Ammonium Hydroxide → 3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

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Reaction Steps

To a stirred suspension of epothilone F (47.12 g, 90.0 mmol) in tetrahydrofuran (942 ml, previously dried over 3A molecular sieves) under argon, was added diphenylphosphoryl azide (29.2 ml, 37.3 g, 135.5 mmol, 1.5 equivalents). The mixture was stirred for about 10 min. 1,8-diazabicyclo[5.4.0]undec-7-ene (24.5 ml, 24.94 g, 163.8 mmol, 1.8 equivalents) was then added gradually, at a rate that maintained the temperature of the mixture below 30° C. The mixture was stirred for 22 hours. To the reaction mixture was added a solution of trimethylphosphine in tetrahydrofuran (1.0 M, 99.0 ml, 86.3 g, 99.0 mmol, 1.1 equivalents), at a rate that maintained the temperature of the mixture below 30° C. The mixture was stirred at room temperature for 30 minutes, and water (244 ml) was added. After 30 minutes, 28% aqueous NH4OH (125.0 ml) was added, and the mixture stirred for 30 minutes. Water (470 ml) was added, and the mixture was extracted with methylene chloride (3×100 ml). The combined organic extracts were washed with aqueous ammonium hydroxide (1.0 M, 3×470 ml). NMR analysis was used to determine the presence of residual diphenylphosphate in the organic phase. The organic phase was then washed with half-saturated aqueous sodium chloride (470 ml), the solvents were removed on a rotary evaporator, and the residual solid was dried in vacuo for 18 hours to afford the crude product (56.72 g, 120.6% yield).

Provenance & Evidence