Tetramic acid derivatives

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. 

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... 

Scheme 1. Retrosynthetic analysis of tetramic acid derivatives.

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

Tetramic acid derivatives are valuable intermediates in the total synthesis of natural substances that is why a great number of experiments were carried out to find more convenient pathways to their preparation. In general, there are two different methods to reach this goal. 

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... 

Trichoderma spp are a well known fungal group that produce a wide range of metabolites with diverse activities [137]. The only tetramic acid derivative isolated so far is harzianic acid (78) which was isolated from a... 

Gossauer A (2003) Monopyrrolic Natural Compounds Including Tetramic Acid Derivatives. Prog Chem Org Nat Prod 86 1... 

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... 

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. 

Miscellaneous Reactions.- A full report has appeared of the use of /er/-butyl 4-diethylphosphono-3-oxobutanthioates (232) in olefination reactions for the preparation of homologated 3-oxobutanthioates and hence of tetramic acid derivatives. The reaction of the phosphonate dianion (234) with the aldehyde (233) is a key step in a total synthesis of the tetramic acid antibiotic ( .)-tirandamycin B (235). Olefinations involving both ylides and phosphonates have been used to construct the triene (236) en route to the spirotetronate subunit of the aglycone of the antitumour antibiotic... 

Asymmetric Synthesis of Tetramic Acid Derivatives. An asymmetric synthesis of tetramic acid derivatives was reported by Fustero et al. The key step is a carbonyl transfer from 1 to a-diimines (24) to form A-aLkyl-4-alkylamino-5-methylenepyrrol-2-ones (25). These can be transformed into tetramic acid derivatives (26) by asymmetric reduction of the exocyclic double bond induced by the chiral R group and subsequent hydrolysis of the A-protected enamine (eq 23). 

C20H23NO5, Mr 357.41, red crystals, mp. 150 °C (dihydrate), an optically active tetramic acid derivative from the yellow plasmodia of the slime mold Fuligo septica (Myxomycetes). F. exists in Fuligo as a stable calcium complex. F. is assumed to possess photoreceptor properties and to play a role in the phototaxis and sporulation of the slime mold. 

Ikarugamycin, C29H3gN204, Mr 478.63, cryst., mp. 228-229 (252-255)°C (decomp.) [0] +390° (DMF). A tetramic acid derivative from cultures of Streptomyces phaeochromogenes with antibacterial and antiprotozoic properties. 

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. 

Further evaluation led us to alkoxy-substituted spiroqrclic tetramic acid derivatives. We took an alternative synthesis route starting from 4-methoxy-l-aminocydohexanecarbonitrile 25, which was prepared by a Strecker synthesis [21], to reduce the synthesis steps [22] and prepared compounds 28a and 28b (Scheme 28.4.4). 

Scheme 28.4.4. Discovery of substituted spirocyclic tetramic acid derivatives.

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). 

Tetramic acids with a pyrrolidine-2,4-dione ring system 90 represent an interesting class of azaheterocycles, which are present as a core structural unit in many natural products endowed with promising biological activihes. A nontoxic and mild I(III) oxidant, PhI(OPiv)2, was successfully utilized for the intramolecular sp C-H aminations of 1-acetyl N-aryl carboxamides 89 to furnish a series of tetramic acid derivatives (Scheme 17) [33]. 

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