Oseltamivir phosphate (Tamiflu) Pt. 5
Shibasaki, Yamatsugu, Yin, Kamijo, Kimura and Kanai. ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200804777.
A fifth appearance for my favourite drug ‘interloper’ in to this natural-product space; alarm bells shouldn’t be ringing – just cause I work in pharma doesn’t mean I’ve turned my back on natural products! Tamiflu is of course based on a natural product, shikimic acid – the starting point for the original synthesis. But as natural sources go, it’s rather hard to get hold of, and thus damned pricey (£248 for 5g on SA just now). Other routes used involved chemistry that was perhaps a mite ‘tetchy’ on scale, such as azides and aziridines. A few years back, Corey announced that the synthesis was solved (which made the national press!!!), with his cracking synthesis that I still love from a chemist’s point of view. However, from a practicle perspective, there were still a few problems, including a -78 degrees or two, which are problematic on a plant scale.
On the same day his former student Masakatsu Shibasaki published his work on Tamifly, which was also a very nice synthesis, but the azides and aziridines were still rocking around the cyclhexane. It appears that he doesn’t think of them as a problem, as this latest synthesis is still loaded with those frisky nitrogenous beasties, but there’s loads more to this synthesis.
It kicks-off with an awesome asymmetric Diels Alder, in which they scoured the top-row of the periodic table for the right addive to induce the asymmetry. Barium isopropoxide did the job, along with a pretty damned complex ligand. A quick look on SciFinder tells us that it’s a five step synthesis, using some pretty nice chemistry in itself! It looks like it’s worth it, too – the result of the DA is very nice, building that asymmetry into the cyclcohexene with apparent ease.
A few steps later – and it’s azide time. Not just one acyl-azide, though; two in this case, all set to do their Curitus rearrangement to impressively build a cyclic carbamate and the Boc-protected amine in one pot. Nice work, as this also differentiates the two amines. However, they were aware of the problems of working with such a tempramental substrate, so they optimised the reaction conditions so the azides were never isolated or removed from their solvent.
After acetylation, they needed to bolt on a carbon, and preffered to use a C1 acyl anion equivalent – in this case, a protected hydroxy malononitrile. An allylic, Tsuji-Trost style opening and decarboxylation of the carbamate did the job nicely, installing the new stereocenter in apparently complete control (not that it matters in this case).
Completeion of the synthesis was a little traumatic – substrate controlled epoxidaiton went well, as did opening of the epoxide. However, the planned displacement of the newly installed hydroxyl to install the 3-pentyl ether was very difficult. They finally surmounted this problem by displacing it with the neighbouring amine (a double Mitsunobu), forming an azidiridine. Opening of this aziridine with Lewis acid and 3-pentanol finally finished the job (after salt fomation).
Nice work, using some impressive chemistry; read the paper for full discussion of all that Diels-Alder work!