User:Mlasky8/sandbox
Oseltamivir total synthesis:
My plan:
My plan is going to be to highlight the total synthesis done by the Hayashi group in 2009. I intended to discuss the synthetic strategies used in each of the three one-pot operations, as well as, highlight how the procedure is suitable for large-scale production. I will also display the overall scheme for the total synthesis. I may also add more information to the introduction of Oseltamivir total synthesis if time permits. Or maybe that can be my next project on here over winter break.
Maddie's Notes:
Great work! The scheme is super clear and you reference it well. A few suggestions:
Link "total synthesis," "one pot" (there's apparently a page for this), "adduct," "column chromatography," and "DMF" pages (as you see fit) for clarity.
In the second paragraph, I bolded/italicized/underlined where I added an "s" to make something plural (just a typo I think).
In the last paragraph maybe cite the paper one more time when giving the yield (I added "***" at that point) just to be overly cautious.
Other than that, great job!! :)
Hayashi Synthesis[1][edit]
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.[1][2] 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)[3] 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 a 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 Cs2CO3 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 Cs2CO3 gives (6) in a 70 % yield after being purified by column chromatography, with the desired isomer dominating.[1]
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.[1]
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 %.[1] 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.
References[edit]
- ^ a b c d e Ishikawa, Hayato; Suzuki, Takaki; Hayashi, Yujiro (2009-02-02). "High-Yielding Synthesis of the Anti-Influenza Neuramidase Inhibitor (−)-Oseltamivir by Three "One-Pot" Operations". Angewandte Chemie International Edition. 48 (7): 1304–1307. doi:10.1002/anie.200804883. ISSN 1521-3773.
- ^ Laborda, Pedro; Wang, Su-Yan; Voglmeir, Josef (2016-11-11). "Influenza Neuraminidase Inhibitors: Synthetic Approaches, Derivatives and Biological Activity". Molecules. 21 (11): 1513. doi:10.3390/molecules21111513.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Hayashi, Yujiro; Gotoh, Hiroaki; Hayashi, Takaaki; Shoji, Mitsuru (2005-07-04). "Diphenylprolinol Silyl Ethers as Efficient Organocatalysts for the Asymmetric Michael Reaction of Aldehydes and Nitroalkenes". Angewandte Chemie International Edition. 44 (27): 4212–4215. doi:10.1002/anie.200500599. ISSN 1521-3773.