Mechanism of Asymmetric Hydrogenation

Reaction 9.1 has been extensively studied to establish the mechanism of asymmetric hydrogenation. The catalytic cycle proposed for the asymmetric hydrogenation of the methyl ester of a-acetamido cinamic acid with 9.14 as the precatalyst is shown in Fig. 9.3. As mentioned earlier, this reaction is one of the early examples of industrial applications of asymmetric catalysis for the manufacture of L-DOPA (see Table 1.1). 

Oxidative addition of dihydrogen to 9.19 and 9.20 produces the intermediates 9.21 and 9.22, respectively. Insertion of the alkene into the Rh-H bonds produces diastereomers 9.23 and 9.24. It is important to note that the coordination site vacated by the hydride ligand, circled for easy identification, is taken up by the O atom of the carbonyl functionality of the acetamido group, and a solvent molecule occupies the original position of the O atom. 

This has the important effect of fixing the opposite of the initial chirality of the prochiral carbon. In other words Re and Si faces bonded to Rh generate S or R chirality, respectively. This is shown schematically in Fig. 9.4. The detailed 

The overall enantioselectivity of the catalytic process obviously depends on the relative speed with which the left and right catalytic cycles of Fig. 9.3 operate. Oxidative addition of dihydrogen is found to be the rate-determining step. Therefore, the relative rates of conversion of 9.19 to 9.21 on the one hand and 9.20 to 9.22 on the other determine which enantiomer of the organic product would be formed preferentially. The reaction between 9.28 and a-acetamido methyl cinamate has been monitored by multinuclear NMR, and both 9.19 and 9.20 have been identified. Depending on the stereochemistry of the chiral phosphine, one of these two diastereomers is preferentially formed. 

NMR data indicate the ratio of the concentrations of the major and the minor isomer to be approximately 10 1. Since the concentration of one of the isomers is almost ten times the other, if the rate constants for oxidative additions of dihydrogen are approximately the same, the major diastereomer should undergo conversion to the dihydride ten times faster. This, however, is not the mechanism for enantioselection. The mechanism of enantioselection is the much larger rate constant (—600 times) for the reaction between the minor isomer and dihydrogen  

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For the mechanism of asymmetric hydrogenation, see Halpem, J. Asymmetric Catalytic Hydrogenation Mechanism and Origin of Enantioselection in Morri-sion, J. D. ed. Asymmetric Synthesis, Academic Press, New York, 1985, vol. 5. 

Figure 22-3 Mechanism of asymmetric hydrogenation of methyl (Z)-a-acetamidocinna-mate using rhodium complexes with chiral diphosphine ligands. The minor complex diastereomer leads to the major (R) product, while the dominant complex in solution leads to the minor (S) isomer. See also C. R. Landis et oL, J. Am. Chem. Soc. 1993,115, 4040.

A number of groups have shown interest in the mechanism of asymmetric hydrogenation, principally of (a)-Z-acetamidocinnamic add and its derivatives. Kagan and co-workers have shown that cis addition of deuterium occurs to the Z isomer. Rhodium complexes of DIOP were used here. Koenig and Knowles obtained similar results with the ligands DIPAMP, cyclohexyl(o-... 

Kitamura, M., Tsukamoto, M., Bessho, Y., Yoshimura, M., Kobs, LI., Widhaim, M., Noyori, R. Mechanism of asymmetric hydrogenation of a-(acylamino)acrylic esters catalyzed by BINAP-ruthenium(ll) diacetate. J. Am. Chem. Soc. 2002, 124, 6649-6667. 

Early supports were designed so that the support had no influence on the catalysts activity. An optically active support, designed to interact with the catalyst and improve its performance, has now been synthesized and used in asymmetric hydrogenations. The influence of the support on the catalyst was surprisingly low. This result can be interpreted in terms of the mechanism of asymmetric hydrogenation. 

The mechanism of asymmetric hydrogenation of dehydroaminoacids has been studied by a combination of kinetic and spectroscopic methods, mainly by Halpern et al. [38] and Brown et al. [39]. It was proved that the substrate bound by both the double bond and the amide group. It was surprising to see that the major diastereomeric rhodium-alkene complex detected in solution was the less reactive one towards hydrogen. This showed the inaccuracy of previous models of the lock and key type between the prochiral double bond and the chiral... 

When our studies commenced it had been assumed that the mechanism of asymmetric hydrogenation by chelating rhodium phosphine complexes followed a similar pathway. It has been demonstrated, however, that the timing is quite different, and that oxidative addition of hydrogen to metal does not occur in the initial stages of reaction. This conclusion follows from studies on the phosphorus-31 NMR spectra of hydrogenated complex solutions made separately by Halpern,... 

Space constraints do not allow description of all the imaginative efforts to prepare, characterize, immobilize, and recover water-soluble transitional metal-phosphine complexes as hydrogenation catalysts. Further examples can be found in [11] and in [7[. For the mechanism of asymmetric hydrogenation of alkenes and that of the hydrogenation of aldeyhydes, see Section 6.2.3. 

Scheme 7.14. Mechanism of asymmetric hydrogenation of iV-acetyl dehydrophenylalanine [111].

More recently Noyori developed asymmetric hydrogenation of simple ketones with BlNAP/diamine-ruthenium complexes.In this system the catalytic process contrasted with the conventional mechanism of asymmetric hydrogenation of unsaturated bonds which requires metal-substrate 7t-complexation. In fact with BlNAP/diamine-ruthenium neither the ketone substrate nor the alcohol product interacted with the metallic centre during the catalytic cycle. The enantiofaces of the prochiral ketones were differentiated on the molecular surface of the coordinatively saturated RuH intermediate. 

Yasumori, L, Inoue, Y., and Okabe, K. (1975) Mechanism of asymmetric hydrogenation on nickel surface coordinated with an... 

Klabunovskii, E.l., Petrov, Yu.l. (1967) On mechanism of asymmetric hydrogenation, Dokl. Acad. NaukSSSR. 173, 1125-1128, Chem. Abstr. 67, 81620k (1967). 

It is probably true to say that more is known about the mechanism of asymmetric hydrogenation than any other process in homogeneous catalysis. This is partly because the complexity of the reaction and its... 

However, based on structural, NMR, and kinetic studies, Halpern found that at room temperature the ratio of diastereoisomeric olefin-phosphine complexes does not influence the optical yield of the product. Formation of an excess of one of the enantiomeric reaction products depends on the rate of hydrogenation of olefin-phosphine complexes A and B. The rate of reaction of isomer A, which occurs in the reaction mixture in a considerably lesser amount, is so great that the main product is formed from this isomer. The mechanism of asymmetric hydrogenation of (Z)-PhCH = C(NHAc)COOEt may be represented by scheme (13.49). 

Sandoval, CA., Ohkuma, T., Muniz, K., and Noyori, R. (2003) Mechanism of asymmetric hydrogenation of ketones catalyzed hy BlNAP/l,2-diamine-mthenium(ll) complexes. J. Am. Chem. Soc., 125, 13490-13503. 

Brown, J. M. Chaloner, P. A. Mechanism of asymmetric hydrogenation catalysed by rhodium(I) DIOP complexes. /. Chem. Soc., Chem. Commun. 1978,321-322. 

Gridnev, I. D. Liu, Y. Imamoto, T. Mechanism of asymmetric hydrogenation of P-dehydroamino acids catalyzed by rhodium complexes Large-scale experimental and computational study. ACS Catal. 2014,4,203-219. 

Gridnev, I. D. Fan G. Pringle, P. G. New insights into the mechanism of asymmetric hydrogenation catalysed by monophosphonite-rhodium complexes. Chem. Commun. 2007, 43, 1319-1321. 

Vaclavik, Sot, P Vilhanova, B. PechiJek, Kuzma, M. Kacer, P. Practical aspects and mechanism of asymmetric hydrogenation with chiral halfsandwich complexes. Molecules 2013,18,6804—6828. 

Scheme 1.12 Preparation of (-)-(Ipc)2BCl and mechanism of asymmetric hydrogenation...

Brown, J. M., and P. A. Chaloner The Mechanism of Asymmetric Hydrogenation Catalyzed by Rhodium(I) DIPAMP-Complexes. Tetrahedron Letters 1978, 1877. 

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