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Pinnatoxin A   

10 March 2008 30,125 views 66 Comments

Zakarian and Stivala. JACS, 2008, ASAP. DOI: 10.1021/ja800435j. Article PDF Supporting Information Group Website

What a beast of a molecule! This ‘un’s been around for a while, though, and has several synthesis to it’s credit – most notably that of Kishi. With a target this size, we’ve got to start with a thorough retrosynthesis. Splitting the molecule in half, separating the two polycyclic systems, the unification was planned via an alkylation of an aldehyde, which could be reoxidised for formation of the A-ring imine. RCM could then be used to complete the macrocycle.

The BCD- dispiroketal would be generated from a 1,4-diketone, built from two fragments unified in a sp2-sp3 Suzuki coupling. The other fragment, which would contain the AGEF system, was built in a more stepwise manner; the A ring from a Staudinger reduction of an azide and cyclisation onto a ketone. The G ring was installed via an intramolecular aldol, with the key quaternary stereocenter generated in a Ireland-Claisen rearrangement. The rearrangement precursor (an unsaturated ester) is easily deconstructed into an alcohol partner stemming from D-ribose, and an acid partner built using an auxiliary-controlled alkylation.

You’re probably thinking “damn, that’s a lot of work” (or at least I did) – but a good chunk of the fragment synthesis was presented in other papers leading up to this synthesis. The manipulation of D-ribose and construction of the G ring is in a Tet Lett paper from last year, and the BCD dispiroketal was presented in an Org Lett then too. I think it’s worth a quick look at that paper, as the results from the spiroketalisation reaction is interesting. Both Kishi and Inoue/Hirama used similar chemistry to build this system (in which the desired product contains double anomeric stabilisation), but got different results, attributed to silyation of the C-15 hydroxyl in Kishi’s case. However, Zakarian also noticed that the two groups used different solvent systems, and so he tried a variety of solvents, removing the protecting groups in MeOH, and then continuing the reaction in a second solvent. The effect this had is startling – with non-polar solvents favouring the desired product far more than sticking with methanol.

Construction of the other large fragment was examined more thoroughly in this JACS paper. With the key cyclisation precursor produced by the means suggested in the retrosynthesis, they were ready for a bit of Ireland anion-accelerated rearrangement action. They treated the unsaturated ester with a chiral Koga-type chiral lithium amide, resulting in a Z-enolate, which was trapped as the trimethylsilyl ketene acetal. Warming to RT, this then underwent the crucial 3,3-sigmatropic rearrangment, leaving the desired quaternary centre in excellent yield.

Reductive cleavage of the new double bond and deprotection of the PMB group left a pair of primary alcohols, which after Swern oxidation performed a sweet regioselective dehydrating aldol to give the desired G-ring.

With the bulk of the two main fragments complete, their next task was to unify, using a distinctly old-school lithium/halogen exchange, and addition into an aldehyde partner. The alcohol product was then reoxidised to a ketone, essential for later imine formation. Before that, though, they needed to complete the macrocycle with a bit of Grubbs. Although this reaction didn’t go badly, it’s of no real surprise that more than one product was formed, if one considered the degree of unsaturation. Normally this wouldn’t be the kind of scheme I’d bother drawing, but I have a particular liking for the structure of the biproduct – it’s just nice!

With the macrocycle complete, it was time to form the EF ketal, removing the benzylidene ketal with LiBF4 in wet IPA – apparently conditions attributed to Lipshutz – and causing spontaneous cyclisation onto the C-25 ketone. And as I said in the preamble, the A ring was finally installed by cyclising a free amine (generated by displacement of a tosylate with azide, and then Staudinger reduction) onto a ketone – but requiring quite harsh conditions, also used by Kishi in his synthesis.

Perhaps not filled to the brim with new chemistry, this paper is still an awesome piece of work completed by an amazingly small team!


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  • Sean Ma says:


    I understand your confusion. However, I think your opinion might benefit from a better perspective on the literature surrounding this problem. See Ref 3 in the paper and note that Corey and Paquette, both terpene experts, could not penetrate even close to the total synthesis.

    While this solution might not help you make you erythronolide, it certainly simplifies the vinigrol problem. For a similarly beautiful solution to a long-standing terpene problem, see Phillips’ synthesis of cyanthiwigin U (DOI: 10.1021/ja0509836), which doesn’t really have any broad impact, but is nonetheless monumental for that terpene class.

    (And no, I’m not one of the authors, just a “trolling fanboy.”)

  • TheEdge says:

    It is an excellent synthesis of the core. Nobody here is disputing that. But the literature contains a lot of good syntheses of complex cores that either never make it to the natural product, or become land wars in Asia on the way there. If you really wanted to change a synthetic paradigm, you’d find a way to couple really complex pieces into a really complex core instead of functionalizing a well-made core. Myer’s tetracycline synthesis is a good example of the former. It’s clear from Baran’s paper that they should be able to do some of that, but it’s also clear that they could take the post-core construction route as well. It will be interesting to see how they finish it. I’d think they would take the former, but that’s certainly the harder route.

  • Madforit says:

    To Sean Ma:I Agree With you..the Phillip’s Syntheses of Cyanthiwigin U is really impressive ,really..

  • TWYI says:

    ”it’s well-established chemistry that could have appeared any time in the last thirty-odd years without any individual step attracting significant comment”

    I think that’s the whole point here.

    Baran has shown how simple it can be when Paquette/Corey et al were struggling with the synthesis for the past 3 decades. As mentioned above, two experts in terpene synthesis.

    This synthesis serves to show Barans versatility – he is not just an alkaloid man.

  • anon says:

    Hmmm. First up, while vinigrol certainly has some interesting bioactivity, it (like most TS targets) is hardly in the Taxol/vancomycin/tetracycline league; any synthesis is likely to be notable more for the difficulty of building the molecule than for any biological insights that arise from analog-bashing. Under the circumstances, talking about ‘the vinigrol problem’, IMO, elevates it to a status the molecule doesn’t deserve on its own.

    Second, while Baran talks a good game re: PG-free synthesis, I find it hard to see how he’s working to provide *general* solutions to this (and I would consider efficiency in synthesis to be a true, long-standing, capital-P Problem). His approaches to vinigrol, to the welwitindolinones, and other molecules are undeniably brilliant, but again, there’s little there that can be learned and applied more generally; in as much as there’s a take-home message, it’s that Baran’s a really smart guy.

    Compare that work to, say, MacMillan’s two-step sugar synthesis or RCM/cross-metathesis, or the Sharpless AD. These are truly general solutions that can be applied by anyone in a huge variety of contexts, and that can afford massive increases in synthetic efficiency. Ultimately, these methods are much more important than a few clever retros because anyone can use them without needing a unique moment of brilliance to spot a key disconnection or two. From where I stand, all Baran’s cleverness is used primarily for letting people know how clever he is; as TWYI said, his route to vinigrol mostly shows that Baran can ‘do terpenes too’. Is that really something that needs to be proved?

  • yonyodonio says:

    “Baran has shown how simple it can be when Paquette/Corey et al were struggling with the synthesis for the past 3 decades”

    Maybe not so simple…still no syntheses of Vinigrol yet though…

  • grob expert says:

    anon – not seeing how sugar synthesis of macmillan changes more than a cute retro. 5 years and who is using this stuff? while metathesis changes the way we make molecules, the quick sugar synthesis looks like a parlor trick to me. in fact, the same thing was published in TL by barbas and list months before. IMO all the organocat stuff is filled with enormous hype but is not delivering any fundamentally new chemistry.

  • fsu says:

    AS I known, the spiroketal fragment was made by others, actually the authors of this publication did not ever do this before the paper published. No credit (names and acknowledgements), Is it common although the fragment already published (Org. Lett.)?
    After all, the fragment (~20 steps) is not commercial available.

  • KCN says:

    Axinellamines, anyone?

  • HB says:

    It is pretty frustrating to me (although not surprising) that a vocal portion you guys still haven’t “got it.” Perhaps my fellow lurkers do, but that’s just wishful thinking.

    The main difference between Corey and Baran, as far as the manner of research goes, is that the former developed tons of very general and very useful methodology. But as mentioned, Baran is young and still has a long way to go and could very well crank out some interesting contributions. But, as of yet he hasn’t.

    But what people continually fail (usually) to mention during discussions of this fashion is that the number #1 value of total synthesis is in its use as a training ground for students to develop and demonstrate solid skills in synthesis, a skill set pharmaceutical companies need to keep their medicinal chemistry (and especially process development) departments running. Generally, the only thing of practical use produced over the course of such a project is a well-trained synthetic chemist, which is probably of greater value than some half-baked methodology.

    What seems to stroke the ire of Baran’s detractors stems from the inconvenient reality that Phil Baran, et al. are just like the rest of us in the respect that they’ve gotta keep the lights on (get funded). This means he has to play the same game as everyone else to get attention, which is usually in the form of touting less-than-honest or overly-sensational claims regarding one’s research – namely:

    1. claiming that a TS will alleviate some shortage of a natural supply
    2. said TS will give rise to analog studies (More often than not, it won’t – not when it is 30 steps long).
    3. claiming that there is something very unique and original about one’s own research (you see what i’m getting at)

    That being said, Baran deserves criticism for the way he pitches his syntheses. It would be nice to have work really appreciated on account of its own merits. But we all have to admit that realism and honesty have never been the cornerstones of great sales pitches, and when you are trying to make it out in the world, you had better be a good salesman lest you get steamrolled by someone who is.

    All in all, I don’t think anyone who knows what’s what is being fooled by Baran’s “protecting group-free synthesis” spiel. But it seemed to work pretty well for the reviewers at Nature, so more power to him.

    Phil B knows – Pimpin’ ain’t easy.

  • kekule says:

    you must be from a lab who Phil has “steamrolled” or just plain dumb

  • Sean says:

    Dr. Zakarian is moving to UCSB in the summer of 08 to start a tenure track position. I know this because I’ll be a 1st year grad student there and I plan to work with him. Until around June though, he is still in Florida.

  • chemist says:

    Although I have a deep respect for Phil’s work, I think that protecting group-free syntheses would be important for biopolymers (polyketides, peptides, carbohydrates, etc.) rather than for terpenoid or alkaloid systems. For the terpenoid and alkaloid systems–creativity is still the determining factor. Putting on and removing a TBS group is not such a terrible thing (it is usually fast and high-yielding), and basing your strategy solely on trying to avoid a protecting group is strange. The other thing is that in polyketides or carbohydrates selective removal of a protecting group may become a nightmare… Moreover, the protecting groups affect the dr./anomeric ratios and often result in the side reactions, etc. For these molecules a protecting group-free synthesis would be an important advance…
    Scott Miller with his selective protection, and Mcmillan with his fast carbohydrate synthesis are good examples of the scientists that try to provide a general solution of the problems. A solution that could be utilized by everybody and would make the synthesis of the biopolymers easier.
    I don’t think that Phil Baran is trying to provide a general solution.

  • gschool says:

    Phil Baran may not be trying to provide a general solution, but he sure is including the creative factor in his alkaloid syntheses.

  • hexanes says:

    First of all koodos to the authors for a beautiful synthesis of Pinnatoxin. Sean (or anybody for that matter) what is up with the Zakarian move to UCSB?

  • Sean says:

    I don’t know for sure, it might be personal reasons. But the good thing is that moving from FSU to UCSB is a step up in career, and he is bringing graduate students with him which is another good sign. It did seem odd to me to spend nearly tenure time at a university and then suddenly transfer to another school. Maybe it is the campus, UCSB has a really really nice campus.