Synthesis 2017; 49(02): 424-428
DOI: 10.1055/s-2016-0036-1588899
paper
© Georg Thieme Verlag Stuttgart · New York

Multistep Continuous-Flow Synthesis of (–)-Oseltamivir

Shin Ogasawara
Department of Chemistry, Graduate School of Science, Tohoku University, 6-3 Aramaki-Aza, Aoba-ku, Sendai 980-8578, Japan   Email: yhayashi@m.tohoku.ac.jp   URL: http://www.ykbsc-chem.com/
,
Yujiro Hayashi*
Department of Chemistry, Graduate School of Science, Tohoku University, 6-3 Aramaki-Aza, Aoba-ku, Sendai 980-8578, Japan   Email: yhayashi@m.tohoku.ac.jp   URL: http://www.ykbsc-chem.com/
› Author Affiliations
Further Information

Publication History

Received: 23 August 2016

Accepted after revision: 29 September 2016

Publication Date:
03 November 2016 (eFirst)

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

Supporting Information

 
  • 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: yukio-matsubara@nifty.com).

    • 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: japan-info@biotage.com).