Noyori scale

The hydrogenation of a number of aromatic ketones is shown in Figure 37.30. Noyori s very effective Ru-diphosphine-diamine technology was developed by several companies. It is not clear on which scale the processes developed by Takasago (dm-binap = 3,5-xylyl-binap) [16] and Dow/Chirotech [109-111] for the reduction of substituted acetophenones are actually applied commercially. Using the Xyl-PhanePhos-dpen catalyst, a highly efficient bench-scale process was developed for the hydrogenation of p-fluoroacetophenone (ee 98%, TON 100000, TOF 50000 IT1 at r.t., 8 bar) [109]. Ru-P-Phos (licensed to Johnson Matthey [112]) achieved ee-values >99.9% and TON up to 100000 for sev-... 

The asymmetric hydrogenation of cinnamic acid derivatives has been developed by Knowles at Monsanto [4], The synthesis of L-dopa (Figure 4.3), a drug for the treatment of Parkinson s disease, has been developed and is applied on an industrial scale. Knowles received the Nobel Prize for Chemistry in 2001 together with Noyori (see below, BINAP ) and Sharpless (asymmetric epoxidation). 

The potential of a catalytic process for use on a large scale can be a good indication of its efficiency. During recent decades there has been an increasing tendency to apply asymmetric catalytic processes in industry [1], The asymmetric Noyori hydrogenation [2] and the Sharpless and Jacobsen-Katsuki epoxidation [3] are representative examples of impressive developments in this field [1]. 

One of the earliest examples of such catalysis was demonstrated in 1966 by the Japanese chemist Hitosi Nozaki, who reacted styrene and ethyl diazoacetate in the presence of a chiral Schiffbase-Cu11 complex [72-74], Although the initial enantios-electivity was modest (<10% ee), the principle was proven. Some years later, the companies Sumitomo and Merck used similar copper catalysts for asymmetric cyclopropanation on a multikilogram scale, in the production of various insecticides and antibiotics [75]. One of Nozaki s PhD students at that time was Rioji Noyori, who later developed the BINAP asymmetric hydrogenation catalysts for which he received the 2001 Nobel Prize in Chemistry [7[. 

Noyori s BINAP catalysts deserve special attention because their chirality is based on the bulkiness of the naphthalene groups, rather than on carbon or phosphorus asymmetric centers (Figure 3.28, inset) [77]. One of the many examples of asymmetric catalysis using BINAP is the synthesis of (—)-menthol, an important additive for flavors, fragrances, and pharmaceuticals. Starting from myrcene, the process is carried out by Takasago International on a multi-ton scale. The key step is the isomerization of geranyldiethylamine to (R)-citronellal enamine [78], which is then hydrolyzed to (R)-citronellal with nearly 99% ee. 

One of Noyori s most remarkable achievements is a commercial synthesis of (-)-menthol 51 used since 1983 by the Takasago International Corporation on a scale of thousands of tonnes a year. This and related processes are discussed in detail by S. Akutagawa and K. Tani in chapter 3 of Ojima s Catalytic Asymmetric Synthesis. The process is summarised here ... 

Resolutions such as this are inevitably lengthy and require numerous stages with handling and purification issues at each one. This makes them expensive to carry out on a large scale. Thus, chiral synthesis or synthesis from a homochiral (only one enantiomer) precursor are always preferable, if they can be found. It is not surprising therefore that the Nobel Prize for chemistry in 2001 was awarded to William S. Knowles, Ryoji Noyori and K. Barry Sharpless for their pioneering contributions to research on chiral catalysts which can be used to introduce chirality into a synthesis starting from achiral precursors. We saw some of the fruits of Noyori s work in the chiral synthesis of menthol described in Chapter 4. 

A pilot process was developed for an intermediate of the NMDA 2B receptor antagonist Ro 67-8867, involving the hydrogenation/dynamic kinetic resolution of a cyclic a-amino ketone using an optimized Noyori procedure with a MeO-biphep ligand (69). The Ru-catalyzed reaction was carried out on a 9-kg scale with excellent enantio- and diastereo-selectivities and very high TON and TOF. 

Ru-Cataiyzed Transfer Hydrogenation of Ketones (Merck, Lanxess). Two Ru-catalyzed transfer hydrogenations have been developed and applied on a multi-10-kg scale. Two variants are applied, one based on Ru/amino alcohol complexes with iPrOH/base and the other based on Ru/Ts-dpen complexes with HCOOH/NEta as a reducing system, respectively. Generally, good enantioselectivities have been obtained for several aryl ketones but with lower activities than for comparable hydrogenation reactions described above (see, eg, the results for 3,5-bis-trifluoromethyl-acetophenone described above (72)). Merck (77) has developed a process for the reduction of 3,5-bis-trifluoromethyl-acetophenone, and Lanxess has applied Noyori s Ru/Ts-dpen system to reduction of aryl y3-keto esters on up to a ton scale (78). 

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