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Allosecurinine   

14 September 2008 11,273 views 36 Comments

Kerr and Leduc. ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200803257. Article PDF Supporting Information Group Website

We’ve not got much to go in terms of biological activity (GABA receptor antagonism by a diastereoisomer…), so lets just assume that we’re in it for the chemistry.  It’s quite a nice looking target, leaving me somewhat surprised that this is it’s first synthesis, so props to Michael Kerr for digging it out of the 1962 bag…

So, to the synthesis – and surprisingly to the very reaction, protection of butenol as it’s PMP ether.  They used a Mitsunobu reaction to do this, which I found kinda interesting.  I’ve never done a Mitsunobu reaction, but from what I’ve head, it seems like it isn’t the kind of reaction one wants at the start of a synthesis.  Anyway, it was all Corey’s idea… I liked the formation of the cyclopropane, though; a very smart way to make enantiomerically pure cyclopropanes.  Some protecting group shennigans were then required to replace the hydroxyl for an hydroxyl-amine (I wonder why they didn’t start with 1-amino-but-4-ene? *hits himself about the head*… durrr…), which they deprotected and cyclised in one pot.  Quite a cyclisation too; working from a JACS paper on the methodology, Kerr suggests that one firstly gets formation of an imine, which opens the cyclopropane leaving the stabilised malonate anion and the first ring.  The anion then shuts-down onto the iminium ion in a Mannich-sense, forming the cyclopentane.  Nice.

To be fair, there’s quite a bit of leg-work between here and the next intermediate; eight steps isn’t unreasonable though.  And I really like the way Kerr finishes-off the natural product, with two of the more important steps following each other to complete two more rings in direct succession.  They actually had a bit of trouble with the order in which to complete these transformations, with the result I’ve shown being the most successful.  Deprotections and cyclisation of the remaining ring by displacement of a mesylate then gave the natural product.

Nothing too dramatic, but that methodology is pretty damned nice, so it’s good to see it put to some use.

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36 Comments

  • anniechem says:

    Neat paper. FYI, the links for the paper and SI bring you to DuBois’ Gonyautoxin 3 papers.

  • Mike says:

    Nice synthesis Paul. Could the reason they didn’t start with 1-amino-but-3-ene be that they needed an O-alkylated hydroxylamine rather than an amine ;-) ?

  • Tot. Syn. says:

    Thanks, both of you!

    I should get more sleep, or find better excuses for my mistakes.

    @Mike – at least I drew it right! I’m too used to phthalimides being use as nucleophiles to displace tosylates, et c…

  • anon says:

    Methodology that requires 8 steps from commercial material to prepare starting material (in crappy yield) is neither interesting nor impressive.

  • gilgerto says:

    Anon, you’re probably doing enantioselective addition of organozinc to cyclohexanone and find it interesting…

    Of course it takes some steps to get to the cyclization precursor, but the methodology is kind of nice. I also like the cyclopropane formation from 1,2-mesylate.

  • gilgerto says:

    I meant cyclohexenone…

  • anon says:

    Pfft, don’t be ridiculous. I’m doing additions to benzaldehyde*

    Crappy/boring/done-to-death methodology with commercially-available substrates is every bit as pointless as novel methodology with substrates that no one else is going to bother making.

    * ligands developed not useful for any other aldehydes. Ligand preparation takes 8 steps and requires purification by chiral HPLC. ee’s obtained by other experimentalists may deviate from those reported by up to 20 %. Performing reaction outside of a glovebox may result in consumption of the experimentalist by Elder Gods.

  • UBChem says:

    Wow someone got up on the wrong side of the bed. Where
    is it taught in the chemistry curriculum that we must always look at the faults of the work? Why can’t we appreciate the key novelties of someone else’s program and look to find creative ways to improve on those to better science, not bring it down. This should be true for everyone’s work, except KCN, he sucks.

  • Pete says:

    Wow UBChem…Spoken like a true future professor of chemistry…Well said.

  • Jose says:

    “This should be true for everyone’s work, except KCN, he sucks.”

    Even his initials are toxic!

  • Matt says:

    Can somebody tell me the role of t-Butanol in PMB deprotection?

  • optional says:

    Hey guys, tell me if I am wrong……If one uses cross-metathesis at an industrail scale, wouldn;t the price of catalyst be a knockout factor? especially in the begining of the synthesis….I recently ran into optimization of CM with my substrate…needless to say……a 100mg aldrich bottle went kaboosh in iike a week…and so did the $100 something that went into buying that catalyst :(

  • MAB1 says:

    Doesn’t Grubbs 2 also have limited use research license?

    therefore no bulk orders. (assuming you are using G2 for the CM)

  • milkshake says:

    In the industry process you would want to optimise for low catalyst loadings, easy purification – and also to skirt patents. If I remember correctly there are several alternatives to Grubbs II catalyst – not all work as great but some of them are not patented. And you can always in-license the technology if it is really important (like for a drug candidate scale -up process)

    In industry the main concern would be heavy metal residue, Ru-methathesis catalyst are notorious in this respect

  • Curt says:

    talking about KCN whats about his lab in singapore..can anybody feed me on that !!

  • lou says:

    KCN will receive the Nobel this year.

  • UBChem says:

    Iou…. you’re dreaming. And so is he.

  • conte says:

    I bet the Nobel prize will be given to some bio-chem, bio-tech, bio-med… chemist, no synthesis for a while in Sweden. By the way, have you seen this OL? http://pubs.acs.org/cgi-bin/abstract.cgi/orlef7/asap/abs/ol801772p.html
    Take a look to the solvents….

  • milkshake says:

    Istituto di Chimica dei Composti OrganoMetallici, Firenze, Via Madonna del Piano

  • Cat Herder says:

    amazing… and to think my labmates and I joked around about trying something like this…

  • Cobalt says:

    Shapless would be proud. I overheard him tell a colleauge once that the Cu cat. azide-alkyne cycloaddition reaction was robust enough that you could run it in minestrone soup. Considering he once brought a bucket of seawater into lab and told his students to run their reactions in it, I half believe he actually tried it.

  • Pete says:

    There’s at least a half dozen chemists I would like to see get the Nobel prize before KCN…

  • TWYI says:

    Only half a dozen :shock:

  • furrowstatin says:

    conte:
    If Sweden gentleman keep their favor to chemists interested in biomedicine. hopefully the winner is not sooo old, just like one among Tsien, Schultz or Schreiber would be great, and they all more deserve that than KCN

  • optional says:

    I totally agree against KC=N, but Why Schreiber?

  • Axinellamine says:

    I think Phil Baran deserves the Nobel Prize more than KCN

  • % says:

    I could see Buchwald or Curran winning it before Schreiber or Schultz. Sweden likes to give the prize to people who extensively develop one area of chemistry, not chemists with less complete, but more diverse accomplishments.

  • anniechem says:

    Off-topic, but since Axinellamine mentioned Phil Baran…..has anyone here seen him speak? He’s speaking next month about two hours drive from where I am. I’m definitely interested…….so, is it worth the drive? Is he a decent speaker?

  • milkshake says:

    Baran is an outstanding speaker – definitely no problem in that department. He goes through things with a gusto, ligtningly fast. Bring bottled holy water and a crucifix, to ward off his spell.

  • conte says:

    furrowstatin:

    it was only to point out that the Nobel prize is often given for researches which have a direct connection to real life, and it is mich easier for biochemistry, material science etc… more difficult for synthesis. I think the Nobel prize given to Corey can be considered “the Nobel for synthesis”, and we’ll have to wait a little bit more.

  • peter says:

    sorry for highjacking thread from Nobel thing, gentlemen, but would anybody of you be so kind and put some light on stereoselectivity of steps leading to coumpounds 22 and 25 (see SI) for me? I have problem with stereoselective outcome of Krapcho decarboxylation providing 22 – if double bond of enolate is hindered more effectively by Boc group than by other two substituents on the ring, why this does’t apply for oxidation with Davis oxaziridine leading to 25? related questions: is it ok not to specify configuration of Davis oxaziridine in SI? authors say this oxidation provided mixture of product together with “tosyl amide” upon workup – where did this tosyl amide come from?
    thanks

  • Tex says:

    Peter:

    The tosyl amide comes from the N-sulfonylimine byproduct derived from the oxaziridine through hydrolysis.

  • peter says:

    sorry for probably dumb question: if tosyl = p-toluenesulfonyl, i still do not see the source of this tolyl moiety :(
    or do they mean camphorsulfonyl?

  • Tex says:

    Peter:

    The problem here, I think, is that Davis oxaziridine gets used for several variants of N-sulfonyloxaziridines developed by the Davis lab. In this work a benzaldehyde-derived oxaziridine was used (see 30, in Scheme 4), which afford an N-sulfonylimine byproduct. On work-up/chromatography, this imine undergoes hydrolysis leading to the formation of the parent benzaldehyde and tosyl amide.

  • Avi says:

    Does Corey still take Grad Students??

  • antiaromatic says:

    Avi:

    Corey no longer takes graduate students, but he does accept post docs. I think, though, every now and again, he has an undergraduate.