Oseltamivir (Tamiflu) Pt. 6
Hayashi, Ishikawa and Suzuki. ACIEE, 2009, EarlyView. DOI: 10.1002/anie.200804883.
It’s back! Not just Tot. Syn., reanimated refreshed after a decent winter break, but Tamiflu too (thanks to all those who flagged this one up for me. In this case, in a (marginally) different guise, as what we’ve got here is Oseltamivir-free base, not the phosphate salt normally isolated. Not an important fact, but the salt formation probably makes quite a difference in-vivo…
However, that doesn’t matter a damn when the synthesis is a sweet at this. To quote Hayashi, this is a ” three one-pot operations” synthesis, so over pretty damn quick; in fact, there’s only one synthesis scheme in the paper. However, to explain more of the chemistry going on, I’ve dismembered the scheme to show more of the intermediates, and give a better idea of what’s going on.
First up is an organocatalytic Michael reaction, using the groups own methodology… here and applications here. This installed the first two stereocenteres, and allows the group to to a futher, diastereocontrolled Michael addition into a vinylphosphonate. The intermediate produced is then perfectly set to do a ring-closing HWE, completing the cyclohexene. This approach is particularly neat, as most previous routes used Diels-Alder chemistry to install the ring, and then upwards of ten steps to functionalise the ring; as we see later, Hayashi is already imparted most of it. However, a flaw is evident; a mixture of diastereoisomers was produced a the C-5 center, bearing the nitro group. Neither acid nor base epimerisation was entirely succsessful, but heating the with toluene thiol and a spot of pot-carb (still present) did the job. This also ‘protected’ the alkene by Michael addition of toluene thiol, completing the first of the ‘one pot’ operations.
Next up is selective acidic deprotection of the t-butyl ester, formation of the acid chloride, displacement with azide and finally Curtius rearrangement and amide formation. Neatly done in one pot, but the use of azides is perhaps a drawback. Completion of the synthesis then only required reduction of the nitro group (using in-situ generated HCl with zinc), then elimination of the thiol to finish the target. This involved passing ammonia gas through the reaction mixture, generating a Zn(II)-ammonia complex (is that just to remove the zinc, or is it providing an active metal complex?), then retro-Michael.
Damn nice work; I’ve been picking though the experimental, and there’s really not much in the way of an industrial scale up of this synthesis that isn’t present in the main text (like the azide, and possibly the use of toluene thiol). Whether we need another synthesis that can be scaled is another story… resistance to Tamiflu is yet another… but lets just start 2009 with a cracking bit of synthesis.