Commercial Enantioselective Hydrogenation

Since the commercial applications of enantiomer-selective hydrogenations are at only the beginning of their career, the state-of-the-art, industrial realizations and most recent development work are complied in Section 3.3.1 (H.-U. Blaser, B. Pugin, F. Spindler). 

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The enantioselective hydrogenation of a,p-unsaturated acids or esters, using 5wt% Pt/Al203 or Pd/Al203 commercial catalysts doped with cinchonidine (CD), was deeply investigated to evidence the specific activity of Pd or Pt and the role of the reaction parameters and solvent polarity. Finally, the steric and electronic effects of different substituent groups were also studied. 

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... 

In a related report, ruthenium-catalyzed enantioselective hydrogenation of 3-keto esters was utilized to prepare the crucial alcohol intermediate 36 (Scheme 14.16). The required (3-keto ester 49 was readily prepared from commercial thiophene carboxylic acid 40. Hydrogenation of 49 then led to the desired (S)-alcohol 50 in quantitative yield and 90% enantiomeric excess, catalyzed by a chiral diphosphine-ruthenium complex generated in situ. Catalyst-substrate ratios used were as low as 1/20,000, rendering this approach amenable to industrial application. Alcohol 50 was then converted to known intermediate 36 in three steps and 60% overall yield. 

Similar equipment for applications on the laboratory scale has been reported (and has recently been commercialized) (69-72). Most of the reported applications had the aim of investigating kinetics of chemical reactions as indicated by changes in liquid-phase concentrations. The equipment can typically be used at elevated temperatures and pressures. Applications to heterogeneous catalytic reactions include investigations of the enantioselective hydrogenation of exocyclic a,p-unsaturated ketones catalyzed by Pd/C in the presence of (A)-proline (73) and the esterification of hexanoic acid with octanol catalyzed by a solid acid (the resin Nafion on silica) (74). 

As a rule, synthetic chemists will consider only those new reactions and catalysts for preparative purposes where the enantioselectivity reaches a certain degree (e.g. >80%) and where both the catalyst and the technology are readily available. For heterogeneous catalysts this is not always the case because the relevant catalyst parameters are often unknown. It is therefore of interest that two types of modified Nickel catalysts are now commercially available a Raney nickel/tartrate/NaBr from Degussa [64] and a nickel powder/tartrate/NaBr from Heraeus [65, 66]. It was also demonstrated that commercial Pt catalysts are suitable for the enantioselective hydrogenation of a-ketoesters [30, 31]. With some catalytic experience, both systems are quite easy to handle and give reproducible results. 

We have identified reaction conditions where intrinsic kinetics can be obtained for the very fast enantioselective hydrogenation of ethyl pyruvate using a commercially available Pt/Al203 powder catalyst, modified with dihydrocinchonidine. We conclude that this is in pan due to i) the egg-shell structure of the catalyst, ii) the high turbulence achieved in the reactor and iii) the density and/or the viscosity of the solvent used. In solvents like ethyl pyruvate, liquid-solid transpon problems can arise. 

Asymmetric catalysis allows chemicals to be manufactured in their enantiomer-ically pure form and reduces derivatisation and multiple purification steps that would otherwise be required. The 2001 Nobel Prize was awarded for two of the most important asymmetric reactions hydrogenations and oxidations. A variety of ligands suitable for asymmetric reductions are available commercially including BINAP, Figure 3.16. A BINAP Rh complex is used in the commercial production of 1-menthol to enantioselectively hydrogenate an alkene bond (Lancaster, 2002). Ru BINAP complexes can be used in asymmetric reductions of carbonyl groups (Noyori, 2005 Noyori and Hashiguchi, 1997). 

As an aside, decades of work have gone into the study of enantioselective homogeneous hydrogenation processes in both organic and aqueous systems. There is increasing commercial interest in this field spurred by the spectacular, time-encrusted development of a complex catalyst for the enantioselective hydrogenation of an imine to a chiral amine needed for manufacture of the important herbicide, (,S )-Metolaclor. The technical success of this program (Scheme l)25 owed much to the perserverance... 

The first transition metal catalysis using BINAP-ruthenium complex in homogeneous phase for enantioselective hydrogenation of P-ketoesters was developed by Noyori and co-workers [31]. Genet and co-workers described a general synthesis of chiral diphosphine ruthenium(II) catalysts from commercially available (COD)Ru(2-methylallyl)2 [32]. These complexes preformed or prepared in situ have been found to be very efficient homogeneous catalysts for asymmetric hydrogenation of various substrates such as P-ketoesters at atmospheric pressure and at room temperature [33]. 

In addition to the enantioselective preparation of 1,3-dithiane 1 -oxides, our group has been concerned with the development of novel methods for the catalytic asymmetric oxidation of other prochiral sulfides our currently preferred system employs an enantiomerically pure sulfonylimine and commercially available hydrogen peroxide.70... 

Another example of how catalysis plays a key role in enabling our lives is in the synthesis of pharmaceuticals. Knowles s development, at Monsanto in the early 1970s, of the enantioselective hydrogenation of the enamide precursor to L-DOPA (used to treat Parkinson s disease), using a Rh-chiral phosphine catalyst (Section 3.5), led to a share in the Nobel prize. His colaureates, Noyori and Sharpless, have done much to inspire new methods in chiral synthesis based on metal catalysis. Indeed, the dramatic rise in the demand for chiral pharmaceutical products also fuelled an intense interest in alternative methodologies, which led to a new one-pot, enzymatic route to L-DOPA, using a tyrosine phenol lyase, that has been commercialized by Ajinomoto. 

Form Supplied in colorless oil commercially available. Analysis of Reagent Purity optical rotation NMR spectroscopy. Preparative Methods the preparation of (5, 5)-ethyl-DuPHOS is based on (3R,61 )-octane-3,6-diol as an enantiomerically pure starting compound. The latter is synthesized by a three-step procedure starting from methyl 3-oxopentanoate, which is transformed to methyl (l )-3-hydroxypentanoate (99% ee) by enantioselective hydrogenation with a Ru-(R)-BINAP catalyst, followed by hydrolysis to the hydroxy acid. The subsequent electrochemical Kolbe coupling reaction leads to (3R,6R)-octane-3,6-diol in a protocol that can be scaled up to multigram quantities (eq 1). ... 

FIGURE 10.12 Nitrogen adsorption isotherms and corresponding pore size distributions of a typical FSP-derived powder and the commercial reference catalyst E4759. Note that the particles of the flame-made catalyst are virtually nonporous. The indicated macropores originate from interstitial voids of the agglomerated particles. (From Strobel, R., Stark, W.J., Madler, L., Pratsinis, S.E., and Baiker, A., Flame-made platinum/alumma structural properties and catalytic behaviour in enantioselective hydrogenation, J. Catal., 213, 296, 2003.)... 

Although more limited in scope than the BINAP-Ru( II)-catalysed hydrogenations, rhodium-catalysed hydrogenations are of enormous commercial importance because of the demand for both natural and unnatural amino acids on a vast scale. It is even economical for the more expensive of the natural amino acids to be made synthetically rather than isolated from natural sources—phenylalanine, for example, of industrial importance as a component of the artihcial sweetener aspartame, is manufactured by enantioselective hydrogenation. 

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