Formal Synthesis of (–)-Oseltamivir Phosphate

Abstract

The formal synthesis of (–)-oseltamivir phosphate (Tamiflu ^tm ) was accomplished starting from (S)-pyroglutamic acid. The synthesis comprised two carbon–carbon bond forming reactions, the first one being a diastereoselective, indium-mediated allylation of a pyroglutamic aldehyde derivative. However, attempts to effect the second carbon–carbon bond formation – cyclohexene ring closure – using an enol-exo aldolization of a dialdehyde resulted in the formation of a product with the opposite regioselectivity. This shortcoming could be overcome by using a reaction sequence of Mannich methylenation/ring-closing metathesis, which provided the desired regioisomer in high yield.

Key words

antiviral agents - allylation - cyclization - metathesis - total­ synthesis

• References

• 1a Kim CU, Lew W, Williams MA, Liu H, Zhang L, Swaminathan S, Bischofberger N, Chen MS, Mendel DB, Tai CY, Laver WG, Stevens RC. J. Am. Chem. Soc. 1997; 119: 681
• 1b Rohloff JC, Kent KM, Postish MJ, Becker MW, Chapman HH, Kelly DE, Lew W, Louie MS, McGee LR, Prisbe EJ, Schultze LM, Yu RH, Zhang L. J. Org. Chem. 1998; 63: 4545
• 1c Karpf M, Trussardi R. J. Org. Chem. 2001; 66: 2044

For review articles on the development of the industrial synthesis, see:
• 2a Abrecht S, Federspiel MC, Estermann H, Fischer R, Karpf M, Mair H.-J, Oberhauser T, Rimmler G, Trussardi R, Zutter U. Chimia 2007; 61: 93
• 2b Abrecht S, Harrington P, Iding H, Karpf M, Trussardi R, Wirz B, Zutter U. Chimia 2004; 58: 621

For improvements and more detailed accounts on industrial synthesis, see:
• 2c Harrington PJ, Brown JD, Foderaro T, Hughes RC. Org. Process Res. Dev. 2004; 8: 86
• 2d Federspiel M, Fisher R, Henning M, Mair HJ, Oberhauser T, Rimmler G, Albiez T, Bruhin J, Estermann H, Gandert C, Gockel V, Gotzo S, Hoffmann U, Huber G, Janatsch G, Lauper S, Rockel-Stabler O, Trussardi R, Zwahlen AG. Org. Process Res. Dev. 1999; 3: 266

For other semi-syntheses from shikimic acid, see:
• 2e Nie L.-D, Shi X.-X. Tetrahedron: Asymmetry 2009; 20: 124
• 2f Nie L.-D, Shi X.-X, Ko KH, Lu W.-D. J. Org. Chem. 2009; 74: 3970
• 2g Karpf M, Trussardi R. Angew. Chem. Int. Ed. 2009; 48: 5760
• 2h Nie L.-D, Shi X.-X, Quan N, Wang F.-F, Lu X. Tetrahedron: Asymmetry 2011; 22: 1692
• 2i Nie L.-D, Ding W, Shi X.-X, Quan N, Lu X. Tetrahedron: Asymmetry 2012; 23: 742
• 2j Kim H.-K, Park K.-JJ. Tetrahedron Lett. 2012; 53: 1561
• 3a Yeung Y.-Y, Hong S, Corey EJ. J. Am. Chem. Soc. 2006; 128: 6310
• 3b Fukuta Y, Mita T, Fukuda N, Kanai M, Shibasaki M. J. Am. Chem. Soc. 2006; 128: 6312
• 3c Shie J.-J, Fang J.-M, Wang S.-Y, Tsai K.-C, Cheng Y.-SE, Yang A.-S, Hsiao S.-C, Su C.-Y, Wong C.-H. J. Am. Chem. Soc. 2007; 129: 11892
• 3d Satoh N, Akiba T, Yokoshima S, Fukuyama T. Angew. Chem. Int. Ed. 2007; 46: 5734
• 3e Yamatsugu K, Kamijo S, Suto Y, Kanai M, Shibasaki M. Tetrahedron Lett. 2007; 48: 1403
• 3f Bromfield KM, Graden H, Hagberg DP, Olsson T, Kann N. Chem. Commun. 2007; 3183
• 3g Mita T, Fukuda N, Roca FX, Kanai M, Shibasaki M. Org. Lett. 2007; 9: 259
• 3h Kipassa NT, Okamura H, Kina K, Hamada T, Iwagawa T. Org. Lett. 2008; 10: 815
• 3i Zutter U, Iding H, Spurr P, Wirz B. J. Org. Chem. 2008; 73: 4895
• 3j Matveenko M, Willis AC, Banwell MG. Tetrahedron Lett. 2008; 49: 7018
• 3k Shie J.-J, Fang J.-M, Wong C.-H. Angew. Chem. Int. Ed. 2008; 47: 5788
• 3l Trost BM, Zhang T. Angew. Chem. Int. Ed. 2008; 47: 3759
• 3m Ishikawa H, Suzuki T, Hayashi Y. Angew. Chem. Int. Ed. 2009; 48: 1304
• 3n Yamatsugu K, Yin L, Kamijo S, Kimura Y, Kanai M, Shibasaki M. Angew. Chem. Int. Ed. 2009; 48: 1070
• 3o Mandai T, Oshitari T. Synlett 2009; 783
• 3p Oshitari T, Mandai T. Synlett 2009; 787
• 3q Sun H, Lin Y.-J, Wu Y.-L, Wu Y. Synlett 2009; 2473
• 3r Sullivan B, Carrera I, Drouin M, Hudlicky T. Angew. Chem. Int. Ed. 2009; 48: 4229
• 3s Osato H, Jones IL, Chen A, Chai CL. L. Org. Lett. 2010; 12: 60
• 3t Weng J, Li Y.-B, Wang R.-B, Li F.-Q, Liu C, Chan AS. C, Lu G. J. Org. Chem. 2010; 75: 3125

Synthesis of racemic Tamiflu ^tm :
• 3u Kamimura A, Nakano T. J. Org. Chem. 2010; 75: 3133
• 3v Ko JS, Keum JE, Ko SY. J. Org. Chem. 2010; 75: 7006
• 3w Wichienukul P, Akkarasamiyo S, Kongkathip N, Kongkathip B. Tetrahedron Lett. 2010; 51: 3208
• 3x Ma J, Zhao Y, Ng S, Zhang J, Zeng J, Than A, Chen P, Liu X.-W. Chem. Eur. J. 2010; 16: 4533
• 3y Zhu S, Yu S, Wang Y, Ma D. Angew. Chem. Int. Ed. 2010; 49: 4656
• 3z Werner L, Machara A, Hudlicky T. Adv. Synth. Catal. 2010; 352: 195
• 3aa Ishikawa H, Suzuki T, Orita H, Uchimaru T, Hayashi Y. Chem. Eur. J. 2010; 16: 12616
• 3ab Trost BM, Zhang T. Chem. Eur. J. 2011; 17: 3630
• 3ac Raghavan S, Babu VS. Tetrahedron 2011; 67: 2044
• 3ad Tanaka T, Tan Q, Kawakubo H, Hayashi M. J. Org. Chem. 2011; 76: 5477
• 3ae Werner L, Machara A, Sullivan B, Carrera I, Mosher M, Adams DR, Hudlicky T, Andraos J. J. Org. Chem. 2011; 76: 10050
• 3af Trajkovic M, Ferjancic Z, Saicic RN. Org. Biomol. Chem. 2011; 9: 6927
• 3ag Gunasekara DS. Synlett 2012; 23: 573
• 3ah Chuanopparat N, Kongkathip N, Kongkathip B. Tetrahedron 2012; 68: 6803
• 3ai Rawat V, Dey S, Sudalai A. Org. Biomol. Chem. 2012; 10: 3988
• 3aj Oh H.-S, Kang H.-Y. J. Org. Chem. 2012; 77: 8792

For review articles on synthetic strategies to oseltamivir, see:
• 4a Magano J. Tetrahedron 2011; 67: 7875
• 4b Magano J. Chem. Rev. 2009; 109: 4398
• 4c Shibasaki M, Kanai M. Eur. J. Org. Chem. 2008; 1839
• 4d Farina V, Brown JD. Angew. Chem. Int. Ed. 2006; 45: 7330
• 5 Suaifan GA. R. Y, Arafatb T, Threadgilla MD. Bioorg. Med. Chem. 2007; 15: 3474
• 6a Tokuyama H, Yokoshima S, Lin S.-C, Li L, Fukuyama T. Synthesis 2002; 1121
• 6b For a review article on this reaction, see: Fukuyama T, Tokuyama H. Aldrichimica Acta 2004; 37: 87
• 7 Trajkovic M, Ferjancic Z, Saicic RN. Tetrahedron: Asymmetry 2012; 23: 602
• 8a Recently, aldehyde 7 was prepared by essentially the same procedure: Hoye AT, Wipf P. Org. Lett. 2011; 13: 2634
• 8b However, the aldehyde 7 was not purified, nor has its optical purity been determined; instead, it was immediately methylenated in a Wittig reaction, to give the product of 70% ee. According to our results, the reported decrease in optical purity of the product is not a consequence of the aldehyde’s inherent instability, but most probably of basic conditions used in the cited work. The optical purity of the aldehyde was determined by its oxidation to acid 8 with Oxone^® and comparison of the optical rotation data. Reduction to the corresponding alcohol proved unsuitable, due to side reactions, such as the migration of Boc group during reduction with NaBH₄.
• 8c For the side reaction, see: Bunch L, Norrby P.-O, Frydenvang K, Krogsgaard-Larsen P, Madsen U. Org. Lett. 2001; 3: 433
• 8d For ¹H and ¹³C NMR spectra of aldehyde 7, see: Rassu G, Zanardi F, Battistini L, Gaetani E, Casiraghi G. J. Med. Chem. 1997; 40: 167
• 9 Dess DB, Martin JC. J. Am. Chem. Soc. 1991; 113: 7277
• 10 Erkkila A, Pihko PM. J. Org. Chem. 2006; 71: 2538
• 11 [1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]di-chloro(phenylmethylene)(tricyclohexylphosphine)ruthenium: Scholl M, Ding S, Lee CW, Grubbs RH. Org. Lett. 1999; 1: 953
• 12 Blot V, Jacquemard U, Reissig H.-U, Kleuser B. Synthesis 2009; 759
• 13 Travis BR, Sivakumar M, Hollist GO, Borhan B. Org. Lett. 2003; 5: 1031