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Platensimycin   

27 September 2007 7,300 views 33 Comments

InChI=1/C24H27NO7/c1-22(7-6-17(28)25-18-14(26)4-3-13(19(18)29)21(30)31)16(27)5-8-24-10-12-9-15(20(22)24)32-23(12,2)11-24/h3-5,8,12,15,20,26,29H,6-7,9-11H2,1-2H3,(H,25,28)(H,30,31)/t12?,15?,20?,22-,23?,24?/m1/s1

Mulzer and Tiefenbacher. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200702852.

It’s back! I’ve not blogged any total syntheses of platensimycin for ohh… at least three months, but this is some smart work by Johann Mulzer at the University of Vienna. Rather than complete a full synthesis, they’ve done the same as a few other groups and taken an intermediate from Nicolaou’s work and completed a synthesis of that structure. This is the same intermediate present in Snider’s synthesis, so I guess the consensus is that this is a good disconnection. High praise indeed!

InChI=1/C12H14O3/c1-15-11-5-4-8-6-10(12(13)14)3-2-9(8)7-11/h4-5,7,10H,2-3,6H2,1H3,(H,13,14) InChI=1/C12H12O2/c13-10-3-4-12-6-8(11(14)7-12)1-2-9(12)5-10/h3-5,8H,1-2,6-7H2 InChI=1/C13H14O2/c1-12-7-13-3-2-9(14)5-10(13)11(15-12)4-8(12)6-13/h2-3,5,8,11H,4,6-7H2,1H3

The synthesis kicks-off with the literature three-step synthesis of the acid shown in the scheme below. This compound is then converted to the acid chloride, and what I think is an Arndt-Eistert homologation. This is a cool piece of classical rearrangement chemistry which goes via formation of an alpha-diazo ketone, which then perfoms a Wolff rearrangement to give the ketene. This is then trapped by any nucleophile present – in this case the methoxy-phenol. This forms the five member ring, and a lot of the complexity is introduced in this step. However, the synthesis is racemic, which is quite a drawback. Mulzer states that if one performed this chemistry on an enantiomerically enriched acid SM, the reaction should be controlled by that centre. This asymmetry could be introduced in the final step in the creation of the acid by doing an asymmetric hydrodgenation or a resolution. So my question is why didn’t they do it??
platensimycin_14.jpg

Anyway, the racemic chemistry is cool, so it’s time to complete the formal synthesis with a further hydrodge. However, they have a selectivity issue in that there are two similar olefins (but one is clearly less accessible). They didn’t get the selectivity required, so simply reduced both moieties, and then reoxidised. I hadn’t seen this reaction before, but the restore the required enone using iodic acid–dimethyl sulfoxide complex. Nice! Hypervalent iodine is awesome :)
InChI=1/C13H16O2/c1-12-7-13-3-2-9(14)5-10(13)11(15-12)4-8(12)6-13/h2-3,8,10-11H,4-7H2,1H3

ChemSpider is currently down, so no InChiKeys for now…

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33 Comments

  • tom says:

    I too thought this was awesome.. I like how the emphasize lack of column chromatography as well!

  • Platensimycin is on CHemSPider at http://www.chemspider.com/RecordView.aspx?id=5257055

    I MUCH prefer your drawing of it though…can you send me the molfile so I can upload it and replace the old ugly version? Thanks

  • TWYI says:

    So this will be a racemic formal synthesis then.

  • Eraser says:

    I think your mechanism is wrong:

    1. As drawn you have one carbon too many (only one carbon is introduced with TMSdiazomethane not two).

    2. A reaction via a Wolff Rearrangement to give the ketene would give the product with the carbonyl next to the hexadienenone ring as dawn or very likely a completely different product.

    Here is my suggestion:

    1. Acid protonates the diazoketone thus activating it for substitution or cation formation.

    2.Attack of the aromatic ring to kick out nitrogen can then take place in two ways. The most likely is that the aromatic ring attacks the protonated diazoketone (assisted by the methoxy group) ina SN2 fashion with loss of nitrogen, to give the resonans stabilized cation. One form of this would be the methylated hexadienonecation.

    3.Trifluoroacetic acid then act as a nucleophile to remove the methyl group and afford the product.

    This product was already reported in the original publication (compound 4):

    D. J. Beames, T. R. Klose and L. N. Mander, Aust. J. Chem., 1974, 27, 1269-75

    The Mulzer group only added the hydrogenation, reintroduction of the double bond to give the enone.

    Unfortunately they only report partial 1H NMR data. The supporting information form the Angew. paper should tell us if the product really has that structure. The Wolff rearrangement you suggest is not an unlikely event, it just would not give that product.

  • Eraser says:

    Oh and of course the methyl introduction and pyran ring formation as well.

  • Liquidcarbon says:

    DOI links to Artochamins

  • Tot. Syn. says:

    Quite a few mistakes, then. Whoops. I’ll fix ‘em when I get home this evening.

  • anon says:

    This is definitely not an Arndt-Eistert homologation, but an acid-catalysed cyclisation of a diazoketone. More accurately, it is an intramolecular ipso-alkylation via a protonated diazoacetyl moiety. As noted by Eraser, Mander reported this chemistry. It formed the basis of both his fantastic syntheses of gibberellic acid [JACS, 1980, 102, 6626 and JACS, 1980, 102, 6628]

  • EH says:

    This was a disappointing and frustrating read. There are a number of problems with this paper that I was surprised to see. First, the most interesting part of this paper is the synthesis of the enone, compound 7. The problem is that this synthesis has been known since 1974. This compound wasn’t even made as a single enantiomer as Tot. Syn. points out. This means that the new chemistry in the paper is encompassed by 5 steps, which ends in another known intermediate. Of the five new steps two are reported BRSM (71 and 78%) with no indication as to what the amount of isolated product really is, and since the paper lacks supporting information the conversion could be 5% for all we know. In addition the reduction of the enone gives at best a 1.3:1 ratio. Finally, why does Mulzer use Nicolaou’s retrosynthesis in scheme 1 and not his own?

  • Eraser says:

    How about a entry on the new diazonamide synthesis from the Magnus group ?

  • Tot. Syn. says:

    I presume you mean this one http://totallysynthetic.com/blog/?p=773 from last week ;)

  • Eraser says:

    Yep, Thats the one :-)

  • lemi says:

    i totally agree with EH, the most important job they have done in this synthesis is success of finding the known intermediate 7 —in fact,i must say i am a little confused why other guys didn’t find this known compound before, anyway,i am not an expert but just a fan of total synthesis, so…..
    once they found 7,the remaining job is simple–from the known compound 7 to KCN’s intermediate 2, maybe this paper can be accepted by ACIEE just because: 1, platensimycin is so popular and so is “Protecting Group Free”; 2,the paper is from Mulzer!!
    maybe we should come to focus on Scott Snider’s first paper in ACIEE http://www3.interscience.wiley.com/cgi-bin/abstract/116322277/ABSTRACT
    since i knew something about professors Ying Li&Zijie Hou ‘ former work on Quadrangularin A, i really enjoy this one by Snider, a style like Baran’s

  • anony says:

    As student at another group at my grad school performed HIO3/DMSO oxidation of a ketone to an enone once (I believe its a KCN published method) and the reaction blew up so violently that the metal on the stirplate was completely torn up. It was pretty amazing.

  • Tot. Syn. says:

    I’ve drawn a mechanism based on Eraser and Anon’s comments… what do you think? Have I got this right? I should have counted carbons… school-boy error.

  • .... says:

    #13

    I found Snyder’s paper to be a pretty impressive entry considering the guy has been working at Columbia for only a year.

  • anon says:

    mechanism looks good

  • secretary says:

    snyder paper is amazing. Please cover.

  • Eraser says:

    Yep That looks about right, but I would draw both the hydrogens on the diazocarbon after protonation. It looks strange when you know there are two of them.

  • chemfanatic says:

    I just saw Snyder’s paper.. Is amazing! Great work and a beautiful start from a young faculty guy..I bet that he is going to become a new Baran! Please cover the article!

  • CGSLackey says:

    TotSyn

    You know that you can generate the InChiKeys using ChemDraw (well at least 11.0 is all I checked). All you have to do is select the structure and then select “Copy As” and then InChi under the “Edit” menu.

  • ZZZZZ says:

    Snyder is the second coming of Jesus, and Baran invented protecting-group-free chemistry, and other related flavors of the week excite me too by the way
    zzzzzz

  • Liquidcarbon says:

    Could you guys explain please why platensimycin is so popular? There were at least 7 syntheses so far, in less than two years since the discovery!

    All I know that it was’s written in the wiki entry. Are we that afraid of methicillin-resistant Staphylococcus aureus?

  • Liquidcarbon says:

    Uhm, maybe I should just read the paper(s).

  • GYA says:

    The reason for the interest is the fact that the architecture is one of the most unique one’s isolated in recent years and it has biological activity to boot. Don’t be surprised if there aren’t 5 or more syntheses of platensimycin on the way still. Guanacastepene inspired a similar surge for the exact same reasons (slightly less excitement about the activity though).

  • milkshake says:

    If you are to pick a new a tot synth project, you have to have a pretty good rationale. Platensimycin right hand portion is exciting yet small enough to showcase some brilliant chemistry even if you don’t have a mammoth group at your disposal. I think this applies especially to situation in some european groups.

  • Paul says:

    You’re totally right milkshake !! ^^

    HS : BTW it’s my first intervention on Tot Syn, but I read it since a long time now, and this blog is really, really good ! Continue on this way !

    HSbis : yeah I know… sorry for my bad english, i’m just a french ! :D

  • Observer says:

    To No. 22 (ZZZZZ) – If Phil Baran invented “protecting-group-free chemistry”, what did people do 40 years ago before Corey et al. invented protecting groups? While Baran and his group may be some of the most accomplished practitioners of our time of the concept, I think you are giving them a bit too much credit.

  • arnold says:

    #28 I totally agree with you, but…Do I notice a little bit of irony on ZZZZZ comentary #22?

  • ZZZZZ says:

    zzzzz

    My sarcasm isn’t always understood on the internets. To clear things up: Baran = genius, Snyder = genius-in-training (bra), and minotaur = my favorite animal.

    zzzzz

  • Tot. Syn. says:

    Minotaurs are great. Mmmm…. Minotaur stew…

  • milkshake says:

    It tastes just like a kitten!

  • TWYI says:

    jeaLOLous