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The synthesis of taxifolin

Dear Reader,

Well back to the synthesis of taxifolin, the last time I blogged I showed how we could disconnect the taxifolin back to an epoxide. Now this time I will show you how we can make the epoxide.

As is common with α,β-unsaturated carbonyl compounds we can treat a chalcone with alkaline hydrogen peroxide to form our epoxide. This is a funny reaction where the hydrogen peroxide is deprotonated to form a nucleophilic anion. The anion then attacks the alkene part of the α,β-unsaturated carbonyl compound to form a carbon oxygen bond and an enolate. The enolate then turns around and forms the second carbon oxygen bond and then kicks out a hydroxide anion as the leaving group.

Formation of an epoxide from hydrogen peroxide and chalcone

The only problem with such chemistry is that alkaline water would react with the phenol groups which are all over the benzene rings. Our solution is to use a protecting group, the idea of a protecting group is to mask off the reactivity of part of a molecule while we get to work on another part of the molecule. It may be best to think of it as a molecular sized dustsheet which we use while painting our house to avoid getting paint on the floor and the furniture.

In this case the methoxymethyl group has been chosen as a protecting group, this is a smart choice. The group is stable against bases but it is taken off with ease by acids. In the step after the epoxide formation we need to use acid to deprotect the phenol groups and make one of them react with the epoxide to form a six membered ring. So we can combine the deprotection step with one of the steps which we need to do anyway to get the molecule made.

As with many things the mechanism helps us understand what is going on, my advice to you is when in doubt is to just experiment with curved arrows to see where they get you. We can protonate the oxygen next to the benzene ring.

Protonation of MOM ether

Then get the cation to spit out a molecule of formaldehyde and form an oxygen ylide (thing with a cation (+) on the heteroatom next to a anionic (-) centre) using the top magenta arrows.

Two fragmentation reactions for the protonated MOM ether

Frankly I think that this would be a very high energy product so we should keep looking for a lower energy, an easy alternative I see is to form a methyl(methylene)oxonium ion and a molecule of the phenol. The methyl(methylene)oxonium is a very stable carbocation where the positive charge is delocalised from the carbocation onto the near by oxygen. This is a good example of neighbouring group participation (NGP) which lowers the energy of the cation. This lowering of the cation’s energy makes it more easy to remove the protecting group.

Now after the MOM groups are gone we are free to use one of the phenols to attack the protonated epoxide to form the ring. Now some of you might ask why does the methanol solvent not attack the epoxide instead, my answer is that while the methanol might attack the protonated epoxide the intramolecular (within the molecule) reaction of the phenol group is faster as the nucelophile (phenol group) is held close to the epoxide (electrophile). Thus the reaction goes faster.

Some of you might also wonder what happens to the methyl(methylene)oxonium, I think that it will react with methanol to form dimethoxymethane.

I think that the smartest of you will either ask how do we get the chalcone or you will be thinking about aldol chemistry. I think that the name “aldol” is a very good name, while many chemists want to give a reaction a name (based on their surname) the aldol reaction is based on the products of the reaction. It is possible to react an aldehyde with another aldehyde in the aldol reaction to form an aldehyde alcohol. We have a choice we could use a MOM protected dihydroxybenzaldehyde (cheap) with a MOM protected 2,4,6-trihydroxyacetophenone (cheap) to form the chalcone in an aldol reaction or we could use wittig chemistry.

Here is the first step of the aldol reaction between acetopheone and benzaldehyde which forms the carbon carbon bond.

The first step of the aldol reaction synthesis of a chalcone

The next step is a dehydration reaction, this will be favoured by the fact that the new double bond will be conjugated to a benzene ring. The first step is a deprotonation which will form an enolate anion which will then eject a hydroxyl group. While a hydroxyl group is not a good leaving group it is better than nothing and it will work.

Second step in the formation of chalcone by an aldol reaction

If we were to obtain 2-bromo-1-(2,4,6-trihydroxyphenyl)ethanone and react this with triphenyl phosphine we could make a phosphonium salt (expensive). If treated with a suitable base this would make a phosphorus ylide which can be reacted with the MOM protected dihydroxybenzaldehyde to form the same chalcone. This would be a more expensive reaction, the product would also be mixed with lots of triphenyl phosphine oxide which would force us to do a more difficult separation to obtain the product than the separation required in the aldol synthesis of the chalcone.

While the wittig reaction does have the problem of the triphenyl phosphine oxide I found an easy solution when I was working in Aberdeen for John Plater. I used to run large scale wittig reactions as a means of making polypyridines with alkyl spacers between the pyridine rings. I then used hydrogenation to convert the alkenes into saturated alkyl spacers. For example I needed 3-(pyridin-4-yl)-acrylaldehyde as an intermediate in one synthesis. I recall the day that I started with half a bottle of aqeuous chloroacetaldehyde this was mixed with a large volume of chloroform and subject to fractional distillation using a very long fractionation column to remove the water from this mixture. After what seemed like all day distilling out water, I added an excess of of triphenyl phosphine and gave the mixture a boil.

After boiling the mixture for a while I cooled it and isolated the phosphonium salt. After the treatment with base I then had the phosphorus ylide. I then heated the 2-(triphenylphosphoranylidene)acetaldehyde with isonicotinaldehyde and I boiled in under nitrogen in benzene. After cooling I had a mixture of 3-(pyridin-4-yl)-acrylaldehyde, isonicotinaldehyde, triphenyl phosphine oxide, benzene and goodness knows what else. This was a horrid mixture but I had a very easy solution, I made a solution of hydrochloric acid in some water and then I shaked the horrid mixture with the hydrochloric acid. This extracted the pyridines into the aqueous layer while leaving the triphenyl phosphine oxide in the benzene layer. In one simple shaking I had separated the carcinogenic benzene and the irksome triphenyl phosphine oxide from the product. I then made the aqueous solution alkaline with sodium hydroxide and then I extracted the product into ethyl acetate. I was then able to evaporate down the ethyl acetate to give a mixture of 3-(pyridin-4-yl)-acrylaldehyde, isonicotinaldehyde and tar which I was able to vacuum distill to give me the product I wanted.

Sadly in many cases (including the synthesis of the MOM protected chalcone) it is not possible to use a acid/base separation of the triphenyl phosphine oxide from the product.


5 Responses

  1. Dr. Foreman,

    Your mechanism regarding the formation of methyl(methylene)oxonium during the deprotection of MOM ether interests me. I have also seen this oxonium in other deprotection mechanisms of MOM when using Lewis Acids as an initiator.

    I am just curious how reliable this is. Do you recall any other examples showing the formation of these types of oxoniums?


    • Dear Ryan,

      If you were to use a hard (HSAB) lewis acid such as AlCl3 or TiCl4 then it would bind the same way to the aryl alkyl ether oxygen as the proton did. You can think of a proton as a superhard lewis acid.

      If you consider the alkylation of benzene with 2-methylpropene (isobutene) then a proton reacts with the alkene to form the carbocation which then does a Friedel-Crafts on the benzene. The proton is clearly acting as a lewis acid.

      I suspect that with the right metal compound you could have a metal catalysed FC reaction of alkenes with aromatic rings. If one of my readers can find such a reaction in the literature. Then tell me and you will get an honourable mention.

      Best wishes


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  3. Taxifolin: Manufacturing, properties, application areas

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