Acyltetramic acids

The tautomerism of aza-analogs of 3-acyltetramic acids of type 180 have been investigated by Langer and coworkers (97LA2553). 

In their acidity 3-acyltetramic acids resemble carboxylic acids (Table II). 

The relatively high acidity of the acids (39) corresponds to the relatively low basicity and the weak nucleophilicity of the corresponding anions (39 ). 3-Acyltetramic acids cannot be alkylated with reagents of type Alk-X in basic solution, under the usual conditions. 

Jones et al. prepared boron complexes and boron compounds of 3-acyltetramic acid [90JCS(P1)1959]. 

As shown above, 3-acyltetramic acids (pKa about 3) form anions whose reactivity toward alkylating agents is low. Successful reaction of 3-acylte-tramic acids with carboxylic acid derivatives are scarce in the literature... 

Acyltetramic acids (39) are almost completely enolized in solution as well as in the crystalline state [80JCS(P1)1057], whereby the exo-enol form (a) is favored. Irradiation of 39a in peroxide-free cyclohexene leads to [2 + 2]-cycloaddition at the exocyclic double bond. Subsequent thermal reaction opens the four-membered ring of cycloadduct 59. 3-(2-Acetyl-cyclohexyl)-l,5,5-trimethyl-2,4-pyrrolidinedione 60 is obtained in 85% yield. In solution, 60 establishes an equilibrium with cyclic hemiacetal 61 (92M93). (See Fig. 28.)... 

CPB4368, 87TL1565). Again, the formation of 4-acyloxy tetramic acids is favored. However, under the conditions of Fries rearrangement or alternatively, in the presence of triethylamine, conversion to 3-acyltetramic acids is observed (87CPB4368). 

Of some interest is the ability of 3-acyltetramic acid to form stable complexes with ions of transition metals, e.g. Cu2+, La3+, Sm3+, Eu +, Gd3+, and boron complexes [1]. Indeed, examples are available in which the tetramic acid occurs naturally as magnesium or calcium salts. Methods of isolation or purification involving acidic solvents generate conditions that... 

While cycloaddition approaches have been discussed extensively in this chapter, there are certain substitution patterns that are not amendable to such approaches. In these cases, the more traditional annelative approaches are necessary. For example, the 5,6-dihydropyrrolo[3,4-rf]imidazol-4(3//)-one (286) is obtained from the diamine (285) and triethyl orthoformate. If formamide is used in excess, 6-(formamidomethylene)-5,6-dihydropyrrolo[3,4-d]imidazol-4(3//)-one (287) is obtained (Scheme 53) <70JPS1732>. A variant of the Thorpe cyclization was employed in the preparation of 3-amino-4//-pyrrolo[3,4-c]isoxazoles (289) from a-cyanooximes (288) (Equation (66)) <68JMC453>. 3-Acyltetramic acid (290 X = NR2) and 3-acyltetronic acid (292 X = O) hydrazones undergo ready cyclization in refluxing xylene with catalytic p-toluenesulfonic acid to afford 4-oxo-l,4-dihydro-6/f-pyrrolo[3,4-c]pyrazoles (291) and 4-oxo-l,4-dihydro-6//-furo[3,4-c]pyrazoles (293), respectively (Equation (67)) <82SC43l>. The novel synthesis of 5-amino-6a-hydroxydihydro-6//-pyrrolo[2,3-j]isoxazole (296) from 3,4-disubstituted 4-(amino)isoxazol-(4//)-ones (294) is hypothesized to occur by the cyclization of the ketene aminal intermediates (295) (Scheme 54) <91S127>. 

Borole, pentaphenyl-, stability, 56, 375 Boron complexes, of acyltetramic acids,... 

Methylpyrrolo[3,4-f]isoxazoles 48, prepared from 3-(l-aminoalkyl)isoxazole-4-carboxylic esters (see Section 4.03.9.1.6), after deprotonation and condensation with aromatic aldehydes afforded compounds 49 that were subjected to N-O bond cleavage the use of Mo(CO)6 gave 3-enoyltetramic acids 50, whereas H2-catalyst allowed further reduction to 3-acyltetramic acids 51 (Scheme 12) <2004SL2815>. 

Boeckman. R.K.. and Thomas, A.J.. Methodology for the synthesis of phosphorus-activated tetramic acids. Applications to the synthesis of unsaturated 3-acyltetramic acids.Org. Chem.. 47, 2823. 1982. 

Pyrrolo[3,4-c]isoxazoles 21 were designed to act as non-polar scaffolds for elaboration to acyltetramic acids. In particular, hydrogenolytic N-0 cleavage followed by hydrolysis of the resultant enaminone afforded the 3-(3-arylpropanoyl)tetramic acids 23, while N-0 reduction by molybdenum hexacarbonyl gave the corresponding 3-arylpropenoyl compounds 22 <04SL2815>. 

Homologation-condensation. 3-Acyltetramic acids are accessible from N-acylacetylglycine esters. In turn the latter compounds may be assembled from a-diazo acetamide derivatives and aldehydes with elimination of dinitrogen. Zirconium chloride is a useful catalyst. 

Scheme 18.2 Fuligorubin A, a polyene acyltetramic acid pigment isolated from the yellow slime mold Fuligo septica (L).

Weber, Lutz laiza, Patrick Biringer, Gerard Barbier, Pierre. Solid-Phase Synthesis of 3-Acyltetramic Acids. Synlett (1998), (10), 1156-1158... 

Pharmacologically more interesting than tenuazonic acid are the melo-phhns, a class of N-methyl-3-acyltetramic acids recently isolated from the marine sponge Melophlus sarassinorum. Melophlins A and B displayed cy-... 

In the latter case a 3-acyltetramic acid intermediate is invoked,and recent reports have outlined the isolation (from an unidentified Actinomvcete strain), structure determination, and semi-synthesis by acylation in low yield of the... 

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