This research is supported by a Marie Curie Action

This research is supported by a Marie Curie Action
This research has received funding from the People Programme (Marie Curie Actions) of the EU (FP7/2007-2013) under REA grant agreement nº PIEF-GA-2013-622413

Tuesday, 1 September 2015

Asymmetric catalysis: how it all started? 3 key experiments.

It is difficult to establish exactly when a new research area is born. Mainly due to the fact that scientific knowledge is generated continuously over the years since a scientist (or group of scientists) achieves a major breakthrough.
However, probably, we can agree that the asymmetric catalysis area was born in 1966. Of course, during the 1950s the introduction of X-Ray crystallography, which was used to determine the absolute configuration of an organic compound by Johannes Bijvoet in 1951 and the contribution of Klem and Reed who first reported the use of chirally-modified silica gel for chiral HPLC chromatographic separation are considered crucial for the analysis of chiral compounds and the further development of asymmetric catalysis during the 60s.
Independently, three different organic chemists, William S. Knowles (USA), Ryōji Noyori (Japan) and K. Barry Sharpless (USA) were the pioneers in the asymmetric catalysis area. For their contributions to this research area they received the 2001 Nobel Prize in Chemistry.

William S. Knowles: "I suspect that no invention has ever been made without some fortuitous help".
Knowles and Noyori started working with the development of asymmetric hydrogenation, which they developed independently in 1968.
Basically, Knowles strategy consisted of replacing the achiral triphenylphosphine ligands in Wilkinson's catalyst ([RhCl(PPh3)3], used as a soluble hydrogenation catalyst for unhindered olefins) with chiral phosphine ligands. This chiral catalyst was employed in a hydrogenation reaction of α-phenylacrylic acid giving the final product with a modest 15% enantiomeric excess (ee).

This modest result was of no preparative value at that time. However, it established for the first time that by using a chiral catalyst the reaction course could be controlled to give an asymmetric bias on the final product. Further development of the chiral catalyst let control the enantioselectivity of the reaction efficiently. Knowles was also the first to apply asymmetric catalysis to industrial-scale synthesis; while working for the Monsanto Company and he developed an enantioselective hydrogenation step for the production of L-DOPA. This molecule is a precursor to neurotransmitters, e.g. dopamine, noradrenaline, and epadrenaline. As a drug, it is used in the clinical treatment of Parkinson's disease.
Ryōji Noyori: "Our ability to devise straightforward and practical chemical syntheses is indispensable to the survival of our species."
Noyori conceived a copper complex using a chiral Schiff base ligand, which he used for the metal-carbenoid cyclopropanation of styrene. Noyori's results for the enantiomeric excess for this first-generation ligand were disappointingly low: 6% ee. However, he continued developing this research that eventually led to the development of the Noyori asymmetric hydrogenation reaction.
Noyori also developed an asymmetric catalysis process at industrial scale in collaboration between Nagoya University and Takasago International Co. for the production of (-)-menthol.

K. Barry Sharpless: "...when I started doing chemistry I did it the way I fished – for the excitement, the discovery, the adventure, for going after the most elusive catch imaginable in uncharted seas".
Sharpless complemented these reduction reactions by developing a range of asymmetric oxidations (the so-called Sharpless epoxidation, Sharpless asymmetric dihydroxylation, and Sharpless oxyamination during the 1970s to 1980's.

Note: Part of the contents of this post has been extracted from Knowles, Noyori, and Sharpless Nobel Laurate Lectures. References below:

Angew. Chem. Int. Ed. 2002, 41, 1998.
Angew. Chem. Int. Ed. 2002, 41, 2008.
Angew. Chem. Int. Ed. 2002, 41, 2024.

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