In 2009, Hayashi et al. successfully produced an efficient, low cost synthetic route to prepare (-)-oseltamivir (1). Their goal was to design a procedure that would be suitable for large-scale production. Keeping cost, yield, and number of synthetic steps in mind, an enantioselective total synthesis of (1) was accomplished through three one-pot operations. Hayashi et al.'s use of one-pot operations allowed them to perform several reactions steps in a single pot, which ultimately minimized the number of purification steps needed, waste, and saved time.
In the first one-pot operation, Hayashi et al. begins by using diphenylprolinol silyl ether (4) as an organocatalyst, along with alkoxyaldehyde (2) and nitroalkene (3) to perform an asymmetric Michael reaction, affording an enantioselective Michael adduct. Upon addition of a diethyl vinylphosphate derivative (5) to the Michael adduct, a domino Michael reaction and Horner-Wadsworth-Emmons reaction occurs due to the phosphonate group produced from (5) to give an ethyl cyclohexenecarboxylate derivative along with two unwanted by-products. To transform the undesired by-products into the desired ethyl cyclohexencarboxylate derivative, the mixture of the product and by-products was treated with CsCO in ethanol.  This induced a retro-Michael reaction on one by-product and a retro-aldol reaction accompanied with a Horner-Wadsworth-Emmons reaction for the other. Both by-products were successfully converted to the desired derivative. Finally, the addition of p-toluenethiol with CsCO gives (6) in a 70% yield after being purified by column chromatography, with the desired isomer dominating.
In the second one-pot operation, trifluoroacetic acid is employed first to deprotect the tert-butyl ester of (6); any excess reagent was removed via evaporation. The carboxylic acid produced as a result of the deprotection was then converted to an acyl chloride by oxalyl chloride and a catalytic amount of DMF. Finally, addition of sodium azide, in the last reaction of the second one-pot operation, produce the acyl azide (7) without any purification needed.
The final one-pot operation begins with a Curtius Rearrangement of acyl azide (7) to produce an isocyanate functional group at room temperature. The isocyanate derivative then reacts with acetic acid to yield the desired acetylamino moiety found in (1). This domino Curtius rearrangement and amide formation occurs in the absence of heat, which is extremely beneficial for reducing any possible hazard. The nitro moiety of (7) is reduced to the desired amine observed in (1) with Zn/HCl. Due to the harsh conditions of the nitro reduction, ammonia was used to neutralize the reaction. Potassium carbonate was then added to give (1), via a retro-Michael reaction of the thiol. (1) was then purified by an acid/base extraction. The overall yield for the total synthesis of (-)-oseltamivir is 57%. Hayashi et al. use of inexpensive, non-hazardous reagents has allowed for an efficient, high yielding synthetic route that can allow for vast amount of novel derivatives to be produced in hopes of combatting against viruses resistant to (-)-oseltamivir.