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Maoecrystal V   

13 December 2010 38,110 views 61 Comments

Yep, I didn’t quite manage a new post – blame it on the ‘flu.  But I also don’t want this article on Maoecrystal V to fall between the cracks.  I think it’s awesome that this target has been conquered, but I’m not sure that this paper is the fullest explanation of the science used to do it.

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61 Comments

  • Gilgerto says:

    Should we understand that you are no more a medicinal chemist?

    [Paul Docherty is a science writer and blogger based in London, UK ]

  • HPCC says:

    Me hates to nitpick; however I understand in your discussion of Scheme 2, the resulting Rh-carbenoid species inserts into the cyclohexyloxy O-H bond, and not the phenolic one, as this one’s suitably protected as the MOM ether (or acetal, for what it’s worth…)

    A tough molecule, really. Possibly 2010′s greatest accomplishment from the synthetic slavery world. :)))

  • Frederic says:

    Mesmerizing work, arguably one of the very best this year. Absolutely LOVE the oxidative acetoxylation!!! :D

  • Joe says:

    The transition states in your fig. 3 are hardly the same molecule as you depict. I mean, the configuration of the new stereocenter has been switched around.

  • krest17 says:

    So, what’s next my friends? Any idea?

  • HPCC says:

    I’d personally like to work on Aphanamolide, the new limonoid in Org. Lett. See link in “What I’m Reading” section above, top-right… It has a few bits and pieces of the evil azadirachtin, my postdoctoral nemesis… :-)

  • Anon says:

    How is the synthesis not based on a stolen idea?

    The OL last year disclosing the strategy is nearly identical to Baran’s article in the same issue of OL (and cited in the JACS paper). I understand that two groups can have the same idea independently, but what I find disturbing is that one of the PIs on this synthesis was a postdoc in Baran’s lab while Baran was working on Maoecrystal (see the footnote in Baran’s OL). Its pretty hard to escape the conclusion that he left Baran’s group knowing the strategy, rushed to repeat the work, and then quickly published in OL so that he would be the first to publish.

  • JJ says:

    The next beast to fall to total synthesis will be bielchowskysin or providencin for sure.

    • harrypotter says:

      Who is working on these targets, any idea?

      • Quality Control says:

        KC is working on bielchowskysin. I was working next to a guy involved in the synthesis. And let me tell you it’s a bitch of a molecule.

        • HPCC says:

          I personally worked (under KC) on bielchowskysin. Believe me. QC is right – it is purely a bitch of a molecule. Amen. :P

          • JJ says:

            Ditto! My buddy worked on the molecule with Sulikowski at Vanderbilt and it is quite troublesome. I also remember seeing a poster from a Stoltz group member on this molecule.

  • antiaromatic says:

    So a few things I wanted to bring up regarding this molecule. First some chemistry for those who are actually interested in that sort of discussion. I think the Me4NBH4 reduction of the ketone to deliver hydride from the more hindered face deserves some comment. In the paper, they say, “We attribute this diastereoselectivity to the directing and accelerating effect of the cationic-pi interaction between between ammonium salt and the phenyl ring…” I simply do not buy this argument. The cation-pi interaction would be present even with NaBH4. Granted the overall effect would probably be lower since the positive charge is actually centered on the protons in the tetramethylammonium borohydride, but even if the cation pi interaction were in effect, it would be INCREDIBLY crowded along the top face, and it’s even less likely that the hydride could be delivered from that face. Second, this type of reagent is exceptionally non-coordinating, so even if cation-pi were in effect, there would be no reason to assume that the hydride was tagging along. Along these same lines, Evans showed some years ago that this type of reagent (in particularl the triacetoxyborohydride variant) is incredibly good at being directed by alcohols or ethers. In this case, the solvent is methanol which is known to form the trimethylborohydride in situ, and the MOM ether on the aromatic ring is almost perfectly poised to direct this hydride source from the top face of the molecule.

    Second, regarding Anon’s claim that this is “based on a stolen idea,” your judgement must be clouded because this synthesis is NOTHING like the original OL disclosure. You can say what you want about the OL’s similarity to Baran’s approach, but there are a few points that I think are worth mentioning. First, the idea of an intramolecular Diels-Alder to establish the core structure is not ground breaking. Essentially EVERY group has had this same retro, and it’s really not that far-fetched. Second, this new approach has absolutely NOTHING to do with Baran’s initial report (or theirs for that matter). If you read the paper, you realize that approach could not be used to fashion the complete skeleton b/c it was too strained to make one of the last bonds. This is why the Rhodium insertion is so fantastically clever. It solves the core issue of how to establish all of the ring systems. Baran absolutely did not allude to this in his OL, and as such, the problem was really solved by their group.

    • robot says:

      the initial oxidative arylation is exactly the same in both papers, and particularly stinks of stolen material, IMHO

      • rhino says:

        is there anything that isn’t “stolen”? every day that you don’t float away from the earth, does someone say that you stole gravity? just do your work, learn, be thankful to those suffered the same kind of anguish as yourself in understanding chemistry, and realize that science is greater than yourself. in other words, just chill. no one person ever did anything alone. saying ideas are stolen is a slippery slope. i’m not trying to be a jerk, and am not experiencing any angst as i write this, rather i’m urging those who are prone to destructive thoughts to step back and realize your place.

        • no mo says:

          rhino has no specific rebuttal to robot’s observation
          just “everything is stolen”

          I’m not experiencing any angst…
          I’m not a racist but…
          don’t out yourself too obviously now

          accusations of “destructive thoughts”!
          hahahaha – give me a break

  • MW says:

    such a neat looking molecule. quite impressive synthesis. there things that surprised/confused me -
    -hinging the synthesis on a late-stage hydrogenation of a C=C to C-C, in the presence of another C=C, using lindlar’s catalyst?
    -no compound “2d” isolated? (the forth assumed IMDA product)
    -interesting allylic oxidation used instead of SeO2?

  • European Chemist says:

    So let me see if I got it right:

    A Chinese research group who this year alone has completed quite a few other nice targets beats the whole synthetic community to Maoecrystal and all of a sudden it’s only because they stole it from Phil Baran? You’re honestly trying to convince me that the guy who made Vinigrol and Palau’amine in the same year would not be able to implement whatever his master plan for Maoecrystal faster than these guys? I had heard of a Baran fan club, but this is waaaay too much IMO.

    • krest17 says:

      Anyway in TS idea is not that important (if at all) as in methodology. I had 100+ ideas how to finish my target – guess what – none of them worked out :-)

    • no mo says:

      an author on the other group’s paper was a post-doc in the baran lab while the synthesis was ongoing – ’nuff said

      at best any outside observer could conclude that it smells bad and that one may never know – not a conclusion which allows a credible, positive view of the group with that former post-doc

      oh, and f*ck Baran and TS

  • Gilgerto says:

    I would quite like to see a ”modern” synthesis of Ryanodol!
    http://stoltz.caltech.edu/seminars/2004_Trend_Zhang_Ebner_Tambar_Krout.pdf

    • The Next Phil McGroin says:

      That Deslongchamps Ryanodol work is just amazing. Well-written papers, beautiful work. While I agree with the premise that modern synthetic techniques might allow for a “shorter” route to ryanodol, I find it hard to believe a more elegant route or subsequent paper possible. Furthermore, is it “worth doing”?

  • CR says:

    Don’t want to rain on the love fest here, but I said it before and will say it again…meh.

  • CantRead says:

    Yeah me too CR,I’ve had enough of this crap. i cant wait for something actually interesting like a good organocatalytic aldol, and neat gold cyclization………

  • domino says:

    I think he was being sarcastic cascade…………

  • CR says:

    Obviously “CantRead” was being sarcastic. His/her opinion aside, I still say this is nothing special. Some have differing opinions and that is good – that’s what we should be doing. “CantRead” wants to express their opinion in the manner with which they did – doesn’t detract from my initial opinion (and continuing opinion) of this synthesis of – meh. Nothing special, nothing of note here. Just another example of being able to synthesize anything.

  • cascade says:

    meh

  • Organic chemist says:

    Here comes the landmark synthesis,
    http://pubs.acs.org/doi/abs/10.1021/ja110198y

  • HPCC says:

    It’s always great to read this blog and look at the “scrumptious schemes” you Chem Draw. Looking forward to your being back sometime soon. Take care!

    The Highly Pressurised Canadian Chromatographer

  • RED-OX says:

    I have a few questions I was concerned about, the first one being the Lindlar Reduction of one olefin over the other how do you explain the selectivity? The other reaction was the Rh assisted O-H insertion, why not at the phenol.

  • cascade says:

    Just read the Begu Sezen case (ya…C&E is a bit late in this part of the world). Anyways, what happens to Sames..is he off the hook? Shouldnt the university fire him first? I heard him boasting about his work in a conference where he said “we did it…’ and now its “Bengu did it”. He should add, I was just writing a paper…ooops did she get charged for plagarism….I had nothing to do with it then…I just happened to be around.
    If the work was real and repeatable, today we would have been calling it “Sames C-H activation” and now its Bengu’s fraud!

    • no mo says:

      yea, it is so
      C&EN must be very late getting to you – it is old news

      however the “mine” vs “hers” observation is correct
      some labs avoid this type of incident by telling a student or post-doc not on the project in question to independently verify representative results PRIOR to publication, this may not be fail safe but would appear to be valuable – particularly in cases of egregious fraud where it’s not a matter of 50% vs 85%, but a matter of whether it works at all

      • stop says:

        both labs i’ve been involved in have done this type of “independent verification.” it also lets the person developing the method know if there is anything unclear about the reaction process, from set-up to work-up. and, it doesn’t really take much effort.

  • No doubt some awesome work!

    Just thought I would also try and spread the word about my new blog. I’m a first year PhD student and I thought I would try and document my (few) successes and (many) failures in blog form.

    http://amonkeywithatypewriter.blogspot.com

    Cheers!

  • Schmon says:

    don’t believe the yields in that paper. The Chinese oftentimes tend to exaggerate’em.

    • jing li says:

      You shut up! You can show your molecular, do not say unrelated to the subject!

      • bad wolf says:

        From now on this will be my response to everything. I can’t wait for the next seminar…

      • Qsar says:

        Too funny! Seriously though, I don’t trust the chinese either.

        • InfMP says:

          that sounds dirty.

          You can show your molecular!!!

          google translate should really be used more. Post Doc applications sound just as bad.

  • jing li says:

    Great! wait for Dr. yang’s other molecular beast that may be completed.

    • KCN says:

      Maitotoxin?

      • Starvinmarvin says:

        Honestly, I hope KC would be the first on that one at least, and judging by his last two back-to-back JACS communications he might be only months away from maitotoxin :)

        • Red-OX says:

          Yah…right I hope KC is not trying to complete maitotoxin by doing wittig/dibal/swerns. That paper was a joke

          • Starvinmarvin says:

            So, you’re saying completing a synthesis of however obscenely complex molecule without gold catalysis, or any other fancy “flavour-of-the-month” chemistry is not good enough for scientific community to appreciate it?

          • cascade says:

            That would have been a joke if this sequence was not targeted towards maitotoxin. However, since KCN group is targeting a structure as huge as maitotoxin I think its ok. Who else if going to make that thing and how different can it be than the current route? This synthesis if completed will be counted as a one of the great feats in organic syntehsis…I think.

          • bad wolf says:

            it will count as one of the great feats in organic synthesis, at least in “Classics in Total Synthesis Volume 4″

  • anon says:

    any new posts? gossips?

  • drm says:

    good post

  • Zeke says:

    New post by Valentine’s?

  • Schmon says:

    Making maitotoxin is a waste of time/resources, nobody is gonna check that synthetic route, therefore, you’ve gotta just trust the KCN group & its chief…..but would you? Instead, developing some new practical methodologies is what everyone should be doing.

  • anonym says:

    chemdraw sucks. what does david macmillan use to draw his chemistry schemes?

    • ChemCowboy says:

      If you start with the ACS 1996 settings, then make all the bonds thicker, and make all of the atoms bold, you start to get something that looks a lot better. Then just start drawing things in perspective, and you’ve got MacMillan- or Baran-looking structures. Then publish it in a journal where most of the bonds disappear when you view it online so it looks like a bunch of floating atoms…

  • nerd says:

    Anyone check out the Vanderwal strychnine synthesis in Chem Sci? 6 step longest linear sequence! Takes a major hit in yield on the penultimate step, but still solid work overall.

    • CR says:

      Okay, I’ll be the first one…really, this is in Nature?!? The Toste work is nothing more than Org. Lett. Nature is really stretching its bounds to get chemistry in there; at least be something worthwhile…

  • Vedran Hasimbegovic says:

    Absolutely jaw-dropping! This synthesis reminds me of Paul Wender’s meta photocycloaddition route to Cedrene in that it will be extremely difficult to match. Looking forward to more from Zhen Yang.

  • Vedran Hasimbegovic says:

    Ooops, forgot to add:

    Quote: “Starting with a rather unconventional coupling, the group quickly built the first quaternary stereocentre. This oxidative coupling reaction is unfortunately not discussed in any detail, and neither is the synthesis of the aryllead intermediate, so we’ll have to wait for a full paper to understand their rationale for using such exotic – and presumably toxic – conditions (figure 1).”

    For a discussion of this method see Organic Syntheses, Coll. Vol. 7, p.229 (1990); Vol. 62, p.24 (1984). Being an Org Syn method we can assume it is fairly reproducible. Anyway, check out the discussion section for more info:

    http://www.orgsyn.org/orgsyn/prep.asp?prep=cv7p0229

    Cheers!

  • [...] member of that family that I’e blogged – the seminal synthesis of Maoecrystal V made my December 2010 column in Chemistry World.  I remember when I wrote that piece that the pseudo-3D structure used to represent the target [...]