Acetamido asymmetric hydrogenation

Table 1 Asymmetric hydrogenation of (Z)-2-(acetamido) cinnamic acid, 2-(acetamido) acrylic acid and their methyl esters...

ASYMMETRIC HYDROGENATION OF ETHYL 4-ACETAMIDO-3-OXO-5-PHENYL-4-PENTENOATE... 

Applications. In the last decade a lot of research has been devoted to the development of catalytic routes to a series of asymmetric carboxylic acids that lack the acetamido ligand as additional functionality. In Figure 4.17 four are listed, which are important as anaesthetics for rheumatic diseases. Their sales in beat many bulk chemicals the turnover of Naproxen (retail) in 1990 was 700 million for 1000 tons. S-Naproxen is now being produced by Syntcx via resolution with a chiral auxiliary. The main patents from Syntex expired in the U.S. in 1993, the reason for a lot of activity to study alternative synthetic routes. Routes leading to an asymmetric centre are o asymmetric hydrogenation of an unsaturated acid, o asymmetric carbohydroxylation of a styrene precursor, o asymmetric hydroformylation of a styrene precursor and oxidation. 

In asymmetric hydrogenation of olefins, the overwhelming majority of the papers and patents deal with hydrogenation of enamides or other appropriately substituted prochiral olefins. The reason is very simple hydrogenation of olefins with no coordination ability other than provided by the C=C double bond, usually gives racemic products. This is a common observation both in non-aqueous and aqueous systems. The most frequently used substrates are shown in Scheme 3.6. These are the same compounds which are used for similar studies in organic solvents salts and esters of Z-a-acetamido-cinnamic, a-acetamidoacrylic and itaconic (methylenesuccinic) acids, and related prochiral substrates. The free acids and the methyl esters usually show appreciable solubility in water only at higher temperatures, while in most cases the alkali metal salts are well soluble. 

Table 2.1 Asymmetric hydrogenation of dimethyl itaconate (A) and methyl (Z)-ot-acetamido cinnamate (B)...

Asymmetric hydrogenation of dimethyl itaconate and methyl (Z)-a-acetamido cinnamate with in situ formed rhodium(I)-diphosphinite catalyst system gave the desired products with high activity and enantioselectivity (Table 2.1). The asymmetric hydrogenation may be applied to a wide range of substrates. 

FIGURE 14.6 Comparison of hydrogenation rates in the asymmetric hydrogenation of Z-ethyl 3-/V-acetamido-crotonate. 

Fig. 3 Conversion curves for the asymmetric hydrogenation of Z-methyl-a-acetamido-cinnamate for the different catalyst generations...

Recently, Reek et al. published the synthesis of a 9H,9 H- [4,4 ]bicarbazole-3,3r-diol (BICOL)-based chiral monodentate phosphoramidite ligand, which was functionalized with two different third-generation carbosilane dendritic wedges (Fig. 26) [57]. As reference reaction in the catalytic study, the rhodium-catalyzed asymmetric hydrogenation of Z-methyl-a-acetamido-cinnamate was chosen. Using a ligand-to-rhodium ratio of 2.2 led to enantio-selectivities which were comparable to the results obtained using the parent BINOL-derived monodentate phosphoramidite MonoPhos. 

The catalyst precursor complex [ Rh(COD) Diop] BF4 has been used for the screening of five substrates containing prochiral C=C double bond (COD = 1,5-cyclooctadiene) [266]. These were methylacetamidoacrylate (SI), Z-a-methylacetamidocinnamate (S2), dimethylitaconate (S3), methone (S4) and rac-a-pinene (S5) (see Figure 4.56). Activated C=C bonds such as those in the two acetamido derivatives were more reactive. The most reactive molecule is the less sterically hindered substrate methylacetamidoacrylate. Reaction was less pronounced for unsubstituted and sterically hindered substrates such as methone. The reduction of C=0 bond in a-pinene is more difficult. These results are in agreement with the general trends reported for asymmetric hydrogenations. 

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). 

Figure 9.3 Catalytic cycles for the asymmetric hydrogenation of a-acetamido methyl acrylate (or cinamate). For clarity the detailed structure of the organic substrate is not shown. In 9.21 and 9.22 for ease of identification the carbon atom to which the metal hydride is transferred is marked by an arrow and the hydride is circled. Note that, excepting the chelating chiral phosphine, the stereochemistries around the rhodium in the left- and right-hand cycles have mirror-image relationships.

What metal and ligand combinations are used for the asymmetric hydrogenation of (a) imines, (b) ketones, (c) alkenes with an a-acetamido group What is the combination for cyclopropanation ... 

What are the similarities and differences in the behavior of a-acetamido-cinamic acid and allyl amine as ligands in asymmetric hydrogenation and isomerization reactions, respectively ... 

Table 1 The Rh(/ -SpirOP) -catalyzed asymmetric hydrogenation of (Z)-2-acetamido-3-arylacrylic acids ...

The enantioselectivities of Rh(f -SpirOP) " in the asymmetric hydrogenation of the methyl esters of (Z)-2-acetamido-3-arylacr-ylic acids were also found to be very high (Table 2). 

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