Publication of the week, number 66, 27th February 2015

It’s not often these days that starting to read a paper makes me sit up and really want to read further. Some that have achieved this “distinction” I’ve commented on here. This week I came across another one! It’s presented by Trapp and Storch from the University of Heidelberg in Germany. It presents us with a new principle where the catalyst selectivity is controlled by temperature alone.

Up until now enantiopure and stereochemically rigid catalyst are employed for asymmetric hydrogenations. This is fine and they work well, but getting the catalyst is or can be a very difficult expensive undertaking. Also obtaining the other enantiomer can be difficult, especially when that is the one you need.

Using chiral biphenyls of binahthyls can alleviate these problems but you still have the problem of making the other enantiomer, if you need it. With the number of such catalysts growing rapidly, it seems that every journal these days has a new one, how do you get round this problem (and others)? Well Trapp has developed a new catalytic system with a tropos 2,2′-bis(diphenylphosphino)biphenyl ligand as a flexible chiral core to allow the switching of the catalyst’s enantioselectivity. Furthermore the core ligand was modified with appropriate functionality allowing attachment of a chiral auxiliary to produce a pair of diastereoisomeric compounds. Because the auxiliary is attached to the ligand core the chiral information is continuously directed to the stereochemically flexible chiral axis of the tropos biphenyl you shift the isomeric ration away from the 1:1 equlibrium. Throw in a metal and you’re set to go.

They needed a tropos biphenyl which had a high rotational barrier towards stereochemical inversion and chose the following compound:

cats01

This is 2,6′-bis(diphenylphosphino)-[1,1′-biphenyl]-3,3′-diol, (3,3′-BIPHEP-OH) and is a 1:1 mixture of interconverting axially chiral enantiomers. The chiral auxiliary was (S)-naproxen because “Enantiopure (S)-naproxen has an extended aryl moiety and a stereogenic center close to the linking carboxy group. It is readily available in large amounts, thus allowing to easily scale-up the synthesis of the targeted catalyst. This 2-aryl propionic acid can be synthesized by enantioselective hydrogenation and exhibits fascinating properties in relation to deracemization, for example, (S)-naproxen can be readily obtained in enantiomerically pure form“. So you now have the following (confirmed by x-ray):

cast002

Now you have a diastereoisomeric ratio of 61:39 (RaxSS):(SaxSS). This reflects the chirality transfer of the auxiliary to the central biphenyl core. The barrier towards epimerisation,as determined by heating the pure diastereoisomers to 70°C in chloroform, was ΔG= 110.6 kJ/mol for RaxSS         →SaxSS and 109.3 kJ/mol for the other direction. So now you throw in the metal rhodium in this case to give the following catalyst:

cats001

where the original d.r of 61:39 is retained. If you heat this to 70°C an interesting effect is observed (from the paper):

cats04

the d.r of 61:39 at 70°C changes to almost pure SaxSS and if you stop the heating and cool you can freeze the d.r at any value you wish. So there we have it a easily controllable d.r of a catalyst from pure (R) to pure (S).

So how does this perform in hydrogenation? They used (Z)-methyl-α-acetamidocinnamate and did the hydrog. to N-acetyl- phenylalanine methyl ester at temperatures between -40 to -10°C with 0.2 mol% catalyst. The pure RaxSS catgave a 96% ee of the (R) amino ester and the pure SaxSS cat. a 96% ee of the (S) amino ester: “This is a remarkable result, since diastereomeric complexes typically exhibit matched or mismatched behavior and therefore the enantioselectivity is decreased for one of the product enantiomers“.

That sample of catalyst which has been frozen at the original d.r.,  61:39, gave 71:29 (R):(S) aminoester at -10°C, and at -40°C 87:13. Various other catalyst d.rs. were studied and all produced the (S) amino esters in around 92% ee for those catalysts where the SaxSS dominated.

From the authorsIn summary, we demonstrated the first example of an easily accessible catalytic system that provides access to both enantiomers of an asymmetric hydrogenation reaction solely by changing the applied temperature. Key features are the stereo-labile tropos ligand core in combination with a remotely bound auxiliary…..We assume that the underlying fundamental principle of this concept is directly transferable to other catalsed reactions. The here presented approach allows decoupling kinetic and thermodynamic control according to the Curtin– Hammett principle of enantiomeric catalysts“.

Well I am not a catalyst expert but this seems to me to be a wonderful result. Simply by heating your catalyst and then rapid cooling you switch the enantio direction of hydrogenation is certainly a lot easier than synthesising both enantiomers of a chiral biphenyl system. With the multitude of such tropos catalysts around this must find lots of other applications.

A tremendous piece of work here and the authors must be commended for having the idea, carrying it through and demonstrating its effectiveness. Let’s hope this is picked up by everyone and widely used.

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Prof. dangerdackel (199 Posts)


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