Hydroxy acid amides, hydrolysis

Scheme 4 Stereoselective synthesis of (f )-2-hydroxy acid amides and (7 )-2-hydroxy acids hy hydrolysis of (f )-cyanohydrins.

Rate Constants for the Hydrolysis of Hydroxy Acid Amides - ... 

Lactams are intramolecular amides of amino acids (especially y-, -e-amino acids) formed similarly to lactones from hydroxy acids. After hydrolysis the acid formed is identified. 

Racemic a-amino amides and a-hydroxy amides have been hydrolyzed enantio-selectively by amidases. Both L-selective and o-selective amidases are known. For example, a purified L-selective amidase from Ochrobactrum anthropi combines a very broad substrate specificity with a high enantioselectivity on a-hydrogen and a,a-disubstituted a-amino acid amides, a-hydroxyacid amides, and a-N-hydroxya-mino acid amides [102]. A racemase (a-amino-e-caprolactam racemase, EC 5.1.1.15) converts the o-aminopeptidase-catalyzed hydrolysis of a-amino acid amides into a DKR (Figure 6.38) [103]. 

Tetrahydropyrrolo[l,4]oxazine 74, obtained by photoinduced electron-transfer (PET) oxidative activation of substituted prolinol, undergoes nucleophilic substitution of the OH at position C-3 with allyltrimethylsilane in the presence of TiCU (Scheme 8). The reaction was highly stereoselective and produced, after hydrolysis of the resultant amide 75, optically active a-hydroxy acid 76 together with the auxiliary (.S )-prolinol that can be effectively recycled <1998TL7153>. 

By analogy with the synthesis of a-hydroxy acids one can envisage a one-pot synthesis of a-hydroxy amides from aldehydes via hydrocyanation and in situ NHase-catalyzed hydrolysis to the amide. Since enantioselective NHases are very rare, the enantioselectivity should be derived from HnL-catalyzed hydrocyanation. The second step has been described for the Rhodococcus erythropolis NHase-catalyzed hydration of (R)-mandelonitrile to give the (R)-amide with retention of enantiopurity [43]. 

Hydroxy Acids 0-10 Hydrolysis of lactones (acyloin) Hydroxyamines and Amides ... 

N-Benzylamides are recommended when the corresponding acid is liquid and/or water-soluble so that it cannot itself serve as a derivative. The benzyl-amides derived from the simple fatty acids or their esters are not altogether satisfactory since they are often low melting those derived from most hydroxy acids and from polybasic acids or their esters are formed in good yield and are easily purified. The esters of aromatic acids yield satisfactory derivatives but the method must compete with the equally simple process of hydrolysis and precipitation of the free acid, an obvious derivative when the acid is a solid. The procedure fails with esters of keto acids, sulphonic acids and inorganic acids and some halogenated aliphatic esters. 

Racemic compounds other than carboxylic acids have also been resolved by reaction with enantiomerically pure (1) and separation of the corresponding diastereomeric mixtures by physical methods. For example, reaction of a racemic p-substituted 7-butyrolactone with (1) yields a mixture of hydroxy amides, which can be separated by fractional recrystallization and chromatography (eq 3). Amide hydrolysis regenerates the chiral hydroxy acids, which spontaneously cyclize to produce the chiral lactones. 

The above example also illustrates another requirement for efficient nucleophilic catalysis, namely that the intermediate that is formed must react rapidly to prevent accumulation of the intermediate. The lactone intermediate is an ester which is much more reactive than the starting amide towards hydrolysis and is rapidly converted to the hydroxy-acid. 

Dibromohydroxynucine has been converted to 2,3-dioxonucine dihydrate (XCIX) by transformation (aqueous ammonia) of the dibromobase to the hydroxy amide CVIII (R = NHj) (167) followed by hydrolysis of the amide to the hydroxy acid, CnHaOsNs (CVIII, R = OH), and oxidation (CrOs) of the hydroxyl to a ketone. The oxidation of the hydroxy acid to 2,3-dioxonucine dihydrate is accompanied by hydrolysis of the lactam. The neutral hydroxy acid, C17H22O6N2, has been obtained directly by hydrolysis of the dibromobase with aqueous barium hydroxide solution (109). 

Hydroxy imine Primary amide Fig. Acid-catalysed hydrolysis of nitrile to carboxylic acid. 

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