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Agelastatin A Pt. 2   

17 November 2008 9,853 views 17 Comments

Tanaka, Yoshimitsu and Ino. Org. Lett., 2008, ASAP. DOI: 10.1021/ol802225g. Article PDF Supporting Information Group Website

Looking at this article, the second thought I had (after being generally impressed with the key steps) was that I’d perhaps blogged this molecule before. I was right – it was one of the first I wrote, back in April of 2006 – by Trost. My writing style may have progressed since then (and I’ve certainly become more, umm, expansive, but I still knew quality when I saw it. Trost’s work centred on his manipulation of allylic chemistry using palladium catalysis – quite different to this approach by Tanaka.

Clearly I wasn’t interested in biological profiles back then (how times change…), but there’s some worth noting here – antiproliferation of ‘several human cancer cell lines’, and a bit of (GSK-3β) inhibition. But a 5,6,5,5-ring system is a good incentive too, especially if one can make it easily. The first ring is bought-in, but that’s forgiveable, as it is cyclopentadiene. An oxidative cycloaddition with Boc-protected hydroxylamine resulted in a dihydro-oxazine, which was reduced to the amino-alcohol using molybdenum hexacarbonyl and borohydride. Of course, this chemistry is racemic, so the next few steps included an enymatic resolution of this cyclopentene.

Formation of the pyrrole was quite nice, and a blast-from-the-past – a Paal-Knorr condensation. Inversion of the hydroxyl was done with a typical Mitsunobu, with only a few more steps to get to the next point of discussion – and the centrepiece of the paper. Formation of an azidoformate (a tricky beast for them to complete), and then heating the crap out of it in a sealed tube gave them an impressive yield of a pretty strained aziridine.

A bit more azide (and do remember exactly how nasty sodium azide is!) opened the three-membered ring, resulting in a net formation of two stereocenters with great control; six more steps and they’d finished the target. Azidetastic.

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  • the dude says:

    Dear Paul,

    I am a regular reader of your blog and enjoy the chemistry very much. Just as a note from someone working in pharmaceutical industry, ‘anti-proliferative activity’ and all the other great activities that academics write about when they publish their syntheses are total junk. This molecule is interesting for it’s synthesis and not because of any cell-tox it exhibits. Now that I write this, I hear all those people screaming: But what about halichondrin, taxol and the epothilones? Yes, I know. But they are, with all due respect, ‘old’ cancer drugs, have huge side effects and are (esp in the case of taxol) not very efficatious. New cancer drugs are not just anti-proliferative. That is not enough. They need to be selective.

    Anyway, just to come back to what I really wanted to say: Keep blogging about interesting syntheses! Forget the ‘interesting biological activity’. ;-)

  • ZZZZZ says:


    …the dude is right, but if academics don’t mention the biological activity they don’t get funding, which of course is nonsense…


  • optional says:

    What about in general sense. If “antiproliferavtive” falls into what a moelcule does, then so be its definition (regardless of whether it has serious or non-serious or any side-effects and whether or not it has efficacy).

  • milkshake says:

    Trosts approach to cyclopentenyl pyrrole is by far nicer and faster. (Enzymatic resolution followed by Mitsunobu inversion seems clumsy in comparison). But if one wishes to do a kinetic resolution on some cheapo material that can be half-thrown away, then cyclopentadiene monoepoxide kinetic resolution with Jacobsen Co catalyst would be the way to go.

    This is not to detract from the achievement – it just bothers me that a more straighforward approach was not used right at the start when one always needs to crank up and push through multigram quantities of homochiral intermediates.

    Btw, there were very easy to make auxiliary-based chiral nitrosos, made from peracetylated hexoses, and they gave good d.e. on cyclopentadiece cycloadditions if I remember correctly. Throwing away14 carbons is not a big problem if the sugar is glucose.

  • Tot. Syn. says:


    You might not have noticed, but I’m also part pharma industry these days, and work for Arrow Therapeutics / AstraZeneca. However, even before that momentous change, I was well aware of the problems with these compounds and statements of biological activity. I’ve seen papers where the targets were described as ‘anti-cancer agents’, but had IC50s in the *milli*molar region.

    However, our sleepy friend is quite correct that one need more than just ‘because no-one else has made it’ or ‘we can make it faster / better’ to get a share of the decreasing grant pot. And it’s also (but not frequently) interesting to see the effects that certain scaffolds and motifs have. Some are expected – any macrolide worth it’s salt had better bust some cancer cell line, or inhibit microtubule formation, and steroids had better do some really funky shit. So I like to mention the data given, but I rarely follow the citation to the biological paper because they tend to be a bit of let-down.

  • Undergrad senior says:

    @Dude + Tot Syn

    Granted you guys both think that drug activity requires much more than what’s offered by these natural products, but isn’t their purpose to serve as a lead hit for Med-Chemists? and if the synthesis allows the compound to be functionalized then you take that and make an array of compounds.

    My favorite total syntheses are the ones that require method development. And sometimes that’s what I think they are for.

  • Pete says:

    I like this synthesis…I think it is reminiscent of DuBois’ work. The key step involving nitrene aziridination and subsequent opening is similar to Gonyautoxin. Nice application of that chemistry in both cases.

  • the dude says:

    @Tot. Syn. I didn’t mean to insult your intelligence. I just noticed that you have an emphasis on the fact that the molecules have some biological activity. I am well aware of the fact that academics have to lie to get money, but I think as chemists, we should know why we make these molecues. Method development is a great reason (as mentioned by undergrad senior). Application of reactions to complex molecules to prove their uility is another. Producing top-rate synthetic organic chemists is one that is never mentioned in NIH grants, but just as important.

    @Undergrad Senior: Yes, we would like to think that once the synthesis to a compound is established, we can make analogs, establish SAR and then modify the compound to make it simpler and more efficatious etc… The sad truth is that natural products are very difficult to work on. The time and effort it takes to make analogs of natural products is often not worth the trouble. Look in the literature at compounds like cyclosporin, which has been investigated over years to be developed into a drug. At the end, the natural product was still the most potent compound. Likewise the epothilones, what is in the clinic now are epothilone A and B. One thing that is never discussed in synthetic papers are the physicochemical properties, but these are of huge importance. What good is a compound that is very potent, but only soluable in refluxing DMSO? I think organic chemistry tought at university leaves out a lot of the aspects of what later becomes your everyday life (or headache depending on the project) in medicinal chemisty.

  • Undergrad senior says:

    I agree with what you say, as I have been doing synthetic Med. Chem. for the last two years, and the challenge to retaining potency while increasing bio-availability is intriguing, but what sickens me about it has been the tedious, non exciting, and poor-yielding chemistry that I have to do to get to my product. Sadly, its filled with a bunch of coupling reactions and maybe thats why I find the total synthesis to be exciting, since it gives one an opportunity to do some elegant intra-molecular chemistry,

  • furrpwstatin says:

    Wonderful season to total synthesis. Any comments to another cortistatin-A from MDS group?

  • Arnab says:

    I am a chemist and I don’t care about biological activity of my molecule. But, you know what, we still need biological activity and this is not going to change. Something good will of course come out of this. Cyclostreptin synthesis by Sorensen, Danishefsky’s SMNP projects, Wender and Keck’s Bryostatin analogue studies will surely do something good for the humanity.

  • Alex says:

    the dude

    Don’t forget there are some compounds in clinical use that are only soluble in DMSO. amphotericin B for example:


    Thats what formulation chemist are paid for. Its only a questions of wether the compound does something important enough to try and fix its properties via formulation/administration That said I agree that you would rather not go there i it can be avoided.

  • BlowUpEverything says:

    I am definitely a fan of syntheses that start from such simple molecules. It’s really quite nice to see your product build up from such a small molecule – especially since it’s just a hydrocarbon in this case.

  • Stockman says:

    This is quite remeniscent of De Clercq’s synthesis of biotin (TL 1993, 4365, TL 1995, 2615). Excellent approach, and rivals Franklin Davis’s synthesis which in my opinion is the best to this molecule so far.

  • Pierre says:

    Well, the cheaper the better. Most of the pharmaceutical companies are now focussing their efforts towards structuraly simple molecules with high biological activities (and added value). Beside the development of news synthetic methodologies, we can now assume that the golden age of total synthesis of complex natural products is gone, since you will always find a simpler structure with the same biological properties.

  • […] third visit to this tightly functionalised little molecule (one – Trost, two – Tanaka, Yoshimitsu), that sterotetrad certainly brings in the players.  I’m not going to […]