Asymmetric hydrogenations with Knowles’ catalyst

Asymmetric hydrogenation with Knowles catalyst, [Rh-DIPAMP-COD]BF4 has been used on a large scale to prepare L-dopa. The general method has been taken and applied to a wide variety of unnatural amino acids that are required by the pharmaceutical industry as starting materials for complex drug candidates. The scope and limitations of the catalytic method are well understood which means that the approach can be applied with confidence to a wide variety of substrates. 

One of the success stories of transition metal catalysis is the rhodium-complex-catalyzed hydrogenation reaction. Asymmetric hydrogenation with a rhodium catalyst has been commercialized for the production of L-Dopa, and in 2001 the inventor, Knowles, together with Noyori and Sharpless, was awarded the Nobel Prize in chemistry. After the initial invention, (enantioselective) hydrogenation has been subject to intensive investigations (27). In general, hydrogenation reactions proceed... 

HORNER - KNOWLES - KAGAN Asymmetric Hydrogenation Enantnselective hydrogenation of prochirai olefins with chiral Rh catalysts... 

Following Wilkinson s discovery of [RhCl(PPh3)3] as an homogeneous hydrogenation catalyst for unhindered alkenes [14b, 35], and the development of methods to prepare chiral phosphines by Mislow [36] and Horner [37], Knowles [38] and Horner [15, 39] each showed that, with the use of optically active tertiary phosphines as ligands in complexes of rhodium, the enantioselective asymmetric hydrogenation of prochiral C=C double bonds is possible (Scheme 1.8). 

A classical example is the development of soluble chiral catalysts for homogenous asymmetric hydrogenation. The story began with the discovery of Wilkinson s catalyst [4]. In 1968, Horner [5] and Knowles [6], independently, reported the feasibility of asymmetric hydrogenations in the presence of optically active Wilkinson-type catalyst. Although the optical yields were rather low, further studies in this direction were the basis of the success of Monsanto s asymmetric synthesis of the anti-Parkinson s drug L-DOPA. The key steps of the synthesis are outlined in Scheme 11.1. 

The mechanism for the asymmetric hydrogenation of enamides by Knowles catalyst is well understood due to the work of Halpern (Fig. 5) [20], The intermediates were identified by spectroscopy. The surprising finding was that two catalytic cycles were possible. The one that contains the lower concentrations of intermediates gives rise to the major product isomer as the reaction rates are faster compared with the cycle that has more detectable intermediates. 

Perhaps the most famous example of the use of asymmetric hydrogenation at scale for the product of an unnatural amino acid is the Monsanto synthesis of L-dopa, a drug used for the treatment of Parkinson s disease (Scheme 9.19). " The methodology with the Knowles catalyst system has been extended to a number of other unnatural amino acids. ... 

One of the first asymmetric catalysts to be successfully employed for asymmetric synthesis was the rhodium complex of (12.372a), due to Knowles [12,56], This ligand, which contains two asymmetric P atoms, was used in the Monsanto process for the production of L-amino acids by asymmetric hydrogenation of acylamino-acrylic acids. Only the L isomer, namely L-dopa is effective in the treatment of Parkinson s disease, and the synthesis of this compound by the route (12.374) represents an early commercial success [48]. The synthesis of L-dopa in yields of up to 95% optical purity can also be secured with the rhodium complex of (12.372b), the asymmetry of the catalyst in this case arising from the C atoms. 

Some of the earliest mechanistic studies on homogeneous catalysis in organic solvents were reported by Halpem on the hydrogenation of olefins with Wilkmson s catalyst and on the mechanism of the asymmetric hydrogenation of dehydroamino acids by Knowles rhodium-DIPAMP system. Two important general conclusions were drawn from these stud-igg 19,20,66-69 gg noted in Chapter 14, the species in a catalytic system that accumulate in sufficient concentration to be identified spectroscopically may or may not lie directly on the catalytic cycle. In some cases, these species are connected to the catalytic cycle by equilibria, while in other cases they are unproductive species formed irreversibly. By associating particular complexes with the kinetic behavior of the catalytic reaction, one can assess whether the observed complex contributes positively or negatively to the rate of the catalytic process. 

In Section 15.9, we saw that sodium borohydride and lithium aluminum hydride reduce ketones to alcohols. The reactions are regiospecific, but they are not stereospecific. However, the Noyori asymmetric hydrogenation of ketones uses chiral ruthenium catalysts for the stereospecific hydrogenation of ketones. Ryoji Noyori shared the Nobel Prize in Chemistry in 2001 with William S. Knowles for the study of asymmetric hydrogenation. 

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