science

Oseltamivir total synthesis

Oseltamivir 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 Oseltamivir total synthesis rather than just read about it. In short: Oseltamivir total synthesis concerns the total synthesis of the anti-influenza drug oseltamivir marketed by Hoffmann-La Roche under the trade name Tamiflu. Its commercial production starts from the biomolecule shikimic acid harvested from Chinese star anise and from recombinant E. coli.

Key takeaways

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Reference excerpt

Oseltamivir total synthesis concerns the total synthesis of the anti-influenza drug oseltamivir marketed by Hoffmann-La Roche under the trade name Tamiflu. Its commercial production starts from the biomolecule shikimic acid harvested from Chinese star anise and from recombinant E. coli. Control of stereochemistry is important: the molecule has three stereocenters and the sought-after isomer is only 1 of 8 stereoisomers.

Commercial production The current production method is based on the first scalable synthesis developed by Gilead Sciences starting from naturally occurring quinic acid or shikimic acid. Due to lower yields and the extra steps required (because of the additional dehydration), the quinic acid route was dropped in favour of the one based on shikimic acid, which received further improvements by Hoffmann-La Roche. The current industrial synthesis is summarised below:

Karpf / Trussardi synthesis The current production method includes two reaction steps with potentially hazardous azides. A reported azide-free Roche synthesis of tamiflu is summarised graphically below:

The synthesis commences from naturally available (−)-shikimic acid. The 3,4-pentylidene acetal mesylate is prepared in three steps: esterification with ethanol and thionyl chloride; ketalization with p-toluenesulfonic acid and 3-pentanone; and mesylation with triethylamine and methanesulfonyl chloride. Reductive opening of the ketal under modified Hunter conditions in dichloromethane yields an inseparable mixture of isomeric mesylates. The corresponding epoxide is formed under basic conditions with potassium bicarbonate. Using the inexpensive Lewis acid magnesium bromide diethyl etherate (commonly prepared fresh by the addition of magnesium turnings to 1,2-dibromoethane in benzene:diethyl ether), the epoxide is opened with allyl amine to yield the corresponding 1,2-amino alcohol. The water-immiscible solvents methyl tert-butyl ether and acetonitrile are used to simplify the workup procedure, which involved stirring with 1 M aqueous ammonium sulfate. Reduction on palladium, promoted by ethanolamine, followed by acidic workup yielded the deprotected 1,2-aminoalcohol. The aminoalcohol was converted directly to the corresponding allyl-diamine in an interesting cascade sequence that commences with the unselective imination of benzaldehyde with azeotropic water removal in methyl tert-butyl ether. Mesylation, followed by removal of the solid byproduct triethylamine hydrochloride, results in an intermediate that was poised to undergo aziridination upon transimination with another equivalent of allylamine. With the librated methanesulfonic acid, the aziridine opens cleanly to yield a diamine that immediately undergoes a second transimination. Acidic hydrolysis then removed the imine. Selective acylation with acetic anhydride (under buffered conditions, the 5-amino group is protonated owing to a considerable difference in pKa, 4.2 vs 7.9, preventing acetylation) yields the desired N-acetylated product in crystalline form upon extractive workup. Finally, deallylation as above, yielded the freebase of oseltamivir, which was converted to the desired oseltamivir phosphate by treatment with phosphoric acid. The final product is obtained in high purity (99.7%) and an overall yield of 17-22% from (−)-shikimic acid. It is noted that the synthesis avoids the use of potentially explosive azide reagents and intermediates; however, the synthesis actually used by Roche uses azides. Roche has other routes to oseltamivir that do not involve the use of (−)-shikimic acid as a chiral pool starting material, such as a Diels-Alder route involving furan and ethyl acrylate or an isophthalic acid route, which involves catalytic hydrogenation and enzymatic desymmetrization.

Corey synthesis In 2006 the group of E.J. Corey published a novel route bypassing shikimic acid starting from butadiene and acrylic acid. The inventors chose not to patent this procedure which is described below.

Butadiene 1 reacts in an asymmetric Diels-Alder reaction with the esterification product of acrylic acid and 2,2,2-trifluoroethanol 2 catalysed by the CBS catalyst. The ester 3 is converted into an amide in 4 by reaction with ammonia and the next step to lactam 5 is an iodolactamization with iodine initiated by trimethylsilyl triflate. The amide group is fitted with a BOC protecting group by reaction with Boc anhydride in 6 and the iodine substituent is removed in an elimination reaction with DBU to the alkene 7. Bromine is introduced in 8 by an allylic bromination with NBS and the amide group is cleaved with ethanol and caesium carbonate accompanied by elimination of bromide to the diene ethyl ester 9. The newly formed double bond is functionalized with N-bromoacetamide 10 catalyzed with tin(IV) bromide with complete control of stereochemistry. In the next step the bromine atom in 11 is displaced by the nitrogen atom in the amide group with the strong base KHMDS to the aziridine 12 which in turn is opened by reaction with 3-pentanol 13 to the ether 14. In the final step the BOC group is removed with phosphoric acid and the oseltamivir phosphate 15 is formed.

Shibasaki synthesis Also in 2006 the group of Masakatsu Shibasaki of the University of Tokyo published a synthesis again bypassing shikimic acid.

… excerpt ends here. Continue reading the full article.

Illustrations

Worked examples

Example 1 — a first encounter with Oseltamivir total synthesis

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

In research: Oseltamivir 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 Oseltamivir 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: Oseltamivir total synthesis is common in secondary-school and first-year university syllabi. It links to neighbouring topics Neuraminidase inhibitors, Total synthesis, so understanding it makes those chapters shorter.
In everyday life: Look for Oseltamivir 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 Oseltamivir total synthesis in 20 minutes

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Frequently asked questions

What is Oseltamivir total synthesis in simple terms?

Why does Oseltamivir 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 Oseltamivir 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 Oseltamivir total synthesis.