A Total Synthesis of Taxol

Abstract

21.tleri\wl from doubly MOM-protected homophthalic anhydride 20. followed by oxidation with phenyliodondium bis(tritluoroacetaie) resulted in a substance which we provisionally formulate a\ 22.""' The proposal advanced in Scheme 5 for the progression from 16 to 22 should be implemented in a formal ruilier than ;I chronological context. When a highly concentrated solution of 22 in T H F was exposed to the action of oxygen : m i daylii~ht. ; t violet-red product presumed to be the protected goal structure 23 was obtained.li5] Deprotection of 23 afforded dynemicin A (1). The ' H NMR spectrum and TLC properties of thc synthetic material matched those of an authentic sample. The relative configuration at C-4 had been independently veritied h! ci-~stallography at an earlier stage."' The comparisons with the severely limited authentic material available. the nature of the s t e p . and the inherent properties of our final product, fully establish that ( & )-dynemicin A ( 1 ) had been synthesized.Studies directed to higher yielding anthraquinone annulation protocols are underway. Also, with increased quantities of dyncinicin nou available to us by synthesis, investigations of sonic ofihe bioorganic issues identified above have already been initiated . Receivcd: April 20. I Y Y S [Z79131E] 18x5 (iei-niaii \crsion: A/i,qc.~. C h r i . 1995. 1117. I XX3

Taxol biosynthesis: Taxane 13α-hydroxylase is a cytochrome P450-dependent monooxygenase

“…These ''second generation'' taxoid drugs, like Taxol itself, still depend on the isolation of natural products from the yew tree. Several elegant total synthetic routes to Taxol and related taxoids have been developed (15)(16)(17)(18)(19)(20); however, low yields and high costs preclude them from commercial production (21) and, for the foreseeable future, sourcing must continue to rely on Taxus species or, potentially, cell cultures derived therefrom (6). Improved biological production methods depend on an understanding of the biosynthetic pathways leading to Taxol and related taxoids and definition of the responsible enzymes and genes.…”

Natural Products in the Chemical Industry

“…[313,314] Almost simultaneously, Kyriacos Costa ("K. C. ") Nicolaou [315,316] published a total synthesis, and a little later Samuel Danishefsky as well. [317,318] Additional total syntheses were published by Wender, Kuwajima and Mukaiyama. [319] However, it became clear very quickly that none of these syntheses would have a chance of being used at an industrial scale for reasons of technical feasibility and overall yield.…”

Pharmaceuticals

“…[313,314] Almost simultaneously, Kyriacos Costa ("K. C. ") Nicolaou [315,316] published a total synthesis, and a little later Samuel Danishefsky as well. [317,318] Additional total syntheses were published by Wender, Kuwajima and Mukaiyama. [319] However, it became clear very quickly that none of these syntheses would have a chance of being used at an industrial scale for reasons of technical feasibility and overall yield.…”