WHAT'S HOT IN... CHEMISTRY , May/June 2008

Nature uses enzymes to catalyze the myriad of chemical reactions in living things. On the other hand, the chemical industry relies mainly on metal-based catalysts to make reactions go at profitable rates. Research chemists, who up to now have generally used similar metal-based catalysts, have now discovered organocatalysts which are more like those of Nature, and which are proving to be just as interesting as the enzyme and the metal-based ones. Their proponents praise them as being non-toxic, highly efficient, and delivering specific products in terms of their stereo selectivity.

Last summer Science Watch reported the work of Steve Ley and his group at the Department of Chemistry at the University of Cambridge (18[4]: 7, July/August 2007). They used modified proline catalysts to obtain remarkable yields of specific products. Now another paper on the subject is in the Hot Ten with an equally dramatic story to tell.

Paper #7 is particularly noteworthy and is the work of a team headed by Dieter Enders of the Institute of Organic Chemistry at the Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Germany. It reports an organocatalyst which directs a complex reaction involving three reactants and does so to produce a product with four stereo centers. The reactants were a linear aldehyde, a nitroalkene, and an a,ß-unsaturated aldehyde, and the organocatalyst was a simple chiral secondary amine trimethylsilyl diphenylprolinol.

A toluene solution of the reactants in approximately equal molar amounts, plus the catalyst, were mixed at 0° C and then allowed to reach room temperature and left for 24 hours or until complete conversion of the starting materials had been achieved, this being monitored by gas chromatography. The reaction yield was in some cases as high as 70% with one diastereomer predominating. In one instance the product was characterized by X-ray structure analysis.

The chirality of the product depends on the chirality of the catalyst. The sequence of reactions was deduced to be aldehyde + nitroalkane, the product of which then combined with the product of a reaction between the a,ß-unsaturated aldehyde and the prolinol catalyst. Finally there was a ring-closure, followed by a catalyzed step involving water, which produced the product and regenerated the catalyst. Although the intermediate compound in the first step of this triple cascade could be identified, the subsequent steps were too rapid for those intermediates to be detected by gas chromatography. The final product of the cascade is also an a,ß -unsaturated aldehyde but it is too sterically hindered to react further.

Extensions of the domino reaction have also been published by Enders’ group in Angew. Chem. Int. Ed., (D. Enders, et al., 46[3]; 467-9, 2007). This reported a one-pot asymmetric synthesis of tri-cyclic carbon skeletons via a triple cascade/Diels-Alder sequence. In another paper he describes the use of chiral N-heterocyclic carbenes as organocatalysts (D. Enders, et al., Chem. Rev., 107[12]: 5606-55, 2007).

Speaking to Science Watch, Enders was upbeat about the future of organocatalysis: "By mimicking Nature it may well be that even more sophisticated cascade reactions can be developed. Currently we are trying the next step towards an asymmetric organocatalytic quadruple cascade." His optimism seems justified as this area of research moves rapidly ahead.

Earlier this year a paper by Tadashi Ema et al., of the Chemistry and Biochemistry Department of Okayama University, Japan, revealed an organocatalyst with three functional centers which could mimic the active site of the enzyme serine hydrolases and showed 3.7 million-fold acceleration of the acyl transfer of vinyl trifluoroacetate to alcohol (Chem. Commun., [8]: 957-9, 2008).

The catalyst itself has a nucleophilic OH group, a pyridine component, and a urea section. Without any of these three sections the catalyst molecule was inactive for this type or reaction in which one ester side chain in a molecule is exchanged for another. The reactivity of the hydroxyl group in the catalyst is boosted by being next to the pyridine moiety and this starts the attack on the ester group in vinyl trifluoroacetate. The urea part of the catalyst serves to stabilise the reaction intermediate by hydrogen bonding.

No doubt this paper will be making the Hot Ten sometime soon. Watch this space!

Dr. John Emsley is based at the Department of Chemistry, Cambridge University, U.K.

Keywords: organocatalysts, stereo selectivity, Dieter Enders, catalysts, chirality, hydrogen bonding