      Sounds trivial – but I’ve seen it happen before: Do you have clammy (greasy) hands? Wipe your NMR tube with a kim-wipe before running your sample.

    • momylation says:

      hexanes/acetonitrile extraction

    • Prince Abooboo says:

      Start by not eating cheeseburgers for lunch and dinner

    • Clean Hands says:

      We used to have similar problems in the past (had to report everything as yellow oils). Then one more clever student took 2.5L of ethyl acetate and concentrated that on the rota vap. What have had left was about 500 mg of yellow grease which he proceeded to take NMR of. We sent the spectrum to the supplier and then switched company. No problems ever since.

  • chinstrap says:

    The little things count when working on a small scale and the amount of grease often depends on how fast you push your compound out. If it is a tough separation and you have go heavy on the non-polar system you will have more grease, especially using hexanes which will have ‘longer chain’ contamination. Try low boiling pentane instead. More expensive but cleaner (also is better for your health than hexanes which should be avoided if you can help it). Distilling petroleum ethers and using the low boiling fraction (35-40 C) is another possibility and for daily used you will be busy keeping the stock up.

    If you still have grease even after this I suggest making a 1 cm plug of silica in a pipette or similar sized vessel and reflash your ‘clean’ compound while push with a light Ar stream or a tapered pipette bulb. Collect fractions of around a milliliter worth of the solvent chosen (I like DCM myself but this is subject to the polarity of your compound) and make sure it id solvent that has only touched glass and no plastics. Tedious yes but highly effective. If you are in a tight spot for a clean NMR, this should sort you out. Good luck

    • Grease Trouble says:

      Thanks for the advice. It’s much appreciated! I will give your suggestions a try.

  • 5thfloorgrad says:

    A shorter synthesis just came out in JACS. 9 steps from citronellal, PG-free as well.


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