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Agelastatin A Pt. 3   

21 April 2009 42,880 views 106 Comments

agelastatin-a

Du Bois, Wehn. ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200806292. Article PDF Supporting Information Group Website

Our third visit to this tightly functionalised little molecule (one – Trost, two – Tanaka, Yoshimitsu), that sterotetrad certainly brings in the players.  I’m not going to go into the biology (hit up the Tanaka post for that), so let get straight into the synthesis.  Du Bois kicks off with an opening of an optically active, bicyclic lactam (2-Azabicyclo[2.2.1]hept-5-en-3-one) – which is commercially available, but not exactly cheap.  Good thing the synthesis is so short…  Protection, reductive ring-opening and sulfamate formation give us the SM for the first scheme – a (very) catalytic aziridination, returning cracking diastereomeric control.  That’s no real suprise, as the intramolecular tether isn’t very long, so forming a cis-ring junction would be heavily disfavoured.  However, the next reaction is more impressive (from a selectivity standpoint), as azide attack occurs with an 9:1 preference for their desired position.  More about that selectivity in this paper.

agelastatin-a_1

With all four stereocenters now inplace about the core, it was time to start building the rest of the tetracyclic ring system.  First-off was getting rid of that tether – done nicely by using the inherent reactivity of sulfamates.  Thinking about sulfonates (highly reactive, good leaving groups) versus sulfonamides (bastard, bastard protecting groups 1), it’s clear why displacement occurs at the desired position to give the desired phenyl selenide.

agelastatin-a_2

Moving on, elimination of the selenide gives the exo-methylene, whilst a Staudinger reduction gave them a carabamate in the end.  Lastly, a Paal-Knorr pyrrole synthesis allowed construction of the lower ring.  Of course, they’ve now destroyed a stereocenter, but that situation was quickly resolved by doing an oxidative cleavage of the alkene.  The intermediate ketone was then attacked by intramolecular cyclisation, providing the N,O acetal as a single stereoisomer.  The final ring was then installed using a bit of base (and a rather exotic alcohol… Du Bois uses this in preference to t-BuOH as it’s easier to keep dry.  Good knowledge.), leaving a literature bromination to complete the target.  Nice work.

agelastatin-a_3

[1] I had to remove a tosyl group from an aniline recently – hadda use 20 equivs. of sodium naphthalimide to get complete deprotection.  Grrr…

PS.  Look at the top of the blog post.  Below the title structure, next the PDF icon – the ChemDraw icon links to my schemes in CDX format.  Might be useful sometime…

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106 Comments

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  • xyz says:

    asdf says:
    25 April, 2009 at 6:29
    How does one go about choosing interesting and novel natural products to target for total synthesis?

    I think it would be based on whether you have ‘totalsynthesis’ strategy
    or some interesting chemistry to showcase. The former is target driven, while the later one is chemitsry driven; There could be activity driven, if you are in some medchem department.

    • asdf says:

      What journals does one read in order to find molecules which showcase a particular reaction?

      • HPCC says:

        When you spend 60 hours a week in the lab developing your own methodology, you will instinctively recognize targets that have that particular structural motif that your methodology allows you to make in a record low number of steps from a deceptively simple starting material. Of course your method is so awesome that it will zip up the natural product enantioselectively as well.

        I am sarcastic here. But yeah, if your method allows for the construction of benzylic quaternary stereocentres, your bias will lead you observe new molecules isolated that bear this functionality.

        Where to look? Natural Product Reports, J. Nat. Prod., Org. Lett., JACS. When an isolation paper is published in JACS, you can be sure of 2 things. A) Big names like KCN have most likely seen the structure a few months before the readers of JACS, and B) it’s most likely biologically active like crazy. These days the structural isolation papers in Org. Lett. are pretty cool molecules – there’s on average 2-3 per month I’d say.

        There may be other journals of which I’m unaware, and I invite the other comments on this board to chip in! ;)

        • Vanadium says:

          Natural Product Updates is a good source. It pulls targets each month from 100+ journals. For isolation, it’s short and sweet: structure, some physical properties, and usually one sentence on the activity or isolation source. It also abstracts total syn and some methodology. The online database search is decent, not great.

  • xyz says:

    Helvetica chemica acta does publish the isolation papers too. ‘Heterocycles’ lists all the alkaloid type of natural products in one place.

    There is a book by gordon titled as ‘modern alkaloids’ which lists many families that are contemporary in organic synthesis area.

    In fact, this blog had a section for that titled as still in the RBF…but Paul might be too busy for doing that. It would be nice if some body can pool all the hot molecules together in one place.

    • Tot. Syn. says:

      Actually, the section was called “Fresh Meat”, but I dropped it fairly early-on, as it didn’t attract any attention. However, I’m happy to take submissions!

  • You don't know me says:

    In regards to contemporary targets, are there any that have been around for quite some time but have just proved too difficult even for the brilliant minds of modern organic synthesis? I mean palau’amine hasn’t been around for too long and everyone is saying that it will be completed very soon.

    I guess I’m wondering about almost holy grail compounds. Or does everyone here hold the believe that anything can be made given enough graduate students and postdocs?

  • tim says:

    I think haplophytine is still unconquered. As is maitotoxin which would be a great demonstration that enough graduate students can make anything.

  • Ian says:

    NPR publish a paper every 3 months on all the natural products that have been isolated in that time..

    ‘Hot off the press..’

  • Harold of the Rocks says:

    I tend to do substructure searches on Beilstein with inp in the topic list… it only shows compounds with the desired motif that are isolated natural products, that way you don’t miss much, however you are a few months out of whack.

    • PotStirrer says:

      So in the end, Woodward and Corey finally succumbed to the ways of Beilstein. And in doing so, each gave just a little bit of his soul away. What a couple of dumbshits.

  • Pete says:

    I, for one, do not believe that our current technology allow us to make anything.

    As for classical targets that have remained elusive…Azadirachtin was recently completed by Ley. Over 20+ years of chemistry and technological developments. Who knows how many postdoc and grad student years.

    • Tot. Syn. says:

      Yep – saw it, read it – and remember to read the preceeding Org. Lett. by the group to make the core. I’ll have a post on it asap.

      • HPCC says:

        Presented that in group meeting 12 hours ago. Freaking nice little beauty of a synthesis!

  • Ian says:

    vinigrol

  • Knut Jacksworthy says:

    Nobody has made lomaiviticin, although several prominent groups are working on it. It’s only been out for about 6 or 7 years though. I’d say that haplophytine is #2 on the most-wanted list after palau’amine.

  • antiaromatic says:

    The polychlorinated sulfolipids are another uncharted land. Carreira’s done some great work, no doubt, but the larger members of this class are still completely lacking, not even to mention the whole problem of asymmetric construction.

  • Fil Barn says:

    Hands off lomaiviticin . . .

  • ZZZZZ says:

    zzzzz

    …Post #100 on Agelastatin?! Wow. OK, now back to making large amounts of Tamiflu for the world…

    zzzzz

  • mr tin says:

    i think we might see haplophytine very soon =)

    • Gram Scale says:

      From the David Chen lab? Will he share the Nobel Prize with Nicolaou? That’ll be an especially bitter pill for that man to swallow, given the pride of synthesis lab principal investigators . . .