Danishefsky Taxol Total Synthesis - AB Ring Synthesis

AB Ring Synthesis

For this synthesis (Scheme 3) the morpholine enamine of ethyl isopropyl ketone was reacted with acryloyl chloride in a combined nucleophilic conjugate addition and nucleophilic acyl substitution to give after hydrolysis diketone 25. Reaction with hydrazine in triethylamine and ethanol afforded hydrazone 26. After an unusual hydrazone iodination that also involved iodination alpha to a carbonyl group and elimination of HI, fully conjugated vinyl iodide 28 was produced in an unexpected dehydrogenation. The ketone was converted into cyanohydrin 29 with trimethylsilyl cyanide, potassium cyanide and a crown ether.

As shown in Scheme 4, the bottom part of the taxol B ring synthesis involved the reaction of ring C aldehyde group of 21. The ketone group was deprotected by action of tetra-n-butylammonium fluoride, and the double bond was epoxidized with meta-chloroperoxybenzoic acid to epoxide 32. This epoxide was then hydrogenated with hydrogen over palladium on carbon to give diol 33, which was protected in the next step as the cyclic carbonate ester (34).

L-Selectride reduction of enone 34 gave ketone 35. The ketone was converted into vinyl triflate 36 using phenyl triflimide and potassium hexamethyldisilazide in tetrahydrofuran at −78 °C. This vinyl triflate was one of the functional groups required for the Heck reaction. For the generation of the other reactive group the acetal group was removed to give aldehyde 37 which was subsequently converted to the terminal alkene 38 in a Wittig reaction involving methylenetriphenylphosphorane. The intramolecular Heck reaction involved tetrakis(triphenylphosphine)palladium(0) and potassium carbonate in acetonitrile at reflux to give diene 39 and to complete the formation of the B ring.