science

Holton Taxol total synthesis

Holton Taxol 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 Holton Taxol total synthesis rather than just read about it. In short: The Holton Taxol total synthesis, published by Robert A. Holton and his group at Florida State University in 1994, was the first total synthesis of Taxol (generic name: paclitaxel).

Key takeaways

Holton Taxol total synthesis belongs to science; place it in that map before memorising details.
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Connect Holton Taxol total synthesis to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of Holton Taxol total synthesis from memory before moving on to harder problems.

Reference excerpt

The Holton Taxol total synthesis, published by Robert A. Holton and his group at Florida State University in 1994, was the first total synthesis of Taxol (generic name: paclitaxel). The Holton Taxol total synthesis is a good example of a linear synthesis. The synthesis starts from patchoulene oxide, a commercially available natural compound . This epoxide can be obtained in two steps from the terpene patchoulol and also from borneol. The reaction sequence is also enantioselective, synthesizing (+)-Taxol from (−)-patchoulene oxide or (−)-Taxol from (−)-borneol with a reported specific rotation of +- 47° (c=0.19 / MeOH). The Holton sequence to Taxol is relatively short compared to that of the other groups (46 linear steps from patchoulene oxide). One of the reasons is that patchoulene oxide already contains 15 of the 20 carbon atoms required for the Taxol ABCD ring framework. Other raw materials required for this synthesis include 4-pentenal, m-chloroperoxybenzoic acid, methyl magnesium bromide and phosgene. Two key chemical transformations in this sequence are a Chan rearrangement and a sulfonyloxaziridine enolate oxidation.

Retrosynthesis It was envisaged that Taxol (51) could be accessed through tail addition of the Ojima lactam 48 to alcohol 47. Of the four rings of Taxol, the D ring was formed last, the result of a simple intramolecular SN2 reaction of hydroxytosylate 38, which could be synthesized from hydroxyketone 27. Formation of the six-membered C ring took place through a Dieckmann condensation of lactone 23, which could be obtained through a Chan rearrangement of carbonate ester 15. Substrate 15 could be derived from ketone 6, which, after several oxidations and rearrangements, could be furnished from commercially available patchoulene oxide 1.

AB ring synthesis As shown in Scheme 1, the first steps in the synthesis created the bicyclo[5.3.1]undecane AB ring system of Taxol. Reaction of epoxide 1 with tert-butyllithium removed the acidic α-epoxide proton, leading to an elimination reaction and simultaneous ring-opening of the epoxide to give allylic alcohol 2. The allylic alcohol was epoxidized to epoxyalcohol 3 using tert-butyl hydroperoxide and titanium(IV)tetraisopropoxide. In the subsequent reaction, the Lewis acid boron trifluoride catalyzed the ring opening of the epoxide followed by skeletal rearrangement and an elimination reaction to give unsaturated diol 4. The newly created hydroxyl group was protected as the triethylsilyl ether (5). A tandem epoxidation with meta-chloroperbenzoic acid and Lewis acid-catalyzed Grob fragmentation gave ketone 6, which was then protected as the tert-butyldimethylsilyl ether 7 in 94% yield over three steps.

C ring preparation As shown in Scheme 2, the next phase involved addition of the carbon atoms required for the formation of the C ring. Ketone 7 was treated with magnesium bromide diisopropylamide and underwent an aldol reaction with 4-pentenal (8) to give β-hydroxyketone 9. The hydroxyl group was protected as the asymmetric carbonate ester (10). Oxidation of the enolate of ketone 10 with (-)-camphorsulfonyl oxaziridine (11) gave α-hydroxyketone 12. Reduction of the ketone group with 20 equivalents of sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al) gave triol 13, which was immediately converted to carbonate 14 by treatment with phosgene. Swern oxidation of alcohol 14 gave ketone 15. The next step set the final carbon-carbon bond between the B and C rings. This was achieved through a Chan rearrangement of 15 using lithium tetramethylpiperidide to give α-hydroxylactone 16 in 90% yield. The hydroxyl group was reductively removed using samarium(II) iodide to give an enol, and chromatography of this enol on silica gel gave the separable diastereomers cis 17c (77%) and trans 17t (15%), which could be recycled to 17c through treatment with potassium tert-butoxide. Treatment of pure 17c with lithium tetramethylpiperidide and (±)-camphorsulfonyl oxaziridine gave separable α-hydroxyketones 18c (88%) and 18t (8%) in addition to some recovered starting material (3%). Reduction of pure ketone 18c using Red-Al followed by basic work-up resulted in epimerization to give the required trans-fused diol 19 in 88% yield.

C ring synthesis As shown in Scheme 3, diol 19 was protected with phosgene as a carbonate ester (20). The terminal alkene group of 20 was next converted to a methyl ester using ozonolysis followed by oxidation with potassium permanganate and esterification with diazomethane. Ring expansion to give the cyclohexane C ring 24 was achieved using a Dieckman condensation of lactone 23 with lithium diisopropylamide as a base at -78 °C. Decarboxylation of 24 required protection of the hydroxyl group as the 2-methoxy-2-propyl (MOP) ether (25). With the protecting group in place, decarboxylation was effected with potassium thiophenolate in dimethylformamide to give protected hydroxy ketone 26. In the next two steps the MOP protecting group was removed under acidic conditions, and alcohol 27 was reprotected as the more robust benzyloxymethyl ether 28. The ketone was converted to the trimethylsilyl enol ether 29, which was subsequently oxidized in a Rubottom oxidation using m-chloroperbezoic acid to give the trimethylsilyl protected acyloin 30. At this stage the final missing carbon atom in the Taxol ring framework was introduced in a Grignard reaction of ketone 30 using a 10-fold excess of methylmagnesium bromide to give tertiary alcohol 31. Treatment of this tertiary alcohol with the Burgess reagent (32) gave exocyclic alkene 33.

… excerpt ends here. Continue reading the full article.

Illustrations

Worked examples

Example 1 — a first encounter with Holton Taxol total synthesis

Start with the simplest possible case. Write down what Holton Taxol 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 Holton Taxol 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 Holton Taxol 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 Holton Taxol total synthesis

In research: Holton Taxol 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 Holton Taxol 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: Holton Taxol 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 Holton Taxol 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 Holton Taxol total synthesis in 20 minutes

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Frequently asked questions

What is Holton Taxol total synthesis in simple terms?

The Holton Taxol total synthesis, published by Robert A. Holton and his group at Florida State University in 1994, was the first total synthesis of Taxol (generic name: paclitaxel).

Why does Holton Taxol 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 Holton Taxol 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 Holton Taxol total synthesis.