Synlett 2013; 24(3): 323-326
DOI: 10.1055/s-0032-1317919
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© Georg Thieme Verlag Stuttgart · New York

Process Development of Halaven®: Synthesis of the C1–C13 Fragment from d-(–)-Gulono-1,4-lactone

Charles E. Chase
Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA   Fax: +1(978)7944910   Email: Bryan_Lewis@eisai.com
,
Francis G. Fang
Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA   Fax: +1(978)7944910   Email: Bryan_Lewis@eisai.com
,
Bryan M. Lewis*
Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA   Fax: +1(978)7944910   Email: Bryan_Lewis@eisai.com
,
Gordon D. Wilkie
Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA   Fax: +1(978)7944910   Email: Bryan_Lewis@eisai.com
,
Matthew J. Schnaderbeck
Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA   Fax: +1(978)7944910   Email: Bryan_Lewis@eisai.com
,
Xiaojie Zhu
Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA   Fax: +1(978)7944910   Email: Bryan_Lewis@eisai.com
› Author Affiliations
Further Information

Publication History

Received: 13 November 2012

Accepted: 22 November 2012

Publication Date:
10 January 2013 (online)


Abstract

A 12-step kilogram-scale synthesis of the C1–C13 fragment, common to halichondrin B and the totally synthetic analogue Halaven® (E7389, INN eribulin mesylate), is described. The synthesis features four crystalline intermediates which facilitates throughput, and enhances quality control of all stereogenic centers in the title compound.

 
  • References

    • 1a Uemura D, Takahashi K, Yamamoto T, Katayama C, Tanaka J, Okumura Y, Hirata Y. J. Am. Chem. Soc. 1985; 107: 4796
    • 1b Hirata Y, Uemura D. Pure Appl. Chem. 1986; 58: 701

      For discovery and development of Halaven® (1), see:
    • 2a Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsky BM, Palme MH, Habgood GJ, Singer LA, DiPietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, Kishi Y, Yu MJ, Littlefield BA. Cancer Res. 2001; 61: 1013
    • 2b Zheng W, Seletsky BM, Palme MH, Lydon PJ, Singer LA, Chase CE, Lemelin CA, Shen Y, Davis H, Tremblay L, Towle MJ, Salvato KA, Wels BF, Aalfs KK, Kishi Y, Littlefield BA, Yu M. J. Bioorg. Med. Chem. Lett. 2004; 14: 5551
    • 2c Littlefield BA, Palme MH, Seletsky BM, Towle MJ, Yu MJ, Zheng W. US 6214865, 2001
    • 2d Littlefield BA, Palme MH, Seletsky BM, Towle MJ, Yu MJ, Zheng W. US 6365759, 2002
    • 2e Littlefield BA, Palme MH, Seletsky BM, Towle MJ, Yu MJ, Zheng W. WO 9965894, 1999
    • 2f Yu MJ, Kishi Y, Littlefield BA In Anticancer Agents from Natural Products . Cragg GM, Kingston DG. I, Newman DJ. CRC Press; Boca Raton: 2005: 241-265
    • 2g Newman S. Curr. Opin. Invest. Drugs 2007; 8: 1057
    • 2h Vahdat LT, Pruitt B, Fabian CJ, Rivera RR, Smith DA, Tan-Chiu E, Wright J, Tan AR, DaCosta NA, Chuang E, Smith J, O’Shaughnessy J, Shuster DE, Meneses NL, Chandrawansa K, Fang F, Cole PE, Ashworth S, Blum JL. J. Clin. Oncol. 2009; 27: 2954
    • 2i Chiba H, Tagami K. J. Synth. Org. Chem. Jpn. 2011; 69: 600

      First total synthesis of halichondrin B:
    • 3a Aicher TD, Buszek KR, Fang FG, Forsyth CJ, Jung SH, Kishi Y, Matelich MC, Scola PM, Spero DM, Yoon SK. J. Am. Chem. Soc. 1992; 114: 3162

    • Total synthesis of norhalichondrin B by Phillips:
    • 3b Jackson KL, Henderson JA, Motoyoshi H, Phillips AJ. Angew. Chem. Int. Ed. 2009; 48: 2346

    • Total synthesis of halichondrin C:
    • 3c Yamamoto A, Ueda A, Brémond P, Tiseni PS, Kishi Y. J. Am. Chem. Soc. 2012; 134: 893

    • Review of synthetic work on halichondrins:
    • 3d Jackson KL, Henderson JA, Phillips AJ. Chem. Rev. 2009; 109: 3044 ; and references therein
  • 4 Aicher TA, Kishi Y. Tetrahedron Lett. 1987; 28: 3463
    • 5a Duan JJ.-W, Kishi Y. Tetrahedron Lett. 1993; 34: 7541
    • 5b Stamos DP, Kishi Y. Tetrahedron Lett. 1996; 37: 8643
  • 6 Choi H.-W, Demeke D, Kang F.-A, Kishi Y, Nakajima K, Nowak P, Wan Z.-K, Xie C. Pure Appl. Chem. 2003; 75: 1
  • 7 Austad B, Chase CE, Fang FG. WO2005118565, 2005

    • Scandium(III)triflate-catalyzed acetalization:
    • 8a Ishihara K, Karumi Y, Kubota M, Yamamoto H. Synlett 1996; 839

    • Scandium(III)triflate-catalyzed acylation:
    • 8b Ishihara K, Kubota M, Kurihara H, Yamamoto H. J. Org. Chem. 1996; 61: 4560
  • 9 Stamos DP. PhD Dissertation. Harvard University; USA: 1996
    • 10a Experimental procedure for conversion of vinyl silane 15 into vinyl iodide 2: Into the reactor were placed 15 (3.23 kg, 4.50 mol), NIS (4.04 kg, 30.2 mol), and TBSCl (0.032 kg, 0.21 mol) in a mixture of toluene (8.5 kg), acetonitrile (15.2 kg). The mixture was stirred at 25–30 °C for 22 hours. An aqueous mixture of Na2S2O3/KHCO3 (Na2S2O3: 1.5 kg, KHCO3: 2.9 kg, water: 29 kg) was added to the reaction mixture at 0–30 °C and stirring was continued for 30 min. After phase separation, the upper layer was washed with 9% aq NaCl (32 kg × 2). The organic layer was concentrated by distillation. The residue was dissolved with n-heptane (9 kg). The solution was purified by column chromatography on silica gel (39.2 kg; preconditioned with 91 kg n-heptane) with n-heptane–MTBE (100:0 → 93:7; 354 kg) as the eluent. The main fractions were combined in the reactor and concentrated by distillation (40–50 °C external temperature). The residue was dissolved with toluene and concentrated by distillation again (40–50 °C external temperature) to afford 2 (3.09 kg, 4.01 mol, 89% yield). Characterization of 2: FT-IR (thin film): νmax = 2953, 2930, 2857, 1745, 1607, 1472, 1361, 1255, 1080 cm–1. 1H NMR (400 MHz, acetone-d 6): δ = 0.07–0.18 (m, 18 H), 0.90–0.99 (m, 27 H), 1.25–1.34 (m, 1 H), 1.31–1.41 (m, 1 H), 1.78–1.83 (m, 1 H), 1.85–1.90 (m, 1 H), 2.47–2.49 (m, 2 H), 3.03 (dd, J = 9.6, 2.4 Hz, 1 H), 3.49 (ddd, J = 10.1, 10.1, 4.5 Hz, 1 H), 3.63 (s, 3 H), 3.78–3.85 (m, 1 H), 3.83 (dd, J = 6.8, 3.6 Hz, 1 H), 4.03 (dd, J = 6.8, 2.8 Hz, 1 H), 4.15 (dd, J = 2.2, 2.2 Hz, 1H), 5.00 (ddd, J = 7.8, 3.8, 0.8 Hz, 1 H), 6.37 (dd, J = 14.8, 0.8 Hz, 1H), 6.88 (dd, J = 14.4, 8.0 Hz, 1H). 13C NMR (100 MHz, acetone-d 6): δ = –4.45, –4.15, –4.18, –3.41, –3.35, –3.12, 18.79, 19.44, 19.70, 26.55, 26.91, 27.16, 29.65, 31.30, 41.14, 51.66, 65.11, 71.56, 73.83, 74.80, 75.10, 77.94, 79.45, 81.72, 147.85, 171.70. ESI-HRMS: m/z calcd for C32H63IO7Si3+Na+: 793.2824 [M+Na]+; found 793.2824. [α]D 20 –39.0 (c 1.25, toluene).
    • 10b ��Characterization of 2: FT-IR (thin film): νmax = 2953, 2930, 2857, 1745, 1607, 1472, 1361, 1255, 1080 cm–1. 1H NMR (400 MHz, acetone-d 6): δ = 0.07–0.18 (m, 18 H), 0.90–0.99 (m, 27 H), 1.25–1.34 (m, 1 H), 1.31–1.41 (m, 1 H), 1.78–1.83 (m, 1 H), 1.85–1.90 (m, 1 H), 2.47–2.49 (m, 2 H), 3.03 (dd, J = 9.6, 2.4 Hz, 1 H), 3.49 (ddd, J = 10.1, 10.1, 4.5 Hz, 1 H), 3.63 (s, 3 H), 3.78–3.85 (m, 1 H), 3.83 (dd, J = 6.8, 3.6 Hz, 1 H), 4.03 (dd, J = 6.8, 2.8 Hz, 1 H), 4.15 (dd, J = 2.2, 2.2 Hz, 1H), 5.00 (ddd, J = 7.8, 3.8, 0.8 Hz, 1 H), 6.37 (dd, J = 14.8, 0.8 Hz, 1H), 6.88 (dd, J = 14.4, 8.0 Hz, 1H). 13C NMR (100 MHz, acetone-d 6): δ = –4.45, –4.15, –4.18, –3.41, –3.35, –3.12, 18.79, 19.44, 19.70, 26.55, 26.91, 27.16, 29.65, 31.30, 41.14, 51.66, 65.11, 71.56, 73.83, 74.80, 75.10, 77.94, 79.45, 81.72, 147.85, 171.70. ESI-HRMS: m/z calcd for C32H63IO7Si3+Na+: 793.2824 [M+Na]+; found 793.2824. [α]D 20 –39.0 (c 1.25, toluene).