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27 March 2008 14,244 views 46 Comments

Baran, O’Malley, Yamaguchi, Young and Seiple. ACIEE, 2008, EarlyView. DOIs: 10.1002/anie.200801138 Article PDF Supporting Information 10.1002/anie.200705913. Article PDF Supporting Information Group WebsiteResearchBlogging.org

There’s been a bit of excitement in the comments about this synthesis, perhaps because it’s completion hints further towards a synthesis of Palau’amine, an ongoing passion of our community. The target of this synthesis contains the tetracyclic bisguanidine core common to these natural products, including eight contiguous stereocenters, making it quite a challenge. No biological activity is mentioned, but when the molecular architecture is as sweet at that, do you need another reason to make it?!

A retrosynthetic analysis of the molecule reveals at least two simple disconnections, that of the amide bonds. (However, the reaction used for this coupling is worthy of a brief mention, as I hadn’t seen if for a little while. The acid-partner used was actually a trichloroketone, a nice way of activating an acid for coupling, which can be made via a haloform reaction.) Far less intuitive was formation of the aminal centre by addition of a free amine onto an imine; quite ambitious if one considers the number of amine moieties in this molecule.

The chemistry starts in the second of the two papers linked above, with a short synthesis of the diazide shown below via a Diels-Alder reaction, followed by ozonolysis to provide both ketones. Formation of the first ring then followed by first forming a pair of enol-ethers, brominating and then an aldol condensation to give the the cyclopentane with great selectivity and a very reasonable yield. The authors reference some work by Ho in “Tactics of Organic Synthesis” for this.

Shortly afterwards it was time to provide the second ring, this time oxidatively. They found that oxidation of the allylic alcohol at RT gave the wrong spirodiasteromer at C-14, but heating to reflux in benzene gave the desired diastereomer in a small excess. A nice way to construct the spirocycle.

The last sequence to consider is the pièce de résistance, and the main topic of discussion in the title paper. Treatment of the bisguanidine with DMDO performed a selective oxidation of the alkene to provide a mixture of diols (where their relative configuration was presumably -cis). This was then dehydrated using TFA (again selectively) to provide the product of intramolecular cyclisation (where the imine intermediate has been attacked by the desired nitrogen in the other guanidine). Again as a mixture of distereoisomers, this product was lastly (need I say selectively…) oxidised by the funky silver reagent (silver(II) picolinate – which is most usefully referenced in this paper) to give the desired tetracyclic core. Bloody awesome.

To finish the synthesis, what was required was a reduction of the azides (using 1,3-propanedithiol – referenced here – leaving the corresponding cyclic dithiane as a biproduct), and coupling of the pyrrole units. This, of course, was received as a mixture of diastereoisomers – which happen to be Axinellamine A & B.

Loads to read here, and most of the papers referenced are worth a thorough read too!

O’Malley, D.P., Yamaguchi, J., Young, I.S., Seiple, I.B., Baran, P.S. (2008). Total Synthesis of (±)-Axinellamines A and B. Angewandte Chemie International Edition DOI: 10.1002/anie.200801138

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  • InfMP says:

    Ian Young grew up in a rural town in Nova Scotia, Canada (pop 3000). As a kid, he influenced a friend of mine (now with Evans) to get excited about organic chemistry and he, in turn got me excited too. Thanks to you Ian, great to have so many good Chemists come from NS!

    His single name paper with M. Kerr last year was one of the top reads in JACS. Check it out!

  • On a More serious Note says:

    what a tour de force in synthesis this was.

  • Dione says:

    Neat work. One more ACIE in his cap. So, now Dr. Baran has several ACIEs and JACS, a couple of Natures one invited Hetrocycles and thats it (as a supervisor)…does anybody else find this amusing.

  • Blogging Betsy says:

    That silver step is pretty wild

  • hexanes says:

    I thought the total synthesis of (-)-Pestaloptipsin A (ACIE) would be posted this week. If you guys have the time I recommend reading it. Its a good read.

  • antiaromatic says:

    I agree, it’s a good paper. A different way to look at how to access the caryophyllene-like core.

    As far as the axinellamines, the work is no doubt impressive, but I have to say that I wouldn’t want to be the one purifying those compounds. I bet it’s all RP HPLC, but still. I don’t think I’m the only one wondering how they’re going to close up palau’amine. I haven’t built a model yet, but those distances required to get the closure have got to be pushing the limits. Best of luck to them!

  • Tot. Syn. says:

    Hexanes, antiaromatic: I’ll do a post on it this weekend. It’s been a busy week, and it only went up on Tuesday…!

  • Anon says:

    I think it will be chain of publications coming from his group on the completion of other PIAs as they have laid their hands on axinellamines so amicably. No doubt they will be the first to beat the Palau’amine. EJC…KCN/Marcus Tius……Phil Baran/Kerr…..Ian Young…..just to trace the origin of Ian Young.

  • Neil Young says:

    Is this a chemistry blog or a hall of fame for young chemists and name dropping??? No comments on chemistry at all.

  • TheEdge says:

    I really like the late stage silver oxidation. Not having to deal with an aldehyde-equivalent at that position greatly simplifies the entire synthesis and should be applicable to a range of targets.

    Has anybody looked up the Ho reference? I’m just curious about how detailed it is.

  • Def Lep says:

    late stage silver oxidation is indeed both cool and remarkable. Few labs are ballsy enough to plan a synthesis with that at the end. Congrats Baran Lab.

  • Rookie says:

    Can a carbamate “NH” after treatment with a base act like a nucleophile. Can anybody please explain this to me. Sorry for asking something that is not related to the current discussion.

  • InfMP says:

    yeah, I depronated a BOC and had it attack MeI this week in THF

  • Didymus says:

    There is no doubting that this was indeed a very sweet synthesis.

  • races says:

    supporting info is a work of art.

  • antiaromatic says:

    Carbamates are still nucleophilic, despite the name “protecting” group. I’ve seen a number of instances when carbamates have been used to open epoxides. I’ve also had my own experience where I was trying to t-butylate an acid with dcc/dmap and found that a CBZ protected amine in my molecule actually added preferentially. Just another reason to avoid protecting groups.

  • TWYI says:

    Doesn’t this very synthesis show a nucleophilic carbamate addition?..sure to an enone..

  • milkshake says:

    Carbamate nucleophility: I cleanly N-methylated FmocNH-R once, by accident, with iPr2NEt and MeI in MeCN at RT. Fmoc survived unmolested.

  • Sr. Bubbles says:

    Baran lab does the work so you don’t have tooooooooooooo……….

  • Jose says:

    Co-injection on an HPLC of isolated and synthetic samples? Badass.

  • TheEdge says:

    Isn’t that a common practice at this point?

  • ZZZZZ says:


    …lol at comments like ‘badass’ and ‘work of art'; sounds like some people are in love…


  • Jose says:

    I’m pretty sure not too many people do co-injections (or mixed mp). The experimentals and spectral data for all his papers are simply in another league from 95% of other PIs.

  • GYA says:

    There are reasons for the diligence shown in the experimentals which goes back to the days of his phd and his postdoc. I agree though. The detail is extraordinary!

  • abc says:

    I guess it’s a few days late, but a good nucleophile for Mitsunobu reactions is Boc-protected toluenesulfonamide.

  • B. Bill says:

    Hey y’all wanna go play bumper pool?

  • Tot. Syn. says:

    You crazy Scripps kids…

  • Joseph says:

    You guys got somethin’ to say to me? Why don’t you say it in the microphone. I got a backup mike right here. Check one two, testing, testing. Yup, they both working and guess what? they don’t like no feed back, what’s up?

  • Tot. Syn. says:

    Joe Dirt is a terrible film. Adam Sandler can barely act, never mind produce a movie.

  • B. Bill says:

    I think you are crazy my friend………BEST MOVIE EVER

  • Joseph says:

    Man, Tot. Syn. isn’t even this critical of A.B. Smith syntheses, and they’re the chemical equivalent of ‘Battlefield Earth.’

  • milkshake says:

    dont make jokes about ABS, he wrote the best basic organic chemistry book and they use it as a standard undergrad textbook in the Purgatory

  • Tot. Syn. says:

    That’s plenty.

  • cvengo says:

    can some one explain me how can someone work with 2 mg?
    How reliable are the result then?

  • Tot. Syn. says:

    It’s tough, but not impossible. The NMRs take forever (if you don’t have a cryoprope machine), the TLCs take lots of spotting and columning is an act of perseverance. As for yields, it all depends on the balance you have, and how well calibrated it is. Most labs have a four-place balance, so a reasonable number can normally be gathered…

  • TheEdge says:

    “can some one explain me how can someone work with 2 mg?”

    I think it depends a lot on your molecular weight. If you have 2 mg’s and 30 TBS groups, you probably run a lot of reaction at reasonably high dilution with a large excess of reagents, and you still need a good microsyringe. If you have 2mg’s and the compound above, you can probably run things in a microvessel with a reasonable number of equiv. You make a lot of stock solutions. You try things that don’t need extensive workups, and you give up your sep funnels for a pipette and a steady hand.
    You purify things on pipette columns or on the HPLC (where you don’t lose anything to your TLC-ing). You mass things in as small a flask or vial as possible so that the value you get is (more) significant. You rely more on mass-spec to figure out what’s going on (because it requires so little material).

    It’s not something people really enjoy, but it does feel empowering to be able to do it.

  • Radical says:

    2 mg reactions can be very useful when the amount of material is limited. One can get a good amount of information out as long as there are no more than two or three major products. Purifying these reactions on preparative TLC is probably the best thing to do, although you do need uv-active compounds for this to work. Of course, the accuracy of the yield is always a concern on such a small scale.

    As strange as it may sound, I really prefer working on the 5-10 mg scale to the 20 mg or larger scale.

  • Tot. Syn. says:

    Radical: ‘Need’ is such a strong word… you can still stain a small slice of the prep plate and go with that…

  • antiaromatic says:

    The slice method works okay, but all too often, you end up cutting out parts that don’t belong, especially when you have compounds that don’t stain all that well in the first place.

    Also, eventhough it doesn’t make a real difference, I’ve just always felt better about working on 2 mg scale when the compounds were solids. Something about being able to see it in your flask makes you feel a little better…

  • HPCC says:

    During my Ph. D. I coined the term “invisible yield” for something that you can’t see at all in your flask, typically a droplet of clear colourless oil, but which still shows NMR signals when you add CDCl3 to it and drop it in a probe! Invisible yield is usually 3 mg or less… :D

  • HPCC says:

    During my Ph. D. I coined the term “invisible yield” for something that you can’t see at all in your flask, typically a droplet of clear colourless oil, but which still shows NMR signals when you add CDCl3 to it and drop it in a probe! Invisible yield is usually 3 mg or less… :D

  • Jose says:

    Looks like Phil and co. have more work to do!

    ASAP Org. Lett., ASAP Article, 10.1021/ol8003904

    Nagelamides K and L, Dimeric Bromopyrrole Alkaloids from Sponge Agelas Species

  • […] up was Baran. He had a theme in mind (chemoselectivity in syntheses) and he used examples from several molecules his team has tackled to drive that point home. I won’t go into all the stories he […]

  • […] starting point to the chemistry should be familiar to regular readers – hark back to Baran’s 2007 synthesis of the axinellamines, and a familiar intermediate crops up.  Using very similar chemistry to that used in the earlier […]

  • […] DOI: 10.1002/anie.200801138 Selected as VIP paper and Inside Cover in Angew. Chem. Int. Ed. Highlighted in Tot. Syn. Dot Com […]

  • […] a look back at my previous post on the Axinellamines (can’t believe that was more than three years ago!!), and perhaps the post on Palau’amine. […]