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6 July 2009 23,477 views 35 Comments


Fukuyama, Tokuyam, Ueda, Satoh, Matsumoto, Sugimoto. ACIEE, 2009, ASAP. DOI: 10.1002/anie.200902192. Article PDF Supporting Information Group Website

And it’s done.  It took almost as long to finish as it took Wiley to finally put it online (are they using dial-up modems?), but it’s finally here, after many (as yet) unsuccessful attempts [Corey, Padwa, Nicolaou].  Unfortunately, its difficult to know exactly what were the more challenging issues, as this is a very compact communication – we’re gonna have to wait even longer for the full paper.  However, we can marvel at the more obvious successes.

The basic strategy was simple – split the molecule in two about the obvious single bond.  This presents aspidophytine, and another bit (that’s the technical term – honest…).  As aspidophytine has been covered, lets start with the other bit, a ‘bicyclo[3.3.1]skeleton that includes bridged ketone and aminal functionalities‘.  The group were able to garner some insight into it’s synthesis from some isolation studies, but first they had built much of the carbon skeleton.  Perhaps the most difficult feature was completed at the start of the synthesis – a chiral quaternary center.  For this they dug into an unfairly buried Tet. Lett. by d’Angelo, using a chiral amine to form a imine intermediate of that ketone.  Then, conjugate addition to an acrylate allowed highly enantioselective C-C bond formation in good yield.  Of course, a quantitative amounts of chiral amine were required, but it’s relatively inexpensive, and easy to recover after hydrolysis.


It was quite a few steps to the next scheme – an enolisation and ozonolysis of the resulting cyclopentene allowed opening of the 5-membered ring, whilst the thio-ester was easily alkylated with a pendant amine.  This allowed construction of an eleven-membered cyclic-amine macrocycle, which they cunningly used to form three smaller rings.  The key to this was a highly diastereoselective Mannich reaction, and the mandatory Overman reference (this is an alkaloid synthesis, afterall…).  [As a brief aid – the acid removes the ketal, freeing the ketone.  Then the thiophenol removed the nosyl protecting group, reading the molecule for Mannich reaction under acidic conditions – the silica.  The ethyl ester was removed in the course of this (probably the pot-carb), so TMS-diazomethane was used to re-esterify.]


Moving next to the other half of the target, a relatively simple indole was elaborated to a dihydro-beta-carboline using efficient if routine chemistry.  A Noyori asymmetric
reduction was used to reduce the carboline across the imine, providing asymmetry in high e.e.  Addition of NIS to this system caused iodation at the indole C-3 postion, and indolenine formation. Treatment of this with silver triflate caused a Friedel-Crafts alkylation, generating the highly congested quaternary center in a 2.4(ish):1 d.r.  Now, the Friedel–Crafts alkylation might be due some new teeth and a hip-replacement op at 132 years old, but that’s a neat job.  Note the use of a mesyl group as a phenol protecting group!


A few steps on, and the original stereocenters been torn-asunder; however, a little mCPBA epoxidises the probably-quite-activated-sorta-bis-enamine thing, allowing rearrangement of the 5,6,6-system into the desired bicyclo[3.3.1], as expected.  I’ve shown the product in two representations – one similar to it’s direct precursor in the mechanism, and the other that used by the authors.


Coupling of the two fragments is nice, but I’m just going to direct you here, as this is a (rather complex and impressive, but still…) Fischer Indole Synthesis. Which you should all know anyway…  So the last scheme is a rather late-stage lactonisation, done in a rather interesting way; basic hydrolysis of the ester, and then lactone formation using potassium
ferricyanide.  If that’s ringing bells, that cause this is lifted directly from Corey’s synthesis of Aspidophytine.  If the chemistry works…


And that’s more-or-less the theme here – no particularly new chemistry, but the world gains 4.2 mg of the target.  Given how much effort has gone in from some particularly successful groups, only to be met with failure, this is an astonishing achievement.  But bring on the full paper!

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  • DiAngelo says:

    Getting the late stage Fischer indole synthesis to work was a real gutsy achievement. I wonder how much material of each precursor was needed for the “extensive optimization” of that step. Considering the acid-lability of the left-hand segment, it’s a pretty remarkable achievement to dig up 40-47% of the desired indolenine product. Regardless, it’ll be interesting to find out later what didn’t work and how the group ended up deciding upon the Fischer indole disconnection to bring to two halves together.

  • TA says:

    In the title structure you have Mesyl-Haplophytine instead of the natural product

  • Heiko says:

    i read this paper last weekend and as always with the fukuyama papers: it’s pretty impressive… really nice chemistry especially the synthesis of the left hand fragment starting from this simple cyclopentanone… great! if you hadn’t reviewed it, i would have done it by myself… :) thx

  • LiqC says:

    Beautiful. Even with protecting groups.
    How does ethyl thioacrylate smell, I wonder?

    Really a minor thing in the grand scheme, but why would they do 1) succinic anh. 2) SOCl2-MeOH instead of MeO2C–COCl?

  • krest17 says:

    Good work, simple reactions, everything straighfovard – I’m crying with bitter tears. My heart is broken.

  • summerundrgrd says:

    I am sorry for offtopic q, but since so many org chemists are reading this blog: is it possible to cleave t-Bu ester in the presence of secondary alcohol benzoyl ester? Would BzOR survive TFA/DCM?

    • milkshake says:

      the answer is yes and yes – generally. The resistance to TFA cleavage depends on the ease of the corresponding carbocation formation. You may have a problem if your benzoyl is on allylic or benzylic oxygen.

      • conte says:

        It also depends on the importance of the reaction: do you have 5 or 6 altrenatives? It will work immediately. No alternative? It will never work. :-)

  • summerundrgrd says:

    Thank you!

  • optional says:

    the best ever alternative to cleave a tert-butyl ester: TMSOTf (3.0 equiv) and Et3N (6.0 equiv), 0 to rt, ca 15 min. Clean reaction to the trimethylsilyl ester after loss of isobuytlene, and then a simple water or NaHCO3 workup to get your acid. I routinely get >95% yield. Just make sure that you dont have free alcohols (but even then, the TMS group is easy to cleave).

  • optional says:

    ooooops, and as you can see, the condtions are totally neutral!!

  • summerundrgrd says:

    TMSOTf sounds very interesting. The only problem is – I am forming a betaine, so extraction may be tricky. But if reaction is so clean, maybe i could extract my betaine into water and do some lyophilization. Anyways, i will try this and see what happens. Thank you.

    • tim says:

      Be careful with TMSOTf if you’ve never worked with it before (I’m assuming undrgrd is short for undergrad). It smokes like crazy and will burn you in a hurry. Otherwise, a lovely reagent to work with. Very easily distilled and usually gives nice clean results. It’s quite easy to make from TMSCl and TfOH if you can’t find it in your department – the recipe is in a Corey TL paper circa 1980 (I think).

      • milkshake says:

        I think he needs volatile reagent here, TfOH – based reagents would not do. (One not-so-brilliant peptide chemist in Prague was using TMS-OTf+TFA mix to cleave peptides off solid phase resin. Then he found out that he could not precipitate his product from the solution, or evaporate the cleavage mix so he put it on lyo. The next day he found the lyo jar destroyed as the TfOH depolymerized the silicon cap and vacuum sucked it in, the vacuum quenched, oil spilled out of the lyo vacuum pump – it was a big mess)

  • palin4prez says:

    RIP Haplophytine, RIP Jason Altom

  • palin4prez says:

    was not trying to be facetious, felt it needed to be stated. Sorry if you disagree

  • bandit says:

    interesting that no-one really has any comments about the total synthesis….

  • bandit says:

    it wasnt a criticism, just an observation. but anyway, i think this is one of the few molecules left that you have to take your hat off for just the achievement irrespective of the way it was done. The fact that recourse was made to Stork-type Fisher indole reaction to couple the right hand side rather than more direct use of their aspidophytine approach says a lot for the unforseen difficulties with the molecule. It does make it nice and convergent though, which was probably key to finishing it.

  • John Wood says:

    I just finished devouring the new Tot syn(full article) of Lyconadin by Sarpong, and the paper was, atleast for my untrained mind, a learning experience. Even though Haplophytine was elusive, this paper is insightful at the very least and gives a great lay out for an AWESOME project.


    I havent read the SI yet, but I strongly suggest the paper.

  • Kiddie Khem says:

    I like the incorporation of the rearrangement when they epoxidize the alkaloid.

  • CuttySap says:

    Any folks at a UC school:

    Are grad student stipends being cut? The proposal said students covered by a union will be subjected to the collective barganing contract, any news on what will mean to us?
    I will be joining a UC chem dept. in the fall, so I am curious to know.

  • ch3mical says:

    No grad student cuts, hopefully. From what I have heard UC positions making over 40k per year have salary cuts of 4%.

    • thx says:

      Actually, the cuts are graded according to your payscale. Staff making 0-40K get a 4% cut, 40-46K is 5% and so on.

      Students will be left alone, for now.

  • hanpisa says:

    A quick question.

    Why didn’t they conducted the Friedel-Craft reaction with aspidophytine?
    sensitive aminal functionality?

    • milkshake says:

      this self-suggesting retrosynthetic disconnection has been tested, and it turned out to be cursed. Build a model to see how awfully crowded the molecule is around that bond/

      C-C forming reactions involving quat carbon very late in the synthesis are risky – imagine that you worked on this thing for five years, have few mg of the advanced intermediate to play with, and it just refuses to work and you will possibly never complete what you set out to do… The very last thing Jason did was some studies with a simplified model system, to find the conditions to do this step – and at one moment he even believed this step worked with the model before it turned out the structure of the assembled product was not quite right.

  • keenbeibei says:

    I have faith in the Freidel-Crafts reaction before the final oxidation.

  • Org Lett Reader says:

    I am pretty damn sure that haplophytine doesn’t contain a mesylate group.

  • ian says:

    Amazing that after all these years the two syntheses appear within a couple of months…

    likewise for Taxol

  • Felix says:

    Why potassium ferricyanide won’t oxidate other tertiary amine?
    Does potassium ferricyanide have any selective rule?
    I feel curious in the last lactonization.