Two-Phase Synthesis of Taxol

Abstract

Taxol (a brand name for paclitaxel) is widely regarded as among the most famed natural isolates ever discovered, and has been the subject of innumerable studies in both basic and applied science. Its documented success as an anticancer agent, coupled with early concerns over supply, stimulated a furious worldwide effort from chemists to provide a solution for its preparation through total synthesis. Those pioneering studies proved the feasibility of retrosynthetically guided access to synthetic Taxol, albeit in minute quantities and with enormous effort. In practice, all medicinal chemistry efforts and eventual commercialization have relied upon natural (plant material) or biosynthetically derived (synthetic biology) supplies. Here we show how a complementary divergent synthetic approach that is holistically patterned off of biosynthetic machinery for terpene synthesis can be used to arrive at Taxol.

Figure 1.

Approaches to the synthesis of Taxol (1): Semi-synthesis, canonical total synthesis, biosynthesis, and two-phase synthesis (this work).

Scheme 1.. Two-phase synthesis of 1.

Reagents and conditions are as follows. (a) Cr(V) (16), HFIP, TMSOH, t-BuOH, 80 °C. (b) CuBr₂, THF, rt, 55%, over 2 steps. (c) NBS, BPO, CCl₄, then DTBMP, AgOTf, TESOH, 4Å MS, PhMe, rt, 68%. (d) LiBr, Li₂CO₃, DMF, 100°C, 88%. (e) MeMgBr, DCM, 0 °C to rt, then DIBAL, −78 °C, DCM, then LiAlD₄, THF, 60 °C, 74%. (f) NaHMDS, TBSCl, THF, 0 °C to rt, 94%. (g) DMDO, 0 °C, 49%. (h) TPAP, NMO, DCM, rt, 81%. (h) Na, i-PrOH, Et₂O, rt, then triphosgene, pyr, DMAP, DCM, −78 to 0 °C. (j) TBAI, BF₃•OEt₂, DCM, −78 °C, then 2-Fpyr, −78 °C, then TMSIm, rt, then DMDO, −78 °C to rt, 43%. (k) Cp₂TiCl, Et₃SiH, THF, −78 °C to rt, 67%. (l) BOMCl, TBAI, DIPEA, DCE, 45 °C, 84%. (m) Burgess reagent, PhMe, dioxane, then HF, H₂O, pyr, MeCN, rt, 32%. (n) MsCl, pyr, 0 °C to rt, then OsO₄, THF, pyr, 0 °C to rt, 68%. (o) DIPEA, PhMe, then IBX, DMSO, H₂O, 80 °C, 62%. (p) KOt-Bu, (PhSeO)₂O, THF, H₂O, −78 to 0 °C, 73%. (q) KOt-Bu, THF, then triphosgene, pyr, DMAP, DCM, −78 to 0 °C, then Ac₂O, DMAP, pyr, rt, 60%. (r) TASF, THF, rt, then PhLi, THF, −78 °C, 48%. (s) β-lactam (35), LHMDS, THF, −78 °C to rt, then Pd/C, H₂, EtOH, 80 °C, 85%.; HFIP, hexafluoroisopropanol; TMSOH, trimethylsilanol; NBS, N-bromosuccinimide; BPO, benzoyl peroxide; DTBMP, 2,6-di-tert-butyl-4-methylpyridine; TESOH, triethylsilanol; DIBAL, diisobutylaluminium hydride; HMDS, hexamethyldisilazane; TBSCl, t-butyldimethylsilyl chloride; DMDO, dimethyldioxirane; TPAP, tetrapropylammonium perruthenate; NMO, N-methylmorpholine N-oxide; pyr, pyridine; DMAP, 4-dimethylaminopyridine; TBAI, tetra-n-butylammonium iodide; 2-Fpyr, 2-fluoropyridine; TMSIm, N-(trimethylsilyl)imidazole; Cp₂TiCl, bis(cyclopentadienyl)titanium(III) chloride; BOMCl, benzyl chloromethyl ether; DIPEA, N,N-diisopropylethylamine; DCE, 1,2-dichloroethane; MsCl, methanesulfonyl chloride; IBX, 2-iodoxybenzoic acid; TASF, tris(dimethylamino)sulfonium difluorotrimethylsilicate.