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Synlett 2013; 24(3): 323-326
DOI: 10.1055/s-0032-1317919
DOI: 10.1055/s-0032-1317919
cluster
Process Development of Halaven®: Synthesis of the C1–C13 Fragment from d-(–)-Gulono-1,4-lactone
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.
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References
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- 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).
For discovery and development of Halaven® (1), see:
First total synthesis of halichondrin B:
Total synthesis of norhalichondrin B by Phillips:
Total synthesis of halichondrin C:
Review of synthetic work on halichondrins:
Scandium(III)triflate-catalyzed acetalization:
Scandium(III)triflate-catalyzed acylation: