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Norhalichondrin B Pt. II   

22 February 2009 9,858 views 5 Comments


Phillips, Jackson, Henderson, Motoyoshi. ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200806111. Article PDF Supporting Information Group Website

I kinda ran out of steam whilst writing the first post on this synthesis, so I stopped basically after the fragment synthesis was complete.  So now it’s time to finish the synthesis, putting the finishing touches to enormous target.  Phillips’ strategy was to assemble the macrolactone first, then append the LHS polyketal, using cross metathesis to stitch the two main fragments together.  The article contains a couple of errors in the caption for this reaction; numbered reagents are miss-labled.  However, in the experimental it’s clear that although two equivalents of the smaller fragment were required, a sizeable chunk of the excess was recovered… which must be quite a relief!


Next up was formation of the ketal, trusting that nature would guide the stereoselectivity in this reaction.  This was mostly the case, with TBAF removing the TBS protecting group and allowing formation of the proximal THF by Michael addition.  A bit of base (or acid as Phillips mentions) causes further cyclisations, and the ketal system.  However, the stereoselectivity wasn’t complete, with 25% of the mass lost as an epimeric intermediate.  In some senses, though, this is quite handy, as it must have been easier to column-out the undesired intermediate rather than an epimer of the product.

Closure of the macrolactone then followed using Yamaguchi conditions, but I was somewhat surprised by this strategy.  I would have thought that ester formation and then RCM would have been the less-risky operation (as cross-metathesis has more options), but this approach was clearly effective.


The last fragment coupling was to bold on the LHS, for which they used a Horner-Wadsworth-Emmons olefination.  Then, once again, they were in the hand of nature (and substrate control) to determine the result of a pair of ketal formations.  Phillips doesn’t comment on this selectivity, but I did a bit of Chem 3D modelling, and I can see that the 6,6-spirofused ketal is definitely anomerically stabilised.  However, I can’t get my head around the smaller system, so I’ll ask you lovely readers to tax your mental processes… 1


I think this is an astounding piece of work.  Phillips’ approach of using the best methods around, regardless of who pioneered them, allows an incredibly short synthesis to be exacted.  For a molecule with such a promising (if truncated) biological profile, this is exactly the right approach.

[1] The SMILES for this subunit is [ [H][C@@]12O[C@H](CC(OC)=O)[C@H](O)C[C@]1([H])O[C@@]3(O[C@](C[C@@]4(O[C@@](C[C@]([H])(O[C@@H](C)[C@@H]5C)[C@]([H])([C@@H]5C)O6)([H])[C@@]6([H])C4)O7)([H])[C@]7([H])[C@@H](C)C3)C[C@@H]2C  ] if you want to model it too.

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  • chinstrap says:

    I wonder if they had any problems with the allylic alcohol being isomerized into an ethyl ketone in the CM step. This side reaction was a problem for me when I heated an allylic alcohol parnter with a type I olefinic coupling partner in the presence of Hov. or Grubbs II. There was J. Organometallic Chem. paper a couple of years back that talked about it.

    I don’t have access to the paper or supplementary material to see if it was an issue. Did they add the allylic alcohol portionwise? Maybe it isn’t an issue with the Stewart-grubbs catalyst or a type I olefinc coupling parner?

    All in all, a dandy piece of work from Phillips!

    • Tot. Syn. says:

      The mass recovery of the allylic alcohol fragment is pretty good, even though they had to use a two fold excess. It’d be interesting to know why a two fold excess was necessary; perhaps they were getting isomerisation of the larger fragment, or cyclisation onto either of the other olefins. Certainly, cyclisation onto the pyran-olefin looks possible, and would probably be faster than cross metathesis.

      It’s also interesting that Phillips used the Stewart-Grubbs catalyst rather than the usual G2. Stewart-Grubbs is supposed to be better in hindered situations, so I reckon isomerism is the issue. They’re slightly unlucky that both fragments have oxygenation very close to the site of reaction, as this can cause problems, but I think that the Ru will be held at roughly the right position. Sometime, if the oxygenation is slightly further away (say a methylene group or two), the catalyst chews up the edges of the molecule and chops-off methylene groups.

      Only done one metathesis reaction – and it worked like a charm :)

  • Ondrugs says:

    Think you are missing a re-protection step with TBSOTf/NEt3 ;) after the ketalization step

  • SN2 says:

    That’s a pretty impressive cross metathesis. Must be the most complicated example yet. Ballsy. Kudos.

  • Bill Pharan says:

    A pretty tasty synthesis of the alkaloid Serratezomine A in JACS today.