Studies on Taxol biosynthesis: preparation of taxadiene-diol and triol derivatives by deoxygenation of taxusin

Abstract

The putative taxol biosynthesis metabolites, taxa-4(20),11(12)-diene-5α, 13α -diol (7), taxa-4(20), 11(12)-diene-5α, 9α, 13α-triol (9), and taxa-4(20),11(12)-diene-5α, 10β, 13α-triol (10), have been prepared by Barton deoxygenation of the C-9 and C10-hydroxyl groups of protected derivatives of taxusin, a major taxoid metabolite isolated from Yew heart wood. The synthetic protocol devised, is amenable for the preparation of isotopically labeled congeners that will be useful to probe further intermediate steps in the biosynthesis of taxol.

The early stages of taxol biosynthesis: An interim report on the synthesis and identification of early pathway metabolites

“…81 Thus, treatment of taxusin with potassium carbonate in methanol, selectively removes the C5 and C13 acetate residues ( 56 , Scheme 14). Protection of the C5 and C13 hydroxyl groups as the triethylsilyl (TES) ethers and LAH removal of the acetates furnished 57 .…”

“…Xanthate formation gave a mixture of 58a and 58b which could be subjected to radical deoxygenation and fluoride-based desilylation to produce taxa-4(20),11(12)-dien-5α,9α,13α-triol ( 60 ) and taxa-4(20),11(12)-dien-56α,10β,13α-triol ( 61 ). 81 …”

“…Final treatment of 63 with HFβpyridine complex afforded taxa-4(20),11(12)-diene-5α,13α-diol ( 64 ). 81 …”

Untitled

“…33 Notes: 1) This is not a comprehensive list of all taxane oxidation patterns; 2) for clarity and discussion purposes, all side chains attached to hydroxyl groups were omitted; 3) all taxanes in the above pyramid are found in Nature, and these natural products are indicated with isolation paper references; 4) any additional oxidations installed onto taxadiene 24 are indicated in red. This diamond array of a set of objects does not merely belong to the realm of chemistry and molecules, but is rather inherent to mathematics and combinatorials.…”

Two-Phase Terpene Total Synthesis: Historical Perspective and Application to the Taxol® Problem

“…32 In pioneering detective work by Williams and Croteau, based on the frequency of oxygenation at various positions in natural taxoids (this variety is expressed in the selection of taxanes in Figure 2A), the oxygenation sequence after C5 oxidation is inferred to be in the order of C10, followed by C9 and C13, then C2 and C7, and finally C1 ( Figure 2C). 33 In order to target many members of the taxane diterpenoids, it appears logical to follow, at least roughly, the assumed order of oxidation that Nature employs, during a 'synthetic ascent' of the oxidase phase pyramid. But is a pyramid really the best option for such a complex family of molecules?…”