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Haouamine A   

18 June 2009 15,441 views 53 Comments

haouamine-a

Baran, Burns, Krylova, Hannoush. JACS, 2009, ASAP. DOI: 10.1021/ja903745s. Article PDF Supporting Information Group Website

Oh, we’re going way back here… a whole three weeks before I started blogging!  This brings us all the way back to Baran’s first conquest of haouamine A (and his eleventh paper), racemic, and in this JACS. It was followed up by an Angewandte two years later, but I’ve apparently only covered Weinreb’s synthesis, also back in 2006.  Part of the reason for all this interest is that the molecule seems to exhibit an unusual isomerism.  Baran realised after his initial work that thee were two isomers of the target, configurationally identical, and sharing the same stereochemistry about the 6,5-ring junction.  This meant that the stereochemical divergence must be unusual – with two candidates – atropisomerism of the bent phenol or slow pyramidal inversion at the THP nitrogen.  The only way to probe this effectively was to attempt a synthesis of the two atropisomers, and compare with the isolate.

The synthesis, yet again, is racemic, and proceeds from an intermediate in their first synthesis.  As I didn’t cover that paper, I’ll describe it’s synthesis firstly to make the route more transparent, and secondly ’cause it’s pretty sweet.  The SM was produced very quickly, using a standard enolisation and trapping with an alkylating agent to generate the quaternary center.  The ketone used was then hydroxylamine-d, and treated with a source of electrophilic bromine, causing a 5-exo-trig cyclisation and formation of a nitrone.  Reduction of the nitrone produced the intermediate I’ve shown, which after tickling with a bunsen gave an aziridine.  Rearrangement of this allowed ring-expansion to give a tetrahydropyridine-N-oxide, reduced with a bit of indium.  Nice work!

haouamine-a_1

A simple (but well executed) Suzuki coupling allowed completion of the macrocyclisation precursor (and an Appel reaction too…), which was simply de-Boc-ed and treated with base to prompt alkylative cyclisation in a pretty decent yield.  Interestingly, a stereochemical bias was found where none would be expect – even if slight.

haouamine-a_21

The key reaction was the oxidation of this cyclohexenone to a fully-aromatic system – a reaction with a wealth of possible reagents.  However, some of the more obvious choices, such as manganese dioxide or palladium prove ineffective, so they leapt on a Mukaiyama protocol.  Initial developed to introduce ?,?-unsaturation to ketones, this one-pot procedure did a pretty decent job of oxidising the chiral cyclohexenone to a planar-chiral phenol, returning a respectable mass-balance.

haouamine-a_3

A few more steps were requred to complete the targets, which Baran mentions was also done with enantiomerically pure material (perhaps after doing a bit of semi-prep chiral HPLC).  This gave them both atrop-isomers, a few crystal structures, and an opportunity to biologically profile both.  As it turns out, their IC50s were with in analytical error…

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53 Comments

  • milkshake says:

    with the racemic material IC50 is an average of two numbers…
    Its a beautiful synthesis though.

    • Tot. Syn. says:

      I assume they did the bio-assays with enantiomerically enriched material, as they went through the synthesis again with single enantiomers.

  • PC says:

    nice

  • The Next Phil Baran says:

    Who cares about the synthesis, it pales in comparison to the science. He used the synthesis as a means of checking a hypothesis, which he adequately addressed. I do like the conversion of the bromonitrone to the tetrahydropyridine, that’s pretty! Why should this be in JACS? There is so little science for science sake that it has become the novelty JACS demands. He tried to pump up the biological activity but it is completely unnecessary. This paper stands alone as a good methodology paper, it doesn’t need the jazz.

  • antiaromatic says:

    So what do you guys think of addressing it as a “point to planar” chirality transfer? Is that accurate? I guess I am having a hard time understanding how it is fundamentally different from a reaction that gives substrate induced stereoselectivity. I guess at the core (and i could be missing something), it appears that all they have are the two different diastereomers in the suzuki coupled piece both ring close to give the diastereomeric products, which in principle would just be substrate controlling the stereoselection. Am I missing something?

    • ,,, says:

      given that Baran is the one making these beauties we’re all missing something :)

    • The Next Phil Baran says:

      I agree. “Point to planar” chirality transfer is flourish.

      • Ian says:

        Obviously his point is that each diastereomer does not ‘equilibrate’ in the final (aromatisation) step, something he could not manage in his previous synthesis (used a pyrone cycloaddition IIRC)

        his terminology is strictly true I guess

  • Lopsided says:

    Did you see the scale of the steps???? Gram scale of something this complex. Incredible. I’m just speechless.

  • John Wood says:

    The Boc deprotection that gives 3:2 of desired product?

    I wouldn’t be too proud of that, I am sure there is an assymetric way of doing that.

    besides all else, Total synthesis seems to be too easy for Baran, sorta like Kobe in the Finals.

    • mommystarr says:

      gram scale? this isn’t outstanding in my opinion.from my experience you can do a lot of reactions on gram scale, it’s just a matter of money! and if you have a closer look to the reagents he used, one can imagine that these are neither suitable for industrial synthesis nor cheap (BBr3 is expensive and vey toxic for instance.
      in times of economic crisis people try to get publications and in succession moneym and lose sight of science (as already The Next Phil Baran mentioned).
      I mean I loved baran’s first paper about haouamine a, but this one is awkward.

      • milkshake says:

        BBr3 sure smokes, eats metal, dissolves fingernails and lungs but its nothing extraordinary in a medchem lab – and hardly too costly for a final step deprotection even on a gram scale. A process scale-up is not a point here: no-one needs to make kilos of the stuff. Compared to BBr3 I think you are probably more toxic and expensive.

        • mommystarr says:

          i just wanted to point out, that this paper isn’t worth being in jacs. besides this: you are right, I’m toxic and expensive.

    • ,,, says:

      Not deprotection, alkylation gave a mixture

      • John Wood says:

        to ,,,

        Your right, I just meant the reaction that led to the alkylation, you think they care enough to come up with a chiral auxillary? or are the happy with 1.45 to 1?

        • ,,, says:

          Where would you put the auxillary? You’d have to lock the rotation along the c-c bond formed in Suzuki… Nothing reasonable on my mind…

    • Joe says:

      The compound is a 1:1 mixture of diastereomers at that point because he couples a racemic ketone to a racemic tetrahydropyridine. He sees a 1.45 : 1 ratio of diastereomers after the alkylation because one diastereomer reacts faster than the other (or one of them decomposes faster than the other). Notice he only gets a 79% yield. At 100% conversion ( and yield), he’d get a 1:1 ratio. Which is what he wanted, because he was looking to see if the two structures in the naturally isolated material were atropisomers or not, and to do that you need both.

      In order to get a single product from the alkylation, he would need to make both fragments enantiopure and then couple.

      As an aside, atropisomerism makes my head hurt.

      • ,,, says:

        disregard my previous comment. totally forgot about the chiral center on the enone. Joe said it all.

  • European Chemist says:

    Don’t lose focus: the chemistry is still remarkable, but it is hardly novel anymore. The passage to gram-scale would definitely warrant a JACS Full Paper, but I don’t really get the “novelty” part in this communication.

    Getting over that, I have to say it again: this stuff is amazing in terms of conciseness and as someone put it above, “since Baran is the one making all these molecules, all we can do is wonder what we’re missing”.

  • e56iwe says:

    Completly off topic but I’m sure everyones interested in this one.
    What should a PhD-Post-doc Med chem expect to earn in the UK?

  • CRH says:

    To #1: The IC50 of a racemic mixture isn’t always the average of the two numbers. There have been many cases where the IC50 of the racemic mixture is…say ~800 nM and one pure enantiomer has an IC50 of ~800 nM and the other completely inactive. Doesn’t always have to be an average.

    • milkshake says:

      I think you have a somewhat noisy assay. Numbers that are twice higher or twice lower on a particular day are considered to be “nearly the same”.
      The only way to really compare two very close values is to test the compounds side-by-side, in duplicate.

      If you have a receptor binding assay where one enantiomer is agonist and the other is antagonist or inverse agonist then the outcome of testing racemate is of course not an average.

  • esxatolog says:

    Recently I have stopped understanding the idea of all discussions here. We are mostly discussing the JACS worthiness and personalities, not chemistry.
    About this synthesis… I completely agree that you can scale up a lot of reactions (1 gram – it is not so much) if you have enough materials and time for experimentations to find the right conditions, so this definitely is a matter of money, with some exceptions of course. In this paper Baran had some specific goal and he did it, but the most part of chemistry was done before… in previous paper…
    One more thing… suggestion to TotallySynthetic – what about posting sometimes less impressive total synthesis, not from the top chemists containing even one highly efficient transformation, which can be universal or useful in different ways, may be some non trivial decisions to common problems in reactivity or in stereochemical issues, some original tactics… I am extremely tired of prejudices which prevent people from discussion and being objective (Baran always means great or some other ideas like this, that was just an example!!!). I am practically sure, everyone who is little bit involved in total synthesis, will never miss the paper from top names… everybody has his/her own opinion about it… but all opinions don’t make this chemistry different or even better… you know, sometimes you want to read something, open your favorite blog and see the same names and papers which already have been discussed by people in your lab and moreover instead of some new points of view the comments about worthiness of the paper…

    • perky says:

      totally agree with esxatolog…Sometimes this great blog, IMHO the best one in organic synthesis, looks like TotallyBaran…(and please, don´t misunderstand me).

      • ,,, says:

        It just means that Baran’s work is highly appreciated by many people here. These are opinions, not agenda-pushing.

    • ,,, says:

      You do have a point, although I disagree with the “Baran-liking issue”. It’s just that vast majority of his papers are really great synthetic achievements. This one does serve the purpose but indeed lacks new chemistry (previous publications on haouamine by Baran were damn good). Seems like that (new chemistry) wasn’t really the point here…

    • Tot. Syn. says:

      I get what you’re saying, mate – but it doesn’t seem to work like that. When I blog syntheses that aren’t perhaps as feature-packed, but feature a neat piece of methodology, I get the same pattern of comments: 1. ‘that method was crow-barred in… and the end game is rubbish’. 2. ‘Did you miss the Baran/Trost/Corey paper in Nature?’ 3. blank. It doesn’t seem to drive interest.

      Of course I prefer discussion about actual chemistry, but I can’t force it. The fact if whether a paper is worthy nor not is a moot point- better qualified and experienced people than us (Milkshake excluded) have decreed it thus. More methodology here would be great, but I don’t have the time to write the posts! BTW, anyone who has a paper they’d like to mention, send me a ChemDraw and a few paragraphs and they’ll get a blog post, full credit, and exposure to a few thousand readers…

      Also, I’m planning a series of RetroSynthetic posts looking back at the careers of the top total-synthesisers. First up will be either Woodward or Stork. Who else do you (all) feel is worthy?

      • esxatolog says:

        Thank you for your answer…
        But now you can see what makes me really unhappy, most of the time a lot of people had read the paper of the big name before you even posted it, like you said… but instead of some analysis they usually say something like great… it is true, I agree, it is rather hard to add something to the Baran synthesis, they are usually very unique and extremely creative, may be sometimes little bit limited in their application… like this final step with oxidation, when they just tried a lot of different oxidizing agents to find the best one, which works probably only in this particular case… so my point of blogging something less popular and impressive that people without saying trash will try to reveal the mistakes, find improvements and stress the best parts… to make everybody think insightfully without touching great personalities and banal admiring of actually great accomplishments… this is problem with Baran papers, they are all communications… he doesn’t publish full papers very often, so we don’t know how he figured out his fascinating routes and why he used these reagents… not much area for the discussion… it is extremely tough to learn from them, you can just accept them…
        May be I am wrong, somebody wants just to admire… but then this person can just write great names in SciFinder and read all papers…

        • Atticus says:

          Actually, Baran has published full papers of several of his earlier syntheses. In fact, part 1 of the full account of Haouamine A just showed up in Tetrahedron (an excellent read, I might add). Furthermore, just let me comment that I learn more chemistry from Baran’s papers than just about anyone else’s.

      • krest17 says:

        Would it be possible to send you “a ChemDraw and a few paragraphs” in order to get them posted, without mentioning my name anywhere???

      • Old Timer says:

        Fischer, Buchi, Woodword, Still. Then current chemists: Corey, Stork, Danishefsky, Evans, Trost, Overman, Roush – probably others.

  • Retry says:

    Any idea how many groups trying to make this? Wipf still working on this for atleast 7 years.

  • Borat Ka Bacha says:

    Nice! Very Nice Synthesis.

  • Fluorine says:

    Paul: I’d fancy Emil Fischer.

    Please, although I somehow agree with esxatolog, avoid methods, peptides or biological activity as a reason for posting. This blog is excellent as is.

    I’d love to see more total syntheses in ChemComm or Org. Lett., both seem to take proof of identity and purity more serious than anie and JACS.

    Has anyone here used one of barans methods?

  • Fluorine says:

    is this a joke?

    DOI: 10.1002/anie.200900667

    • milkshake says:

      No its an exciting subfield of catalysis that opens up of a completely new synthetic methodology toolbox. (In few years they will discover that Grignards and organolithiums are even better than zinc reagents, and those carboxylations can be actually carried at the atmospheric pressure and catalyzed by the reaction flask alone).

  • don't bring it back says:

    Great synthesis…Baran’s the man. I just came across a Williams’ paper from a few weeks back. Pretty nice. Any thoughts?

  • mt says:

    Baran is interviewed about his terpene synthesis work in the newest Chemistry podcast from Chemistry@Nature (Scott Miller also comments on the work):

    http://www.nature.com/chemistry/podcast.html

    Direct link to MP3: http://www.nature.com/chemistry/podcast/mp3/chemistry-2009-06-22.mp3

    • The Next Phil Baran says:

      Sounds like the quality of coverage offered by the Discover Channel on scientific matters. Is the average Nature/Science reader actual scientists or are they Time and National Geographic subscribers? He does have a good radio voice though.

  • krest17 says:

    Just an idea: Let’s imagine I am young Professor K.C. Taran. Every year I need new students – and I would like to have the best over the best. What should I do??
    I would take the most popular between students blog (obviously “TotSyn”) and send time to time already prepared posts describing my papers. Additionally, I would put time to time references on myself (like in Nature – Chemistry podcast) and so on. What impression students will get – my chemistry is great – they believe in “TotSyn” choice.
    My chemistry will be popular and it would be always cool to say: “I’m working in K.C. Taran lab – everybody understands, everybody knows.”
    How about that?
    Let’s discuss chemistry finally.

    • BareSterns says:

      eh?

    • Richard Nielsson says:

      Try again.

    • PC says:

      ???????????
      where is the chemistry?

      • HPCC says:

        to paraphrase Krest: in science nowadays, many things have to do with how well you “sell your stuff”. Average chemistry can make it in top journals if well sold – and if iffy cause-to-effect relationships, or dubious claims of being unprecedented go uncaught. Also, if you actually give a compelling lecture, average chemistry can actually be seen as attractive by conference attendees.

        Likewise, doing good public relations (PR) seems to be Baran’s many good tactics. At the end of the day, no one can deny it does create a positive spin for his chemistry, which cannot be detrimental to his attracting outstanding students and post-doctoral researchers.

  • Grant hopeful says:

    Hey Guys,

    I am awfully sure you fellas are more than experienced with writing up grants, and I wanna write one for the NSF. Surprise surprise its a total synthesis, but I feel like I am only using chemistry other people have developed and just using it on a different but similar system. So would anyone know if that is good enough or do you think I should propose some precedence for developing new methodology?

    all suggestions are welcome

  • bandit says:

    i suggest ur in trouble if ur starting point is here….

  • who_cares says:

    Baran has published essentially the same work in Tetrahedron
    Volume 65, Issue 33, 15 August 2009, Pages 6600-6610, JACS (above) and N.Z. Burns and P.S. Baran, Angew. Chem., Int. Ed. 47 (2008), pp. 205–208. Are there special rules for Baran or am I missing something? If I was to do the same thing the journals world reject the manuscript on basis that the work has been published before and/or that it lacks novelty.

    • Martyn says:

      Yes, there are special rules. They aren’t just for Baran though, they’re for anyone lucky enough to be invited to contribute to a special issue of Tetrahedron, where the authors get a “free” full-length publication and Elsevier get to claim that all the big names still do publish there. It’s a pretty clever marketing ploy, because the spam emails they send inviting professors to contribute appeal to their weakest spot: their ego.