Dihydro-4-hydroxy-2-pyrrolones Tetramic Acids

Disidea Herbacca, obtained the /8-ketoester HjN—CH(iPr)—CO— CHj—COOEt from L-valine. The ester was cydized to 5-isopropyl-tetramic acid in toluene in the presence of potassium 2-methyl-2-butoxide (84HCA1783). In other cases esters of 4-amino-3-oxobutanoic acid, subsequently cydized in the presence of base, were synthesized using special heterocycles, such as /3-lactams (91TL3115), imidazoles (91IZV437) or pyrones (89TL3217). (See Fig. 30.) 

A frequently employed route comprises preparation of 3-alkoxycar-bonyltetramic acids from malonic acid derivatives and a-aminocarboxylic esters (77MI1 84CPB3724) or, alternatively, a-aminonitriles (86UP1) followed by hydrolysis and decarboxylation [72JCS(P1)2121 85AJC1847 86ZN(B)219]. 

Similar to other cyclic 1,3-dicarbonyl compounds, tetramic acids in solution predominantly exist in their enol form. As Iran -configured enols they do not give a color reaction with FeCl3. The pK of unsubstituted tetramic acid 2a was determined to be 6.4 [72JCS(P1)2121]. 

As lactams of 4-amino-3-oxobutanoic acids, tetramic acids react with amines (87JPJ858) and with phenylhydrazine. The latter reaction is catalyzed with para-toluenesulfonic acid. Thus, for example, l/2b give phenyl-hydrazone 65 in 80% yield that, in turn, under the conditions of the Fischer indole synthesis, may give rise to pyrrolo[4,3-fe]indolene 66 (90TH1). (See Fig. 31.) 

Aromatic aldehydes react very easily with tetramic acid under acidic conditions to give 3-benzylidene compounds (41). The yields are moderate, because often there are subsequent reactions. As a,/3-unsaturated carbonyl compounds, (41) react in a Michael addition with excess tetramic acid to form (67), but it can also react with other acyclic and cyclic 1,3-dicarbonyl compounds. In these reactions the aryl substituents may vary over a wide range. Thus, (67) and (68) can be cyclized with ammonium acetate to afford pharmacologically interesting compounds (70) and (71) (90TH1). The latter are dihydropyridines. Curiously, (69) does not cyclize under these conditions. (See Fig. 32.) 

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Anions of tetramic acids show, as expected, only limited nucleophilic properties. Indeed, O-alkylation requires strongly alkylating agents. Acylation preferentially gives 4-acyloxy-l,5-dihydro-2-pyrrolones which, in the presence of Lewis acids, may undergo rearrangement to 3-acyl-l,5-dihydro-4-hydroxy-2-pyrrolones (Section III). 

Z) is provided in Section II. Section III deals with the rntyor reactions of 3-acyl-l,5-dihydro-4-hydroxy-2-pyrrolones (Y), compounds representing a wide variety of natural substances. Finally, Section IV presents an overview on the chemistry of the actual tetramic acids (X). 

Bis-p-nitrophenyl malonate (55M29) reacts with a-alkylamino-isobutyr-onitriles in xylene to give derivatives (16b) of tetramic acids with yields of 30-50% (86UP1 88UP1). The reaction of derivatized malonic acids with a-amino acid esters to 3-alkoxycarbonyl-l,5-dihydro-4-hydroxy-2-pyrrolones presents the same problems (see Section III). (See Fig. 8.)... 

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