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7-Methylomuralide   

5 April 2009 33,991 views 55 Comments

7-methylomuralide

Corey, Shenvi. JACS, 2009, ASAP. DOI: 10.1021/ja901400q. Article PDF Supporting Information Group Website

It was Corey that first brought this website properly off-topic back in 2006 with his synthesis of Tamiflu, which of course, isn’t a natural product (but is thusly derived).  It’s a similar situation with this target, 7-methylomuralide, which is a derivative of muralide, a target quite popular with Corey (with syntheses back in ’98 and ’03).  In this case, a simplification was made to ‘racemise’ the C-7 methyl group by converting it into a gem-dimethyl group – and retaining most of the activity in the process.  In this case, the activity is ‘potent proteasome inhibition’ – a useful tool for biologists and biochemists, and may cause apoptosis of cancer cells.  It’s also a neat, compact target!

Key to the synthesis is a rather neat preparation of beta-keto lactam using a protected glycine and dimethylmalonyl dichloride.  It was then their plan to do an aldol condensation with isobutyraldehyde, basically completing the carbon skeleton in only a couple of steps!  However, this approach came slightly unstuck, as the reaction couldn’t be driven to completion when using their initial substrate, which was PMB protected.

7-methylomuralide_1

They then moved to using carbonyl protecting groups, and the Boc group, initially.  This, at least, gave them the desired product, but unfortunately predominately as the wrong diastereoisomer.  A further attempt, using the Troc protecting group (trichloroethoxycarbonyl), was thankfully pretty awesome in turning over that selectivity, returning a 11:1 d.r.

Next up was an asymmetric variant of the reaction, using a chiral naphthalene-sulfonyl cyclohexanol directing group developed by the group for asymmetric Diels-Alder chemistry.  This choice led to pretty damn nice selectivity (and of course, planarity at the ‘alpha,alpha-position’), setting two new stereocenters in one go.

7-methylomuralide_3

It only took a few more steps to finish the prep – a nice bit of tandem reduction / deprotection was used to prevent retro-aldol, leaving them with only removal of the auxiliary, and beta-lactone formation.  Neat work!

7-methylomuralide_2_1

The paper is spoiled somewhat by a bit of mis-referencing – of Corey’s own work!  Reference ten, which should lead to a paper about the chiral auxiliary and some asymmetric Diels-Alder work… doesn’t.  However, given that the same authors, Corey and Sarakinos, published in the same journal twice in one year, I guess they can be forgiven!  If you dig out the correct paper, Org. Lett., 1999, 1, 1741–1744, you’ll see a rather nice prep of the auxiliary.  Opening of cyclohexene oxide with thionaphthalene, enzymatic resolution and oxidation gives them one enantiomer, with the other only requiring one more step.  Nice stuff!

7-methylomuralide_4

I liked this synthesis a lot, and think the auxiliary directed aldol is a good approach.  However, I wonder if there’s any scope for a chiral-Lewis acid directed synthesis – although there are perhaps too many Lewis basic sites.

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55 Comments

  • ,,, says:

    Let’s see if Shibasaki comes across this molecule – looks like his kind of target with an enantioselective aldol as a key step

  • European Chemist says:

    Chiral auxiliaries, a target with only 3 stereocenters and still it made it to JACS?… Sorry to frown, but I fail to see the “remarkable” bit of chemistry here.
    Anyway, Tot. Syn’s description and comments are, as usual, spotless and extremely clear. You should have become a Professor – if you could give a lecture the way you summarise things here in your blog, every single student would pick Organic Chemistry as their specialisation field. Keep up the great work!

  • Madforit says:

    this target is quite familiar to me…the beta keto ester intermediate is relly unstable, i am pretty sure that the double methylation at the alfa position is to suppress the enolic form of the ketone!Anyway nice target and really good chemistry.

  • Pete says:

    I agree with ‘European Chemist’…The target is nice and I can appreciate the advances made to the previous syntheses (done by Corey himself), but I would have liked to see this in OL instead. I didn’t think Corey was one to use his name to get works into a particular journal, but in this case…maybe he did? Or why not publish a full account of all the work with these recent advances…Maybe that would be more ‘JACS worthy.’

  • MattW says:

    DOi seems wrong

  • Paul says:

    It’s a nice paper and a good summary, but it’s 7-methylomuralide, a derivative of muralide. Not muralide. Named after Omura, the guy who isloated the beta-lactone form of it.

  • snack says:

    you guys need your heads checked. impressed me more than making some goliath halichondrin analog by 80 steps and a cross metathesis. the most impressive chemistry is what gets the most criticisms here.

  • chinstrap says:

    @ snack,

    It is nice work, I don’t think that is disputed, but…JACS? For an methyl analogue when the real deal had been previously reported? As was mentioned earlier, perhaps a full paper would merit it, but I am not sure a communication is in the appropriate journal in this case. If it wouldn’t have been corey or another big name it wouldn’t have been accepted, but that is the nature of game.

    For me, I like goliath 80 step syntheses, but not necessarily CM! and criticism should always be waranted as long as it is constructive or thought provoking/

  • ... says:

    I think that a name other than Corey could easily have published this work in JACS. It’s an important molecule for the biological community. It’s a popular family of synthetic targets. Corey and Shenvi got a synthesis hammered out in 6 steps. 6 steps! Maybe the brevity of the route is what makes this paper seem less JACS-worthy to some. I see this as a pretty serious contribution to the synthesis of this family of molecules.

  • ,,, says:

    Looks likes you’re bending it a little, Snack… Paper is great, no doubt. But there is something about this gem-dimethyl analogue which really simplifies the target… I, personally, really like this communication.

  • ? says:

    The chemistry is decent; however, there is no doubt that if Corey’s name or the like hadn’t been on it that it would have never got into JACS. I don’t quite see what is so spectacular with this work that warrants a communication in JACS. If they had developed a nice catalytic asymmetric rxn, they could have made the molecule in 4 steps. Now that would be spectacular! Furthermore people seem to forget that they had to make the aux. which took 3 steps. Therefore the molecule was made in 9 steps and not 6. Also the starting material, N-trocglycine is not commercial, so including making that its a 10 step synthesis.

  • The Next Phil Baran says:

    Wow! Now compare this beaut with Ciguatoxin. Small compound, lots of stereocenters, lots of neat tricks used to create selectivity, very few reagents (mostly bases and reductions). This deserves JACS if Ciguatoxin does. And for those end justifies the means people its biologically active. Me likey.

  • chinstrap says:

    “The end justifies the means people it biologically active”

    Honest question. Should a strong biological activity be the major factor in journal acceptance (without testing data being given) when the synthesis may be considered light for that publication?

    In this case I am not so sure. We all know abut handwaving and the biological activity issue gets thrown around alot to merit journal rank which the work may not meet.

  • Dazed and Confused says:

    Don’t know what total synthesis of ciguatoxin you are referring to “the next phil baran”. The current one appears in ACIE not JACS. The first was reported in 2006 and is published in JACS, but comparing papers being accepted in 2009 for JACS to those accepted in 2006 is not a valid comparison. Furthermore I don’t see any reason why biological activity alone should merit JACS acceptance. The original target is rarely the compound which becomes the drug; usually an analogue becomes the commercial drug. If they had prepared some analogues, considering how “short” the route is, then maybe it would be more suitable for JACS.

  • The Next Phil Baran says:

    Sarcasm! Hard to express on a website. I don’t care about the biological activity, but it has been considered important before. That’s my point. The synthesis is nice, period. If the awesomeness of this synthesis can’t be seen then I don’t know what to call a great synthesis. Yes the target is small but it has a lot packed into it. It doesn’t use complex catalysts, just good old fashioned chiral auxilaries, etc.

  • fReakNaSty says:

    A short and straightforward synthesis with simple reagents will never please most of you. Lets wait for a 30-step asymmetric shibasaki synthesis and we can have this discussion all over again………

  • ,,, says:

    Come one, people! It’s bryostatin discussion all over again except here it’s pointless.

  • e says:

    I like that the synthesis has something for everyone: clever tricks around problems, insightful analysis, interesting reaction conditions, and applicability to the outside world

  • ludovic says:

    Hi guys,
    for those of you who do not have access to internet or still read Mickey mouse magazine, Shibasaki published Lactacystin in 2006 (which is nearly similar compounds isn’t it?) using asymmetric Strecker reaction.

    Nice blog Paul.
    Cheers.

  • Tot. Syn. says:

    Folks – just a quick heads-up – there’s going to be an absolutely awesome Movassaghi paper in Science tomorrow. I can’t say much more, as it’s ‘embargoed’ until then, but this bad-boy is already odds-on for best paper so far this year. It’ll be going into my Chemistry World column for May, so it won’t be on here until then.

  • sweetcheekz says:

    mickey mouse club for life ludovic

  • Tom says:

    DOI for the Movassaghi paper? I looked on there and I can’t seem to locate it.

    • Tot. Syn. says:

      Steady on tiger – I did say tomorrow. It’ll be on the web sometime today, probably towards the evening. Occasionally I get these articles ahead of the general populous…

      • PotStirrer says:

        Paul, you know you have arrived when groups are sending you their papers ahead of time to get on your blog. Congrats!

  • Phil Grace says:

    i think paul meant that he gets advanced papers through his work with rsc chem world, which in turn gets them directly from science.

  • WestCoast85 says:

    Excuse me but what’s your favorite website to find a post-doc ? If you know a chemist who is looking for a young talent chemist unfortunately without publication, please contact the webmaster… Enjoy the organic chemistry ;)

  • InfMP says:

    the first scheme on this page is very clever in its use of color

  • Boron bodger says:

    The Movassaghi paper is out now. Very impressive. I particularly like the Co-mediated dimerisation

  • hanpisa says:

    I agree. very impressive.

    I like the oxidation step the best. Setting up 4 stereogenic centers in one transformation like that is not an easy task.

    Concise synthesis. No add-hoc! What else can I say but “Wow”!

    • % says:

      Considering what I’ve heard about the Movassaghi group, and how gnarly this substrate is, the words “extensive experimentation” take on a new meaning…

      very impressive synthesis, from a 2nd yr graduate student (& post doc) no less.

  • InfMP says:

    a canadian postdoc too. cool.

    Ok, so this science paper is amazing. The synthesis is unreal, and the written language is extremely elegent. Last time we saw tot syn in Science?? 2005 I think, with Miyashita’s Norzoanthamine.

    There is no debating Science-worthy and all that endless crap. This is seriously cool.

    J’d in my P

  • The Next Phil Baran says:

    That paper sucks! how is that science worthy?

  • GYA says:

    must agree to some extent. the biosynthetic hypothesis is fairly obvious. the synthesis has been done already aside from the sulfur aspect and the placement of the sulfurs is fairly obvious. the work is impressive though so i don’t have too much of a problem, but not a overwhelming choice.

  • The Next Phil Baran says:

    Yay for the non-cheering section. Science (the journal) does not equal good. Good Science equals good!

    • *rolls eyes* says:

      Not sure if you realize this, but your idol is targeting verticillin and its related “non-Science worthy” natural products…

      • The Next Phil Baran says:

        Do you understand sarcasm? The Next Phil Baran is a play on “the next Woodward”. Sheesh. Baran is an amazing synthetic chemist but he is not my idol. I like good strategy, good science, etc. I just hate hype.

  • InfMP says:

    haters.
    how many science papers do you have?
    I have none.

  • advil says:

    baran is not and has never targeted verticillin. too obvious of a biosynthesis.

    You’ll see what indole problem he has targeted in a few days in JACS.

  • GYA says:

    nice! can’t wait to see phil’s latest conquest. can’t even share the molecule? It doesn’t matter any longer.

  • mushroom says:

    My main concern with Baran is the inability of reproduce his supporting information… they are really bad, always things missing… no matter how hot a molecule is, people should be more careful with that!!!

  • mushroom says:

    sorry hit the button to early.
    however have you check Movassaghi SI, it is absolutely amazing, every single detail!!! that ca give you an idea of how rigorous an author is… And not only in the science, any other paper is the same, easy to follow and super easy to repeat!!
    Anyway i think Movassaghi paper is amazing!!!

  • Hamburgler69 says:

    baran has some of the best supp infos. out there. editors dont even require them for angewandte, yet he makes his students do them anyway. Check out some if not most others (cough, du bois, cough) and they pale in comparison in terms of spectral data and procedures…..

  • GYA says:

    i agree. i haven’t looked recently, but Baran’s SI has been top notch since his independant career started. look more closely!

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