Tetronic acid, reaction with aldehydes

Regio-directed metallations have been used this year to good effect in the synthesis of tetronic acids. Two papers have appeared on the lithiation of the acrylates (8) at the p-position to yield tetronic acids (9 X = H) after reaction with aldehydes, ketones, and esters. " The tetronic acids (9 X = H) can then be lithiated to give (9 X = Li) and further reacted to provide the substituted tetronic acids (9 X = E). " " In this way isomers of the naturally occurring gregatins and aspertetronins have been synthesized. "... 

Partially hydrogenated quinoline cores are also present in some important bioactive compounds. For example, the 4-aza-analogs of Podophyllotoxin, a plant lignan that inhibits microtubule assembly, revealed to be more potent and less toxic anticancer agents. In 2006, Ji s group reported a green multicomponent approach to a new series of these derivatives, consisting of the reaction of either tetronic acid or 1,3-indanedione with various aldehydes and substituted anilines in water under microwave irradiation conditions (Scheme 26) [107]. For this efficient and eco-friendly transformation, the authors proposed a mechanism quite similar to the one that was postulated for the synthesis of tetrahydroquinolines in the precedent section. 

As mentioned above, cyclic / -diketones such as cyclohexane-1,3-dione and other cyclic / -dicarbonyl compounds are known to function well in Biginelli condensations (see Figure 4.3). However, for tetronic acid the reaction takes an entirely different course, following a pseudo-four-component pathway to furnish spiro het-erobicydic products in good yields (Scheme 4.11) [158], The reaction proceeds by a regiospecific condensation of two molecules of aldehyde with the other reagents... 

N. G. Kozlov, S. L. Bondarev, A. P. Kadutskii, L. I. Basalaeva, F. S. Pashkovskii, Russ. J. Org. Chem. 2008, 44, 1031-1037. Tetronic acid in reaction with aromatic aldehydes and 2-naph-thylamine. Investigation of fluorescent and nonlinear-optical characteristics of compounds obtained. 

Tu et al. have reported the synthesis of 4-aza-podoplyllotoxin via a three-component reaction of an aldehyde, aniline and cyclic diones in H2O under MWl. Use of tetronic acid as the cyclic diketone provided the 4-aza-podophyllotoxin derivatives (76) (Scheme 6.30). The reaction proceeded via the attack of Schiff s base, formed through the condensation between aldehyde and aniline, on tetronic acid resulting into an intermediate which underwent intramolecular cyclization and dehydration to yield the product. The scope of the strategy was enhanced by replacing tetronic acid with 1,3-indanedione to generate indenoquinoline derivatives (77) [69]. 

Aza-podophyllotoxins (158) have been prepared in a cascade reaction of tetronic acid with aldehydes and anilines. A mechanistic investigation shows evidence for an electron-deficient aniline acting as a sacrificial component in the sequence. 

Tetronomycin (102), a structurally challenging 3-acyltetronic acid ionophore antibiotic, was isolated from a Streptomyces strain in the early 1980s [71]. The only total synthesis reported so far was accomplished in 1992 by Yoshii and coworkers (Scheme 1.14) [72]. By using as chiral building blocks the ethoxyethyl ether 98 and L-rhamnal diacetate 99, Yoshii reached aldehyde 100, a suitable precursor for the installation of the tetronic moiety. This was achieved by a reaction with the lithium anion of methyl tetronate 101 at —100°C that led to the target after pyridinium chlorochromate (PCC) oxidation and careful deprotection. 

Tetronic Acids.—The vinyl lithium species (102) reacts with aldehydes to provide a quick if not particularly efficient (11—57% yields) entry into O-methyltetronic acids (103), which can be converted into the ylidenetetronic acids (104) by standard methodology (LDA, PhSSPh, and oxidize 32—40% yield).Both (103) and (104) give the free tetronic acids on reaction with 48% HBr. It has been re-emphasized that tetronic acids can be O-alkylated using methanol (or ethanol) and hydrogen chloride. 

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