Totally Synthetic by Paul H. Docherty, 3 August 2009
Total Synthesis of Hygromycin A
T. J. Donohoe, A. Flores, C. J. R. Bataille, F. Churruca, Angew. Chem. Int. Ed. 2009, 48, 6507-6510.
The synthesis starts with prolonged heating of D-arabinose, use of some protecting groups, oxidation and then a Grignard reaction. There’s nothing particularly new, except for an interesting removal of an allyl protecting group. Instead of using a Pd catalyst, Grubbs 2nd generation catalyst (G2) isomerises the allylic group, and then NBS removes it. Donohoe notes that G2 works by decomposing to the ruthenium hydride species, which does the dirty work.
Next follows the core of the chemistry; the groups own aminohydroxylation methodology. They’ve made some improvements here, certainly since they first examined this chemistry in a paper in Org. Lett. back in 2005, reducing the loading of osmium to 1%. However, it’s notable that they’re using potassium osmate, which is not volatile. The result is a very useful amino-hydroxylation in high yield.
Next they removed the ‘chiral auxiliary’ by reductive opening of the tetrahydronfuran ring, and perforing, a retro-Diels-Alder.
For the construction of hygromycin A; 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.