The synthesis of oseltamivir

Our second example of the use of chemistry to save lives is more recent. Several times in the last century major epidemics of influenza have caused deaths, sometimes running into mil lions. Virologists tell us that a global influenza pandemic is a constant danger, and a number of times in recent years highly aggressive forms of the flu virus have found their way from other animals (often poultry or pigs) into the human population. Fortunately, at the time of writing, none has caused more than a few thousand deaths, the most serious being the swine flu pandemic of 2009–10, which claimed the lives of 18,000 people, many of them in Mexico.

To put this in context, the 1918 fl u epidemic, which was caused by the same strain (H1N1) of virus, killed 50–100 million, 3% of the world’s population at the time. Vaccination can prevent the spread of flu, but influenza vaccines are slow to produce and difficult to generalize because of the rate of mutation of the virus. So the first line of defence is a class of antiviral compounds known as neuraminidase inhibitors. Neuraminidase is an enzyme used by the flu virus that targets human cell-surface carbohydrates containing neuraminic acids and allows the virus to release itself from the host cell. Inhibition of this enzyme prevents the new virus particles from spreading. The drug oseltamivir (Tamifl u), developed by the companies Gilead and Roche, is a neu raminidase inhibitor. Like the HIV proteases described above, it has enough structural similarity with the enzyme’s substrate to bind to the enzyme, but once bound it blocks the enzyme’s activity. No-one knows how much oseltamivir might be needed if ever a flu pan demic took hold, but clearly the safest course of action is to stockpile the compound in readiness for such an event. The fi rst manufacturing route to oseltamivir made use of the natural product (–)-quinic acid as a naturally derived starting material. Quinic acid is found in coffee beans, but is not available in sufficient quantities for widespread use.

A preferable starting material, and the one that for several years now has been used as the source of the commercial drug, is (–)-shikimic acid. Shikimic acid is the plant metabolite that provides the biochemical precursor to the aromatic amino acids such as phenylalanine, tyrosine, and tryptophan. It is abundant in the spice star anise, grown in China, which can yield 3–7% of shikimic acid. The similarity of both quinic and shikimic acid with the target drug is obvious; what is perhaps remarkable is just how many steps it takes to get from one to the other. The majority of these steps are concerned with the introduction of the two amino substituents with inversion of stereochemistry at the coloured stereogenic centres. Chiral pool syntheses often have to take long convoluted routes to correct relatively minor ‘errors’ of structure and stereochemistry. Here this is simply the price we have to pay for a starting material that has the valuable qualities of enantiomeric purity and the right hydrocarbon skeleton. Oseltamivir is an ethyl ester, and esterification comes fi rst, followed by selective protection of the cis diol (the cis-6,5-ring system is more stable than the alternative trans) and conversion of the remaining hydroxyl group to a methanesulfonate leaving group.

The dioxolane, which is crystalline and easily purified, is then exchanged for the acetal derived from pentan-3-one, ready for a reduction to the rather challenging hindered ether (direct alkylation with a hindered alkyl halide would struggle to avoid competing E2 elimination).

The reduction of the acetal is catalysed by a Lewis acid and goes via an oxonium ion, which collects hydride from the mild reducing agent triethylsilane. Silanes react only with cationic electrophiles. The oxonium ion could open either way, but this one is less hindered and possibly allows the titanium some favourable interaction with the mesylate substituent.

As often in the synthesis of 1,2-difunctionalized compounds, an epoxide is a key intermediate, and in this case an epoxide forms by closure of the newly revealed hydroxyl group onto the mesylate leaving group in base.

Two amino groups now need introducing with rather specific stereoselectivity, and the next key intermediate is an aziridine, the nitrogen analogue of an epoxide. Azide is not completely regioselective in opening this epoxide, but both regioisomers are formed with complete inversion of configuration. Azides may be reduced to amines with triphenylphosphine in what is known as the Staudinger reaction. The probable mechanism involves attack of triphenylphosphine on the azide and formation of a phosphinimine via a four-membered intermediate—notice the similarity with the Wittig reaction!

The phosphinimine, in the presence of water, hydrolyses to an amine—overall a molecule of nitrogen is lost and a molecule of water is ‘dismembered’ and shared between the reagents.

When the azide has an adjacent hydroxyl group, something more interesting happens: the phosphinimine intermediate in the reaction is intercepted by the alcohol, which turns itself into a leaving group. Extrusion of the stable phosphine oxide gives an aziridine, with inversion of stereochemistry as the nitrogen displaces the leaving group. Here is the result with the major azide from the oseltamivir synthesis:

In this case, it doesn’t matter which azide you start with: triphenylphosphine converts them both to the same aziridine. Like epoxides, aziridines open with nucleophiles under acid catalysis, and azide is used again to put in the second amino group by attack at the less hindered end of the aziridine. To get the right amino group acetylated, the amide is formed before the azide is reduced, this time with tributylphosphine. The drug is formulated as a stable phosphate salt by treatment with phosphoric acid.

This is not, by any stretch of the imagination, an efficient synthesis, not least because there are two uses of potentially explosive azides, and large amounts of waste are produced from the phosphine steps. However, for several years it was the best route available, and Roche operated it as a manufacturing process on a tonne scale. In the last few years, however, several modifi cations have been published, and among the most efficient of the alternatives was one devised in 2006 by the Nobel prize-winning chemist E. J. Corey. Corey’s route built on the fact that oseltamivir is a cyclohexene.

Corey’s research group combined the two very cheap reagents butadiene and trifluoroethyl acrylate in the fi rst step of their alternative synthesis: the cycloadduct already has the scaffold of oseltamivir. Not starting with a natural product has its advantages and disadvantages: no longer is supply limited by the world production of coffee beans or star anise, and no longer is there a need to make do with a compound of the wrong relative stereochemistry, wasting valuable resources inverting stereogenic centres in the course of the synthesis. However, as you know from Chapter 41, making an enantiomerically pure compound like oseltamivir must involve a natural compound somewhere along the line. Diels–Alder reactions are catalysed by Lewis acids, and so by using a catalytic amount of the chiral Lewis acid (whose structure is evidently based on that of the CBS catalyst) it was possible to induce the cycloaddition to proceed enantioselectively. The product of the Diels–Alder reaction has the ester substituent in place, and the stereo chemistry at the single chiral centre has to be used to control stereochemistry at new centres in the molecule. in this case the use of a tethered nucleophile allowed the fi rst amino group to be introduced with the correct stereochemistry. Conversion of the ester to an amide followed by treatment with iodine induced in the nitrogen equivalent of an iodolactonization (an iodolactamization), placing the nitrogen syn to the ester and the iodide trans.

The next key intermediate is a diene, which is reached by an overall oxidation of the iodide: protection of nitrogen and elimination of the iodide gives the only possible alkene. Radical bromination with NBS followed by treatment with base in ethanol both hydrolyses the lac tam and eliminates bromide to give the diene.

Now for the second nitrogen substituent. Bromination of the less electron deficient end of the diene with N-bromoacetamide in the presence of SnBr4 leads to an intermediate bromonium ion which is opened by the acetamide by-product at the more reactive end adjacent to the alkene, giving a trans diaxial product.

Treatment with base leads to cyclization to an aziridine, and this time the ether is introduced by a copper-catalysed ring opening of the aziridine with 3-pentanol. Treatment with phosphoric acid removes the Boc protecting group and converts the product to oseltamivir phosphate.

Overall, Corey’s route uses just 12 steps, and gives a yield of 30%—about double that of the route from shikimic acid. But much work remains to be done: several of the steps require

conditions or solvents (such as carbon tetrachloride) that are unsuitable for industrial use. Advances are still being made, with even shorter routes being reported since 2006. In some ways it would be best if this vital work were never made necessary, but across the world chemists are working in similar ways to relieve suffering, and potential suffering, caused by illness and disease.

اخر الاخبار

اخبار العتبة العباسية المقدسة

المجمع العلمي: نحو 300 ألف مستفيد من مشروع القراءة الصحيحة في كربلاء وباقي المحافظات

صحفيون: استحداث المركز الإعلامي لزيارة الأربعين أسهم في تسهيل عمل الإعلاميين وتوفير بيئة مهنية لإنجاز مهماتهم

موكب عميد بني هاشم (عليه السلام) يقدم 4500 وجبة طعام يوميًّا لزائري الأربعين

بمشاركة زائري الأربعين.. إقامة صلاة الجماعة عند مرقد أبي الفضل العباس (عليه السلام)

المزيد

الآخبار الصحية

حجم جزء محدد من الجسم يعكس الصحة العامة ومخاطر الأمراض

تفشي عدوى بكتيرية بفرنسا يحتمل ارتباطها بنوع من الجبن الطري

دراسة حديثة تكشف ما تفعله الشاشات بـ"قلوب الأطفال" !

متلازمة المبنى المريض.. هكذا يتحول تكييف الهواء إلى خطر صحي ؟؟

المزيد

الآخبار التكنلوجية

كيف تتعامل مع حرارة الطقس أثناء القيادة؟

لماذا يجب عليك إيقاف تكييف السيارة قبل إطفاء المحرك؟

دراسة تكشف سببا محتملا وراء زيادة خطر إصابة الأطفال بالتوحد

تشيلي.. العثور على متحجرة حيوان ثديي صغير من زمن الديناصورات

المزيد

مواضيع ذات صلة

The future of organic chemistry

The synthesis of indinavir

Chemistry vs viruses

Terpenes are volatile constituents of plants

Aromatic polyketides

Fatty acids and other polyketides are made from acetyl CoA

Benzyl isoquinoline alkaloids are made from tyrosine

Pyrrolidine alkaloids are made from the amino acid ornithine

Alkaloids are made by amino acid metabolism

The shikimic acid pathway

Phosphoenolpyruvate

Nature’s enolate equivalents: lysine enamines and coenzyme A