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Pinnatoxin A   

4 August 2008 7,175 views 10 Comments

Hashimoto, Nakamura and Kikuchi. ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200802729. Article PDF Supporting Information Group Website Hashimoto, Nakamura, Inagaki, Sugimoto, Kudo, Nakajima. Org Lett, 2001, EarlyView. DOI: 10.1021/ol0168364. Article PDF Supporting Information ResearchBlogging.org

A second synthesis of this beast (the first being Zakarians) and, it’s not looking any less complex.  I had a look back at the Zakarian post, and I was surprised to see that I didn’t mention any biological activity.  However, Hashimoto and Nakamura only mention ‘…reported to activate Ca2+ channels…’, so I guess that counts as a reason to make more and discover what else it does.

With a target this size, it’s all about the retrosynthesis – and to be fair, the main disconnections are quite different to what we might be used to.  The key to this was a separation of the ‘northern and southern hemispheres’ (to use typical Tot. Syn. parlance), with the southern fragment mostly developed in the Org. Lett. from 2001.  This poly-ketal would be constructed as usual from an acyclic poly-ketone, and hope that nature was kind…

Construction of that intermediate went rather smoothly, grabbing some sugar-type of thing for the bottom tetraol, and constructing the rest of the molecule with typical unification protocols.  (Interesting proc for the dithane removal: NCS, AgNO3, γ-collidine, CH3CN-H2O, 87%).  However, it’s the cyclisation that you’ve got to love – a bit of acid, a bit of base and we’re up three rings and three stereocentres.

A few (okay, quite a few) steps later, and it’s time to do that tasty Roush Diels-Alder.  Unfortunately, they had to use a massive excess of the dienophile, and at that temperature, I wouldn’t rate their chances of recovering the remainder (they don’t mention it in either the paper or the SI).  The result wasn’t amazing either, with a 45:27:18:10 mixture of products that had to be separated by prep TLC.  However, it does provide the A ring and leaves them with suitable functionality for the G ring, so it was time to move on.

They used a rather tasty piece of Trost chemistry to complete the macrocycle, and in an impressive yield, considering the complexity of the substrate.  There’s not much discussion of this reaction, or what happened to the other 21%, but that can be forgiven if one considers how much of challenge this must have been with only 12mg of material to work with.

Completion of the target from here took a not-inconsiderable eleven steps (all high-yielding), but they isolated it as a nice white solid!  However, I guess many of your will have realised from my tone that I wasn’t set-on-fire by this synthesis.  I dunno why – it’s an amazing achievement, but still somewhat lacking in new chemistry.  Is that just me?

Nakamura, S., Kikuchi, F., Hashimoto, S. (2008). Total Synthesis of Pinnatoxin A. Angewandte Chemie International Edition DOI: 10.1002/anie.200802729

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  • TWYI says:

    Seems like a standard connection to me.

  • *yawn* says:

    I agree w/ your assessment Tot Syn – as cool as it looks on paper to go from linear precursors to polycyclic spiroketals, and as impressive as it is to finish a synthesis of such a complex natural product, there really wasn’t much that caught my eye in this one. At least Zakarian saw the cyclohexene in the natural product and immediately default to a Diels-Alder.

  • ale says:

    Nice synthesis, standard disconection, but not new chemistry. As mentionated, very interesting the dithane removal way!

  • milkshake says:

    Anyone who climbs Everest and makes it back to the base camp by his own should be congratulated for his stamina. This is one cool-looking molecule and there is a number of nontrivial steps – the spiroketal formation is quite jaw-dropping. And they were gutsy to do few hard steps late in the game. (I wonder if the dienophile could be modified by some removable grop like halogen or phenylsulfone – something that could be burned off at the same time when their benzyl ether deprotection is removed)

  • Penn Chem says:

    The dithiane removal has been around for awhile, Corey disclosed a very similar varient (NCS, AgNO3) in 1971 (JOC). It works really well for sensitive substrates, especially compounds prone to elimination from the resulting ketones.

  • Shin says:

    Very consise use of anomeric effect/1,3 diaxial interaction for the formation of pyran-furan-pyran system. Could be used as a very good example for their effect.

  • Shin says:

    Very tempting to run iminium activated dienophile for Diels-Alder reaction (intramolecular sense if possible). Without any doubt, their seems to be a couple of difficulties to execute them.

  • salinosporamide says:

    hey you guys, as interested in total synthesis as i am, i should say you are not so particular about most of the works published, but this one is really boring,right?

  • Tot. Syn. says:

    I don’t normally look-up the IP addresses of comments unless they are spamming me, or being particularly obtuse, but I was disappointed to see that ‘salinosporamide’ was posting from Hokkaido, the home of this paper…

    As I said in my summary, the chemistry used is a little pedestrian at times, but the end result is a significant result and achievement. Sometimes, you just use the chemistry that *works*.

  • milkshake says:

    Few months ago there was Angewandte paper from a well-known european Tot synthesis group, a linear synthesis of a dimeric natural product that used Evans auxiliary methodology wholesale, to make a molecule within a fairly short linear sequence. There were few good steps, like 1,5-diastereocontrol, all precedented and it was enjoyable to see a well-understood methodology put in a good use. It is also a good thesis project for a grad student because he was able to finish this class of molecules with his own hands, and get two first-author papers out of it, in good journals. As it happens he got a postdoc job at our institute (in the best group here) and they are happy to have him.

    Also, Salino, I have met some incredibly arrogant grad students in one group at Harvard and I noticed that the more insecure + frustrated + eager they were, the more they relished talking other professors/groups/people down. Several jerks excelled not at chenmistry but rather at hazing like cadets in a military academy – they emulated each other and though that since they were made to suffer by jerks like themself, after year or two they earned right to inflict the same on a fresh batch of juniors – quite incredible. I suggest that your try not to think that way.