Norhalichondrin B Pt. I

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

As I said in the last post, it was a rather quiet fortnight for total synthesis, at least as the big journals go.  However, I think Andy Phillips can feel justified in his absence when he’s been cooking molecules like this ‘un up.  Norhalichondrin B is part of the halichondrin family, isolated about twenty years ago – plenty of time for a bit of synthetic action, kicked off by Kishi back in ‘92.  Impressively, the synthesis hasn’t been entirely academic, with the peeps at Eisai Pharma also working on analogues.  So how to start (lots of grant-application forms…)?   Retro time:

The bulk of the fragment couplings are shown above, but there’s a hell of a lot of work before we get there.  Phillips’ route to even the smallest fragments is remarkably interesting, starting with that of the left-hand-side pyranopyran.  Beginning with a diazobutenoate and a chiral auxiliary, a bit of rhodium caused insertion into furan, resulting in the rather interesting bicycle.  This chemistry was developed by Huw Davies back in ‘96, and is apparently better suited to this synthesis than Phillip’s own ideas.  A few functional-group beating steps (methanolysis, Curtius rearrangement, reduction and acetal formation) left them set to do a bit of RORCAM (ring-opening-ring-closing-alkene-metathesis).

Next up is a bit more diazo chemistry, using a chiral ?-hydroxy ketone (asymmetry installed using a Noyori hydrogenation).  Treatment with copper ack-ack lead to a 2,3-sigmatropic rearrangement, building the THF in a cracking yield.  This works (unsurprising) by extrusion of nitrogen and then addition of the resulting carbene to the allylic ether.  This leaves an intermediate  oxonium ylide which rearranges to give the THF –more about this here.

A few steps further on (Wittig methylenation, hydroboration, oxidation), and the group were ready for a rather nice asymmetric NHK coupling, developed of course by the man himself.  The catch, of course, is the high loading of catalyst – half an equiv.  However, I’m sure the aniline / dihydrooxazole moiety is recoverable, so it’s probably not a disaster.  And the result is pretty sweet, allowing the two new stereocenters to be installed quickly, if only in moderate yield.  One thing I’ve been pondering, though, is the stereochemical control issues; the ‘catalyst’ imparts reagent control, whilst both substrates themselves apply induction.  The THF is probably the weaker factor, whilst the iodide is more complex with that ?-methyl.  Any thoughts?

Moving on to another fragment, we’re still dealing with furans, though in their more oxidised state.  Stereochemistry in this fragment was installed using addition of (-)-Ipc₂-(E)-crotylborane into a furfural precursor; a Brown crotylation.  I think a lot of readers will know that particular named reaction, but the next was one I’d almost forgotten – an Achmatowicz oxidation.  This chemistry takes an ?-hydroxy furan and performs a stereoselective ring expanion by incorproating the hydroxyl stereocenter; however, the reagents used by Phillips seem slightly rarefied, so I’m not sure where these particular conditions originate from.  He does explain, though, that the immediate product is a pyranone
hemiacetal – this is then reduced in-situ using TFA-mediated ionic hydrogenation.  Nice yield, too…

Time to start unifying fragements, and a bit more from the top row of the periodic table (please Carol… btw, do undergrads at many universities still have to memorise the periodic table like I had to?  Top row was SCottish Television Cannot Make Films COncerning NIce CUte Zebras.  Not exactly poetic genius, but it sat in the mind rather well… thanks Jim).  In this case, a fairly-well prescedented domino reaction was used to perform the key NHK and mesylate displacement, building the pyran ring in exactly the same way Kishi did almost two decades ago.  If it works… and all that.

I’m going to pause here… and add a second post to finish the synthesis later this week.  Bloody awesome stuff, highlighting some superb modern chemistry.