Progress toward the total synthesis of paclitaxel (Taxol).

摘要

Described herein is the continuation of efforts focused towards the synthesis of Taxol utilizing a route that is amenable to novel analog formation from advanced Taxol precursors. Elaboration of (1S)-(+)-10-camphorsulfonic acid to a highly functionalized taxane skeleton has been achieved in a total of twenty-two synthetic operations. Highlighting the brevity and efficiency of this series is the fact that only five operations thus far are protecting group manipulations, which tend to significantly increase the length and complexity of a synthetic route.; Entry to a completed D-ring has been made by prevous researchers in a six-step sequence. After the revelation that formation of the densely functionalized A-ring in the presence of a completed D-ring was not possible, the focus became one of elaboration of the A-ring using the very useful diosphenol intermediate 3.1.; Two areas of research have been explored and are described. First, the route to the bridge-migrated taxane 1.85 was reviewed and problems existing in the key alkenyl iodide coupling, dihydroxylation, C2 oxygenation, and bridge migration were investigated and resolved.; With an efficient synthesis of 1.85 in hand, attention was focused on completion of the A-ring beginning with routes originating from 1.85. It was quickly realized that use of the diosphenol intermediate 3.1 would be advantageous, the optimization of its synthesis was explored and realized.; A-Ring completion from 3.1 was attempted to no avail via early functionalization of the northern sector utilizing various methods. Attention was then focused on the southern sector in an attempt to bring about C14 deoxygenation at an early stage. Again, progress was halted and a new route had to be envisioned. Protection of C1 was employed to stave off undesired retro-aldol fragmentation of the A-ring; however, deoxygenation was again thwarted.; The final approach explored has given rise to an oxygenation strategy that has allowed for the synthesis of the C12 ketone 3.49. With this ketone, arrival at the A-ring might be realized through four more transformations. At that point, the route would be at a point utilized in previous Taxol syntheses and arrival at 1.1 would be imminent providing a new method of entry into natural and unnatural taxanes.