Process Development of Halaven®: Synthesis of the C14–C35 Fragment via Iterative Nozaki–Hiyama–Kishi Reaction–Williamson Ether Cyclization
Received: 13. November 2012
Accepted: 22. November 2012
10. Januar 2013 (online)
Multikilogram manufacturing process of the Halaven® C14–C35 fragment is described. The synthesis features convergent assembly of subunits by iterative asymmetric Ni/Cr-mediated coupling executed in fixed equipment.
References and Notes
- 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
- 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, FL: 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
- 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
- 3b Jackson KL, Henderson JA, Motoyoshi H, Phillips AJ. Angew. Chem. Int. Ed. 2009; 48: 2346
- 3c Yamamoto A, Ueda A, Brémond P, Tiseni PS, Kishi Y. J. Am. Chem. Soc. 2012; 134: 893
- 3d Jackson KL, Henderson JA, Phillips AJ. Chem. Rev. 2009; 109: 3044 ; and references therein
- 4a Kim D.-S, Dong C.-G, Kim JT, Guo H, Huang J, Tiseni PS, Kishi Y. J. Am. Chem. Soc. 2009; 131. 15636
- 4b Dong C.-G, Henderson JA, Kaburagi Y, Sasaki T, Kim D.-S, Kim JT, Urabe D, Guo H, Kishi Y. J. Am. Chem. Soc. 2009; 131: 15642
- 4c Shan M, Kishi Y. Org. Lett. 2012; 14: 660
- 4d Liu L, Henderson JA, Yamamoto A, Brémond P, Kishi Y. Org. Lett. 2012; 14: 2262
- 5 Austad B, Chase CE, Fang FG. WO 2005118565, 2005
- 6 Broughton DB, Gerhold CG. US 2985589, 1961
- 7 Mitsunobu O. Synthesis 1981; 1
- 8 Tokunaga M, Larrow JF, Kakiuchi F, Jacobsen EN. Science 1997; 277: 936
- 9a Wan Z.-K, Choi H.-W, Kang F.-A, Nakajima K, Demeke D, Kishi Y. Org. Lett. 2002; 4: 4431
- 9b Choi H.-W, Nakajima K, Demeke D, Kang F.-A, Jun H.-S, Wan Z.-K, Kishi Y. Org. Lett. 2002; 4: 4435
- 9c Kurosu M, Lin M.-H, Kishi Y. J. Am. Chem. Soc. 2004; 126: 12248 ; and references cited therein
- 10a N-Tosyltriethylammonium chloride presumably undergoes reductive elimination to generate the corresponding sulfinic acid. Formation of the mixed anhydride by reaction of the sulfinic acid with the sulfonyl chloride, followed by sulfinylation of 9 results in the sulfinate. For a plausible mechanism of a similar reaction, see ref. 10b. The use of alternate base, such as DMAP or 1-methylimidazole, serves to suppress formation of the C17 sulfinate.
- 10b Schreiber SL. Tetrahedron Lett. 1980; 21: 1027
- 11 Acid-induced cyclization to form the halichondrin C17–C20 tetrahydrofuran ring was first noted by Yu and co-workers at Eisai. Acidic acetonide cleavage of erythrose derivative A resulted in clean in situ cyclization to furnish the C14–C21 subunit (Scheme 7). See: Yu MJ, Tremblay L, Davis HA, Palme MH, Sexton KA, Zheng W. Book of Abstracts, 219th ACS National Meeting, San Francisco, CA, March 26-30, 2000. American Chemical Society. Washington DC: 2000 ; Abstract ORGN-739.
- 12 Choi H.-W, Demeke D, Kang FA, Kishi Y, Nakajima K, Nowak P, Wan Z.-K, Xie C. Pure Appl. Chem. 2003; 75: 1
- 13 Kishi and co-workers recently reported a synthesis of Halaven® C27–C35 subunit which avoids C31 benzylation/debenzylation and the use of silver salt for C31 methylation. For detail, see: Yang Y.-R, Kim D.-S, Kishi Y. Org. Lett. 2009; 4516
- 14 Selection of counterion is critical for chemoselective C31 methylation. The use of KOt-Bu resulted in a several percent of sulfone α-methylation byproduct.
- 15 Experimental procedure for C26–C27 NHK coupling (3+4→43): (S)-Ligand 19 (2.69 kg, 9.08 mol) was dissolved in THF (17.6 kg) and the solution was flushed with N2 to achieve O2 content 200 ppm. CrCl2 (1.11 kg, 9.03 mol) was added and the mixture was warmed to 28–32 °C. Et3N (0.92 kg, 9.1 mol) was added between 30–35 °C and the suspension was stirred at 28–32 °C for at least 2.5 h before cooling to –10 to 5 °C. NiCl2 (0.030 kg, 0.23 mol) was added followed by a N2-flushed solution of C27–C35 aldehyde 3 (1.169 kg, 1.95 mol) and C14–C26 triflate 4 (1.48 kg, 2.56 mol) in THF. The reaction mixture was warmed up to 23–25 °C and stirred for 10–16 h. Upon complete conversion, the reaction mixture was cooled down to –10 to 5 °C and ethylenediamine (1.54 kg, 26 mol) was added between 0–5 °C. The reaction mixture was stirred for 1 h and warmed to 20–25 °C. Water (12 kg) was added over 10 min followed by n-heptane (20 kg) and the mixture was stirred for 30 min. The aqueous phase was removed and extracted with MTBE (22 kg). The combined organic layers were washed with a solution of NaHCO3 (1.5 kg) and NaCl (4 kg) in water (25 kg) and concentrated under reduced pressure at 25 °C. The solution was azeotroped with THF (10 kg) to achieve water <500 ppm. The solution was used as is in the next stage.
- 16 Cyclization is initiated once residual S-ligand 19 from the previous step is fully deprotonated. Careful monitoring is required to avoid decomposition of 44 caused by excess charge of KHMDS.
- 17 Experimental procedure for Williamson ether cyclization (43→44): The solution of the NHK coupling product 43 in THF was diluted with THF (140 kg) and cooled down to –20 to –15 °C. 0.5 M KHMDS in toluene was added (18.0 kg; 4 equiv) at –15 to –20 °C. The final charge of KHMDS was determined based on HPLC reaction conversion (titrated to >99% conversion). Upon complete conversion, the reaction mixture was transferred to NH4Cl (8.1 kg) in water (112 kg) at –5 to 0 °C. n-Heptane (71 kg) was added and the mixture was warmed to 22 °C. The aqueous layer was removed and extracted with MTBE (77 kg). The organic layers were washed with a solution of NaCl (24 kg) in water (66 kg), and then concentrated under reduced pressure at 25–30 °C. n-Heptane (61 kg) was added, and the resulting slurry of ligand 19 was cooled down to –15 to –10 °C for 1 h. The suspension was filtered and the cake of 19 was washed with n-heptane (10–20 kg). The filtrate was concentrated and n-heptane (2 kg) was added to the residue. Ligand 19 was filtered off and rinsed with n-heptane (0.5 kg). The combined filtrates were concentrated and the residue purified by flash chromatography on silica gel (Biotage 400 L cartridge × 2) eluting with n-heptane (1200 kg) and MTBE (350 kg) to give 44 (1.2 kg, 1.3 mol, 65% yield from 3), which was dissolved in n-heptane (4.0 kg) and used directly in the next stage.
- 18a Hori N, Nagasawa K, Shimizu T, Nakata T. Tetrahedron Lett. 1999; 40: 2145
- 18b Sakamoto Y, Tamegai K, Nakata T. Org Lett. 2002; 4: 675
- 19a Experimental procedure for reductive deprotection of 44 and crystallization of 2: The solution of 44 in n-heptane from the previous step was concentrated to dryness (2.54 kg, 2.72 mol). Toluene (15 kg) was added and the resulting solution was cooled to –75 to –60 °C. A solution of DIBAL-H (1 M solution in toluene, 5.24 kg, 6.1 mol) was added over 30 min keeping the temperature between –75 and –60 °C. Upon complete conversion, MeOH (0.25 kg, 7.8 mol) was added over 30 min. keeping the temperature between –75 °C and –60 °C. The reaction mixture was warmed up to 15–25 °C, and 32% HCl (3.12 kg, 27 mol) in water (24.2 kg) was added over 1 h between 15 and 25 °C. MTBE (50.4 kg) was added and the mixture was stirred. The aqueous layer was extracted with MTBE (30.9 kg). The combined organic layers were washed sequentially with water, 9 wt% aqueous NaHCO3 (8.4 kg) and 26% aqueous NaCl (8.6 kg). The organics were concentrated to dryness and dissolved in MTBE (1.9 kg) and n-heptane (4.5 kg). The resulting solution was purified by flash chromatography on silica gel (Biotage 400 L cartridge × 1) eluting with MTBE (1225 kg) and n-heptane (250 kg). Fractions containing product were pooled and concentrated to dryness. The residue was azeotroped with n-heptane. The residue (2.03 kg, 2.38 mol, 87% yield) was dissolved in n-heptane (13.5 kg) at 20 °C and cooled to –5 to 0 °C. The solution was seeded with 2 (1 g) and the solution was stirred for 3 h at –5 to 0 °C. The suspension was cooled to –20 to –15 °C and held for 3 h. The suspension was filtered and the cake was washed with –20 °C n-heptane (3–5 kg). The solids were dried to constant weight to provide 2 (1.85 kg, 2.17 mol, 91% crystallization recovery, 79% yield based on 44).
- 19b Characterization of 2: mp 58–60 °C. [α]D 20 –17.6 (c 1.05, EtOH). IR (neat oil, KBr): 3455, 3073, 2929, 1651, 1363, 1152, 777 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.93–7.97 (m, 2 H), 7.66–7.72 (m, 1 H), 7.57–7.64 (m, 2 H), 4.90–4.92 (m, 1 H), 4.85 (s, 1 H), 4.78 (d, J = 3.0 Hz 1 H), 4.65–4.67 (m, 1 H), 4.28 (s, 1 H), 3.92–4.01 (m, 1 H), 3.78–3.89 (m, 3 H), 3.53–3.74 (m, 5 H), 3.44–3.52 (m, 1 H), 3.32–3.44 (m, 5 H), 2.98–3.10 (m, 2H), 2.53–2.67 (m, 2 H), 2.15–2.29 (m, 3 H), 1.98–2.08 (m, 1 H), 1.20–1.92 (m, 11 H), 1.00–1.12 (m, 4 H), 1.02–1.10 (m, 4 H), 0.90 (s, 18 H), 0.09 (s, 3 H), 0.08 (s, 3H), 0.05 (s, 3 H), 0.04 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 134.0, 129.5, 127.9, 104.9, 85.8, 80.7, 79.5, 78.3, 77.2, 76.9, 75.3, 71.4, 67.8, 62.6, 58.1, 57.5, 43.3, 42.6, 39.0, 37.5, 35.5, 33.1, 32.2, 31.7, 31.3, 29.6, 26.0, 26.0, 17.9, –4.1, –4.7, –5.3. HRMS (ESI): m/z calcd for C45H79O9SSi2 [M+H]+: 851.4983; found: 851.4983.
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:
New syntheses of Halaven® C14–C35 and halichondrin C14–C38 building blocks: