Multistep Continuous-Flow Synthesis of (–)-Oseltamivir

Dedicated to Professor Dieter Enders on the occasion of his 70^th birthday

Abstract

A continuous-flow synthesis of (–)-oseltamivir composed of five flow units was accomplished. In each unit, the following reactions proceed efficiently: (1) a diphenylprolinol silyl ether mediated Michael reaction, (2) a domino reaction of Michael and intermolecular Horner–Wadsworth–Emmons reactions, (3) protonation, (4) epimerization, and (5) reduction of a nitro group to an amine. (–)-Oseltamivir was obtained in 13% total yield through a single flow with a residence time of 310 minutes.

Key words

Tamiflu - continuous flow - time economy - total synthesis - organocatalysis

• References

• 1 Kim CU, Lew W, Williams MA, Liu H, Zhang L, Swaminathan S, Bishofberger N, Chen MS, Mendel DM, Tai CY, Laver WG, Stevens RC. J. Am. Chem. Soc. 1997; 119: 681
• 2a Hayashi Y, Ogasawara S. Org. Lett. 2016; 18: 3426 ; and references cited therein

For reviews, see:
• 2b Farina V, Brown JD. Angew. Chem. Int. Ed. 2006; 45: 7330
• 2c Shibasaki M, Kanai M. Eur. J. Org. Chem. 2008; 1839
• 2d Magano J. Chem. Rev. 2009; 109: 4398
• 2e Andraos J. Org. Process Res. Dev. 2009; 13: 161
• 2f Magano J. Tetrahedron 2011; 67: 7875
• 2g Shibasaki M, Kanai M, Yamatsugu K. Isr. J. Chem. 2011; 51: 316
• 2h Li N.-G, Shi Z.-H, Tang Y.-P, Shi Q.-P, Zhang W, Zhang P.-X, Dong Z.-X, Li W, Duan J.-A. Curr. Org. Chem. 2014; 18: 2125
• 3 Ishikawa H, Suzuki T, Hayashi Y. Angew. Chem. Int. Ed. 2009; 48: 1304
• 4a Ishikawa H, Suzuki T, Orita H, Uchimaru T, Hayashi Y. Chem. Eur. J. 2010; 16: 12616
• 4b Ishikawa H, Bondzic BP, Hayashi Y. Eur. J. Org. Chem. 2011; 6020
• 5a Hayashi Y, Gotoh H, Hayashi T, Shoji M. Angew. Chem. Int. Ed. 2005; 44: 4212

For reviews, see:
• 5b Palomo C, Mielgo A. Angew. Chem. Int. Ed. 2006; 45: 7876
• 5c Mielgo A, Palomo C. Chem. Asian J. 2008; 3: 922
• 5d Xu L.-W, Li L, Shi Z.-H. Adv. Synth. Catal. 2010; 352: 243
• 5e Jensen KL, Dickmeiss G, Jiang H, Albrecht L, Jørgensen KA. Acc. Chem. Res. 2012; 45: 248
• 5f Wroblewska A. Synlett 2012; 23: 953
• 5g Gotoh H, Hayashi Y. Diarylprolinol Silyl Ethers, Development and Application as Organocatalysts . In Sustainable Catalysis . Dunn PJ, Hii KK, Krische MJ, Williams MT. John Wiley & Sons; New Jersey: 2013: 287-316
• 5h Donslund BS, Johansen TK, Poulsen PH, Halskov KS, Jørgensen KA. Angew. Chem. Int. Ed. 2015; 54: 13860
• 6 Zhu S, Yu S, Wang Y, Ma D. Angew. Chem. Int. Ed. 2010; 49: 4656
• 7 Rehak J, Hut’ka M, Latika A, Brath H, Almassy A, Hajzer V, Durmis J, Toma S, Sebesta R. Synthesis 2012; 44: 2424
• 8 Weng J, Li Y.-B, Wang R.-B, Lu G. ChemCatChem 2012; 4: 1007
• 9 Mukaiyama T, Ishiakwa H, Koshino H, Hayashi Y. Chem. Eur. J. 2013; 19: 17789

For selected reviews, see:
• 10a Yoshida J, Nagaki A, Yamada T. Chem. Eur. J. 2008; 14: 7450
• 10b Webb D, Jamison TF. Chem. Sci. 2010; 1: 675
• 10c Wiles C, Watts P. Green Chem. 2012; 14: 38
• 10d Poechlauer P, Manley J, Broxterman R, Gregertsen B, Ridemark M. Org. Process Res. Dev. 2012; 16: 1586
• 10e Hartman RL, McMullen JP, Jensen KF. Angew. Chem. Int. Ed. 2011; 50: 7502
• 10f Newman SG, Jensen KF. Green Chem. 2013; 15: 1456
• 10g Tsubogo T, Ishikawa T, Kobayashi S. Angew. Chem. Int. Ed. 2013; 52: 6590
• 11 Hessel V. Chem. Eng. Technol. 2009; 32: 1655
• 12 Tsubogo T, Oyamada H, Kobayashi S. Nature 2015; 520: 329
• 13 Snead DR, Jamison TF. Angew. Chem. Int. Ed. 2015; 54: 983
• 14a Schreiner PR. Chem. Soc. Rev. 2003; 32: 289
• 14b Zhang Z, Schreiner PR. Chem. Soc. Rev. 2009; 38: 1187
• 15 A micromixing device, ‘Comet X-01’, is available from Techno Applications Co., Ltd., 34-16-204, Hon, Denenchofu, Oota, Tokyo, 145-0072, Japan (e-mail: [e-mail]).

For papers using ‘Comet-X-01’, see:
• 16a Tanaka K, Fukase K. Synlett 2007; 164
• 16b Tanaka K, Motomatsu S, Koyama K, Tanaka S.-I, Fukase K. Org. Lett. 2007; 9: 299
• 16c Tanaka K, Motomatsu S, Koyama K, Fukase K. Tetrahedron Lett. 2008; 49: 2010
• 16d Tanaka K, Miyagawa T, Fukase K. Synlett 2009; 1571
• 16e Fukuyama T, Chiba H, Kuroda H, Takigawa T, Kayano A, Tagami K. Org. Process Res. Dev. 2016; 20: 503
• 17 The yield was determined by ¹H NMR analysis using 1,3,5-trimethoxybenzene as internal standard.
• 18 ‘SNAP Empty cartridge’ is available from Biotage Japan Co., Ltd., 1-4-14, Kameido, koto-ku, Tokyo, 136-0071, Japan (e-mail: [e-mail]).