Asymmetric Hydrogenations

Actually this account is the story of the genesis of an invention[1]. The inventative process is not clearly understood, but one factor that seems to be important is to have a heavy infusion of naivety. That is why so frequently it is not the experts that do the inventing, but they are the ones who, that once the lead is established, come in and exploit the area. Our work is an excellent illustration of this phenomenon. In the study of any of the life sciences, chiral compounds are important. In the past when chiral compounds were needed, chemists have had to use biochemical processes or make racemic mixtures followed by laborious resolutions. In industry the problem is particularly severe since resolution with its numerous recycle loops and fractional crystallizations, is an inherently expensive process. Thus, large volume products like monosodium L-glutamate, L-lysine and L-menthol have been made traditionally by biochemical routes even though efficient procedures are available to make their racemic forms. In the early 1960’s we became aware of this problem, when we made a paper evaluation of a monosodium glutamate process. The racemic mixture was easy to obtain, but by the time we had resolved, the projected costs doubled, even though we racemized and recycled back the unwanted D-isomer. It looked as though if one wanted to beat “the bug” it would be necessary to have a catalyst which, when an asymmetric center was formed, would direct the reaction to give a predominance of the desired isomer. For this purpose the 100% efficiency of enzymes would not be needed to have something of real value. At this point in time I was aware of the extensive studies by Akabori, starting in the mid fifties, modifying heterogeneous catalysts like Raney Ni and palladium with a chiral agent. Always the asymmetric bias was too small to be of preparative interest. All these thoughts remained fallow for several years. In the interim, I became part of a program for doing exploratory research. I was given a new Ph.D. to train for a year before going into more pressing things. Industrial labs are always wrestling with the problem of how much undirected research they should do, and this was just one of many ways to achieve this goal. I had been thru several new employees on a number of projects when I became aware of Professor Wilkinson’s discovery of chlorotris(triphenyl-phosphine) Rhodium, [RhCl(PPh3)3], and its amazing properties as a soluble hydrogenation catalyst for unhindered olefins. Homogeneous catalysts had been reported before but this was the first one that compared in rates with the well known heterogeneous counterparts.