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Himandrine   

28 June 2009 41,296 views 63 Comments

himandrine

Movassaghi, Tjandra, Qi. JACS, 2009, ASAP. DOI: 10.1021/ja903790y. Article PDF Supporting Information Group Website

Okay, I missed my ‘I’ll blog it by Saturday‘ deadline by a day, but it’s taken quite some time to get my head round these structures.  And beer.  However, I think I’ve got there – so ladies and gents – on with one of the best syntheses this year.

First up scheme-wise is a rather nice Suzuki coupling.  Taking a standard boronic acid, mixing in a vinyl-gem-dibromide, they achieved a selective E,E- product in cracking yield.  However, this came at a price, as they had to use thalium carbonate in the mix; not a pleasent compound.  Quoting directly from the SI, ‘Tetrakis(triphenylphosphine)palladium (1.54 g, 1.30 mmol, 8.00 mol%) and thallium carbonate (15.7 g, 33.0 mmol, 2.00 equiv) were added sequentially…’ – urgh!  I’m sure Movassaghi tried several sets of conditions, but I’d have used quant. tetrakis before I touched the thalium bottle!  However, the student in question get permission from me to use the Bas-Ass Pot-Stirrer badge in this post.

himandrine_1

The free vinyl bromide (the less-reactive of the pair) was then avaliable to a bit of Buchwald chemistry, doing a copper-mediated coupling with azetidinone.  Normally these amides are crap with BH amination chemistry, but I reckon the strained-ring improves the avaliability of the N lone-pair, and gives the reaction a bit of a poke.  A bit of enolate shennanigans, and they were set to use their tetra-ene in the Diels-Alder fashion.  Four stereocenters were set in excellent yield and selectivity, but that wasn’t enough – a bit of tickle-four allowed a Mukaiyama aldol to complete a third ring, and provide a nice synthetic handle.

himandrine_21

Time to put in two more rings – but this time they bought one in (no point in over-doing it…).  Lithiation of the imine and Michael addition into the enone provided the expected imine intermediate.  This tautomerised to the enamine, which added back into the ketone, providing a cyclohexanol in cracking yield and efficiency (I don’t have the actual figures for this).  This follows a hypothesised biosynthetic route, but it’s still pretty inventive!

himandrine_3

As can be seen from the tightly caged structure, they had a few more ring junctions to form.  Even though they’ve only got one protecting group in place, a remarkable selectivity was had.  A bit of the Vilsmeir reagent allowed an enolate-type addition into the chloro-imine to form a highly-activated imine intermediate (+ 1 carbon).  The free (but highly hindered) tertiary alcohol was then able to add-into the imine, spitting-out dimethyl amine to give a dihydrofuran.

himandrine_4

This DHF didn’t hang-around long – addition of DDQ opened the ring to form an alcohol and an aldehyde, which was immediately oxidised to the free-acid and methylated.  (No pussy TMS-diazamethane for the Movassaghi group – they’re using free diazamethane for this!  Gotta look-after that non-ground-glass kit!).  Removal of the sole protecting group then had them ready for yet another impressive cyclisation.  Treatment of the cyclohexenone with NCS promoted addition of the now-free piperidine into the ring, and completion of the carbon skeleton.

himandrine_5

I’m not going to get into the mechanism for that transformation Movassaghi did quite a bit of work on it, and if I did I’d have transribed almost all the paper.  Read it.  Really, one of the best paper so far this year, cementingMovassaghi as a top-rank total-synthesiser.

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63 Comments

  • thiosulfate says:

    The intermolecular michael-mannich cascade somewhat differs from the biosynthesis (at least proposed by Baldwin) which comes from a linear polyketide precursor. If you read the SI, it’s pretty amazing how they handle this cascade due to its oxygen sensitivity (addition of thiophenol, workup with degassed solvents strictly under argon). I was wondering why this particular imine/enamine are so air sensitive… could the copper salts from the michael addition be playing a role?

  • esxatolog says:

    It is extremely fascinating synthesis, everything is very, very impressive and [3+3] annulation and spirocyclization are real masterpieces.
    I was looking through experimental part and came up with some thoughts… One important thing – it is not a critique and I am not trying to discuss particularly this paper … just want to hear some general opinions… May be it is rather irrelevant after such incredible synthesis… sorry for this…
    I strongly dislike experiments operating with 5 mg or less… especially if they are in the experimental part of a paper and this is 5 step away from the target, last step is ok, I totally accept it. (if you are researching some new reaction with chiral material, it is the only way to go)… but if it is 5 steps away it means that you are definitely going to build more material and not five times per 3 mg, so it makes me feel wired, may be you got your best yield on 3 mg scale?!! I don’t even want to talk about reproducibility, yields (two “dust or silicagel particles” can change your yield on 30% easily) and opportunities to scale up these steps. Please, without blaming comments, I know what is the last steps of synthesis with a few mg and a constant building of starting material, I have run 3*40 mg in parallel instead of 120 mg reaction just to get better yields, but is it fair? May be Baran is totally right when he is doing gram scale synthesis?
    Moreover I really like NMR spectra of complex molecules… but when I see only chloroform peak, and then can admit that these relatively “big” singlets are the methyl groups and everything else is just something, no multiplicity, no integrals… I don’t understand what is the purpose of the putting such NMR spectra in a paper, if it is impossible to get any information from them, at least people can put some expansions on the same page with full spectrum (I know it is extremely easy to do it on Brukers and Varians). Furthermore paper usually says: stereochemistry was confirmed by two dimensional experiments, where are they??? Or if everybody thinks it is just a routine procedure, why we need to mention it Sometimes I want to see them not because I don’t believe the author, it usually means that I want to get some data which can be useful for me.
    So my idea wasn’t to diminish somebody’s strongly deserved achievements. For example I want to use the same conditions as was used on 3 mg scale, could I really get the same result on 100 mg scale or suddenly I will need not one but 1.5 equivalents of the reagent only because of some logical mistake in the measurements on such scale…
    What is total synthesis – romantic art without the rules where creativity, accomplishments and superior techniques of manipulating minute amounts of substances are dominant or still science? What do you think guys???

    • ,,, says:

      “I have run 3*40 mg in parallel instead of 120 mg reaction just to get better yields”
      Now that sounds like cheating! (I don’t think 120 mg vs 40 mg would really make much difference)

      • esxatolog says:

        Sorry, I didn’t write it properly, of course in experimental part I have put my real yields based on 40 mg of starting material, the point of my words was that I couldn’t scale up this reaction properly and I’ve got my best yields using 40-50 mg, so I had to use this scale to build a lot of material, what makes this reaction rather limited and ineffective overall …

        • ,,, says:

          So your reaction ran worse on 120 mg scale or due to grease from your hands etc the 40 mg reactions were giving “better yields”? (now I don’t mean to accuse anybody, you brought it up yourself :) )

          • esxatolog says:

            ok, I was forming a quaternary carbon center using nucleophile addition to the iminium ion at – 100 to achieve appropriate diastereoselectivity, it was necessary to run it with the huge concentration of nucleophile (5 equiv) because hydrogen elimination was extremely competitive process (practically 1:1 with comparison to a solvent), so when I used twice more material yield decreased aproximately on 5-8%, on 40 mg – 70-75%, on 120 mg scale – 57-65%, for me 10% of chiral material was a lot!!!

          • krest17 says:

            You are completely right (I like part about NMR’s). It’s your point of view – but discussion here is useless, sorry.

    • Knut Jacksworthy says:

      The point of putting NMR spectra in a paper is to establish purity and to serve as a visual aid for the experimental data. If you looked closely at the experimental you’d see that there are full proton and carbon assignments for every single compound leading up to the target molecule. That’s thoroughness for you.

      • jurel says:

        that small of scale means little to me……proof of principle only. good chemistry can be done on any scale, and i very much doubt that scaling this stuff up would be routine. if you put a million monkeys in a room with a million typwriters………

  • Jose says:

    “diazamethane” or “diazOmethane?

  • TWYI says:

    Absolutely awesome paper

  • ,,, says:

    Good stuff, good stuff… Totally agree with Paul’s statement “one of the best papers so far this year”

  • itipiti says:

    maybe you should check out the synthesis of the galbulimima alkaloid (jacs, 126, 8126) before saying things such as “the best synthesis of the year”… the two syntheses are more than 80% similar.

  • Kiddie Khem says:

    Is anyone more familiar to the iminium cloride attack forming groups 16-18, I dont understand why they aren’t getting a mix of the methyl attack and the di-substituted carbon within the ring attacking as well.

  • Chemist@ASU says:

    Great paper from Movassaghi,AGAIN!
    Movassaghi and Baran, the best two (young) synthetic chemists around.

  • Oleksandr Zhurakovskyi says:

    Khm…
    >The DOI you requested — 10.1021/ja903790y
    >– cannot be found in the Handle System.

  • excimer says:

    16 g of Tl2CO3… woof. I have to wonder about that Suzuki… They make the boronic acid from the alkyne and pinacol borane followed by oxidation in a previous paper… and there, too, they use Tl2CO3 for the coupling. I wonder if doing a Negishi didn’t work, either. I agree, I’d have tried anything before dumping in the rat poison. Tetrakis was probably used because it’s not active enough to appreciably produce disubstituted product.

    It’s papers like this that make me still enjoy reading TS papers, even though I’m typically so far removed from the subject.

  • Quality Control says:

    Don’t post here often, but this synthesis is awesome.

    IMHO Movassaghi’s work is nicer than Barans.

  • hanpisa says:

    I think it is a very good work.

    The formal [3+3] reaction and the oxidative cyclization are nice.

    I think comparing Movassaghi and Baran is not a productive discussion. They are both good chemists and I assume they both have good students and postdocs. Although, I have to admit that they have somewhat different styles in approaching and presenting chemistry.

  • ILikeCarbon says:

    Anyone who knows anything about total synthesis will know that these syntheses took years of work and a lot of no reactions to be completed. The michael-mannich sequence probably required a lot of perspiration and pints to complete. Outstanding work.

  • fair monster says:

    to compare baran and movassaghi is premature. Mo needs a few years still to catch up to barans level of accomplishment. as of my count baran has about a dozen different natural prod families conquered and has pushed the envelope of synthesis in a way that will inspire others (atleast it has inspired me). Mo has now 2 really nice syntheses after 6+ years but has he really brought the field to a new level and set a new bar? Hard to convince me with so few accomplishments.

    now can we talk about vannusal? KC is king.

    • HPCC says:

      KC and Zhang and Ortiz are kings, you mean. I was fortunate to work near these people, and they were the ones taking NMRs of a zillion wrong vannusals, at the same time facing KCN’s deception, and yet, those work horses never gave up.

      And the paper itself reads like a bedtime story. There’s almost a plot. One of the major achievements of KCN, of late! Can’t wait to read the post.

      • Ian says:

        deception?

        • HPCC says:

          When you’re so near the end, the paper’s often already written… so you can imagine telling you PI, no, this one wasn’t the right one either. After the umpteenth repeat… I would have lost confidence in myself I think.

      • krest17 says:

        Adrian and Hongjun – my very warmest congratulations, you deserve it – I love your paper.
        PS for HPCC: I know them too :-)

  • Heiko says:

    i think it’s a bit presumbtuous to call that suzuki coupling highly efficient if you need that much of toxic co-reactant…
    efficient means to me less than 5mol% of catalyst, maybe 20mol% of ligand and some co-reactants…
    i do agree that the end justifies the means but i think that this can’t be the end of it all…

    … and it’s really not the best published paper until now this year…

    • ,,, says:

      nobody called it “the best”

    • Tot. Syn. says:

      Synthetic efficiency can be measured in a whole manner of ways, including atom economy, the speed of reaction, the amount of reagent/catalyst used, the excess of coupling partners, the amount of solvent or silica required… However, in this case, they were simply referring to the yield. It’s fair enough – this definition has been used many times in the past.

      And I only said that ‘one of the best paper so far this year’. And it is.

      • ... says:

        Superstoichiometric quantities of base are necessary for Suzuki coupling reactions in order to generate a boronate, hydrolyze by-products, etc. You can’t run this reaction with only 20 mol% Tl2CO3. Take some time to look at the mechanism before you bash on other peoples’ work…

        • Tot. Syn. says:

          I’ve seen a few cases where catalytic Tl was used in conjuction with another base, such as Cs2CO3, so it’s more than possible. It’s also possible to use other ionic addatives such as silver salts to push the reaction. They’re thought to intercept the oxidative addition step, and allow the silver halide to precipitate and remove it from the equilibrium.

          It’s also worth bearing in mind that the mechanism for the Suzuki coupling is not done and dusted. There have been several reports of Suzuki type coupling proceeding using Pd/C,H2 conditions, in the abscence of base! And there are the cases of Pd couplings whre the catalyst has been impurities in the glassware. Thus complicates the mechanism hugely. Add to that that we still don’t know what the actual active catalyst species yet!

      • Heiko says:

        yeah,
        but as paul mentioned you can run suzuki’s with a combination of bases… maybe you can regenerate the Tl2CO3 with a second base… there are so much different conditions explored yet, there could be an alternative…
        and yes: i know the mechanism… and i’ve done some suzuki’s to know that under the right conditions they work but maybe cause i’m working for a pharma company I’m a bit cautious with using environmentally harzardous chemicals…

  • lovable says:

    Drawing things in 3D is a great way to make the accomplishment look like more than it actually is. Even a steroid would look amazing if you do this. Halichondrin would look like the most complicated molecule on the planet.

    you guys need a reality check.

    • ,,, says:

      Ooo! Did you just make something like Palau amine? Check yourself

    • Hap says:

      Polycyclic bridged compounds are generally hard to draw flat without making them really ugly and useless for any sort of accurate representation. That’s why perspective drawings exist in the first place. Or are you just really bored?

  • Ortizzle says:

    3-D drawings were used not for “dramatic effect”, but to allow the reader to more clearly see relationships between functionalities and provide a more realistic conformational view of the molecule. Both of which aren’t completely obvious in a 2-D depiction and are essential in interpreting the 1-D and 2-D NMR spectral data.

  • lovable says:

    the same argument could be made for a lot of molecules. I drew the molecule in 2D and the chemistry is easier to follow. it also looks simpler…

    • Tot. Syn. says:

      I disagree… I tried drawing lots of the molecules in 3D, but I had a bit of trouble towards the end. I also found the 3D representation led to a better understanding of the stereoselectivites and ease of ring formation, as it turns out the functional groups in question are closer together.

  • Tok says:

    This kind of reminds me of people that watch the Olympics and say, “That doesn’t look so hard.”

  • lovable says:

    this love fest, and the one on Jamison (i.e. cheap macrolactone), sponsored by MIT chemistry department.

  • I am reviewing Phil Baran's NIH grant says:

    Fantastic work…make my day……

  • jcreater says:

    This synthetic work looks really nice .
    I read all of the comments and come to realize that movasaghi is one
    of the big-fish in synthetic chemistry.(sorry,never heard of him before).
    I choose this paper for my literature seminar and this website really
    help me a lot .

  • Pilky01 says:

    I agree, this synthesis is fantastic, even down to the Z-deprotection! Every problem they came across has been conquered elegantly (minus the thallium ;p). Hats off to the three of them.

  • ZZZZZ says:

    zzzzz

    …I like the formal [3+3] annulation used here…

    …Now, what does everyone think of The King of Pop dying? Was he a pedophile or just misunderstood?…

    zzzzz

  • GYA says:

    its (basically) the same synthesis. the impact would have been greater had it all been published at once. too bad the diff. is the -OMe group. Nice though.

  • LW says:

    would someone be able to clarify the use of the azetidinone coupling here? i’ve been trying to open the paper with no such luck. i think the heat in the uk, yes thats right, is killing my laptop and burning my thighs as i lie in bed with it.

  • xyz says:

    _______________________________________________________________________ ZZZZZ says:
    1 July, 2009 at 15:33
    zzzzz

    …I like the formal [3+3] annulation used here…

    …Now, what does everyone think of The King of Pop dying? Was he a pedophile or just misunderstood?…

    zzzzz
    _______________________________________________________________________

    Here the discussions are only on elctrophiles or nucleophiles…..Sorry….no pedophiles….even if they are popkings….

  • ZZZZZ says:

    zzz

    …electrophiles and nucleophiles? Word on the street is that The King of Pop liked backside attack between these two. This is only hearsay and conjecture though…

    zzz

  • Phil says:

    I’m pretty sure the reason he used real diazomethane and not the TMS-kind is that the price of TMS-diazomethane has skyrocketed recently. $428 for 100 mL of 2M in ether on the Aldrich website. The student whose hood shares a back wall with mine has to make his own diazomethane about twice a month. I take those days off.

  • Sajid says:

    Very Bad Synthesis

  • i will really miss the King of Pop. michael jackson is truly the best pop artist in this lifetime.:,”

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