3- Substituted tetramic acids

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. 

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]. 

Benzo-l-thia-2,4-diazine-substituted tetramic acids such as 140 result from a one-pot treatment of precursors 139 with amino acid methyl esters followed by base-induced cyclization (Equation 24) <20050L5521>. The products 140, and C-3-pyrimidinyl analogs <2003W02003037262>, which are closely related to the 4-hydroxy-2(l/7)-quino-lones 138 (Equation 23), are also potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase. 

The a-aminonitrile intermediates resulting from these MC Strecker strategies have been found useful for the synthesis of more complex and interesting structmes [106]. This is the case of Fitch and coworkers, who developed an efficient two-pot synthesis for the asymmetric preparation of benzothiadia-zine-substituted tetramic acids 83 (Scheme 10.37) [107],... 

D. M. Fitch, K. A. Evans, D. Chai, K. J. Duffy, Org. Lett. 2005,7,5521-5524. A highly efficient, asymmetric synthesis of benzotfaiadiazine-substituted tetramic acids potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase. 

Several examples of glycosides in which the aglycone is a substituted tetramic acid have been isolated from... 

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.)... 

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... 

Condensation of acetyl-tetronic or -tetramic acids with methyl- or phenyl-hydrazine leads to 3-(l-hydrazinoethyl)-tetronic and -tetramic add, respectively, which upon dehydration form 1-substituted 4-oxo-l,4-dihydro-6//-furo[3,4-c]pyrazoles (X=0) and -pyrrolo[3,4-c]pyrazoles (X=NH) (equation 20) (82SC431). 

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. 

Table 28.4.1 Acaricidal efficacy of some pivaloyl substituted bicyclic tetramic acids 4 depending on the phenyl substitution pattern.

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.

Schobert R, Jagusch C, Melanophy C, Mullen G (2004) Synthesis and Reactions of Polymer-bound Ph3P=C=C=0 A Quick Route to Tenuazonic Acid and Other Optically Pure 5-Substituted Tetramates. Org Biomol Chem 2 3524... 

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