Studies toward the synthesis of taxol: An intramolecular Diels -Alder approach

Taxol 1.1 is a diterpene with potent anticancer activity. It was discovered in 1966 as part of a government sponsored search for new compounds in the treatment of the cancers* that were then becoming the leading cause of deaths due shifts in epidemiological patterns. It was not synthesized until nearly thirty years after its discovery and isolation. However, it has now succumbed to the synthetic efforts of six different research groups. Unfortunately, these syntheses were not efficient enough to supplant the semisynthetic methods currently used for the production of taxol. Additionally these efforts have been too long to produce analogs in either sufficient number or quantity. Therefore we began synthetic efforts within the Winkler group to prepare taxol and taxol analogs in a simplified and efficient fashion. The methodology we chose to employ in these efforts was the intramolecular Diels-Alder approach as shown below.* The intramolecular Diels-Alder (IMDA) substrate was generated from a series of bicyclic lactone as shown in the scheme below.* They could be easily elaborated to produce taxane tricycles in both a short an efficient manner. The tricycles were made using variations on the original bicyclic lactone motif as shown below.* Unfortunately, we were unable to reduce the C2-ketone to the desired C2α-alcohol. Nor were we able to invert its stereochemistry. We were thus forced to synthesize an IMDA substrate with that functionality already in place. It, however, did not undergo cyclization. This result was in line with the failure of a similar IMDA substrate synthesized by the group Alex G. Fallis (U. of Ottawa) to undergo cyclization.* *Please refer to dissertation for diagrams