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…