Tetramic and Tetronic Acids as Scaffolds in Bioinorganic and Bioorganic Chemistry

Hindawi Publishing Corporation Bioinorganic Chemistry and Applications Volume 2010, Article ID 315056, 11 pages doi:10.1155/2010/315056 Review Article Tetramic and Tetronic Acids as Scaffolds in Bioinorganic and Bioorganic Chemistry G. Athanasellis,1, 2, 3 O. Igglessi-Markopoulou,1 and J. Markopoulos2 1 Laboratory of Organic Chemistry, School of Chemical Engineering, National Technical University of Athens, 15773 Athens, Greece 2 Laboratory of Inorganic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, 15771 Athens, Greece 3 ALAPIS Pharmaceuticals, R & D Centre, Pallini, 15302 Attiki, Greece Correspondence should be addressed to J. Markopoulos, Received 28 December 2009; Accepted 23 February 2010 Academic Editor: Spyros Perlepes Copyright © 2010 G. Athanasellis et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Tetramic and tetronic acids are naturally occurring molecules with a variety of biological activities. In this review article, we present the general strategies for the synthesis of these compounds and we reveal the functionalized groups that are responsible for their properties. We also set out their coordinating modes with up-to-date bibliographical references. 1. Introduction Tetramic acids, pyrrolidine-2,4-dione derivatives, are naturally occurring molecules synthesized by numerous organisms and found in a variety of natural products [1, 2]. This class of five membered heterocycles has attracted significant attention due to the broad range of biological activities they exhibit. This activity comprises of antibiotic and antiviral, cytotoxicity, mycotoxicity, as well as inhibition of the cell cycle. Various examples of tetramic acid derivatives isolated from the nature are streptolydigin which inhibits RNA polymerase [3], the melophlin family of compounds which have shown antimicrobial activity [4], equisetin and its homologue trichosetin with inhibitory activity against Gram positive bacteria [5, 6], and reutericyclin which exhibits a wide range of pharmacological activities [7, 8]. In addition, a series of derivatives have been patented by Bayer CropScience as ingredients for fungicidal and herbicidal use [9]. On the other hand, tetronic acids, 4-hydroxy-[5H] furan2-ones, are compounds with antibiotic, antiviral, antineoplastic, and anticoagulant activity [10, 11]. Compounds which have been isolated from natural products and exhibit such activity are tetronasin [12], RK-682 [2, 13], the wellknown family of compounds named vulpinic acids [14, 15] and many others. For a long time, we have been involved in the chemistry of tetramic and tetronic acids and the design of new strategies for the preparation of small heterocyclic molecules. Their synthesis has been accomplished based on a similar strategy starting from the appropriate precursors, suitably protected α-amino acids for tetramic and α-hydroxy acids for tetronic acids, using the N-hydroxybenzotriazole methodology for the synthesis of their active esters. 2. Synthesis of Tetramic Acids Owing to the importance of tetramic acid derivatives, numerous approaches to their synthesis have been developed. They mainly make use of amino acid-derived precursors whose stereochemical integrity remains more or less conserved in the structure of the products. Significant studies on the synthesis of such optically active compounds have been made by Ley et al. [16] who used a series of β-ketoamides as intermediates for the preparation of enantiomerically pure 3-acyl tetramic acids, based on the Lacey methodology for the synthesis of tetramic acids by Nacylation of α-amino acids (Scheme 1). On the other hand,Andrews et al. [17] provided an Nacyloxazolidine derivative of L-serine as a suitable precursor for the construction of chiral substituted tetramic acids with high enantiomeric excess. Other methodologies based on the enantioselective Lacey-Dieckmann cyclization, requiring strongly basic conditions, have also been reported [18, 19] 2 Bioinorganic Chemistry and Applications O O O O O R1 CHO (OEt)2 P S-tBu NaH S-tBu R1 R3 AgO2 CCF3 R2 HN OH O O O OH− R1 R3 CO2 R4 N O NR2 R1 R4 O 2 C R3 R2 Scheme 1: Synthesis of optically active tetramic acids by Leyet al. [16]. whereas Jouin and coworkers have proposed the use of Meldrum acid in the presence of isoprenyl chloroformate and DMAP reagents [20]. Recently,Schobert and Jagusch proposed an expedient synthesis of tetramic acids from α-amino esters, in which the cyclization route involved a domino addition-Wittig alkenation reaction with immobilized triphenylphosphoranylidene ketene under neutral nonracemizing conditions [21]. Acylation to 3-acyltetramic acids was then performed with the appropriate acyl chloride and boron trifluoride-diethyl etherate under microwave irradiation. This route was followed in the synthesis of natural products like reutericyclin (Scheme 2). Our first attempt to use N-hydroxybenzotriazole in the synthesis of heterocyclic compounds was made in the field of tetramic acids [22]. We applied the ”one-pot” synthetic strategy which comprises of a C-acylation reaction between the N-hydroxybenzotriazole ester of the appropriate optically active amino acid 1 and diethyl malonate 3. When the product was not the corresponding tetramic acid 4–6 but the C-acylation compound A, a cyclization reaction under basic conditions was performed to afford the corresponding tetramic acid 7–9 (Scheme 3). The crucial parameter on the synthesis of the Nacylated-3-ethoxycarbonyl tetramic acids 4–6 or N-H-3ethoxycarbonyl tetramic acids 7–9 is the molar ratio between the N-acylated amino acid 1 and diethyl malonate 3. We observed that when diethyl malonate 3 was used in molar excess (2 equiv.), the oily product containing the C-acylation compound A and diethyl malonate 3 was obtained. On the other hand, when diethyl malonate 3 was used in stoichiometric ratio (1 equiv.), the N-acetyl-3-ethoxycarbonyl tetramic acids 4–6 were obtained as white solids. The enantiomeric purity of the final products was tested by HPLC and the results were in the range 82%–96%ee. These results indicate the success of the proposed methodology to maintain the stereochemical integrity of the corresponding α-amino acids. Another advantage of the proposed methodology is that there is no need for isolating the intermediate N-hydroxybenzotriazole esters of the chiral α-amino acids, in contrast to previously described methodologies. This fact reduces the time for the synthesis of the desired products and is beneficial for the overall yield of the reaction (45%–75%). Therefore, the reaction is simple, inexpensive, easily scaled up and proceeds with low racemization. 3. Synthesis of Tetronic Acids Given our interest on the synthesis of tetramic acids and their coordination compounds, w (...truncated)