Trifluoroacetic Acid-Mediated Cleavage of a Triethylsilyl Protecting Group:  Application in the Final Step of the Semisynthetic Route to Paclitaxel (Taxol)

Singh, Ambarish K.; Weaver, Raymond E.; Powers, Gerald L.; Rosso, Victor W.; Wei, Chenkou; Lust, David A.; Kotnis, Atul S.; Comezoglu, F. T.; Liu, Mark; Bembenek, Kenneth S.; Phan, Bich D.; Vanyo, Dale; Davies, Merrill L.; Mathew, Rachel; Palaniswamy, Venkatapuram A.; Li, Wen-Sen; Gadamsetti, Kumar; Spagnuolo, Ciro J.; Winter, William J.

doi:10.1021/op020221k

Cited by 19 publications

(5 citation statements)

References 4 publications

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“…To test this hypothesis, we examined conditions to convert 1a to its corresponding β-keto ester. Among the desilylation methods attempted, we found TFA in chloroform to be the most effective (eq ), and β-keto ester 4a was isolated in 90% yield by this method. …”

Section: Resultsmentioning

confidence: 99%

Chiral 3-Acylglutaric Acid Derivatives from Strain-Induced Nucleophilic Retro-Claisen Ring-Opening Reactions

et al. 2020

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A nucleophilic retro-Claisen ring-opening of donor–acceptor cyclobutenes, formed with high stereocontrol by [3 + 1]-cycloaddition of TIPS-protected enoldiazoacetates with α-acyl sulfur ylides, has been developed. Removal of the TIPS group to form the isolable β-keto ester precedes the strain-induced ring-opening. Various amines, alcohols, thiols, and amino acid derivatives are effective nucleophiles, and their products are formed in very high yields via stoichiometric reactions. The chirality of the reactant donor–acceptor cyclobutenes is fully retained in the ring-opening reactions. The 3-acylglutaric acid products are converted to various valuable structures, including amido-diols, γ-aminobutyric acid (GABA) derivatives, and heterocycles.

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Section: Resultsmentioning

confidence: 99%

Chiral 3-Acylglutaric Acid Derivatives from Strain-Induced Nucleophilic Retro-Claisen Ring-Opening Reactions

et al. 2020

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“…Importantly, under these conditions C2‘−OTBS remains intact as confirmed by 1 H NMR analysis (see Supporting Information). Acetic acid has been shown to minimize the formation of side products when used in the synthesis of paclitaxel 1 Synthesis of a Paclitaxel Analogue Featuring a Hexaethylene Glycol Linker at the C-7 Position …”

Section: Resultsmentioning

confidence: 99%

Paclitaxel-Functionalized Gold Nanoparticles

2007

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Here we describe the first example of 2 nm gold nanoparticles (Au NPs) covalently functionalized with a chemotherapeutic drug, paclitaxel. The synthetic strategy involves the attachment of a flexible hexaethylene glycol linker at the C-7 position of paclitaxel followed by coupling of the resulting linear analogue to phenol-terminated gold nanocrystals. The reaction proceeds under mild esterification conditions and yields the product with a high molecular weight, while exhibiting an extremely low polydispersity index (1.02, relative to linear polystyrene standards). TGA analysis of the hybrid nanoparticles reveals the content of the covalently attached organic shell as nearly 67% by weight, which corresponds to approximately 70 molecules of paclitaxel per 1 nanoparticle. The presence of a paclitaxel shell with a high grafting density renders the product soluble in organic solvents and allows for detailed (1)H NMR analysis and, therefore, definitive confirmation of its chemical structure. High-resolution TEM was employed for direct visualization of the inorganic core of hybrid nanoparticles, which were found to retain their average size, shape, and high crystallinity after multiple synthetic steps and purifications. The interparticle distance substantially increases after the attachment of paclitaxel as revealed by low-magnification TEM, suggesting the presence of a larger organic shell. The method described here demonstrates that organic molecules with exceedingly complex structures can be covalently attached to gold nanocrystals in a controlled manner and fully characterized by traditional analytical techniques. In addition, this approach gives a rare opportunity to prepare hybrid particles with a well-defined amount of drug and offers a new alternative for the design of nanosized drug-delivery systems.

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“…The C‐7 epimerization can readily take place in solvent under heating, or under mildly basic conditions such as physiological pH 7, 8. It has been reported that 7‐ epi ‐paclitaxel ( 1b ) and other 7α‐hydroxyltaxanes can be detected from natural sources, in the manufacturing process for paclitaxel‐active pharmaceutical ingredients (APIs), as well as from taxane‐related metabolic samples 3, 9–11. As a common impurity and metabolite of taxane drugs, the monitoring of 1b and other 7α‐hydroxyltaxanes is important for quality control and pharmacological research of taxane drugs.…”

Section: Methodsmentioning

confidence: 99%

Stereochemical differentiation of C‐7 hydroxyltaxane isomers by electrospray ionization mass spectrometry

Zhang

et al. 2009

Rapid Comm Mass Spectrometry

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In this study, different electrospray ionization mass spectrometric (ESI-MS) methods were utilized to analyze several pairs of taxane stereoisomers including paclitaxel and 7-epi-paclitaxel. Both ESI-MS and tandem mass spectrometry (MS/MS) techniques provided stereochemically dependent mass spectra in negative-ion mode, and all studied stereoisomers could be easily distinguished based on their characteristic ions or distinct fragmentation patterns. MS/MS experiments for several taxane analogues at various collision energies were performed to elucidate potential dissociation pathways. The gas-phase deprotonation potentials were also calculated to estimate the most thermodynamically favorable deprotonation site using DFT B3LYP/6-31G(d). The results of the theoretical studies agreed well with the fragmentation patterns of paclitaxel and 7-epi-paclitaxel observed from MS/MS experiments. In addition, it was found that liquid chromatography (LC)/ESI-MS was a useful and sensitive technique for assignment of C-7 taxane stereoisomers from realistic samples.

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Trifluoroacetic Acid-Mediated Cleavage of a Triethylsilyl Protecting Group: Application in the Final Step of the Semisynthetic Route to Paclitaxel (Taxol)

Cited by 19 publications

References 4 publications

Chiral 3-Acylglutaric Acid Derivatives from Strain-Induced Nucleophilic Retro-Claisen Ring-Opening Reactions

Chiral 3-Acylglutaric Acid Derivatives from Strain-Induced Nucleophilic Retro-Claisen Ring-Opening Reactions

Paclitaxel-Functionalized Gold Nanoparticles

Stereochemical differentiation of C‐7 hydroxyltaxane isomers by electrospray ionization mass spectrometry

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