Studies on Taxol Biosynthesis. Preparation of Taxa-4(20),11(12)-dien-5α-acetoxy-10β-ol by Deoxygenation of a Taxadiene Tetraacetate Obtained from Japanese Yew

Abstract

Taxa-4(20),11(12)-dien-5 alpha-acetoxy-10 beta-ol 6 has been identified as an early stage intermediate involved in the biosynthesis of taxol (Paclitaxel). This compound has been efficiently prepared by Barton deoxygenation of the C-2- and C-14-hydroxyl groups on a derivative semisynthetically prepared from taxa-4(20),11(12)-dien-2 alpha,5 alpha,10 beta-triacetoxy-14 beta-(2-methyl)butyrate (7), a major taxoid metabolite isolated from Japanese yew heart wood. The synthetic methodology 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

“…We acquired over 100 kg of Japanese yew heartwood from a wood sculptor in Japan (Hida Ichii Ittoubori Kyoudou Kumiai of The Engraving Craftsman Association, Japan; see Figure 2) and have extracted more than 3.5 grams of 2α,5α,10β-triacetoxy-14β-(2-methyl)-butyryloxytaxa-4(20),11-diene ( 40 ) as a raw material for the preparation of a host of lightly oxygenated taxoids. We have completed the semisynthesis of taxa-4(20),11(12)-dien-5α-yl-acetate-10β-ol ( 47 ) 79 and taxa-4(20),11(12)-dien-5α-yl-acetate-2α,10β-diol ( 49 ) 80 as shown in Schemes 10 and 11. Thus, selective manipulation of the hydroxyl groups of this substrate has led to the synthesis taxa-4(20)-11(12)-diene-5α-yl-acetate-10β-ol ( 47 , Scheme 10) in tritium-labeled form in preparatively useful amounts.…”

“…80 Substrates bearing the 5α-acetate residue have proven particularly important and, in some cases, difficult to selectively prepare.…”

Administering cultured Taxus cells with early precursors reveals bifurcations in the taxoid biosynthetic pathway

“…The preparations of (±)- (12)-diene and the corresponding C5-acetate (both at 11 Ci/mo1) have been previously described (Walker et al, 1999,Rubenstein et al, 2000,Lovy Wheeler et al, 2001,Horiguchi et al, 2002. (+)-[13-3 H] Baccatin III (9.5 Ci/mol) and (±)-[1-14 C]β-phenylalanine (5 Ci/mol) were prepared by modification of published methods, as described elsewhere (Walker et al, 2002).…”

A New Metabolite with a New Substitution Pattern from the Seeds of the Chinese Yew, Taxus mairei

“…It is of great interest to note that this compound is the first example of a taxane without substitution at C(10) [4 -6]. Biosynthetic studies indicated that the oxygenation sequence of taxane at C(10) is priory to C(9) [21]. This finding suggested that the esterification pattern might have great relevance in the biogenesis of taxanes.…”