science

Paclitaxel total synthesis

Paclitaxel total synthesis is a science topic covered in the lgStudy science library. This page brings together a partial reference excerpt, illustrations, worked examples, real-world applications and a short study plan, so you can understand Paclitaxel total synthesis rather than just read about it. In short: Paclitaxel total synthesis in organic chemistry is a major ongoing research effort in the total synthesis of paclitaxel (Taxol). This diterpenoid is an important drug in the treatment of cancer but, also expensive because the compound is harvested from a scarce resource, namely the Pacific yew (Taxus brevifolia).

Key takeaways

Paclitaxel total synthesis belongs to science; place it in that map before memorising details.
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Reproduce the core statement of Paclitaxel total synthesis from memory before moving on to harder problems.

Reference excerpt

Paclitaxel total synthesis in organic chemistry is a major ongoing research effort in the total synthesis of paclitaxel (Taxol). This diterpenoid is an important drug in the treatment of cancer but, also expensive because the compound is harvested from a scarce resource, namely the Pacific yew (Taxus brevifolia). Not only is the synthetic reproduction of the compound itself of great commercial and scientific importance, but it also opens the way to paclitaxel derivatives not found in nature but with greater potential. The paclitaxel molecule consists of a tetracyclic core called baccatin III and an amide tail. The core rings are conveniently called (from left to right) ring A (a cyclohexene), ring B (a cyclooctane), ring C (a cyclohexane) and ring D (an oxetane). The paclitaxel drug development process took over 40 years. The anti-tumor activity of a bark extract of the Pacific yew tree was discovered in 1963 as a follow-up of a US government plant screening program already in existence 20 years before that. The active substance responsible for the anti-tumor activity was discovered in 1969 and structure elucidation was completed in 1971. Robert A. Holton of Florida State University succeeded in the total synthesis of paclitaxel in 1994, a project that he had started in 1982. In 1988 Jean-Noël Denis had also developed a semisynthetic route to paclitaxel starting from 10-deacetylbaccatin III. This compound is a biosynthetic precursor and is found in larger quantities than paclitaxel itself in Taxus baccata (the European yew). In 1990 Bristol-Myers Squibb bought a licence to the patent for this process which in the years to follow earned Florida State University and Holton (with a 40% take) over 200 million US dollars.

Total synthesis

The total synthesis of taxol is called one of the most hotly contested of the 1990s with around 30 competing research groups by 1992. The number of research groups actually having reported a total synthesis currently stands at 11 with the Holton group (article first accepted for publication) and the Nicolaou group (article first published) first and second in what is called a photo finish. Some of the efforts are truly synthetic but in others a precursor molecule found in nature is included. The key data are collected below. What all strategies have in common is synthesis of the baccatin molecule followed by last stage addition of the tail, a process (except for one) based on the Ojima lactam.

Holton Taxol total synthesis - year: 1994 - precursor: Patchoulol strategy: linear synthesis AB then C then D - references: see related article Nicolaou Taxol total synthesis - year: 1994 - precursor: Mucic acid strategy: convergent synthesis A and C merge to ABC then D - references: see related article Danishefsky Taxol total synthesis - year: 1996 - precursor: Wieland-Miescher ketone strategy: convergent synthesis C merges with D then with A merges to ABCD - references: See related article Wender Taxol total synthesis - year: 1997 - precursor: Pinene strategy: linear synthesis AB then C then D - references: Kuwajima Taxol total synthesis I. Kuwajima, - year: 1998 - precursor: synthetic building blocks strategy: linear synthesis A then B then C then D Mukaiyama Taxol total synthesis - year: 1998 - Precursor: L-serine strategy: linear synthesis B, then C, then A then D. References: see related article. Takahashi Taxol total synthesis - year: 2006 - Precursor: geraniol strategy: convergent synthesis A and C merge to ABC then D Sato-Chida Taxol total synthesis - year: 2015, formal synthesis to a Takahashi intermediate Nakada Taxol total synthesis - year: 2015, formal synthesis to a Takahashi intermediate Baran Taxol total synthesis - year: 2020, total synthesis via a two-phase divergent synthetic approach. Li Taxol total synthesis - year: 2021, total synthesis via B ring closure by forming C1–C2 bond. Ongoing research efforts are directed at the synthesis of taxadiene and taxadienone intermediates. The synthesis of related taxanes decinnamoyltaxinine E and taxabaccatin III has been reported

Semisynthesis The commercial semisynthesis (by Bristol-Myers Squibb) of paclitaxel starting from 10-deacetylbaccatin III (isolated from the European yew) is based on tail addition of the so-called Ojima lactam to its free hydroxyl group:

Another commercial semisynthesis (by the company Natural Pharmaceuticals) relies on the isolation of a group of paclitaxel derivatives isolated from primary ornamental taxanes. These derivatives have the same skeleton as paclitaxel except for the organic residue R of the terminal tail amide group which can be phenyl, or propyl or pentyl (among others) whereas in paclitaxel it is an explicit phenyl group. The semisynthesis consists of conversion of the amide group to an amine with Schwartz's reagent through an imine followed by acidic workup and a benzoylation.

In the production process Michigan grown yews which mature in 8 years are periodically topped and dried. This material is shipped to Mexico for a first extraction step (10% paclitaxel content) and then to Canada for further purification to 95% purity. The semisynthesis to final product takes place in China.

Biosynthesis

The biosynthetic pathway to paclitaxel has been investigated and consists of approximately 20 enzymatic steps. The complete scheme is still unavailable. The segments that are known are very different from the synthetic pathways tried thus far (Scheme 1). The starting compound is geranylgeranyl diphosphate 2 which is a dimer of geraniol 1. This compound already contains all the required 20 carbon atoms for the paclitaxel skeleton. More ring closing through intermediate 3 (taxadiene) leads to taxusin 4. The two main reasons why this type of synthesis is not feasible in the laboratory is that nature does a much better job controlling stereochemistry and a much better job activating a hydrocarbon skeleton with oxygen substituents for which cytochrome P450 is responsible in some of the oxygenations. Intermediate 5 is called 10-deacetylbaccatin III. A biochemical kilogram-scale production of taxadiene was reported using genetically engineered E. coli in 2011.

References and notes

External links Paclitaxel Total Syntheses @ SynArchive.com Taxolog for Taxol research, founded by Holto The complete Taxol story from Chemical & Engineering News: Article Extensive Florida State University article Story of taxol total synthesis

Illustrations

Worked examples

Example 1 — a first encounter with Paclitaxel total synthesis

Start with the simplest possible case. Write down what Paclitaxel total synthesis claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In science, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Paclitaxel total synthesis before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Paclitaxel total synthesis ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Paclitaxel total synthesis

In research: Paclitaxel total synthesis appears in science research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Paclitaxel total synthesis in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Paclitaxel total synthesis is common in secondary-school and first-year university syllabi. It links to neighbouring topics Taxanes, Total synthesis, so understanding it makes those chapters shorter.
In everyday life: Look for Paclitaxel total synthesis outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

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How to study Paclitaxel total synthesis in 20 minutes

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Close the page and write down what Paclitaxel total synthesis means in your own words.
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Frequently asked questions

What is Paclitaxel total synthesis in simple terms?

Why does Paclitaxel total synthesis matter?

Because it connects several science ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Paclitaxel total synthesis?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on Paclitaxel total synthesis.