Modern synthetic pathways towards eribulin and its subunits
- Sebastian Dominik Graf
Beilstein J. Org. Chem. 2026, 22, 495–526, doi:10.3762/bjoc.22.37
Graphical Abstract
Figure 1: Eribulin with common synthetic precursor fragments and halichondrin B.
Scheme 1: Overview of the industrial process pathway for the large-scale production of the mesylate salt of 1...
Scheme 2: Synthesis of 22. (a) i. 2,2-dimethoxypropane, p-TsOH, MeOH, 65 °C; ii. NaBH4, MeOH, rt; (b) i. NaH,...
Scheme 3: Synthesis of 27. (a) i. NaH, BnBr, THF, rt; ii. iodobenzoic acid, MeCN, 80 °C; iii. (EtO)2POCH2COOE...
Scheme 4: Synthesis of 31 and 33. (a) i. MMTrCl, iPr2NEt, DCM, rt; ii. K2CO3, MeOH, DCM, rt; iii. TBDMSCl, im...
Scheme 5: Synthesis of 1. (a) CrCl2, 37, 38, 39 (proton sponge), LiCl, Mn, ZrCp2Cl2, MeCN, EtOAc; (b) SrCO3, t...
Scheme 6: Synthesis of 45. Above: Reaction conditions: (a) methoxyacetic acid, BF3·OEt2, DCM, −30 °C; (b) Pd(...
Scheme 7: Synthesis of 64. Reaction conditions: (a) i. acetone, I2, rt; ii. vinylmagnesium bromide, THF, −20 ...
Scheme 8: Synthesis of 79. Above: Reaction conditions: (a) i. K2CO3, MeOH, 60 °C; ii. 2,2-dimethoxypropane, H2...
Scheme 9: Synthesis of 92. Reaction conditions: (a) TESCl, imidazole, DCM, 0 °C to rt; (b) i. oxalyl chloride...
Scheme 10: Synthesis of 104. Above: Reaction conditions: (a) cyclohexanone, p-TsOH, toluene, 110 °C, crystalli...
Scheme 11: Synthesis of 117. (a) i. acetone, CuSO4, rt; ii. H2O2, K2CO3, H2O, rt; iii. EtI, MeCN, 70 °C; (b) i...
Scheme 12: Synthesis of 121. Reaction conditions: (a) i. TBDPSCl, imidazole, DMF, rt; ii. O3, DCM, −78 °C; iii...
Scheme 13: Synthesis of 131. (a) i. 2,2-dimethoxypropane, p-TsOH, MeOH, 60 °C; ii. LiAlH4, THF, 0 °C to rt; (b...
Scheme 14: Synthesis of 143. (a) i. I2, PPh3, imidazole, DCM; ii. HMPA, CuI, vinylmagnesium bromide, THF, −20 ...
Scheme 15: Modified synthesis of 104. Reaction conditions: (a) (EtO)2POCH2COOEt, KOt-Bu, THF, 15 °C; (b) TBAF,...
Scheme 16: Synthesis of 161. Reaction conditions: (a) crotyl bromide, Sn, TBAI, NaI, DMF/H2O, rt; (b) NaH, BnB...
Scheme 17: Synthesis of 169. Reaction conditions: (a) i. Co2(CO)8, BF3·Et2O, DCM, 23 °C; ii. CAN, acetone, 0 °...
Scheme 18: Synthesis of 181. Reaction conditions: (a) i. Co2(CO)8, BF3·Et2O, DCM, 23 °C; ii. (NH4)2Ce(NO3)6, a...
Scheme 19: Synthesis of 186. Reaction conditions: (a) NEt3, LiCl, MeCN, 0–23 °C; (b) HF·pyridine, MeCN, 23 °C;...
Scheme 20: Modified synthesis of 181. Reaction conditions: (a) i. Ni(cod)2, P(n-Bu)3, Et3SiH, THF, 23 °C; ii. ...
Scheme 21: Synthesis of 200. Reaction conditions: (a) i. Co2(CO)8, DCM, 23 °C; ii. BF3·Et2O, 0 °C; iii. (NH4)2...
Scheme 22: Modified synthesis of 186. Reaction conditions: (a) DDQ, 2,6-di-t-Bu-4-hydroxytoluene, hv, MeCN, 23...
Scheme 23: Synthesis of 1. Reaction conditions: (a) i. CrCl2, NiCl2, 206, NEt3, THF, 23 °C; ii. DBU, toluene, ...
Scheme 24: Synthesis of 217. Above: Reaction conditions: (a) TBDPSCl, imidazole, DCM, 0–5 °C. (b) m-CPBA, DCM,...
Scheme 25: Synthesis of 231. Reaction conditions: (a) i. AcCl, MeOH, 0 °C to rt; ii. TrCl, pyridine, 50 °C; (b...
Scheme 26: Synthesis of 239. Reaction conditions: (a) i. Boc2O, K2CO3, THF, rt; ii. Ru(acac)3, NaBrO3, EtOAc, H...
Scheme 27: Synthesis of 247. Reaction conditions: (a) NCS, 248, MeCN, 0 °C to rt; (b) LDA, 249, THF, −78 °C; (...
Scheme 28: Synthesis of 255. Reaction conditions: (a) i. LiHMDS, THF, −78 °C to rt; ii. m-CPBA, DCM, −78 °C to...
Scheme 29: Synthesis of 261. Reaction conditions: (a) allyltrimethylsilane, TiCl4, DCM −78 °C; (b) LiBH4, EtOH...
Scheme 30: Synthesis of 265. Reaction conditions: (a) (R,R)-Ru-cat (0.2 mol %), DCM, NEt3, HCOOH, rt; (b) TBAF...
Scheme 31: Synthesis of 272. Reaction conditions: (a) LDA, THF, −78 °C; (b) DMP, NaHCO3, DCM, 0 °C to rt; (c) (...
Scheme 32: Synthesis of 292. Reaction conditions: (a) TsCl, NEt3, DCM, rt; (b) K2CO3, MeOH, 45 °C; (c) vinylma...
Scheme 33: Synthesis of 296. Reaction conditions: (a) 171 (see Scheme 17), Cr-cat, CoPc (see Scheme 17), Mn, NEt3·HCl, LiCl, TMS...
Scheme 34: Synthesis of 299. Reaction conditions: (a) 172 (see Scheme 17), CrCl2, NEt3, NiCl2, THF, rt; (b) KHMDS, THF,...
Scheme 35: Synthesis of 305. Reaction conditions: (a) i. p-TsOH, MeOH, 40 °C; ii. MeLi, LiBr, THF, −25 °C; (b)...
Scheme 36: Synthesis of 1. Reaction conditions: (a) i. 41 (see Scheme 6), LDA, THF, −78 °C; ii. DMP, NaHCO3, DCM, rt; ...
Scheme 37: Synthesis of 324. Reaction conditions: (a) i. acetone, CuSO4, rt; ii. H2O2 (30%), K2CO3, rt; iii. E...
