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

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.

Key words

carbohydrates - chiral pool - drugs - glycosylation - stereo­selective synthesis

• References

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For discovery and development of Halaven^® (1), see:
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• 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
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• 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
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Scandium(III)triflate-catalyzed acetalization:
• 8a Ishihara K, Karumi Y, Kubota M, Yamamoto H. Synlett 1996; 839

Scandium(III)triflate-catalyzed acylation:
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• 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): ν_max = 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): ν_max = 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).