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Fusicoauritone   

17 January 2007 4,610 views 6 Comments

fusicoauritone.jpg

Williams, Robinson, Nevill, and Reddy. ACIEE, 2006, EarlyView. DOI: 10.1002/anie.200603853.

Another appearance for the Nazarov rearrangement in this smart synthesis of Fusicoauritone, an interesting terpene with a dicyclopenta[a,d]cyclooctane ring system. Of course, many related structures have been made before, but this appears to be the first synthesis of this molecule. Williams et al. have used a partially-biomimetic approach to the ring system, first creating an eleven-member ring, then closing to form a 5,8-system. However, the cyclisation precursor is hardly non-trivial, so lets look at that first:

The synthesis of that beast begins with a Johnson-Claisen ortho-ester rearrangement, used again a few steps later. This, in conjunction with a nice hydroboration/oxidation/alkylation sequence allows facile construction of this precursor.
fusicoauritone_1.jpg

The eleven-member ring was then formed via a modified the Julia condensation. This reaction is course related to both the Julia olefination and the aldol condensation, and worked rather well. However, subsequent dehydroelimination of the sulfonyl group failed, so the group had to think again.

fusicoauritone_2.jpg

Success, however, was had with a phenylselenation of the sulfonyl ketone, allowing elimination to give the divinyl ketone, and then perform that cracking Nazarov rearrangement.
fusicoauritone_3.jpg

Now, in what must be a biomimetic step, an air oxidation allowed transformation of this via a putative “enolisation and capture of the conjugated enol by dissolved oxygen”. This returned the hydroperoxide of the natural product in a cracking yield (additional: however, check the comments for a possible error with this), but over three days. The hydroperoxide was then reduced to the alcohol (and to the target) in high yielding step. However, the air oxidation takes three days, so a faster alternative was direct conversion with tert-butylhypochlorite.

fusicoauritone_4.jpg

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6 Comments

  • Eraser says:

    You have a drawing mistake in the Nazarov cyclization and subsequent oxidation. The starting material is the enone and not the allylic alcohol. The allylic alcohol was formed after reduction with DIBAl and is of course not a product of the Nazarov cyclization. After removal of the sulfonyl group the alcohol is rexoidazed to the enone with MnO2.

    The paper also has a mistake as to where conditions e in the last scheme sould be. It should be on an arrow from 24 to 1 (compare with text). This is an alternative to the auto oxidation method (40% yield). They claim this is more efficient although the auto oxidation apperas to give a 95% yield (2 steps) if I understand the scheme correctly.

  • Tot. Syn. says:

    I corrected the mistakes – sorry about that, I was preoccupied with the example of the Nazarov rearrangement on the analogous system. I agree that the yield must be wrong, but I’m not changing it until we know for sure. I really liked this synthesis, but I found the paper hard-work. I don’t know why, but some of the schemes seemed rather hard to follow, and the descriptive text was at times ambiguous. Still, nice work!

  • Eraser says:

    There is still a mistake in your second scheme.
    The air oxidation was also on the enone. The allylic alcohol was only to “protect” the enone system during the sulfone removal.

  • Russ says:

    One thing that strikes me at a quick glance of the paper is the minimal usage of protecting groups (only one MEM ether, if I haven’t missed anything). Mind you, the molecule’s only got two heteroatoms, so it miay not be that big of a deal.

    I recently saw Baran speak, and he mentioned a set of criteria for elegant total syntheses (and he borrowed these from someone else – Evans or Danishefsky maybe?) They included things like:
    - minimal protecting groups
    - molecular weight always increasing from one intermediate to the next
    - overall oxidation state is always (going up or down – I can’t remember which – the point being not a lot of back and forth)

    Has anyone else heard these criteria before? Know the original source? Are they committed to paper anywhere?

    Cheers

  • regularchem says:

    To Russ, these all are standard and wellknown to anyone who knows about total synthesis. At least you or him miss the “convergent part”.

  • Russ says:

    To regularchem:
    Yeah, I wasn’t suggesting they were all new to me or surprising, but the way he presented them suggested they were from some seminal paper or something, and if he said what that was at the time, I didn’t write it down. And yeah, there undoubtedly were other criteria in his list and convergence was probably one of them.

    Cheers