A concise synthetic approach toward tamiflu (oseltamivir phosphate): cis-aziridine as the key synthon and RCM

Abstract

The key synthon cis-aziridine has been efficiently utilised for the synthesis of tamiflu (oseltamivir phosphate), using Wittig olefination, Barbier addition, Mitsunobu reaction and ring closing metathesis (RCM) as key essentials.

Furan‐Derived Chiral Bicycloaziridino Lactone Synthon: Collective Syntheses of Oseltamivir Phosphate (Tamiflu), (S)‐Pipecolic acid and its 3‐Hydroxy Derivatives

“…Syntheses of tamiflu, ( S )‐pipecolic acid, and its 3‐hydroxy derivatives were undertaken to showcase the accessibility of diverse skeletons of bioactive molecules from synthon 7 . Furthermore, the synthetic approach described in this manuscript was inspired from the drawbacks of our previous syntheses of these molecules which employed chiral pool strategy and the disadvantages of these syntheses which involved separation of the diastereomeric mixture of aziridine synthon, protection‐deprotection sequence and the sensitive acetal deprotection using Lewis acid in case of tamiflu synthesis. The current protocol utilizing common chiral synthon 7 overcomes most of the drawbacks encountered in our previous syntheses.…”

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

“…229) [606], diaminocyclohexenes [607], maeocrystal V (an earlier step in the synthesis employs enantioselective rhodium carbene-mediated C-H activation) [608], tamiflu (e.g. 230) [609], 6-O-benzoylzeylenol [610], the cembranoid skeleton [611], cyclohexenes fused to polycycles (two-fold metathesis) (e.g. 231) [612], cyclohexenes that feature spiro fusion to an angular triquinane system [613], cyclohexenes fused to carbohydrate systems [614], and cyclohexenes fused to a naphthalene system for preparation of the core ring system of kosinostatin [615];…”

Synthetic Advancement of Neuraminidase Inhibitor “Tamiflu”

“…Tamiflu from cis ‐aziridine by RCM reaction : A new route to Tamiflu intermediate aziridine 27 , from cis ‐aziridine compound (Scheme ) 405 , precursor from D‐mannitol was initiated by Chavan and team members . The DIBAL−H inspired a reduction of the ester group of 405 followed by one carbon Wittig homologation presented olefin 406 .…”

“…2014 Chavan synthesis [122] * One-carbon Wittig homologation * Mitsunobu inversion * Barbier addition * RCM in the presence of Grubbs second-generation catalyst 73.…”

“…Tamiflu from cis-aziridine by RCM reaction: A new route to Tamiflu intermediate aziridine 27, from cis-aziridine compound (Scheme 78) 405, precursor from D-mannitol was initiated by Chavan and team members. [122] The DIBALÀ H inspired a reduction of the ester group of 405 followed by one carbon Wittig homologation presented olefin 406. Next, derivative 406 underwent acetonide cleavage, oxidative cleavage and Barbier addition followed by Mitsunobu inversion and ester hydrolysis yielded compound 408 via intermediate 407.…”