1Org. Lett. 2007, ASAPPresented by: Edmund YehJan. 8th 2007Outline• Background information• Previous synthesis and their limitations• Improved synthesis form Shibasaki• ConclusionA.-H. YehChem 23201/16/20072Current Treatments for Influenza• There are two classes of drugs currently used astreatment for influenza (flu).• Adamantanes: amantadine and rimantadine• Neuraminidase Inhibitors: zanamivir and oseltamivir• Avian influenza is resistant to adamantane drugs• Oseltamivir phosphate (TamifluTM) was found tobe the only effective treatment for avianinfluenza virus (H5N1)Moscona A. N. Engl. J. Med. 2005, 353, 13, 1363Neuraminidase InhibitorMoscona A. N. Engl. J. Med. 2005, 353, 13, 1363A.-H. YehChem 23201/16/20073Previous Synthesis of TamifluTM• Karpf et al. synthesis used (-)-quinic acid or (-)-shikimic acid as starting material.Limitations:1. Starting materials are expensive.2. Use of azide to open up epoxide ispotentially hazardous.Karpf, M.; Trussardi, R. J. Org. Chem. 2001, 66, 2044Rohloff, J. et al. J. Org. Chem. 1998, 63, 4545Previous Synthesis of TamifluTM• Corey et al. used Diels-Alder reaction toconstruct the cyclohexene core.Limitations:1. Some of the transformation requireslow temperature conditions.2. Some reagents used could be hard toscale up, i.e. CCl4.Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. am. Chem. Soc. 2006, 128, 6310A.-H. YehChem 23201/16/20074Previous Synthesis of TamifluTM• Shibasaki et al. showcased his catalyticasymmetric ring opening of meso-aziridine.Limitations:1. This synthesis has a low overall yield.2. Use of toxic Se reagent isundesirable.Shibasaki, M. et al. J. am. Chem. Soc. 2006, 128, 6312M. Shibasaki TamifluTM Synthesis(part deux)Shibasaki, M. et al. Org. Lett. 2007, ASAPA.-H. YehChem 23201/16/20075M. Shibasaki TamifluTM Synthesis(part deux)Shibasaki, M. et al. Org. Lett. 2007, ASAPConclusion• Shibasaki presented an alternative way ofTamifluTM synthesis.• SeO2 allylic oxidation step from first paperwas replaced by non-toxictransformations.• Overall yield improved dramatically but stillnot as high as current method.• New ways of obtaining (-)-shikimic acidhas been found and will be massproduced soon.A.-H. YehChem
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