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Totally Synthetic by Paul H. Docherty, 13 January 2007

Total Synthesis of Merrilactone


W. He, J. Huang, X. Sun, A. J. Frontier, J. Am. Chem. Soc. 2007, 129, 498-499.

DOI: 10.1021/ja068150i

A great JACS article was 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 interesting Nazarov Cyclisation to build the central C ring, and then use a radical cyclisation to complete the B ring. The implementation was sweet:

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.

Selected Comments

15 January, 2007 at 23:08, 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.
16 January, 2007 at 18:45, .... 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?
16 January, 2007 at 22:08, 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).
17 January, 2007 at 15:32, 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 Mukayama rxn or pericyclically by Nazarov)
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