Hygromycin A

Donohoe, Flores, Bataille, Churruca. ACIEE, 2009, ASAP. DOI: 10.1002/anie.200902840. 

Sugar bashing time!  It’s been ages since I glanced at sugar synthesis, probably because I developed an irrational phobia whilst at Oxford.  Not because of the intricate syntheses, the illogical reactivity patterns, or the ridiculous names (psychose psicose, anyone??) – but for the shear quantities of potassium cyanide used by the Fleet group in their Kiliani Ascension chemistry.  Probably time I got over that, so we’re staying with the folks at the old place, and a bit of tethered aminohydroxylation from Tim Donohoe (hi Tim!).

The synthesis starts with beating the crap out of D-arabinose, differentially protecting, oxidising and then Grignarding.  There’s nothing particularly new, except for an interesting removal of an allyl protecting group.  Normally, I would reach for the palladium cupboard, but they did something pretty different here.  Firstly, a bit of G2 isomerises the allylic group, and then NBS removes it; Donohoe notes that the G2 works by decomposing to the ruthenium hydride species, which does the dirty work.  I mentioned this as a curse of metathesis chemistry a few months ago, but it’s pretty neat when you want it to work.

Next up is the real meat of the chemistry; the groups own aminohydroxylation methodology.  They’ve made some improvements here, certainly since they first examined this chemistry in an Org. Lett. back in 2005, reducing the loading of osmium to 1%.  A good thing too – I hate that stuff even more than cyanide.  However, it’s notable that they’re using potassium osmate, which is a hell-of-a-lot easier to work with, as it’s not volatile. The result is a pretty dandy amino-hydroxylation in high yield.

Next they removed the ‘chiral auxiliary’ (except it’s not really) by reducing opening the THF, and doing a retro-Diels-Alder.  However, you’re gonna have to look in that Org. Lett. to see more about that chemistry.

Lastly, we’ve got the crucial stitching together of the molecule; one third was coupled using standard peptide chemistry, whilst they had something far more interesting planned for the other side.  The idea was to use a Mitsunobu displacement of the hemiacetal hydroxyl, but as usual they’re running into that anomer-selectivity problem.  Their bet was that by choosing the correct protecting group in the C-2 position, and the right conditions, they might get the correct stereochemistry.  However, I’m not sure I understand the reasons for this selectivity. Any sugar-bashers want to enlighten me?

Neat work, folks…