Ethyl methoxyacetate

Kim et al. have developed a practical procedure for the DKR of primary amines illustrated by substrate 56c (Scheme 2.28). They employed a supported palladium nanocatalyst as the racemization catalyst and commercially available CALB as the enantioselective catalyst for acylation of the amine using ethyl methoxyacetate as the acyl donor. High yields and enantiomeric excesses were achieved [30]. 

The last two catalytic systems available are intimately based on the stoichiometric ligands 22 and 23, derived from the dipeptide and the chiral phosphoric acid, respectively. The addition of basic additives to slow down or suppress the background reaction allowed the use of catalytic amounts of the ligand. In his initial report, Shi and coworkers have shown that adding 1 equivalent of ethyl methoxyacetate allowed the catalyst loading to be decreased to 0.25 equiv (equation 96) . Under these conditions, the enantioselectivities are similar to those reported in Figure 7. 

Figure 57 Some of the biocatalytic steps using lipase developed at BASF Lipase-catalyzed kinetic resolution of a) phenyl ethanol 18 using succinic anhydride, b) Secondary amine 120 using ethyl methoxyacetate as acyl...

Note that in step 4 ethyl methoxyacetate is included as a reagent in the tree diagram because it is part of the balanced chemical equation leading to the desired amide product. 

Ethyl methoxyacetate yields a fast reactimi rate in lipase-catalyzed aminolysis... 

In 2007, Kim et al. reported the direct DKR of primary amines using a recyclable palladium nanocatalyst combined with a lipase in the presence of ethyl acetate or ethyl methoxyacetate as the acyl donor. As shown in Scheme 4.52, a series of primary amines and one amino acid amide were efficiently resolved with good yields and high enantioselectivities. The catalyst, Pd/A10(OH), was prepared as palladium nanoparticles entrapped in aluminium hydroxide. Because this catalyst was highly thermostable, the DKR reactions could be operated at 100°C with multiple recycling of the catalyst. 

Ethyl methoxyacetate (EtOMeOAc) has also been employed successfully for the resolution of racemic amines such as l-aryl-2-fluoroethylamines [192], l-phenylbut-3-en-l-amine [193], or 1-arylallylamines [194]. The use of this acyl donor improves the results for sterically hindered aminoalkylpyridines with respect to the ones obtained with EtOAc in some cases (Table 9.4) [195]. Significantly, the kinetic and stereoselectivity values of the reactions dramatically decrease with bulkier alkyl substituents. 

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