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Marinomycin   

16 September 2006 13,488 views 28 Comments

marinomycin.jpg

Nicolaou, Nold, Milburn, and Schindler. ACIEE, 2006, Early View. DOI: 10.1002/anie.2006018677.

A very nice synthesis of this potent antibiotic (and believe me, we need new antibiotics), with top MRSA and VREF killing action. Using it’s dimeric nature to their advantage, they started with the synthesis of the monomers. Very early in this synthesis, they have need of a trisubstituted olefin, which they produce from the propargyl alcohol in a nice prep:

marinomycin_1.jpg

Now, I’ve used Red-Al many times to reduce an acetylene, and have been impressed with it, but this really nice. I guess it’s similar to the hydroalumination/iodation prep for vinyl iodides; any way – here’s the original reference.

A little later in the fragment synthesis, they have to do the first of their suzuki reactions, starting with an acetylene, which they hydroborate to produce the required boronic acid. For the hydroboration, though, they used a reagent I’ve never seen before, taken from a top Snieckus prep:

marinomycin_2.jpg

So how does this one work? Well, I had a look at the original paper, and their explanation goes like this:

marinomycin_3.jpg

Now that I like. In fact, I think I’ll give it a go later this month. The paper also mentions a prep for the hydroboration reagent using sodium borohydride and (MeO)2SO2. Certainly cheaper and less “exciting” than borane-THF, but I have a feeling that the sulfone may smell…

With a later boronic acid in hand, it was time to do the dimerisation. However, things certainly didn’t go to plan (taken from the pdf):

marinomycin_4.jpg

300 equivs of TlOEt?!! Now that is one reaction I wouldn’t want to repeat! And yes, they only got a 2% yield of dimer. In the event, the monomeric ring closure was favoured massively, which the authors presume was caused by configurational predisposition for that ring formation. Ah-well. So they simply did the dimerisation stepwise – coupling of two ends followed by macrocyclisation. A great paper, with some top reactions!

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28 Comments

  • movies says:

    Dimethyl sulfate stinky? No, but it’s hella toxic!

    I wonder what the sulfur containing side product is in that borane prep though.

  • milkshake says:

    Do you remember how “magic methyl” or MeOTf was bad for you (people coming down with sudden lung edema)? Well, dimethyl sulfate does the same thing, although its volatility is lower. It does not help that dimethyl sulfate is practically odorless and used on massive scale in industry. People have actually died from its vapor exposure.

    The regioselective DIBAL addition to propargyl alcohols is a textbook case, it has been used in terpenoid tot.synth. for decades. You need to have the free propargylic OH, to coordinate Al. I remember this vividly because I was learning chemistry english by translating a big Marcus Tius review on synthesis of cembranolides, from 1987 I think :)

  • yepyep says:

    It’s a complex molecule and that synthesis probably required huge amounts of work but after reading the paper I was not impressed at all. I am a hardcore total synthesis fan, so don’t get me wrong but this kind of a paper is probably the reason why some people think that total synthesis is a complete waste of time. I didn’t notice any new methodology and I didn’t get that “wow that’s a nice approach” feeling that you get with some papers. To me this looks like solid work using standard chemistry but please somebody enlighten me if I missed something important.

  • guigui le chimiste says:

    I agree with yepyep

  • ddd says:

    agree with above. This is why I never waste my time reading some of that kind of papers. And please please, put your conditions and reagents on the arrow, but not in the bottom of the scheme. I hate those “a) i., ii., iii., b) i, ii…” and so on. And guess what, if you have so many reagents and steps that you are run out of space, then it says your synthesis is long and inefficient.

    What would be the mechanism of action of this compound in cell? Seems like it should insert itself into membranes

  • Tot. Syn. says:

    Okay, so this isn’t the most inspired synthesis in the world. But it did need to be done. You might think that the biological activity was basically an aside, but it’s not. We’re running out of antibiotics that are still effective, and the best kind to find are those that operate via a new mechanism. This beast is certainly active enough, but making it through total synthesis isn’t an option. I don’t know what kind of scale we can isolate it from nature in… but any less complex analogues would be useful.

    Did you know that none (that is zero, nil) of the big pharma companies are working on new antibiotics? They don’t see enough money in them… Dave Spring at Cambridge has done a load of work in the area of new target discovery, using diversity oriented synthesis (I guess that post-doc with Stuart Schrieber rubbed-off on him). They’ve had a remarkable amount of success, with one new target (named Emmamycin after the student, Emma Wyatt) looking fantastic. But the industry needs to pickup the ball and run with it for a while

    ddd: Correct me if I’m wrong, but I think the journal dictates what kind of scheme the authors can use. Also, in terms of mechanism, I think you’re right. It certainly seems to have the handles to sit in membranes, with distinct lipophillic / hydrophyllic regions.

  • ddd says:

    JACS for example lets you put reagents on the arrow. But KCN always does it this way

  • HOMO-LUMO says:

    I am not a big fun of KCN, but I think some of you are missing some points:

    1.How many reactions have you done which works perfectly work on paper, but cannot be used on your substrates for some reason.

    2. Strategy in natural product synthesis is a key issue.

    Otherwise, by the same token according to #2,3,4. 80% of the total synthesis of natural products published to date are useless information, because “there is not innovative chemistry”. Why then, there is a clear separation line between methodology an Tot. Syn. projects guys?

    Would be sugar chemistry of nucleic acids chemistry, rubbish, just because is chemistry well stablished applied to one particular family of molecules?

    Finally, what´s the point in doing organic chemistry when the new reactions and transformations left to discover (in comparison with the situation 30 years ago)are not many. Shall we focus our efforts the in medchem and bioorgchem and biochem?

    Sorry for being so laxative, but to me any new synthetic route with more of 10-15 steps to a complex natural product deserves a lot of credit.

  • HOMO-LUMO says:

    Sorry, my previous comment was about #3,4,5.

  • Tot. Syn. says:

    Milkshake: As I said, I’ve used Red-Al many times, I just appreciated the substitution of the Al by I as an extra synthetic handle. I never claim that the methodology I discuss is band-new; it’s just new to me. I’m only in the second year of my PhD, so I’ve still got loads to learn :)

  • whatever says:

    “To me this looks like solid work using standard chemistry but please somebody enlighten me if I missed something important.”

    LUMO – let me translate

    Solid work – +A for effort; they got the job done and it was a lot of work; They did not spend their time making esters. They are good chemist.

    Standard chemistry – Work has precedent; Chemistry does not push the boundaries of any known chemistry. The monomer of the natural product is a task of forming alkenes as the proper isomer and specific 1,3-diols systems. Many have done this work: The Aldol Groups, The Pd Groups, and The Reduction of Aldol Product Groups.

    enlighten me if I missed something important – enlighten me if I missed something important.

    ?Reworded ?
    Would sugar chemistry of nucleic acids be rubbish, just because the chemistry is well established or applied to one particular family of molecules?

    Yes, in short.
    Every group of molecules has its own particulars, which can lead to interesting chemistry. Unfortunately most Nucleic acid, sugar, peptide chemist are not “Hardcore” synthetic chemist. They are chemists who want to make something for the ends and not the means. Does the molecules have different biological activity. This is very important, but not to synthetic chemistry. If someone discovers chemical knowledge from nucleic or sugar chemistry then it is good chemistry otherwise it is good biochemistry or biology.

    “Finally, what´s the point in doing organic chemistry when the new reactions and transformations left to discover (in comparison with the situation 30 years ago)are not many.”

    There are LOTS. Odds are on my side here. There have always been people that said we understand almost everything and they have been wrong ( if your mind needs to be blown or you know everything check out: Collum’s J. AM. CHEM. SOC. 2003, 125, 14411-14424
    paper especially the graph with a question mark as a variable. Did you hear that question mark that is a variable?
    Or the asap O.L. paper by Paton and Goodman). The Strong history of synthetic chemistry and physical chemistry or methodology could come back and bite your comments.

    “A very nice synthesis of this potent antibiotic”
    “Okay, so this isn’t the most inspired synthesis in the world”
    Most stuff is garbage. You will have to search through the garbage to find the good work. Sometimes the work is so good it is boring because it is just chemistry and does not invoke saving Africa, the US, babies, mothers with baby, Aids, Cancer or anything else.
    Be careful what you buy because that the present rate of organic syntheses we have not done much saven’ for a lot money and time. Do you know the structure of most drugs (like vioxx) or High throughput screening chemistry or Comb. chem.?
    Peace

  • guigui le chimiste says:

    Don’t get me wrong, this synthesis probably required a huge amount of work and the molecule is worth doing it because of the biological activity but the synthesis in itself is not the most impressive one I have seen on paper. That does not mean that it was easy to make. I know what it takes to complete a total synthesis of that kind of complexe target. Moreover it is really difficult to be very inovative in the synthesis of that kind of macrolide.

  • European Chemist says:

    Precisely! It’s easy to say that there’s no new chemistry in the paper, and that this gives people the feeling that Organic Chemistry is a “dead science”.
    But how many innovative steps can you place in the total synthesis of a large beast such as this one? (t’as raison guigui)

    For example, Overman’s synthesis of strychnine (if my memory is correct) is considered by many “a masterpiece of synthesis and a pearl of contemporary organic chemistry”, mainly because it’s a beautiful illustration of the Cope rearrangement. But isn’t it a shame that it takes him a whole bunch of steps to reach the precursor for the rearrangement?

    However, I do think that for every molecule, no matter how dull or complex it looks, there are at least one or two so-called “elegant solutions” in terms of total synthesis. It all depends wether you’re searching for “elegance” or “efficiency”. Beware though: “elegant” usually means “will take a loooot of hard work to put from paper to practice”.

    I surely don’t agree with HOMO-LUMO when he says that

    “Finally, what´s the point in doing organic chemistry when the new reactions and transformations left to discover (in comparison with the situation 30 years ago)are not many. Shall we focus our efforts the in medchem and bioorgchem and biochem?”

    I beg your pardon but for me there are ENORMOUS problems still to be solved in organic synthesis and TONS of reactions waiting to be discovered! The problem nowadays is that people don’t want to adress these tricky and seemingly “impossible” problems because the way in which research funding agencies evaluate one’s work. It’s much easier to tackle “simple” issues or to repeat reactions using fashionable/exotic metal reagents, and call them “catalytic selective whatever” …, because it will assure you a steady flow of publications (aka “scientific production”).
    Don’t get me wrong, but if you really approach organic chemistry with the feeling that “most of the nice stuff was already discovered”, you’re just limiting yourself. Your imagination should be the only limit.

    Finally, please go on highlighting these great papers, Tot. Synth. This is a veeeeeery good blog indeed.

  • HOMO-LUMO says:

    European chemist,

    I quite agree with what you said, my point was that a total synthesis like that one can be critisized, but not quiting all the credit just because there are not many eye-catching transformations on it.

    However I agree that in total synthesis always are needed 2 or 3 key steps, which should be a proof-of-new concept.

    When I said that there are not many reactions to discover and we should moved to other fields, I was trying to be ironic.

    Intrisencally new reactions to discover there are not many. The major part of the basics are discovered and well stablished, but enormous troubles to sort out, as you said, a lot.

    Organic chemistry is not a dead science, IMHO just the opposite.

  • HOMO-LUMO says:

    Ahh, and the blog (effort,time and enthuthiasm)that Tot. Syn. has created, is CHAPEAU.

  • synthon says:

    milkshake…if memory serves on the DIBAL reduction the mechanism is actually bimolecular to give the trans substituted alkene. Pretty slick chemistry from Corey (I think) back in late 60s

  • guigui le chimiste says:

    One good thing about this synthesis is that the authors showed that there are other ways than metathesis to make substituted alkenes .

  • ddd says:

    yea there are other ways…Gues what? HWE reaction…yea cool one and …old

  • jonnyofthedead says:

    Tot. Syn.:
    >Did you know that none (that is zero, nil) of the big pharma
    >companies are working on new antibiotics? They don’t see
    >enough money in them…

    I take it you missed Merck’s Nature paper on platensimycin, then… http://dx.doi.org/10.1038/nature04784

  • Tot. Syn. says:

    Ah, I did miss that. I’m actually quoting your supervisor’s lecture on antibiotics from a few months back -  but it’s always good to see big pharma working on antibioics. Thanks for that!

  • yepyep says:

    I’ve been waiting for the first total synthesis of platensimycin to appear. Not very big a molecule but nevertheless contains 6 chiral carbons, 2 of them quaternary. If it has already appeared and I’ve missed, could somebody put a link here please.

  • Not enough DEAD says:

    I think that the merit of a total synthesis should be entirely judged based on its purpose. If the aim is proof of principle, then it does not matter how you reached your goal as long as you reached it. Are we going to criticize R B Woodward for using the simplest of reagents? Certainly not, because his whole point was the proof of principle, to show that complex molecules could be synthesized. On the other hand, the elegance of the syntheses was unparalleled. The point is that ‘standard chemistry’ does not necessarily mean ‘inelegant synthesis’. Also, there are many natural products out there, and just because one was synthesized using standard chemistry does not make the synthesis a significant one. But if the molecule synthesized turns out to be one which has unprecedented properties and/or use, then the synthesis is important. By that token, I agree with Tot. Syn. that the target is an important one; any new antibiotic that helps us fight resistance is an important target for synthesis. In any case, KCN has always received criticism for doing fairly standard chemistry, although we cannot deny that some of his syntheses have been like Overman’s strychnine syn, which demonstrated the elegance and importance of a particular reaction for the first (or maybe second…) time. For simplicity, I won’t usually give him top marks.

  • Jingojango says:

    The only reason to make this molecule is if you’re going to follow up on it, make analogs, and learn something about the mechanism of action. I highly doubt that KCN (and students) will do this. Is the monomer active? What part of the cell is being hit? Furthermore, it states in the paper that these compounds aren’t stable… unstable drugs are useless. Also the dosing on antibiotics is typically pretty high. You need a lot of this compound and total synthesis isn’t going to get it for you.

    I highly doubt that these molecules are “selective”. They’re likely just cytotoxic.

    The route isn’t really that bad. It just isn’t all that creative. If I were editing ACIE, I would have bounced this paper. It deserves publication… just not here.

  • Guy says:

    Alright, I can explain the regiochemistry of the vynilic iodination or the stereochemistry of the iodination, but I can’t explain both at the same time. Anyone want to enlighten me?

  • Guy says:

    and when I say vynilic I mean vinylic, of course. My aixelsyd gets the best of me sometimes.

  • regular chem says:

    The red-Al reduction may not have been done by corey. What he has did is to use LAH/NaOMe to achieve the same transforamtion. If you use DIBAH and BuLi(Corey’s procedure), you get the different regioisomer in about 5/1 ratio. If you use homoallyl alcohol, the desired stereoisomerization only take place if the substitutent on the propargylalcohol is vinyl or phenyl groups (Alami chem).

  • stork naked says:

    this is an odyssey of mental masturbation

  • The only reason to make this molecule is if you’re going to follow up on it, make analogs, and learn something about the mechanism of action. I highly doubt that KCN (and students) will do this. Is the monomer active? What part of the cell is being hit? Furthermore, it states in the paper that these compounds aren’t stable… unstable drugs are useless. Also the dosing on antibiotics is typically pretty high. You need a lot of this compound and total synthesis isn’t going to get it for you.