Domino syntheses of bioactive tetronic and tetramic acids

Abstract

Natural products containing tetronic acid or tetramic acid moieties continue to attract the interest of chemists, biologists, and physicians due to their challenging structures and to the wide range of biological activities they display. This review portrays the structural varieties of tetronic and tetramic acids and the spectrum of possible therapeutically relevant effects in man for exemplary derivatives. Their biosynthetic origin from alpha-amino and alpha-hydroxy acids is briefly discussed as is the relationship between their structures and their modes of interaction with biochemical effectors such as metal cations or enzymes. A short overview of laboratory syntheses of the heterocyclic core structures of tetramic and tetronic acids is provided with an emphasis on those emulating the biosynthesis. A synthesis from the alpha-amino or alpha-hydroxy esters and the cumulated phosphorus ylide Ph(3)PCCO based upon a domino addition-intra-Wittig alkenation sequence is presented with applications to the preparation of the antibiotics reutericyclin and tenuazonic acid, the cytotoxic melophlin B, and the enzyme inhibitor RK-682. Procedural advantages of immobilizing either starting component by attaching it to a resin and its exploitation in the parallel synthesis of libraries of potential drug candidates are described. The basic domino reaction can even be extended by further C-C bond forming steps when starting from suitable alpha-hydroxy or alpha-amino allyl esters. Depending on the chosen reaction conditions, bioactive intermediates of formally three to seven step long cascades can be obtained. Among them, herbicidal 3-alkyltetronic acids and lactone endoperoxides with antiplasmodial activity exceeding that of the natural antimalarial lead artemisinin. Hence, this domino reaction gives access to diversely functionalized derivatives of tetronic and tetramic acids. As it can also be ported to solid phase, it is ideally suited for parallel and combinatorial processing. Future developments might include running such domino sequences in continuous mode in arrays of "labs on microchips".

Analysis of the Tetronomycin Gene Cluster: Insights into the Biosynthesis of a Polyether Tetronate Antibiotic

“…[1] They include spiro-A C H T U N G T R E N N U N G tetronic acids, [2][3][4][5] such as the antitumour compound chloro-A C H T U N G T R E N N U N G thricin (1; [2] Figure 1) and the protein phosphatase inhibitor RK-682 (2). [6] Particular interest attaches to the tetronate polyethers tetronomycin (TMN) 3 [7] and tetronasin (TSN) 4 [8] because, although they are chemically almost identical, they differ from one another in their configuration at every one of ten comparable asymmetric centres ( Figure 1).…”

Penicillenols from Penicillium sp. GQ-7, an Endophytic Fungus Associated with Aegiceras corniculatum

“…6) These isolated compounds exhibit a wide range of biological and pharmaceutical activities 7,8) (including potent antibiotic 6,9) and antiviral 10,11) properties, mycotoxicity, 12) and cytotoxicity [13][14][15][16][17][18] ) and have attracted much attention of chemists, physicians, and biologists. 19,20) Biosynthetic studies have shown that the tetramic acid ring (2,4-pyrrolidinedione ring) is formed from a C 2 unit, and the nitrogen atom and the remaining two carbon atoms are derived from an amino acid. 21) All the 3-acyl tetramic acids can be considered as the results from the substitution of the hydrogens of C-5 with other functional groups and the substitution of the methyl group of C-7.…”

Synthesis and Antifungal Activity of Novel Furan‐2,4‐dione Derivatives Containing Substituted Phenylhydrazine Moiety

“…20 The entire synthetic route was efficient and simple. The cyclization of compound 2 was not a usual Lacey-Dieckmann reaction, 21 but rather an esterification. The ester group and the tert-butoxy group in compound 2 were converted to the carboxyl and hydroxyl group separately under acidic conditions.…”