Synthesis of Paclitaxel. 2. Construction of the ABCD Ring and Formal Synthesis

Abstract

A formal synthesis of the antitumor diterpenoid paclitaxel (Taxol) is described. The ABC ring of paclitaxel, synthesized starting from 1,3-cyclohexanedione and tri-O-acetyl-d-glucal by SmI2-mediated cyclization as the key transformation, was successfully converted to Takahashi's tetracyclic oxetane intermediate. A double Chugaev reaction was employed for introduction of the strained bridgehead olefin, and stereoselective formation of the oxetane ring afforded the known synthetic intermediate, completing the formal synthesis of paclitaxel.

Diterpenoids of terrestrial origin

“…178 Further synthetic studies directed at paclitaxel continue to be reported. 179 A large number of esters of jatrophanes, lathyranes, myrsinanes, daphnanes, tiglianes and ingenanes have been isolated, particularly from members of the Euphorbiaceae and Thymelaeaceae. Care must be taken in the separation of these compounds to avoid conditions that may lead to acyl migration and transesterication.…”

Short, Enantioselective Total Synthesis of Highly Oxidized Taxanes

“…Indeed, Taxol™ ( 1 , Figure 1) can be treated as a barometer to measure progress and advances in the science of chemical synthesis. This iconic natural product has been prepared on ten separate occasions (seven total syntheses 4–12 and three formal syntheses 13–16 ), elegantly demonstrating the feasibility of its reconstitution by purely chemical means. Notwithstanding the beauty of these landmark accomplishments, they are 8–9 orders of magnitude less efficient than biological production.…”

Chemistry: Why synthesize?

“…Every year brings its bounty. In 2015, chemists published a new and elegant route to the anticancer drug paclitaxel (Taxol) 1 , and syntheses of a nodulisporic acid that might act as an insecticide 2 and, in this journal, of an anti-HIV alkaloid 3 . There are also less utilitarian reasons for making molecules.…”