page_title: Oseltamivir total synthesis
section_title: Fukuyama synthesis
hierarchical_section_title: Oseltamivir total synthesis / Fukuyama synthesis
caption_attribution_description: synthesis Oseltamivir Fukuyama Part I
context_page_description: Oseltamivir total synthesis concerns the total synthesis of the antiinfluenza drug oseltamivir marketed by Hoffmann-La Roche under the trade name Tamiflu. Its commercial production starts from the biomolecule shikimic acid harvested from Chinese star anise with a limited worldwide supply. Due to its limited supply, searches for alternative synthetic routes preferably not requiring shikimic acid are underway and to date several such routes have been published. Control of stereochemistry is important: the molecule has three stereocenters and the sought-after isomer is only 1 of 8 stereoisomers.
context_section_description: An approach published in 2007  like Corey's starts by an asymmetric Diels-Alder reaction this time with starting materials pyridine and acrolein.
  Pyridine (1) is reduced with sodium borohydride in presence of benzyl chloroformate to the Cbz protected dihydropyridine 2. The asymmetric Diels-Alder reaction with acrolein 3 is carried out with the McMillan catalyst to the aldehyde 4 as the endo isomer which is oxidized to the carboxylic acid 5 with sodium chlorite, monopotassium phosphate and 2-methyl-2-butene. Addition of bromine gives halolactonization product 6 and after replacement of the Cbz protective group by a BOC protective group in 7 (hydrogenolysis in the presence of di-tert-butyl dicarbonate) a carbonyl group is introduced in intermediate 8  by catalytic ruthenium(IV) oxide and sacrificial catalyst sodium periodate. Addition of ammonia cleaves the ester group to form amide 9 the alcohol group of which is mesylated to compound 10.  In the next step iodobenzene diacetate is added, converting the amide in a Hofmann rearrangement to the allyl carbamate 12 after capturing the intermediate isocyanate with allyl alcohol 11. On addition of sodium ethoxide in ethanol three reactions take place simultaneously: cleavage of the amide to form new an ethyl ester group, displacement of the mesyl group by newly formed BOC protected amine to an aziridine group and an elimination reaction forming the alkene group in 13 with liberation of HBr. In the final two steps the aziridine ring is opened by 3-pentanol 14 and boron trifluoride to aminoether 15 with the BOC group replaced by an acyl group and on removal of the other amine protecting group (Pd/C, Ph₃P, and 1,3-dimethylbarbituric acid in ethanol) and addition of phosphoric acid oseltamivir 16 is obtained.
caption: Fukuyama Tamiflu SynthesisPart I
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