Norhalichondrin B Pt. II

Phillips, Jackson, Henderson, Motoyoshi. ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200806111. 

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.