Two-Phase Synthesis of Taxol

Abstract

Taxol® is widely regarded as amongst the most famed natural isolates ever discovered, and has been the subject of innumerable studies in both basic and applied science. Its documented success as an anticancer agent, coupled with early concerns over supply, stimulated a furious worldwide effort from chemists to provide a solution for its preparation through total synthesis. Those pioneering studies proved the feasibility of retrosynthetically-guided access to synthetic Taxol, albeit in minute quantities and with enormous effort. In practice, all medicinal chemistry efforts and eventual commercialization have relied upon natural-(plant material) or biosynthetically-derived (synthetic biology) supplies. Here we show how a complementary divergent synthetic approach that is holistically patterned off of biosynthetic machinery for terpene synthesis can be used to arrive at Taxol®. File list (2) download file view on ChemRxiv Manuscript.pdf (1.42 MiB) download file view on ChemRxiv Supporting Information.pdf (67.60 MiB)

Exploiting the Biosynthetic Potency of Taxol from Fungal Endophytes of Conifers Plants; Genome Mining and Metabolic Manipulation

“…In 1960s, National Cancer Institute of the United States started its program of screening natural products for anti-cancer activity including bark of Taxus brevifolia. That leads to discovering a potent anti-cancer drug, paclitaxel [89]. Needles of T. brevifolia have been reported to contain other taxane, brevifoliol, a novel diterpene [38], with potent cytotoxic activity against breast (MCF-7), liver (HepG-2), oral (KB) and colon (CaCO 2 ) cancer cell lines [73].…”

Recent advances in the synthesis of taxoids: 2015-2020

“…Baran's approach for taxol synthesis is inspired by the biosynthesis of terpenes via a two-phase process 50 which his group has applied to other target molecules [51][52][53][54] including taxabaccatin III (79), 55 and most recently taxol. 56,57 Retrosynthetically, the oxidase phase introduces oxygens onto the taxendione skeleton 80, which was assembled through Diels-Alder cycloaddition of 81 (Scheme 15). The Diels-Alder precursor was prepared from 3-bromo-2,4-dimethyl-1,3-pentadiene, 3-vinyl-2-cyclohexenone and acrolein.…”

“…In their recent synthesis of taxol, 56,57 Baran's group reported using n-butyl lithium (in place of s-butyl lithium used in their original 58 synthesis) for the lithium halogen exchange of 83. A further improvement reported in the recent Baran synthesis concerned a telescoping of the cuprate addition/aldol condensation/oxidation sequence from 86 to the Diels-Alder precursor 81a/b.…”

“…The oxidase phase commenced from the diketone (+)-80 (Scheme 18), 56,57 and utilized oxidation protocols at C13 and C10 similar to those pioneered in the (-)-taxuyunnanine D 54 and (+)-taxabaccatin III 55 syntheses. Thus, allylic oxidation using the Cr(V) oxidant 94 proceeded at both C13 as well as at C11 to generate a mixture of 102 and 103; regio-and enantioselective bromination of this mixture using CuBr2 gave 104 after purification.…”

Reinforcing the Supply Chain of COVID-19 Therapeutics with Expert-Coded Retrosynthetic Software

“…AI-recommended conditions of Oxone® with potassium bromide 32 for the C-H oxidation of 27 were unsuccessful in our hands. An extensive survey of oxidants revealed the recently disclosed Baran-Roček oxidation [33][34][35] as the solely productive condition we could identify to oxidize C14. Treatment of 27 with commercially available 28 gave 17 in 62% yield, thus intercepting the previous route to 3.…”