28 ノイラミニダーゼ阻害剤、(-)-オセルタミビルの効率的全合成(口頭発表の部)

抄録

A great deal of attention has been paid both in the scientific literature and teh general media to the high potential risk of a worldwide spread of avian H5N1 influenza virus, the death reate of which is over 50%. Indeed, shoud this virus acquire the ablility to become capable of spreading easily and directly from human to human it could very possibly cause a disastrous pandeic. (-)-Oseltamivir phosphate (Tamiflu), a neuraminidase inhibitor used in the treatment of both type A and type B human influenza, is one of the most promising therapeutics, and many nations have plans to stock a significant amount of this compound in case of a possible influenza outbreak. An efficient, enantioselective total synthesis of (-)-oseltamivir (1 via separated three one pot operation has been accomplished, demonstrating the power of asymmetric reactions catalyzed by organocatalysts, in particular diphenylprolinol silyl ether. The present synthesis has several noteworthy features: 1) A highly functionalized chiral cyclohexane framework of the correct configuration is synthesized in the first one-pot operation, which consists of a succession of reactions, including a diphenylprolinol silyl ether-mediated asymmetric Michael reaction, a domino Michael reaction/Horner-Wardsworth-Emmons reaction combined with retro-aldol and retro-Michael reactions, a thiol-Michael reaction, and a base catalyzed isomerization. 2) Three reactions occur in the third one-pot operaton: a Curtius rearrangement, the reduction of a nitro group to an amine, and a retro-Michael reaction of the thiol. 3) The Curtius rearrangement proceeds at room temperature without heating, decreasing the potential hazards. 4) The domino reaction consisting of a Curtius rearrangement and amide formation is a direct method for the synthesis of 14. This synthesis requires nine reactions, a toal of three separate one-pot operations, and one purificaton by column chromatography. The total yield of (-)-oseltamivir from nitroalkene 4 is 57%. All the reagents are inexpensive. The metal-based reagents employed in the present total synthesis contain either alkali-metal ions (Na, K, and Cs) or nontoxic Zn. No special care is needed to exclude water or air. Thus, the present procedure is suitable for large-scale preparation.