A New Deoxygenation Method for Taxanes Using Hypophosphorous Acid

An efficient and practical radical chain deoxygenation method by phosphorus centered radicals generated from hypophosphorous acid was developed in the synthesis of analogues of paclitaxel.     

A Large Scale Separation of Taxanes from the Bark Extract of Taxus yunnanesis and 1H‐ and 13C‐NMR Assignments for 7‐epi‐10‐Deacetyltaxol

A large‐scale separation of paclitaxel from semi‐purified bark extract of Taxus yunnanesis was investigated. The chromatographic behavior of paclitaxel and two dose editing analogues, cephalomannine and 7‐epi‐10‐deacetyltaxol were systematically studied on a C₁₈ bonded phase column with different mobile phase in reverse phase mode. According to the notably different selectivity of the methanol and acetonitrile with water in the mobile phase and the most important requirement of capacity in preparative chromatography, the optimum suitably mobile phase used in a large‐scale isolation of paclitaxel and 7‐epi‐10‐deacetyltaxol on a preparative C₁₈ column was given. Cephalomannine was eliminated by ozonolysis and after then separated throughout a normal phase silica column. The whole large‐scale process for high purity paclitaxel from the bark extract of Taxus yunnanesis consisted of a preliminary purification with Biotage FLASH 150i system based on a prepacked normal phase silica cartridge followed by using a C₁₈ Nova‐pak? column in Waters PrepLC? 4000 preparative HPLC system. The structure of 7‐epi‐10‐deacetyltaxol was elucidated by 2D NMR technologies of TOCSY, DQF‐COSY, HMQC and HMBC, etc.     

Biocatalytic and Regioselective Exchange of 2-O-Benzoyl for 2-O-(m-Substituted)Benzoyl Groups to Make Precursors of Next-Generation Paclitaxel Drugs

A taxane 2-O-benzoyltransferase (mTBT, derived from Accession: AF297618) biocatalyzed the dearoylation and rearoylation of next-generation taxane precursors of drugs effective against multidrug-resistant cancer cells. Various taxanes bearing an acyl, hydroxyl, or oxo group at C13 were screened to assess their turnover by mTBT catalysis. The 13-oxotaxanes were the most productive, where 2-O-debenzoylation of 13-oxobaccatin III was turned over faster compared to 13-oxo-10-O-(n-propanoyl)-10-O-deacetylbaccatin III and 13-oxo-10-O-(cyclopropane carbonyl)-10-O-deacetylbaccatin III, yielding ~20 mg of each. mTBT catalysis was likely affected by an intramolecular hydrogen bond with the C13−hydroxyl. Oxidation to the 13-oxo recovered catalysis. The experimental data for the debenzoylation reaction was supported by Gaussian-accelerated molecular dynamics simulations that evaluated the conformational changes caused by different functional groups at C13 of the substrate. These findings also helped postulate where the 2-O-benzoylation reaction occurs on the paclitaxel pathway in nature. mTBT rearoylated the debenzoylated 13-oxobaccatin III acceptors fastest with a non-natural 3-fluorobenzoyl CoA among the other aroyl CoA thioesters evaluated, yielding ~10 mg of each with excellent regioselectivity at laboratory scale. Reducing the 13-oxo group to a hydroxyl yielded key modified baccatin III precursors (~10 mg at laboratory scale) of new-generation taxoids.     

液-质联用研究红豆杉提取物中紫杉烷类化合物

建立了一套利用反相高效液相色谱和大气压化学电离质谱联用技术分析红豆杉提取物中微量紫杉烷类化合物的方法。通过研究已知的10种紫杉烷类化合物的保留时间、质谱特征，初步建立了一个紫杉烷类化合物的数据库，利用这些数据可快速鉴定红豆杉提取物中已知的紫杉烷类化合物，并能够对未知化合物做一定程度的结构分析。这种研究方法同样对其他天然产物特别是微量成分结构分析具有指导作用。     

Quantification of taxanes in a leaf and twig extract from Taxus baccata L. using 13C NMR spectroscopy

In the course of our ongoing work on the chemical characterization of Taxus baccata L. growing wild in Corsica, we have developed and validated a method for direct quantification of taxane derivatives by ¹³C NMR using 10‐deacetylbaccatin III as reference compound and 1,6‐hexanediol as internal standard. We have observed good accuracy (relative errors between 0.3% and 3.5%), linearity (R² = 0.999) and precision (reproducibility 8.5 mg ± 1.1%) of the measurements. The experimental procedure was applied to the quantification of six identified taxanes in a fraction of chromatography of a methanol extract of T. baccata leaves. This method can be applied to other compounds bearing the taxane skeleton. Copyright © 2013 John Wiley & Sons, Ltd.     

新乡红豆杉中多种紫杉烷类化合物的反相高效液相色谱分析

采用反相高效液相色谱法(RP-HPLC)研究了新乡种植红豆杉树皮中的多种紫杉烷类化合物.结果表明,新乡种植红豆杉树皮中的10-去乙酰巴卡丁Ⅲ、巴卡丁Ⅲ、7-木糖-10-去乙酰基三尖杉宁碱、7-木糖-10-去乙酰基紫杉醇、7-木糖-10-去乙酰基紫杉醇C、10-去乙酰基紫杉醇、三尖杉宁碱和紫杉醇的平均含量(质量分数,n=...     

Cascade Metathesis Reactions for the Synthesis of Taxane and Isotaxane Derivatives

Tricyclic isotaxane and taxane derivatives have been synthesized by a very efficient cascade ring‐closing dienyne metathesis (RCDEYM) reaction, which formed the A and B rings in one operation. When the alkyne is present at C13 (with no neighboring gem‐dimethyl group), the RCEDYM reaction leads to 14,15‐isotaxanes 16 a , b and 18 b with the gem‐dimethyl group on the A ring. If the alkyne is at the C11 position (and thus flanked by a gem‐dimethyl group), RCEDYM reaction only proceeds in the presence of a trisubstituted olefin at C13, which disfavors the competing diene ring‐closing metathesis reaction, to give the tricyclic core of Taxol 44 .     

Synthesis of 2‐Ene‐1,4‐diols by a New Cascade‐Opening of 1,3‐Diepoxides: Towards an Efficient Synthesis of Dihydroxytaxoid Derivatives

Taxing taxanes : A new method for the preparation of alk‐2‐ene‐1,4‐diols from 1,3‐dienes, especially for geometrical constrained derivatives, via dioxirane derivative formation followed by Ti^III‐induced oxirane ring opening, is described. The strategy has been very efficiently implemented to the construction of the 11‐ene‐10,13‐diol moiety present in taxol derivatives.