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Pitt CHEM 2320 - SYNTHESIS

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III-B. TOTAL SYNTHESISMMeeOOMMeeOOMMeeOONNHHOOOOMMeeOOCCoollcchhiicciinnee Dr. P. WipfPage 1 of 324/16/2008Synthesis DefinitionsChemical Synthesis is defined as the intentional construction ofmolecules by means of chemical reactions (Sir J. W. Cornforth,Aldrichimica Acta 1994, 27, 71).Total Synthesis is defined as the chemical synthesis of complexmolecules, usually natural products, from relatively simple,commercially available starting materialsDr. P. WipfPage 2 of 324/16/2008# of papers in the general area of organic & natural product synthesisfrom 1905-1979: ~50,000from 1980-1992: ~47,000!from 1993-2005: ~90,000!!!Dr. P. WipfPage 3 of 324/16/2008Organic Synthesis is Unequivocally UsefulHNONHODr. P. WipfPage 4 of 324/16/2008Dr. P. WipfPage 5 of 324/16/2008Dr. P. WipfPage 6 of 324/16/2008Corey!s Porantherine Synthesis- Corey, E. J. et al. J. Am. Chem. Soc. 1974, 96, 6516. Double Mannich reaction!Retrosynthesis:Synthesis:Dr. P. WipfPage 7 of 324/16/2008Dr. P. WipfPage 8 of 324/16/2008Dr. P. WipfPage 9 of 324/16/2008Heathcock!s Homodaphniphyllate- Heathcock, C. H. J. Org. Chem. 1992, 57, 2585.Dr. P. WipfPage 10 of 324/16/2008Dr. P. WipfPage 11 of 324/16/2008Anti-Influenza Drug Targets1 zanamivir (Relenza)2 oseltamivir phosphate (Tamiflu)3 shikimic acid4 quinic acidOCO2HHNHNHONH2NHOHOHAc1COEtO NH2NHAc2• H3PO4CO2HOHOHHO3OHOHHO4HOCO2H• Strategy-Level Decisions in API SynthesisDr. P. WipfPage 12 of 324/16/2008Tamiflu-Synthesis Bibliography• Rohloff, J. C.; Kent, K. M.; Postich, M. J.; Becker, M. W.; Chapman, H. H.; Kelly, D. E.; Lew, W.; Louie,M. S.; McGee, L. R.; Prisbe, E. J.; Schultze, L. M.; Yu, R. H.; Zhang, L., "Practical Total Synthesis of theAnti-Influenza Drug GS-4104." J. Org. Chem. 1998, 63, 4545-4550.• Karpf, M.; Trussardi, R., "New, Azide-Free Transformation of Epoxides into 1,2-Diamino Compounds:Synthesis of the Anti-Influenza Neuraminidase Inhibitor Oseltamivir Phosphate (Tamiflu)." J. Org. Chem.2001, 66, 2044-2051.• Abrecht, S.; Harrington, P.; Iding, H.; Karpf, M.; Trussardi, R.; Wirz, B.; Zutter, U., "The syntheticdevelopment of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu): A challenge forsynthesis & process research." Chimia 2004, 58, 621-629.• Harrington, P. J.; Brown, J. D.; Foderaro, T.; Hughes, R. C., "Research and Development of a Second-Generation Process for Oseltamivir Phosphate, Prodrug for a Neuraminidase Inhibitor." Org. Proc. Res.Dev. 2004, 8, 86-91.• Farina, V.; Brown, J. D., "Tamiflu: The supply problem." Angew. Chem. Int. Ed. 2006, 45, 7330-7334.• Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M., "De Novo Synthesis of Tamiflu via a CatalyticAsymmetric Ring-Opening of meso-Aziridines with TMSN3." J. Am. Chem. Soc. 2006, 128, 6312-6313.• Yeung, Y.-Y.; Hong, S.; Corey, E. J., "A Short Enantioselective Pathway for the Synthesis of the Anti-Influenza Neuramidase Inhibitor Oseltamivir from 1,3-Butadiene and Acrylic Acid." J. Am. Chem. Soc.2006, 128, 6310-6311.• Mita, T.; Fukuda, N.; Roca, F. X.; Kanai, M.; Shibasaki, M., "Second Generation Catalytic AsymmetricSynthesis of Tamiflu: Allylic Substitution Route." Org. Lett. 2007, 9, 259-262.• Satoh, N.; Akiba, T.; Yokoshima, S.; Fukuyama, T., "A Practical Synthesis of (-)-Oseltamivir." Angew.Chem. Int. Ed. 2007, 46, 5734-5736.• Yamatsugu, K.; Kamijo, S.; Suto, Y.; Kanai, M.; Shibasaki, M., "A concise synthesis of Tamiflu: thirdgeneration route via the Diels-Alder reaction and the Curtius rearrangement." Tetrahedron Lett. 2007, 48,1403-1406.• Bromfield, K. M.; Graden, H.; Hagberg, D. P.; Olsson, T.; Kann, N., "An iron carbonyl approach to theinfluenza neuraminidase inhibitor oseltamivir." Chem. Commun. 2007, 3183-3185.Dr. P. WipfPage 13 of 324/16/2008Star Anise (Illicium verum)• 30 kg plant provide 1 kg of shikimic acid, resulting in 800 g of oseltamivir-phosphate (assuming 35% yield)Dr. P. WipfPage 14 of 324/16/2008Tamiflu-Synthesis Strategiessymmetricalstarting materialsCO2EtONH2•H3PO4AcHNcleave cyclohexaneconserve cyclohexane in SMCO2HHOOHHOCO2HHOOHHOOHshikimic acidquinic acidOMeHOMeObenzenepyrogallol 1,3-dimethyl etherone C,C-cleavageRCMtwo C,C-cleavagesDiels-AlderEsix possible disconnections, four of which have so far been realizedwhat is the apparent disadvantage of the remaining two?ShibasakiCoreyFukuyamaRoche (Karpf)TandemMichael-WittigDr. P. WipfPage 15 of 324/16/2008Synthesis Strategies based on Cyclohexane ScaffoldGilead ApproachRohloff et al. "Practical Total Synthesis of the Anti-Influenza Drug GS-4104." J. Org. Chem.1998, 63, 4545-4550.Dr. P. WipfPage 16 of 324/16/2008Synthesis Strategies based on Cyclohexane ScaffoldGilead Approach12 steps / 4.4%Dr. P. WipfPage 17 of 324/16/2008The remainder of the synthesisfollows the Gilead route, andtherefore the dependence onusing azide chemistry toconvert the intermediateepoxide into oseltamivirphosphate was considered aweakness in the first-generationmanufacturing process.The First Generation Large Scale ProcessApproach to Tamiflu (Roche)Federspiel, M. et al., "Industrial Synthesisof the Key Precursor in the Synthesis ofthe Anti-Influenza Drug OseltamivirPhosphate (Ro 64-0796/002, GS-4104-02): Ethyl (3R,4S,5S)-4,5-epoxy-3-(1-ethyl-propoxy)-1-cyclohexene-1-carboxylate."Organic Process Research & Development1999, 3, 266-274.Dr. P. WipfPage 18 of 324/16/2008Azide-Free Approach to Tamiflu (Roche)Karpf, M. et al. "New, Azide-Free Transformation of Epoxides into 1,2-Diamino Compounds: Synthesis ofthe Anti-Influenza Neuraminidase Inhibitor Oseltamivir Phosphate (Tamiflu)" J. Org. Chem. 2001, 66, 2044-2051.Dr. P. WipfPage 19 of 324/16/2008Roche 2003 Patent; reviewed in Angew. Chem. Int. Ed. 2006, 45, 7330.Roche’s Symmetry-Based Approach to Tamiflu - PyrogallolDr. P. WipfPage 20 of 324/16/2008J. Am. Chem. Soc. 2006, 128, 6312.Shibasaki’s Symmetry-Based Approach to Tamiflu - Benzene17 steps / 1%Dr. P. WipfPage 21 of 324/16/2008Shibasaki’s Second Generation ApproachMita, T.; Fukuda, N.; Roca, F. X.; Kanai, M.; Shibasaki, M., "Second Generation Catalytic AsymmetricSynthesis of Tamiflu: Allylic Substitution Route." Org. Lett. 2007, 9, 259-262.Dr. P. WipfPage 22 of 324/16/2008Synthesis Strategies based on one C,C-Bond CleavageMetathesis ApproachCong & Yao, J. Org. Chem. 2006, 71, 5365.J. Org. Chem. 2004, 69, 5314.Dr. P. WipfPage 23 of 324/16/2008Synthesis Strategies based on two C,C-Bond CleavagesDiels-Alder ReactionsEShibasakiCoreyFukuyamaRoche (Karpf)• several steps require high dillution•


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