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Marcfortine B   

21 March 2007 6,293 views 16 Comments

marcfortine_b.jpg

Trost, Cramer, and Bernsmann. JACS, 2007, 129, 3086-3087. DOI: 10.1021/ja070142u.

Another article I’ve managed to bypass over the last few months, and what a stunner it is too. Marcfortine B certainly has a diverse structure, with a particularly intimidating bicyclo[2.2.2]diazaoctane core; perhaps more usefully, the family it belongs to also has potent anthelmintic activity. With the focus on the spirocyclic cyclopentanone moiety, Trost envisaged that their own TMM (trimethylenemethane) chemistry might produce that complex functionality with ease:
marcfortine_b_1.jpg

They get to that juicy part of the chemistry rather quickly, with the starting material produced from a dehyrating aldol reaction with acetone. This material was then treated with TMM synthon 3 and palladium catalyst to generate the quaternary spirocyclic cyclopentane in one step – quite an amazing transformation.

marcfortine_b_2.jpg

This was the first time I’d seen this reaction, so I actually thought that the transformation of carbonate to acid was a typo, and that one of the structures had to be wrong. However, the mechanism of the reaction accounts for this, through a rather involved process:

marcfortine_b_3.jpg

The palladium actually inserts into the C – O bond, and after loss of MeOTMS rearranges twice to produce the species that does the [3 + 2]. Top stuff. A few less dramatic steps later, they’d appended a piperidine (tetrahydropyridine?), and were set to cyclise onto their unsaturated ester; the Michael addition went well, quantitatively generating the complex product as a single isomer. The authors attribute this to shielding of the re-face of the Michael-acceptor by the aromatic portion of the molecule.
marcfortine_b_4.jpg

Next came the exciting radical chemistry (I’m a radical chemist – I get excited about these things!); they made the Xanthate ester, allowing radical generation in a Barton-McCombie fashion, which cyclised onto the olefin completing the bicyclo[2.2.2]diazaoctane core. However, rather than picking-up a hydrogen atom and continuing the radical chain reaction in the expected manner, it trapped AIBN and eventually eliminated to give the formal oxidative radical cyclisation product (always a winner…). Thus, they used (super)stoichiometric AIBN and catalytic tributyltin hydride!
marcfortine_b_5.jpg

As can be seen, they were only a few steps from the end, and completed a rather tasty synthesis in remarkably few steps.

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16 Comments

  • TWYI says:

    This is as good a total synthesis as I have seen this year, pretty amazing stuff.

  • provocateur says:

    co2 as a ligand!hmm..i wldnt be buying tht !!!!!!theres another mech…i will leave tht to sumbody to put it on the blog!

  • Fan says:

    Best synthesis of the year.
    Ever.

  • do liu says:

    biomimetic route is much more short. over engineered nearly 30 steps to show that trosst chemistry good.

  • .... says:

    If you draw the structure differently, marcfortine C is very similar to notoamide recently made by R. Williams through a biomimetic route. A synthesis of Marcfortine C by Williams is actually in early view in tetrahedron (march 7)

  • do liu says:

    please compare for reader so they see how good trosste synthetuc really is

  • pi* says:

    what I like about this synthesis is the way that the initially formed stereocenter and the simple reactions chosen completely dictate the rest of the stereochemistry of the newly formed centers. No auxilaries or fancy reagents, just planning. The michael addition (forming the quaternary center), protonation sequence that you highlight forms one stereoisomer and is a particulary sexy bit.
    Have you seen todays nature?

  • TWYI says:

    As above, Baran’s superb JACS/nature combo is a must read, if not for the XeF2 step alone.

    Awesome stuff, March has been a good month

  • Tot. Syn. says:

    I’m writing it! I’ll have a post on the Baran paper soon. And, yes, I’ve seen Nature today – I’m in it :) !!! (in the NatureJobs section…)

  • Rof5 says:

    Dude, you had a typo in the structure of AIBN on your post. The N atom is missing!
    One of the best synthesis for sure

  • ddd says:

    where is baran’s nature paper?

  • HR says:

    baran’s nature paper: doi:10.1038/nature05569

  • ddd says:

    I meant Totallysynthetic do not forget to discuss that paper on your website

  • PD says:

    Since Paul was too modest to post a link:

    http://www.nature.com/naturejobs/2007/070322/full/nj7134-464a.html

    (Scroll down…)

  • pi* says:

    Hey,
    Nice job! When you said “I’m in it (in the NatureJobs section)” I didn’t realize you were actually IN it. I thought you were in the process of reading it or something.
    Congrats!

  • Tot. Syn. says:

    Cheers! It’s always nice to push the PR wagon out… I’m available for children’s birthdays, church fêtes and shopping centre openings…