Studies on Taxol<sup>®</sup> biosynthesis. Preparation and tritium labeling of biosynthetic intermediates by deoxygenation of a taxadiene tetra‐acetate obtained from Japanese yew

Horiguchi, Tohru; Rithner, Christopher D.; Croteau, Rodney; Williams, Robert M.

doi:10.1002/jlcr.1529

Cited by 8 publications

(10 citation statements)

References 25 publications

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“…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.…”

Section: Syntheses Of Lightly Functionalized Taxoidsmentioning

confidence: 99%

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

2012

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The biosynthesis of the anti-cancer drug taxol (paclitaxel) has required the collaborative efforts of several research groups to tackle the synthesis and labeling of putative biosynthetic intermediates, in concert with the identification, cloning and functional expression of the biosynthetic genes responsible for the construction of this complex natural product. Based on a combination of precursor labeling and incorporation experiments, and metabolite isolation from Taxus spp., a picture of the complex matrix of pathway oxygenation reactions following formation of the first committed intermediate, taxa-4(5),11(12)-diene, is beginning to emerge. An overview of the current state of knowledge on the early-stages of taxol biosynthesis is presented.

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Section: Syntheses Of Lightly Functionalized Taxoidsmentioning

confidence: 99%

“…This has proven significant since the totally synthetic route initially devised to prepare 47 described above, requires extensive time and effort to repeat. 79 …”

Section: Syntheses Of Lightly Functionalized Taxoidsmentioning

confidence: 99%

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

2012

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“…In alkene and alkyne tritioborations, the boron adds preferentially to the less hindered side of the multiple bond, so that the label should be located mostly at the adjacent atom; this is evident in the isotope distribution in [ 3 H]safrole (264) and [ 3 H]isosafrole (265) 238 , resulting from reactions with the respective isomeric alkyne precursors. In a reaction that nicely exploited the differing reactivity of functional groups towards B 3 H 3 ÁTHF, the a,bunsaturated carbonyl function of 7-triethylsilyl-13-oxo-baccatin III (266) The ability of B 3 H 3 .…”

Section: Thf)mentioning

confidence: 99%

“…The reagent similarly prepared was also applied to the selective tritiodehalogenation of the a-bromosteroids 281 and 282 possessing other potentially reducible substituents (F, Cl, saturated and a,b-unsaturated carbonyl systems) 258 carbonate esters of C-ribonucleosides have been converted to their corresponding 2 0 -desoxy [2 0 -3 H]-derivatives. The method has recently been applied to the preparation of tritiated taxanes for use in investigations of paclitaxel biosynthesis 264 . Applied to the 4-p-fluorophenoxythiocarbonate ester of cholesterol (287), the reduction led to the formation of the same ratio of [3-3 H]cholest-5-en isomers 288 (22 Ci/mmol, 70% 3a, 30% 3b) independent of the stereochemistry of the starting ester 263 .…”

Section: Tri-n-butyltin Tritide (N-bu 3 Sn 3 H)mentioning

confidence: 99%

Preparation of Tritium‐Labeled Compounds by Chemical Synthesis

2009

Preparation of Compounds Labeled With Tritium and Carbon‐14

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In contrast to isotope exchange methods, which utilize the target compound or a late intermediate as substrate for labeling, chemical synthesis involves transformation of some precursor chemical with concurrent introduction of tritium. Four basic types of transformations are distinguished for discussion each in turn. They are catalytic tritiations (Section 4.1), which usually involve the reduction of a precursor compound using a catalyst and tritium gas; catalytic tritiolyses (Section 4.2), involving the replacement of functional groups by tritium, again using a catalyst and tritium gas; tritide reductions (Section 4.3), utilizing tritiated versions of hydridic reducing reagents; and the use of small tritiated building blocks (Section 4.4) in synthetic operations to construct target molecules.A phenomenon strongly relevant to the catalytic methods discussed in Sections 4.1 and 4.2, and of some relevance also for tritide chemistry (Section 4.3) is solvent exchange. Most catalytic tritiations and tritiolyses are conducted in solution, and a wide variety of solvents have been used, ranging from nonpolar ones to highly polar, hydroxylic media. The properties of the solvent, however, influence not only the course and rate of a heterogeneously catalyzed reaction, but also the extent to which solvent hydrogen may exchange with tritium gas as a side reaction and thereby dilute the isotope introduced into the substrate: solvent exchange. It is commonly recognized that the use of protic solvents for tritiations and tritiolyses increases the risk of obtaining products of less than maximal specific activity, although it is equally clear that such reactions often succeed without dilution of label. The crucial factor in each experiment is the relationship between the rate of the tritium-incorporation reaction and the rate(s) of any tritium-diluting reaction(s). It is documented that the rate of metal-catalyzed exchange between elemental hydrogen and water is significant, especially at low pH 1 , but little quantitative data are available to guide practice. Recently a turnover number of 17.3 h À1 was reported for the exchange between H 2 and 2 H 2 O catalyzed by 10% Pd/C at room temperature and a pressure of 1 atm 2 ; this is rapid enough to provide the basis for an economical method of catalytic deuterium exchange Preparation of Compounds Labeled with Tritium and Carbon-14 Rolf Voges, J. Richard Heys and Thomas Moenius

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“…127 A few highlights of our initial total synthesis of taxadiene are shown in Scheme 48. 122 Access to these lightly oxygenated substrates, has been extensively exploited in the selective removal and addition of oxygenation to the taxoid core.…”

Section: Introductionmentioning

confidence: 99%

Natural Products Synthesis: Enabling Tools To Penetrate Nature’s Secrets of Biogenesis and Biomechanism

Williams

2011

J. Org. Chem.

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Selected examples from our laboratory of how synthetic technology platforms developed for the total synthesis of several disparate families of natural products was harnessed to penetrate biomechanistic and/or biosynthetic queries is discussed. Unexpected discoveries of biomechanistic reactivity and/or penetrating the biogenesis of naturally occurring substances were made possible through access to substances available only through chemical synthesis. Hypothesis-driven total synthesis programs are emerging as very useful conceptual templates for penetrating and exploiting the inherent reactivity of biologically active natural substances. In many instances, new enabling synthetic technologies were required to be developed. The examples demonstrate the often un-tapped richness of complex molecule synthesis to provide powerful tools to understand, manipulate and exploit Nature’s vast and creative palette of secondary metabolites.

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Studies on Taxol^® biosynthesis. Preparation and tritium labeling of biosynthetic intermediates by deoxygenation of a taxadiene tetra‐acetate obtained from Japanese yew

Cited by 8 publications

References 25 publications

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

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

Preparation of Tritium‐Labeled Compounds by Chemical Synthesis

Natural Products Synthesis: Enabling Tools To Penetrate Nature’s Secrets of Biogenesis and Biomechanism

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Studies on Taxol® biosynthesis. Preparation and tritium labeling of biosynthetic intermediates by deoxygenation of a taxadiene tetra‐acetate obtained from Japanese yew

Cited by 8 publications

References 25 publications

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

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

Preparation of Tritium‐Labeled Compounds by Chemical Synthesis

Natural Products Synthesis: Enabling Tools To Penetrate Nature’s Secrets of Biogenesis and Biomechanism

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Studies on Taxol^® biosynthesis. Preparation and tritium labeling of biosynthetic intermediates by deoxygenation of a taxadiene tetra‐acetate obtained from Japanese yew