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Platensimycin   

17 October 2009 22,189 views 57 Comments

platensimycin

Njarðarson , McGrath, Bartlett, Sittihan. ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200903347. Article PDF Supporting Information

It’s back!  Twice in as many weeks, too, as KC has decided to drop the details on his many syntheses of platensimycin and platensin into a full JACS paper.  However, I’ve spent enough time looking at his work in this area, so it’s a pleasure to examine this synthesis by Jon Njarðarson of Cornell.  I should point out that I don’t feel that this is necessarily the best route, but it’s got some damn smart chemistry in it, so what more do you want?

The first bit of chemistry to catch my eye was his use of Molander’s ‘BeeEffThreeKay salts’ (or at least that’s what I call ‘em).  I’d be remiss not to mention them for two reasons – 1) my lab-mate Keith worked on these for his post-doc, and 2) it’s pretty smart stuff, and a lot nicer to work with than boronic acids.  Sure, sometimes one can use boronic esters directly, or even use disiamyl-boranes (like I did in my PhD), but these salts are a more stable way to go.  There is some concern that they can let-go of a bit of HF (and are often delivered in plastic pots), but you’ve really gotta maltreat them to provoke that kind of reaction.

platensimycin_19

This is one of the more impressive implementations of this chemistry I’ve seen, as sp3-aryl couplings aren’t the easiest chemistry even with ‘normal’ Suzuki conditions. However, Njarðarson has achieved a decent yield here with pretty respectable catalysis.  </salespitch>

Sweet as that was, it wasn’t Njarðarson’s chemistry – this is.  What we’ve got here is a neat, selective epoxidation of an alkene and rearrangement of the allylic system to give a DHP.  More on this methodology here.  The use of the trityl hydroperoxide was key to the regioselectivity of the nucleophilic epoxidation – more about that in this JACS by John Porco.

platensimycin_20

With that tricyclic system in place, a bit of reduction installed a further stereocenter, and left the group ready to perform a radical reaction to close the final ring in the core.  However, in the earlier work the group did, no product could be found.  They tried a few simple structural modifications to bring the prospective partners closer together, but to no avail.  This is an unfortunate problem with radical chemistry – if the reaction decides not to work, switching reagents rarely works.  Often the only solution is to change the substrate, but in target-oriented synthesis, this is not only a synthetic bastard, but a bit more ‘diversity’ oriented.

platensimycin_23

Luckily, the group had a further idea on how to do this – switch to an ionic reaction, and try that way.  First they had to prepare the desired functionality, requiring silyl protection on the phenol.  Using a little triethyl silane and a more exotic borane (which looks pretty pokey!), they achieved both removal of the methyl ether and reprotection.  Cool chemistry – more here.  Now set to go, a high-temperature deprotection produced a species with plenty nucleophilcity to spare, closing on the primary tosylate to give the desired ring, converging with literature synthesis to finish a formal synthesis.

platensimycin_22

Now, who hasn’t learnt something neat (put you hand down, Milkshake…)

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57 Comments

  • UBChem says:

    Is it just me or does it seem like Njarðarson has never used chemdraw before.

  • excimer says:

    I went to a talk by him just to see how his name is actually pronounced. Turns out I was way, way off.

  • Nicolaou's Mustache says:

    I’ve worked with the trifluoroborates in Molander’s lab…the reactions work beautifully.

  • Mediator says:

    Is it pronounced “Nyar thar son”?

    • Cornellian says:

      He doesn’t use his father’s name. He prefers to be called Jon (Not John, use a soft J and a long o == yone)

  • stork naked says:

    UB Chem – sounds like you’re a hater. i saw him talk a few months ago and he gave an impressive overview of his chemistry, and he has a nice philosophy on synthesis

    • UBChem says:

      My comment has nothing to do with whether Prof. Njarðarson is a nice guy or good philosophisor. I just find the way he draws his structures to be amusing. I would freely talk about how obnoxious the Corey standard for drawing molecules is as well as the finger-paintings that come out of the Nicolaou lab. I’m not a hater, I’m an observer. Stop trying to start useless arguments that have no place in this blog.

  • Marvin the fish says:

    Saw him talk a few months ago too. He was invited to talk by his old classmate (Iceland) who’s now a professor in my university. I think these two were the only people in the room who could pronounce his name, even after the talk!

    The posters on his homepage are pretty nifty too. Top 200 drugs every year. Suitable for printing out A0 size!

  • advil says:

    lets see if he can finish vinigrol…

  • bubbles23 says:

    Can anyone finish vinigrol?

    • krest17 says:

      Baran – I guess

      • UBChem says:

        Baran couldn’t finish vinigrol. It was nice application of Barriault’s Diels-Alder approach and Corey’s grob (from Goodman’s thesis), but who ever does finish that molecule should have everyone’s respect.

        • ,,, says:

          are you one of those people who have issues with Baran?

          • UBChem says:

            I have absolutely nothing against Prof. Baran or his work. I think his lab has produced some incredibly elegant solutions to some very complicated problems. If in fact his lab has successfully finished vinigrol I incredibly excited. That little bastard has eluded some of the best chemists in the world. I put vinigrol on a pedestal, for it’s vast biological importance and beautiful architecture. I don’t know why people feel that I’m a ‘hater’ from anything that I have said. But let’s try to keep this forum to chemistry related dialogue. This is second time that I have had to address this, I don’t understand.

          • ,,, says:

            good to know. second time – well, you should’ve cited your old comment then instead of going through so much typing…

  • stork naked says:

    UB-Chem

    You sound like you’ve been bitter from being in a cold winter – you should read write something funny in the back of your hood ;)

  • bitterbeerface says:

    UB Chem,

    Maybe you could’ve made vinigrol if your eyes weren’t so glued to this blog.

    • The Next Phil Baran says:

      Wow guys. Ok, so UBchem made a statement, which was directed at any of the other bloggers, nor totally synthetic, and yet even if he had a beef with baran’s work, not baran, which is his right, then why do you attack him? He never attacked any other blogger on here, yet he is being challenged on his work ethic, his sincerity, and his intelligence. Are you guys for real? Phil Baran’s personal bodyguards? Attack his statement, not who he is, or what he does or how he does it. If an idiot came out of nowhere and found a way to make cold fusion happen, would it be any less useful? It’s funny how you can’t have an opinion unless it agrees with someone else around here. This reminds me of high school, or worse grade school. It’s nerds picking on nerds (yes, we are all nerds on here!) This is not how a group of intellectuals, scientists and philosophers are supposed to act towards each other. It doesn’t help anything. If you have an argument state it, if not then why bother. Calling someone a poopy head is not an argument it is a judgement, and it is not related to the topic at hand. Next up, girls can’t do science because they are girls and have cooties, give me a break.

      • poopy head says:

        I think its ironic that UB chem says Baran “stole” Corey’s grob, when if you look at his thesis he “stole” coreys radical based biomimetic strategy (one which corey attempted albeit unpublished results). Even funnier is the fact that in UB Chem’s mind he was actually close to finishing it.

        • The Next Phil Baran says:

          As though Corey owns that pathway: the Corey Grob, which means Corey stole Grob’s reaction. Baran, a synthetic chemist, used a reaction developed by Corey in a new and unique way towards an unsynthesized molecule: the art of synthesis. By this logic, does that mean that Grubb is partly responsible for all of the molecules synthesized by using his catalyst (patent laws aside.) Most of the time, if you are synthesizing anything requiring a couple of steps, then you are “stealing” someone’s reaction. Diels-Alder are still publishing well into their 100s!

          • mr.here and now says:

            whats even crazier is that Corey never even tried the grob, he just had it written on paper! Its very likely that this bond disconnection would be seen by others with clever minds. So If write down a 100 routes to palau’amine, i dont even have to get them to work or make it? And if someone else makes it using anything even remotely similar, they are using “my” strategy. We arent in theoretical chemistry people! this is an experimental science. Yes If you copied someones route that would be bad, but Barans “reality-based route” and Coreys “imagined” route share almost no similarities aside from 1 reaction, that has been used in countless terpene syntheses.

        • UBChem says:

          You’re an assbag. You obviously can’t read. Where did I say Baran ‘stole’ anything? Where in my thesis did I ‘steal’ anything? I clearly stated that Corey proposed a biomimetic synthesis that was untested (and yes, it was untested.) And where in the hell did I say I was close to finishing the molecule? You have no idea what I’m thinking and to post comments about what I say or ‘think’ is over the line and inappropriate.

      • ,,, says:

        get over it. Notice that your comment is the longest here. I bet UBchem doesn’t even give a damn about this…

  • bitterbeerface says:

    And us “part-time” bloggers are going to hold you to your word (“who ever does finish that molecule should have everyone’s respect”) when Baran’s total synthesis is published :)

  • advil says:

    Vinigrol = Taxol of the 21st century

  • krest17 says:

    10$ on Baran :-)

  • Remev says:

    No way. $20 on shair. $5 on barriault. Barans an alkaloid man only.

  • antiaromatic says:

    It wouldn’t surprise me in the least if not only Baran is the first to finish, but if he’s already finished it off. I think the interesting question will be what route he’ll use. I saw him give a talk not too long ago where the route he published in ACIEE appeared to be a dead end.

  • Rike says:

    $10 on Corey.

  • John Wood says:

    $10 John Wood?

  • Yesman23 says:

    Baran already finished it, he presented it at my company in NJ last month.

  • Tom says:

    I second that that Baran has finished vinigrol.. he gave a talk last month where mentioned it at the end.

    • anon says:

      I have a newbie question; besides vinigrol and palau’amine what would you guys consider to be hot molecules that a lot of groups are working on?

  • Beef Supreme says:

    communesins and cortistatin are two off the top of my head

  • gya says:

    as far as uncompleted targets go, vinigrol and palau are the most hotly pursued. nothing else comes close.

  • ch3mical says:

    which groups are still actively working on palau’amine?

  • Konrad says:

    Can anybody confirm the rumors about Baran finishing vinigrol? Thanks

    • TourdeForce says:

      Konrad,

      A friend of mine saw him present it about a month ago, I havent personally seen it, but I believe it is finally completed.

  • krest17 says:

    here is the one from me:
    The structure of hyperforin was elucidated by a research group from the Shemyakin Institute of Bio-organic Chemistry (USSR Academy of Sciences in Moscow) and published in 1975.[3][4] Hyperforin is a prenylated phloroglucinol derivative. Total synthesis of hyperforin has not yet been accomplished, despite attempts by several research groups.[5] http://en.wikipedia.org/wiki/Hyperforin

  • krest17 says:

    and perforatumon

  • Posters says:

    http://www.chem.cornell.edu/jn96/outreach.html

    Are there any such posters useful for the chemsitry out reach? Needn’t be organic; Not interested in Pka lists etc. It should be of general in nature.