Tetramic acid structure

Royles, B.J.L. (1995) Naturally occurring tetramic acids structure, isolation and synthesis. Chem. Rev., 95, 1981-2001. 

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. 

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... 

Vermisporin (41) is produced by the fungus Ophiobolus vermisporis [76]. Its structure was determined by chemical degradation to the derivative (42) which was studied by X-ray crystallography and provided the absolute configuration [77]. Vermisporin exhibits antimicrobial activity towards Bacteroides spp (0.25-2 lg/ml), Clostridium perfringens (0.25-2 pg/ml) and methicillin-resistant Staphylococcus aureus (0.12-0.5 pg/ml). A metabolite of Ophiobolus rubellus produces the tetramic acid (43) that has been claimed to be an inhibitor of proline hydroxylase (IC5019pM) [78]. 

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. 

Cylindramide (90) is a cytotoxic compound isolated from Halichondria cylindrata (7.10 s % wet wt.), but very likely of bacterial origin [148]. The structure was deduced from spectroscopic analysis, the relative stereochemistry (only) of the bicyclo[3.3.0]octene unit by NOESY techniques, and the absolute stereochemistry of the amino acid of the tetramic acid ring (25,35) from the recovery of erythtro-L-(3-hydroxyomithine from oxidative degradation of 90. It showed cytotoxicity to B16 melanoma cells (IC50 0.8 (ig/ml). 

However, it requires rather hindered /3-ketocstcrs to observe a significant drop in the yield of the arylation reaction with />-rn ethoxy phenyl lead triacetate 1 (Equation (3)).16 On the other hand, if the /3-dicarbonyl moiety is inserted into a cyclic structure, this difference disappears. For example, in the synthesis of functionalized tetramic acid derivatives, reaction of phenyllead triacetate 2 with the two five-membered cyclic pyrrolidinediones 3 and 4 afforded the diphenyl derivative 5 with a similar efficiency of the arylation step (Equations (4) and (5)).17... 

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. 

Cylindramide (1) is structurally related to a number of other tetramic acids 2, for example to discodermide (3) and ikarugamycin (4). Besides the tetramic acid unit, a substituted bicydo[3.3.0]octane skeleton is characteristic for this macrocycle. 

Tetramic acids are substructures of natural products that show antimicrobial activity. An access to these structures started from Wang resin-bound Fmoc-protected amino acids, which were deprotected and reductively alkylated. These intermediates 111 were transformed into amides, for example with malonic acid monoesters or aryl acetic acids (112 and 114, respectively). Cyclative cleavage was induced with 0.1 M NaOEt at 85 °C and gave substituted tetramic acids 113 and 115 in yields and purities of generally >95% (Scheme 30) [46]. 

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 2,4,6-trimethylphenyl (mesityl) compound 4i [8] showed an improved acaricidal potential against Tetranychus urticae (TETRUR) but were not satisfactory active under field conditions regarding another important mite species, Panony-chus ulmi (PANOUL). To increase the efficacy against PANOUL a broad synthesis and screening of substituents on positions 1 and 5 of the lead structure was performed. The monocyclic 5,5-dimethyl tetramic acid derivatives 5a and 5b [9] (Pig. 

One of the most toxic components among Alternaria my cotoxins is tenuazonic acid (741) (475) (Fig. 11.4), a tetramic acid derivative, which was first isolated from the culture filtrates of Alternaria tenuis in 1957 by Rosett et al. (476) and shows potent biological activity (475). Tenuazonic acid is biosynthesized from L-fro-leucine and its structure was revealed four years later by Sticicings and his group (477). 

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