Of tetramic acid

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). 

Scheme 1. Retrosynthetic analysis of tetramic acid derivatives.

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).

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.)... 

Diaminoethane and 1,2-diaminobenzene do not furnish cyclic derivatives of tetramic acid. Independent of the reaction time and the molar ratio of the reactants, the corresponding 3-carboxamides 18 and 19 are the only products [88UP1 cf, 67JCS(C)693]. Heating 19 in a sublimation apparatus to 220-240°C gives benzimidazole 20 in 65% yield (88UP1). (See Fig. 10.)... 

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... 

Direct synthesis of tetramic acids (1/2) (see retrosynthesis X, Scheme 1) starting with an alkanoic acid and an amino acid have rarely been described. One example is a patent of the synthesis of 3,3-dipropyl-2,4-pyrrolidindione formed by bubbling HC1 gas through a mixture of valproic acid and glycine in methanol at 25°C (90JAP01/311061). 

Under carefully worked out reaction conditions, 2b can give the 3-bromo compound 94 (CHC13,0-5°C) or the 3,3-dibromo compound 95 (2M NaOH, 0-5°C). The reactions of 94 and 95 with N-nucleophiles proceed differently. Refluxing 94 in ethanol gives dimer 96, which is clearly distinct in structure and properties from other self-condensation products of tetramic acid (85AJC1847). Otherwise, 95 and yV-methyl-A-phenylhydrazine under refluxing in ethanol form 3-hydrazone 92a in 60% yield (90TH1). (See Fig. 42.)... 

It is somewhat surprising to find that there have been only three published reviews on tetramic acids. The first reports on the advances in tetramic acid chemistry up to 1993 [1], another describes the synthesis of tetramic acid antibiotics [3], and a third, dealing with the structure, isolation and synthesis of naturally occurring tetramic acids, was published in 1995 [4]. The present review is an attempt to cover the field of tetramic acid metabolites with particular emphasis on the structure, biosynthesis and biological activity of these compounds. 

For the purpose of this review, it has been necessary to circumscribe the type of tetramic acid metabolites to be considered. Thus, the large group of cytochalasins, chaetoglobosins and penchalasins, e.g. 3, will not be included here as they have been covered in detail elsewhere [5-7]. For these metabolites, a tetramic acid species has been postulated as the putative precursor 4 that undergoes a Diels-Alder reaction [8-10],... 

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... 

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. 

A series of derivatives of tetramic acid were synthesized and complexed to cop-per(II) (Cu-TA,Fig.21) [176,177]. At 300 MHz,the Rt value of Cu-aTA is 0.073 0.004 mM 1 s-1 and the R2 value is 0.091 0.006 mM 1 s 1 [176]. The ability of the Cu-TA derivatives to cross membranes was measured using defolliculated Xeno-pus laevis oocytes as model cells. Using MR microscopy techniques, Cu-aTA, Cu-bTA, Cu-cTA and Cu-eTA were all found to cross into the cytoplasm of the cells [177]. Additionally, atomic absorption spectroscopy revealed the presence of Cu-dTA and Cu-fTA, suggesting that while the complexes failed to cross the cell membrane that they were stored in the membrane-bilayer. Liquid chromatography experiments demonstrated that Cu-aTA crosses membranes intact [176]. 

In the first of several natural product structure characterization reports published in the Journal of Natural Products during 2003, Schmidt et a/.163 reported the isolation and characterization of a series of tetramic acids and pyridone alkaloids, militarinones B, C, and D from the insect pathogenic fungus Poaecilomyces mi-litaris. The structure of militarinone D (82) is shown. 

This is a new class of pesticides that are derivatives of tetramic acid. Spirotetramat is a broad-spectrum insecticide with systemic action effective against sucking insects. 

As an example of scaffold synthesis rather than decoration, we adapted the Lacey-Dieckmann synthesis of tetramic acids to a combinatorial strategy (Figure 6). The overall sequence is only three steps, and all the three reaction inputs involve readily available building blocks amino acids, aldehydes, and carboxylic acids. We published both solution- and solid-phase protocols, and this was followed soon thereafter by similar reports from industrial groups. Clearly, the ability to access this heterocycle with ample room for diversification was highly attractive, and each of us had independently developed this idea. 

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). 

In another approach, the two applications were combined and an ion-exchange resin was used both as a reagent and as the purification agent in a synthesis of tetramic acids [42] (Scheme 13). Starting from amino add esters 38, reductive amination and subsequent couphng with acids led, after extractive work-up, to... 

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. 

The variety of tetramic acid-containing natural products is remarkable, the area having been reviewed recently [130]. These compounds have attracted a great deal of interest, due mainly to their biological activity as potent antibiotics, because of their antiviral and antiulcerative properties, cytotoxicity and mycotoxicity, their inhibition of tumors as well as. fungicidal action. Other members are responsible for the pigmentation of certain molds and sponges. 

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. 

The strongly acidic character of tetramic acids and their usual low solubility prompted us to delay the assembly of this heterocyclic unit until very late in the synthesis. Accordingly, the appropriate ornithine segment was constructed next (Scheme VII). The known amino acid 57 [26b] was transformed via the fully protected derivative 58 to 59 by chemoselective unmasking of the y-amino group with formic acid. The remaining two substituents on the a-amino group are to be removed at different times, with the allyl carbamate destined to precede the 2,4-dimethoxybenzyl functionality. 

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