Two-Phase Total Synthesis of Taxanes: Tactics and Strategies

Abstract

This Perspective goes into the fine details of our laboratory’s quest to answer a longstanding fundamental question: Could any new approach to terpene synthesis, perhaps one patterned on biosynthesis, enable a divergent synthetic approach to the taxane family of natural products? We targeted Taxol, the flagship taxane, as the upper limit of chemical complexity and employed two-phase terpene synthesis logic as the guiding strategy. The first synthesis target was taxadiene, the lowest oxidized member of the taxane family, followed by three site-selective allylic oxidations at C5, C10, and C13, which led to the two-phase synthesis of taxuyunnanine D. Successful C9 oxidation enabled access to a wider range of taxanes, which was demonstrated by the two-phase synthesis of decinnamoyltaxinine E and taxabaccatin III. The final two sp3 C–H oxidations at C1 and C7 were attained by dioxirane-mediated C–H oxidation and an oxidation relay based on judicious substrate design, culminating in a two-phase synthesis of Taxol. The purpose of this Perspective is to articulate strategies and tactics developed for the two-phase synthesis of taxanes, whose lessons can be potentially extrapolated to medicinal chemistry endeavors in the taxane family, as well as to the synthesis of other terpene families.

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“…For example, the Baran group introduced the biomimetic concept of ‘two‐phase′ total syntheses of the terpenes 1 and 3 – 6 in 2009 (Figure 2A), [98] in order to make use of nature's highly efficient approach of accessing maximum diversity of natural products in a minimum number of steps by the modification of common structural scaffolds ( 3 ; Figure 2B) [99] . Starting with a chemical cyclase phase to build up the target compound's hydrocarbon skeleton employing C−C bond‐forming reactions, Baran introduced functionality in the following chemical oxidase phase via sequential, site‐selective C−H activation of unactivated (sp 3 ‐hybridised) positions [100] . Such late‐stage functionalisation often renders protecting groups unnecessary.…”

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“…To this end, addition of the Grignard reagent from (chloromethyl)trimethylsilane yielded the tertiary alcohol 56. Reduction of 56 with hydrogen in the presence of Pearlman catalyst proceeded via addition at the less substituted C13-C14 olefin as well as cleavage of the C10 benzyl ether; the resultant secondary alcohol was oxidized to a ketone, and elimination of the -silylalcohol rendered the exocyclic olefin (57). The C7 benzoate ester was exchanged for a triethylsilyl ether over a three-step sequence to afford 58.…”

“…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.…”