Figure 11
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Regarding asymmetric ketone hydrogenation, the technology in-licensed from the JST is a valuable method for producing chiral
alcohols on an industrial scale. These catalyst systems were originally based on the BINAP ligand with an extremely expensive
non-C2 symmetric diamine, DAIPEN (1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine). As there are several patents covering
the use of ruthenium-BINAP complexes, especially for the more relevant precatalysts employing Xyl-and Tolyl-BINAP ligands,
our strategy was to develop novel systems, leading to the development of the HexaPHEMP RuCl2 Diamine and the PhanePhos RuCl2 Diamine systems, both of which are highly active and selective catalysts. Both systems use readily available and relatively
inexpensive diamines, and are an alternative to BINAP-based systems. The PhanePhos precatalyst systems have been used to manufacture
many 1-phenylethanols on multi-100 kg scales. For example, 4'-fluoroacetophenone is hydrogenated at a molar substrate-to-catalyst
ratio of 100,000/1, equivalent to a weight/weight ratio of 13,000/1 (or 1 kg of catalyst for 13 metric tons of product) (see
Figure 11) (21). To achieve the high substrate-to-catalyst ratios, the substrate was purified using short-path distillation.
A further distillation of the product afforded pure material and completely removed the catalyst complex.
The number of large-scale applications for the in-licensed JST technology necessitated the ability to manufacture the precatalysts
efficiently. We originally prepared these complexes using the procedures of Noyori (22), whereby the ligand was reacted with
an [(arene)RuCl2]2 species in dimethylformamide at 100 °C, followed by treatment with a suitable diamine, typically DPEN (1,2-diphenylethanediamine),
DACH (1,2-diaminocyclohexane) or DAIPEN to provide the desired product. When this methodology was applied for the larger scale
manufacture of these catalyst systems, significant byproduct formation and yields lower than desired for precatalyst manufacture
were observed.
Figure 12
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As these complexes contain valuable chiral phosphines, chiral diamines, and metal precursors, we sought a more efficient synthetic
method. Quite surprisingly, we found that an isolated [diphosphine(arene)RuCl]Cl complex could be reacted with a diamine at
moderate temperatures in ethereal solvents, routinely leading to >95% yield of the desired complexes in excellent purity (see
Figure 12) (23).
Figure 13
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Although the JST technology works well with aryl ketones or enones, it is of little utility for the asymmetric hydrogenation
of alkyl-alkyl systems. Professor Reetz recently published an asymmetric transfer hydrogenation (ATH) catalyst that gives
excellent results for a range of alkyl-alkyl ketones, thus making these alcohols more readily available (24). The catalyst
consists of a xanthyl-based chiral diphosphonite and a [RuCl2(p-cymene)] complex. Dowpharma recently obtained a license to this technology for the manufacture of chiral alcohols using
ATH, which complements the JST technology (see Figure 13).
Conclusions
Asymmetric hydrogenation is a fully accepted method for the manufacture of a wide range of chiral compounds in the pharmaceutical,
agrochemical, fragrance, and fine-chemical industries. The design of an effective catalyst system relies on manufacturing
metal precatalysts and ligands.With effective design, a range of catalytic systems and substrates may be developed to allow
for the systematic use of chiral catalytic technology.
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