Tetramic acid,

As has already been pointed out for 3-acyl-tetronic and -thiotetronic acids, the corresponding 3-acyl-tetramic acid can exist as internal tautomers (136 137,138 139) as a result of prototropy between the two oxygen atoms and as external tautomers (136,137 138,139) as a result of rotation of the side-chain acyl group. 

Osterhages work has led to further analysis of bioactive products from the marine fungus A. salicorniae. In addition to the novel tetramic acid derivatives (38, 39), this fungus also produces two new epimeric lactones, the cycloethers ascolactone A (43) and B (44), similar to known cephalosporide compounds, and ascochitine (45), ascochital (46), and halopyrone (47), which were previously known.Compound 45 exhibited moderate inhibition of a tyrosine phosphatase B from Mycobacterium tuberculosis. 

While in most reported cases the nucleophiles were amines, there were few examples involving heterocyclic nitrogens [40], alcoholic oxygens [27] or carbon nucleophiles [42, 43] too. Figure 4 shows a recent example of tandem Ugi-Dieckmann protocol [42]. Ugi convertible isocyanide 2, which requires a basic activation, was used, allowing a domino activation-cyclization of the intermediate 20 to give pyrrolidinediones (tetramic acids) 22. 

Spatz JH, Welsch S J, Duhaut DE, lager N, Boursier T, Fredrich M, Allmendinger L, Ross G, Kolb J, Burdack C et al (2009) Tetramic acid derivatives via Ugi-Dieckmann-reaction. Tetrahedron Lett 50 1705-1707... 

The title phosphonate and related substances undergo thermal decomposition to B-acyl ketenes at temperatures in excess of 50°C. Thus thermolysis in the presence of alcohols, amines, a-hydroxy esters, and a-amino esters affords the corresponding g-keto esters and amides the latter two classes can be cyclized upon subsequent base treatment to unsaturated tetronic and tetramic acids and the related phosphonate reagents. ... 

Two alternative methods for the preparation of phosphorus-activated tetramic acid reagents have recently been described.These reagents have served to provide a workable solution to the problem of construction of the dienoyl tetramic acid unit required for the synthesis of tirandamycin-A, - " ... 

Holtzel, A. G9nzle, M.G. Nicholson, G.J. Hammes, W.P. Jung, G. (2000) The first low molecular weight antibiotic from lactic acid bacteria reut icyclin, a new tetramic acid. Angew. Chan. Int. Ed. Engl., 39, 2766-8. 

Tetrahydropyrrolo[4,3-. ]pyridines can be synthesized from 5,5-dimethyltetramic acid, 84, in a sequence of steps that begins with aryl aldehydes to generate arylmethylene-substituted tetramic acids. A Michael reaction with methyl acetoacetate followed by treatment with ammonium acetate yields the tetrahydropyrrolopyridine derivatives (Scheme 20) <2005H(65)377>. A similar reaction can be carried out with aroyl-substituted butenolides to give substituted furopyridine derivatives. 

In 1901 Anschutz suggested the denotation tetramic acid for 1,5-dihydro-4-hydroxy-2-pyrrololone 2a, a tautomer of 2,4-pyrrolidinedione la (09LA55). By analogy to the term tetronic acid, denoting the lactone of 4-hydroxy-3-oxo-butanoic acid (60QR292), tetramic acid is used to name the lactam of 4-amino-3-oxo-butanoic acid. (See Fig. 1.)... 

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). 

The majority of syntheses for tetramic acids described in the literature follows a strategy that is derived from the following retrosynthetic consideration (Scheme 1). (The scissions of bonds are given as imaginary hydroly-... 

Scheme 1. Retrosynthetic analysis of tetramic acid derivatives.

Thus, in the case of 3-unsubstituted tetramic acids (X), the synthesis would start from acetic acid and an a-amino carboxylic acid. (In practice the acid will be replaced by suitable carboxylic acid derivatives.) The problem in these syntheses is the low reactivity of the methyl group of acetic acid. 

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). 

The various published syntheses of tetramic acids and their derivatives may be divided into two basic methods, according to the retrosynthetic scheme (Scheme I). The two methods differ only in the order of steps... 

Scheme 3. Two different pathways for the construction of tetramic acid derivatives (V).

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