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Bryostatin 16   

4 December 2008 101,323 views 143 Comments

Trost and Dong. Nature, 2008, 456, 485. DOI: 10.1038/nature07543. Article PDF Supporting Information Group Website

Ah, back in to Nature for another nibble at organic synthesis for the biologists, and some slightly-odd looking structures. It took me rather a while to get used to COOMe rather than CO2Me… However, one thing guaranteed with chemistry in Nature is quality, and it certainly shows in Trost’s latest work.

The target is one he’s been working on for quite a while, but with good reason, as it’s quite a tasty number. To quote the paper, they speak of ‘exceptional biological activity’ and back this up with references to use of bryostatins in the clinic. However (and isn’t this always the stickler…) it’s not exactly bountiful in abundance – apparently only 18 grammes were isolated from 14 tonnes!! That’s quite a column…

Anyway, on with the synthesis – and the starting point, as usual, is assembly of the fragments. One of those was already discussed in a previous Trost paper on this molecule (last year), but a different, and shorter synthesis is used here. One step I found particularly interesting was a propargylation of an aldehyde using chemistry developed by Teck-Peng Loh a few years back. Interesting brew of reagents, but it’s a neat way to build this homo-propagylic alcohol. However, the result is still racemic, so an oxidation and CBS reduction was used to induce an enantiomeric excess.

For the coupling of this fragment with a (somewhat) related partner, Trost used his own funky ruthenium chemistry. In this case, the situation is complicated by the highly functionalised nature of the partners; ligation of the metal to the olefins in both SMs or the product is the reason given for the lowish yield. However, the starting materials were easily isolated, resubmitted and a decent amount brought through.

Transformation of the vinyl silane into a vinyl bromide was done with a bit of NBS – not a reaction I’d thought of as being so high yielding (98%) or selective in such a substrate. Next up was a rather sweet series of acid-mediated reactions in one pot, selectively removing the TBS group and performing a neat transesterification/ketalisation. Really, a very neat way to put in that ketal.

The vinyl bromide was carbonylated rather nicely using fairly traditional reagents to get a decent yield (83%). More traumatic to my eye was the required selective saponification of the beta-hydroxyl methyl ester. I’d probably be thinking about ways to use that hydroxyl to differentiate the esters, but no way would I have fell upon the reagent used by Trost. A bit of trimethyl tin hydroxide, and tickle with the bunsen did the job amazingly well, which Trost suggests is down to the lewis acidity of the reagent. This allowed it to be directed by the hydroxyl, and deliver the impressive selectivity. I’m again impressed with the robustness of the substrate, though – heating under (admittedly mildly) Lewis acidic conditions…

Last is a seriously impressive run of reactions – firstly, a palladium mediated coupling of the diyne, using Trost’s chemistry again. The selectivity, again, is hugely impressive, though as with most macrocyclisations, dilution was key to keeping the reactivity intramolecular. Quite an impressive example of a new means for macrocyclisation, though (even if the yield is only moderate). More impressive was the fact that they were now perfectly set up for the final cyclisation. After attempting this with a few different gold catalysts (a regioselectivity problem was apparent), they struck gold with the reagents shown (I should write the Angewandte captions…).

After that, all that remained was pivalation and deprotection; again done with apparent ease, rounding off an incredible synthesis, using impressive methodology in exactly the right way. A master class…

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143 Comments

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  • vik says:

    crabs…wonder which country you are from

  • ,,, says:

    More than 100 comments! Can we call this paper “the most blogged”?

  • InfMP says:

    i did not understand the english in the crabs post eithier

  • John Wood says:

    @ tot. syn.

    I think we are about ready for another post.

  • lovechem says:

    I love it

  • yugo says:

    massadine

  • TWYI says:

    Absolutely superb stuff from Aggarwal.

    A shoe in for one of the Oxbridge chairs when the current incumbents retire

  • name says:

    All of those backing the publication of this article in Nature are total douches… seriously – just because we don’t think this particular paper merits being published in Nature doesn’t mean we don’t think any organic synthesis deserves to get published in nature. Don’t confuse the two issues…

    In fact, many of us would love to see more organic papers in Nature/Science. But it should be the best papers – not the ones with the most influential authors.

    I, for one, think that Nature and Science should lead the way in trying to demystify the reviewing process. And it’s so simple – just remove the name of the authors when the article is being reviewed. For God’s sake, this is NOT something totally revolutionary that will mess up the system they have in now. It’s a very simple modification to the process and could be implemented tomorrow if they chose to do it..

  • Devil's advocate says:

    You all seem to agree that Aggarwal’s work is nature worthy; however, while it is a useful reaction, its not really new. Again it is just an extension of what Aggarwal has already been able to accomplish with primary alcohol carbamates (ACIE 2007, 7491) using stereodefined secondary alcohol carbamates instead. Maybe it doesn’t deserve to be in nature either?

  • ? says:

    Aggarwal’s work is defintely nice but as Devil’s Advocate pointed out, is just extension of idea from previous work. Even for the ACIE 2007 paper, the original ideas have been put forth before by several people, albeit with less of marketing skills (see for ex. Synlett 2004, 2275-2280).
    Aggarwal has definitely improved the protocol and a method for tertiary alcohols with such high selectivity is most welcome but due credit should also be given to previous workers who thought of it first.

  • How About Some Alkaloids says:

    Not to take this discussion off its retracking into a battle for or against publication in Nature, but it seems to me that there have been lots of good total syntheses recently that have not been discussed or blogged. What about Baran’s massadine? With all the interest in paluamine, I would be curious to see what people thought of that work.

  • name says:

    OK… regardless of whether the precedence had been set for the Aggarwal paper or not… it seems that people get upset about a paper like Trost’s simply because they assume that a Professor at a small university without a name could not fathom getting the SAME EXACT synthesis published on Nature… right?

    So the question comes down to… does the author name matter or not? And if it does (and for the record, it absolutely does), then why not fix that part of the process so people can argue about the merit of the work and not whether politics was involved!

  • Johnny Bravo says:

    Name, do you think removing author names will really make a difference? Yes, it’s a simple ‘solution’ and that’s why it won’t work. Really, how often do you see papers where authors don’t start a sentence with “We recently…” followed by a reference to one of their own papers? Oops, now the reviewer knows where the paper came from.

  • name says:

    I understand that many times it’ll still be possible to figure out who the authors are… but at least it keeps the reviewers guessing sometimes… and although this wouldn’t fix the problem completely, it would be a start – and isn’t a little fix better than no fix at all?

  • European Chemist says:

    Hi everyone

    Interesting discussion started here, although it shouldn’t be overshadowing the chemistry. Maybe the commenters here don’t really have much to say about some of those amazing reactions.

    We have to face it: in the world of peer-reviewing, there’s always going to be a fair amount of injustice. And that’s simply because peer-reviewing is SUBJECTIVE.

    Any reviewer can ditch a good paper by saying things like “it’s an extension of previous work” (as if PLANNED RESEARCH wasn’t a succession of small extensions to something we already know!!), “the chemistry isn’t really unpredictable” (as if any serious researcher would routinely try reactions where he had no clue of the outcome) or “the yields aren’t really spectacular” (unless they are all above 90%!). An editor knows his reviewers and can really make a world of a difference when choosing whom to send a manuscript to for reviewing.

    It would be dumb to come here and pretend it doesn’t make a difference whether the chemistry being evaluated comes from Trost or from some obscure, unknown research group in Asia (or Europe). The bottomline is, you’ve got to earn a reputation before you can aspire to get something like this Total Synthesis in Nature. But if Trost, Baran and whoever are making that kind of thing happen, why should ANYONE be negative about it? It definitely increases the exposure of our field and definitely helps make the point that Organic Chemistry is not dead and is still quite “the thang”. And it further sets a precedent for more total synthesis work to get into Science and Nature, which is something we ALL should be pleased about.

  • name says:

    “The bottomline is, you’ve got to earn a reputation before you can aspire to get something like this Total Synthesis in Nature. ”

    I couldn’t disagree more! You don’t earn the right to publish on Nature/Science based on your previous work or reputation. You earn it based on what’s on the manuscript – end of story! People like you believe that Trost has earned a freebie and that should not be the case at all!

  • Liquidcarbon says:

    name: unless it’s a new assistant prof., reviewers know from the first few lines who is writing it. There is no guessing. Do new assistant profs often have smoking hot material ready in <5 years? I doubt it.

  • Barry says:

    Quit picking on me, you big meanies!

  • John Wood says:

    Got any Assistant Profs in mind that you think will be putting out hot stuff in 5 yrs? Eric Ferriera @ CSU? Abigail Doyle @ princeton? Sarah Reisman @ CalTech? Anyone else in mind!

  • optional says:

    vy dong at UT

  • Herr Lipp says:

    Toby Ritter @ Harvard? Seth Herzon @ Yale?

  • Gilgerto says:

    Scott Snyder @ Columbia
    Neil Garg @ UCLA
    Tristan Lambert @ Columbia

  • % says:

    corey stephenson @ BU

  • John Wood says:

    the ones above stephenson were a given, but I was unsure about that one

  • SB says:

    I think if you go back and read Trost’s two Science papers from the 80’s on chemoselectivity and atom economy, this paper kick’s some pretty serious atom ass. I think you have to take this paper with respect to these ideas as he defined in mind, and then it seems to warrrants a Nature publication.

  • name says:

    SB… my guess is you are either from the Trost group… or another big name group that gets away high publishing undeservedly in high profile journals because of your boss’ name

  • SB says:

    lol. No, I am not so pretentious. I am from a rather small group at a modestly good department. I do, however, find it amusing how cynical and belittling people are in this field. I enjoyed the paper very much. Not any groundbreaking work, but a very nice application of his chemistry is demonstrated. Before you so readily attack people, perhaps the time would be better spent improving your own chemistry. Maybe then you would learn to appreciate the elegance of such work, and the short-comings of your own.

  • name says:

    SB… I’m not bitter… I’m moving up the food chain too and soon I’ll be publishing undeservedly at high profile journals when my work is mediocre… so don’t get me wrong – I understand how the game works and so I’ll try to get my share of the pie. But at least, when I do I hope to have the presence of mind to have a look at my work and say that it should have gone to a lower journal but only went to a higher journal because of my boss’ name.

    Meanwhile, you have all these people sitting on their high horses ALWAYS claiming their work was worthy of a high profile journal. Although many times it may very well be, you cannot be blind to the times it is absolutely not worthy of it.

  • A. Sagadevan says:

    I am really appreciate that this total synthesis is really good and to publish in such valuable journals is so great.
    good luck…………….

  • Mr. Johnson says:

    I really like how he installed the northern hemisphere with a Finkelstein reaction. Really nice use of modern atm’s.

  • SB says:

    Crab Syndrome:

    This is otherwise known as the “leveling effect” in psychology.

  • orgchem says:

    Hey guys did you notice that Keck has published a more complicated bryostatin analogue in the Org Letter. So it seems that the publishing journal depends not on what you do but who you are.

  • @ orgchem says:

    @ orgchem

    If you had bothered to look at the references you would notice the same strategy has been published in JACS earlier this year (JACS, 130, 6660). So if you want to compare this with a ‘big name’ guy I would look to Wender, who published byro analogues in JACS and then published extensions of the same synthetic strategy in OL. I’m not talking down on either synthesis, but the prestige factor is obviously going to go down when the synthetic strategy isn’t new, and you just switch some functional groups.

    While I’m on the subject it’s also worth noting that the Trost synthesis is a fair number of linear steps shorter than this ‘simplified’ analogue. What’s the point of an analogue when you can make the natural product in fewer steps?

    • GoSynth says:

      What’s the point in making the natural product if the natural product isn’t biologically active (the simplified analogue from Wender is). Don’t forget to check your activity profiles!

  • Cat Herder says:

    more potency and/or better PK

  • @ orgchem says:

    Well more power to them if they get a drug out of it, but I would say that the difficulty of doing so increases greatly (more than exponentially) with the number of steps in the route. Analogue synthesis should be shorter than natural product synthesis not the other way around.

    I never feel like anything comes out of these projects, but I have never worked on one. Are there any marketed drugs that are the product of academic analogue studies?

  • orgchem says:

    @orgchem, let me explain why analogues are made,
    1. Natural products are not made by nature to cure human disease, but serve different purpose required by organism such as self defence etc.
    2. So the analogues are made to increase potency as well as to improve ADME
    3. Once that total synthesis of natural product is done, it is dead. it doesnot add anything to literature unless new nethodology is developed/applied.
    4. Analogues are made first a. to find the pharmacophore in a molecule and once it is done, the synthesis is shortened by the process chemists.

  • LW says:

    Now the credit crunch has started to hit in now, and the pharma cash cow is going to stop flowing as richly as it has done in the past, it’s going to get the new set of chemists coming through to dig deep into their brains and start thinking a hell of a lot more innovatively.

    Thank god, because I honestly do despair sometimes when I’m trawling through the ASAP’s.

    Here’s to our governments to screwing up our economies….maybe this will save organic synthesis. Yay…..I think. :s

  • […] Lots of places covered this synthesis, but Guangbin specifically mentioned that he enjoyed reading TotSyn’s coverage of the bryostatin […]

  • fuliman says:

    i can say nothing but good