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Merrilactone   

13 January 2007 6,117 views 9 Comments

merrilactone_a.jpg

Frontier, He, Huang and Sun. JACS, 2006, ASAP. DOI: 10.1021/ja068150i.

Well, I’m back. Not quite up to speed – there’s been loads of totally synthetic action over the last three weeks, but I’m working my way through the journals, and posting as I go. As an aside, I’d like to thank everyone at Oxford for their welcome, kindness and support – moving labs isn’t easy or fun, but they’ve been great (especially the Fleet group :))

On with the synthesis! I’m starting with a great JACS article, posted at the close of last year by Alison Frontier at Rochester. Merrilactone has been a popular target, with syntheses by Danishefsky, Mehta and Inoue. Frontier’s approach was to use the incredibly funky Nazarov Cyclisation to build the central C ring, and then use a radical cyclisation to complete the B ring. The implementation was sweet:

merrilactone_a_1.jpg

Although by no means convergent, this path allowed them to build up molecular complexity at an astonishing rate. Completion of the target took around nine steps, again in a linear fashion, and using more routine chemistry, but their judicious use of conditions allowed substrate directed additions and reductions, generating some useful distereomeric control.

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9 Comments

  • Welcome back! Hope you enjoy your new labs!

    As a Magdalene graduate, Prof Fleet couldn’t be anything other than a smashing bloke.

    It is a shame you have turned to the Dark Side, as Cambridge is much nicer.

  • HOMO-LUMO says:

    Thats the best racemic total synthesis of merrilactone A ever published, and including as the key step a new Nazarov reaction developed in her labs. However there is no chance that they could make asymmetrically the molecule with that route.

  • aa says:

    this is a great synthesis, but one thing that I was not 100% convinced of was the Nazarov cyclization. Is there any reason to believe this reaction doesn’t go through an Iridium-catalyzed Mukayama-Michael mechanism? To me, that would give the same relative stereochemistry. Of course, I am asking only out of curiousity and not to disparage the work.

  • .... says:

    aa,

    I think that Mukaiyama-Michael is forbidden by Baldwin’s rules – it’s a 5-endo-trig. I’m having a difficult time seeing how the Nazarov isn’t a 5-endo-trig – do electrocyclic closures not obey Baldwin’s rules?

  • milkshake says:

    This is the first time I see aryl iodide as a chelating metal ligand… And it’s not a typo. The structure of this catalyst is something one hopes to wake up from (and reassure himself that the bad dream has passed).

  • WillisWill says:

    Baldwin’s rules don’t say anything about “forbidden” ring closures, only that if a molecule has several possible ring closing mechanisms available to it, it will proceed by the one most energetically favorable (max orbital overlap between nucleophilic electrons and empty orbital that receives them, least strain in transition state, entropy cost of forming larger rings (ie 11 vs 12) ect..)

    Evaluating whether a particular ring closure will proceed following Baldwin’s rules also depends on the local enviroment of the two electrophilic carbons. In this case, the carbon beta to the carbonyl is much more receptive to bond forming reactions (whether electrophilicly by Mukiyama rxn or pericyclically by Nazorov)

    Lots of similar (and also more straightforward) examples of overcoming Baldwin’s “preference” can be found in Nicoloau’s polyether syntheses back in the late 80′s or Frank McDonald’s tungsten catalyzed oxygen addition to alkynes to make glycals. Trost came in later with a Ru (or Rh?) version of the same reaction. I’m sure there’s a lot more but I can’t think of any specific examples

    Cheers

  • dtb says:

    another violation of Baldwin’s “rules”: the formation of ethylene glycol acetals goes via 5-endo trig attack…

  • aa says:

    thanks for giving it a shot.. the reason i didn’t think it was a nazarov cyclization is that this reaction are “normally” akin to the FC reaction where the resulting carbocation is quenched by alpha proton loss and alkene formation. In that case the Nazarov product should be a 2-siloxyfuran fused to a cyclopentanone. has anyone else got an idea of how to distinguish the two mechanisms?

    thanks

  • HOMO-LUMO says:

    The key is in the stereochemistry. A Mukaiyama-Michael wouldnt give exclusively a product with that stereochemistry, while a Nazarov mechanism gives that by the conrotatory nature of the electrocyclic ring-closure.