“As expected, the reaction occurred exclusively from the less hindered face of the enamide to produce coupling product 23 with the desired stereo- and regiochemistry. It should be noted that this crucial intermolecular Heck reaction was carried out on a multigram scale in excellent yield. ”

Note the “as expected” here! The product of the coupling was progressed without purification through the next step which is an osmium tetroxide dihydroxylation of the very hindered double bond with a yield of 50% for the two steps. Some interesting conditions here; 2.99mol% OsO4 using K3[Fe(CN)6] as a co-oxidant in the presence of quinuclidine and methanesulfonamide. Quinuclidine appears to significantly enhance the rate of dihydroxylation. This is apparently in contrast to that found by Sharpless.

To scale-up a 28 step synthesis with an overall yield of 1.1% is no mean feat. A rough examine of this route exposes several reactions with severe scale-up issues: For example the use of osmium tetroxide, all be it in 3mol% represents a major issue. I am not aware of any suppliers that make such large quantities of this toxic and volatile compound. Along with personal protection issues how do you treat the waste? There are also several heavy metal catalysed reactions, mostly Pd. So quality control will no doubt set very low limits for the amounts of these elements in the final API.  The diazonium tetrafluoroborate as well as the use of hydrazine contribute to the possible thermal hazards of this process. Exactly how one would avoid them I’m not sure but at the end it will be rewarding to have optimised such a synthesis leading to a very valuable compound in our armoury against such aggressive diseases.