3-Acyl 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. 

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. ... 

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). 

As with other enaminones, aqueous KOH effects addition of OH- to C-4 and subsequent elimination of ammonia involving conversion to 3-acyl tetramic acids (14) (Section III). The reaction pathway, according to this mechanism, depends on the steric requirements of the substituents at C-5. The reaction proceeds rapidly and to completion in the case of R2 = R3 = Me and R2—R3 = —(CH2)4—. Slightly more sterically hindered substituents like R2 = R3 = Et considerably hinder the reaction (87TH2 89MI1). (See Fig. 6.)... 

Chances may be better, however, when a cyclic starting material includes the acyl group R4—CO. Here, the pathway based on Meldrum s acid was proven very useful [87JCS(P1)1177, 87TH1]. De Shong et al. started with R4-substituted isoxazoles (83JOC1149). The isoxazolium salts, obtained from ethyl bromoacetate, convert into /3-ketoamides, where best results were observed in two-phase systems. These /3-ketoamides cyclized to 3-acyI-tetramic acids by adding base. (See Fig. 13.)... 

Treatment of tricarbonylmethane compounds with acid effects cleavage of the acyl group [59BJ332 78JA4225 81ACS(B)667). Correspondingly, heating of 39a in the presence of hydrochloric acid provides tetramic acid 40 in quantitative yield after 30 min. 

Intramolecular ring closure between N-2 of the isoquinoline part and C-4 of the tetramic acid moiety followed. This example shows that the 3-acyl group of tetramic acids is not only used for the syntheses of natural... 

From a biosynthetic perspective, naturally occurring tetramic acids can be regarded to arise from the assembly of an amino acid and an activated acyl entity derived from an acetyl group or a more complex activated ester, Fig. (1). Alternatively, the simple tetramic acid formed can undergo substitution at C-3 with a second acyl group. On this basis, compounds such as lactacystin (5) have not been considered [11]. The carboxylic acid... 

In this section, tetramic acids with an acyl group substituent at C-3 are discussed. The simplest of the naturally occurring 3-acyl tetramic acids, tenuazonic acid (6), was first isolated from the culture filtrate of Alter-naria tenuis [18] and, subsequently, from other fungal species (A. alternate, A. longipes, Pyricularia oryzae) [19,20]. Species of Altemaria are known to produce more than 70 secondary metabolites, many of which, particularly those from the Altemaria altemata complex, are mycotoxins [19]. The absolute stereochemistry of 6 (55,65) was deduced from the formation of L-isoleucine on ozonolysis followed by acid hydrolysis [21]. 

A number of tetramic acid derivatives acylated with a liposaccharide unit have recently been discovered in marine sponges. The first example was uncovered in the sponge Ancorina sp using a bioassay to detect inhibition of blastulation in starfish embryos. The structure of the compound (27), named ancorinoside A, was determined by spectroscopic techniques... 

The gross structural features, presence of a tetramic acid and E-decenoyl side chain, could be inferred from NMR studies. Methanolysis (HCl/MeOH) of 47 and pentane extraction of the quenched reaction mixture gave two compounds that were determined to be the methyl esters of decenoic acid and N-(2-decenoyl)leucine. The nature of the 3-acyl tetramic acid was deduced from the identification of 48 and 49 in the aqueous portion of the methanolysis reaction mixture following treatment with trifluoroacetic acid anhydride. The unusual C-C bond fragmentation under acidic conditions, and the structure of the antibiotic was confirmed by synthesis of racemic 47 [86]. The configuration at the lone chiral centre was established as R by chiral GC. The carbon NMR spectrum of 47 indicated an equilibrium between three tautomers in which the A2-pyrrolin-4-one form is preferred (60%) and the two internal tautomers (50, 51) make equal contributions (20% each). 

The plasmodia of the wild type of Physarum polycephalum are bright yellow and produce an orange-red pigment that is also present in a white mutant [120]. This compound, named physarorubinic acid (64), binds calcium and other metals very well and this made acquisition of the H-NMR spectrum difficult (line broadening) unless the sample was washed with aq. EDTA solution. The structure contains a decapentaene system and signals at 5 102.4 (C-3), 172.6 (C-7), 174.5 (C-2) and 194.0 (C-4) are characteristic of C-3 acylated tetramic acid unit. 

The formation of the pyrrolidone group involves condensation of an acetate with L-serine. Since a significant proportion of L-[l,2,3-l3C, 15N]serine was incorporated into pramanicin, the carbon skeleton of serine is incorporated intact. Acylation with the 14-carbon moiety then ensues leading to the conjugated dieneone tetramic acid intermediate 122. In fact, this compound co-occurs with 121 and, interestingly, is almost exclusively produced when 123 and 124 are used as precursors. The remaining steps involve formation of the trans-diol at C-3 and C-4 and ep-oxidation of the terminal alkene in the dienone chain. 

A substantial number of the metabolites isolated still require resolution of stereochemical ambiguities, particularly those examples in which the C-3 acyl groups contain multiple stereogenic centres. A point of interest relates to the isolation of tetramic acid metabolites as salts and whether or not these salts represent the natural form of the metabolites. 

Numerous examples of the preparation of tetramic acids from N-acylated amino acid esters by a Dieckmann-type cyclocondensation have been reported (Entries 7-9, Table 15.4). Deprotonated 1,3-dicarbonyl compounds and unactivated amide enolates can be used as carbon nucleophiles. In most of these examples, the ester that acts as electrophile also links the substrate to the support, so that cyclization and cleavage from the support occur simultaneously. The preparation of five-membered cyclic imi-des is discussed in Section 13.8. 

Acylation of tetramic aclds. This Lewis acid is generally superior to BFs etherate or SnCU for acylation of tetramic acids (pyrrolidine-2,4-diones), particularly when the acyl group is unsaturated. An example is shown in equation (I). 

When N-acylation of the amino acid derivatives 111 was performed with acylated Meldrum s acid 22, the products were 3-acyl-tetramic acids 116. In this case, fhe optimal conditions for cleavage proved to be DIEA/dioxane (3 7) at 80 °C (Scheme 31) [47]. 

Hori, K., Aral, M., Nomura, K., and Yoshii, E., An efficient 3(C)-acylation of tetramic acids involving acyl migration of 4(O)-acylates, Chem. Pharm. Bull., 35, 4368, 1987. 

There are many compounds in this family, which contain a polyunsaturated chain bound to the tetramic acid moiety as a 3-acyl derivative. Royles has proposed the following classification for these compounds ... 

Other types of tetramic acid derivatives are A-acyl-4-methoxy-3-pyrrolin-2-ones or 4-O-methyl ethers of A-acylated tetramic acids. The only metabolites of this type containing a dienic structure are pukeleimides A (87), G (88), B (89) and F (90). They are nontoxic compounds isolated from the marine cyanophyte Lyngbya majuscula [158], a blue-green algae. 

Acylation of the amino acids 12, (synthesized from a ketone via a Strecker amino acid synthesis) with aryl-acetyl chloride 13 leads to the intermediate 14, which is cyclized to the tetramic acid 15 with potassium tert-butylate in refluxing toluene [62]. 

Acylation of 37 with 42 leads to the phenylacetylaminoester 43. In a Dieckmann-cyclization with KOtBu the tetramic acid 44 is formed, which is finally acylated with ethyl-chloroformate to spirotetramat 32, (Scheme 28.4.5c). 

Parker, Marshall H. Ruiz, James M. Schmitzer, Paul R. Outside the Matrix The Combinatorial Exploitation of Acyl Tetramic Acids. Abstracts, 36th Central Regional Meeting of the American Chemical Society, Indianapolis, IN, United States, June 2-4 (2004). 

Tenuazonic acid (741), a phytotoxin produced by Alternaria spp., is structurally related to the tetramic acid family of compounds, and has been found to exhibit antibiotic activity (511). Since 1964, there have been several publications on the total synthesis of 741 (512-515), including the report by Poncet and his group in 1990 (516) (Scheme 11.10). A general method to synthesize the tetramic acids is an intramolecular Dieckmann cyclization of (V-acyl amino esters. Beginning with methyl L-isoleucinate 780, the A/-acyl compound 782 was obtained through a nucleophilic reaction (512), which then cyclized to tenuazonic acid 741 under basic conditions and neutralization by acidic work-up. The synthetic product showed a diastereomeric excess of 89%, with the major epimer presenting the same configuration as its precursor (517). 

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