An expedient synthesis of 3-acyltetramic acids of the melophlin family from α-aminoesters and immobilized Ph3PCCO

Schobert, Rainer; Jagusch, Carsten

doi:10.1016/j.tet.2005.01.036

Cited by 45 publications

(21 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This matches the information from the 13 C NMR spectrum. The amide carbonyl carbon atom peaked at d = 169.2 ppm, which is similar to the shift reported for a melophlinate-BF 2 complex (d = 170.8 ppm) of known Z-structure [23]. A minor signal at d = 172.5 ppm could stem from an uncomplexed amide carbonyl carbon atom of the E-isomer by-product.…”

Section: Synthesis and Characterizationsupporting

confidence: 79%

“…The melophlins A (1-H) and C (2-H) were synthesized according to a published method [23]. The melophlin A complexes were prepared by addition of an aqueous solution of the corresponding metal acetates, Mg(OAc) 2 Â 4H 2 O or Zn(OAc) 2 Â 2H 2 O, to a methanolic solution of two equivalents of melophlin A analogously to a recently published method for the preparation of complexes of b-diketoacids [24].…”

Section: Synthesis and Characterizationmentioning

confidence: 99%

“…The La(III) complex also featured broadened 1 H NMR signals for these protons. For comparison the NMR data of melophlin A as recorded in CDCl 3 [23] A ruthenium(II)(arene) complex 3 of (5S)-melophlin C was obtained in 78% yield by reacting the latter in DMF solution with 1 equiv of triethylamine and then with half an equivalent of [Ru(p-cymene)Cl 2 ] 2 (Scheme 2). The 1 H NMR spectrum of chlorido(g 6 -p-cymene)(melophlinato C)ruthenium(II) (3) suggests that it is actually a 5:4:1 mixture of three isomers.…”

Section: Synthesis and Characterizationmentioning

confidence: 99%

See 2 more Smart Citations

Metal complexes of natural melophlins and their cytotoxic and antibiotic activities

Biersack

Diestel

Jagusch

et al. 2009

Journal of Inorganic Biochemistry

View full text Add to dashboard Cite

Section: Synthesis and Characterizationsupporting

confidence: 79%

Section: Synthesis and Characterizationmentioning

confidence: 99%

Section: Synthesis and Characterizationmentioning

confidence: 99%

See 1 more Smart Citation

Metal complexes of natural melophlins and their cytotoxic and antibiotic activities

Biersack

Diestel

Jagusch

et al. 2009

Journal of Inorganic Biochemistry

View full text Add to dashboard Cite

“…The melophlins P (1p), Q (1q) and R (1r) were prepared in four steps as previously described for the congeners B and C (Scheme 1) [11]. N-methylalanine t-butyl ester 2 was reacted with 3, the cumulated ylide Ph 3 P=C=C=O, immobilized on polystyrene [12] to give the tetramate 4 in 92% yield as product of a domino addition / intra-Wittig alkenation process.…”

Section: Chemistrymentioning

confidence: 99%

First Syntheses of Melophlins P, Q, and R, and Effects of Melophlins on the Growth of Microorganisms and Tumor Cells

Biersack¹,

Diestel²,

Jagusch³

et al. 2008

Chemistry & Biodiversity

Self Cite

View full text Add to dashboard Cite

((Abstract))The marine tetramic acids melophlin P, Q and R were synthesized for the first time in only four steps. Together with the congenerous melophlins A-C, and G they were also tested for antimicrobial and cytotoxic effects. Melophlins B, C, P, Q and R which share a 5-methyl residue showed some antibacterial activity, mainly in Grampositive bacteria. Melophlins B, C and R which have methyl branched 3-acyl side chains in common, inhibited the growth of cells of human KB-3-1 cervix carcinoma, A-498 kidney carcinoma and U-937 leukemia at IC 50 < 10 µM. They were similar in activity to cisplatin. Melophlin Q, also methyl branched, was astoundingly specific in inhibiting A-498 kidney cancer cells while melophlin P inhibited U-937 leukemia cells particularly well. The position of the methyl branch is decisive for the magnitude of the antiproliferative effect of the melophlin couples B/C and R/Q. 3 IntroductionThe melophlins 1 are N-methyl-3-acyltetramic acids that differ only in the substituents at C(5) (H or Me) of the pyrrolidine-2,4-dione core and in the chain length (C 12 to C 16 ) and branching of the 3-acyl residue (Fig. 1) Results and Discussion ChemistryThe melophlins P (1p), Q (1q) and R (1r) were prepared in four steps as previously described for the congeners B and C (Scheme 1) [11]. N-methylalanine t-butyl ester 2 was reacted with 3, the cumulated ylide Ph 3 P=C=C=O, immobilized on polystyrene [12] to give the tetramate 4 in 92% yield as product of a domino addition / intra-Wittig alkenation process. Since the natural products 1p-r had been shown by oxidative degradation to be 1:1 mixtures of (5R)-and (5S)-stereoisomers [3], racemic 2 was employed. Immobilization of the phosphorus ylide greatly facilitated removal of by-product phosphine oxide. Quantitative cleavage of the ester 4 with trifluoroacetic acid (TFA) gave 1,5-dimethylpyrrolidine-2,4-dione 5. This was 3-acylated under Jones' conditions [13] with BF 3 -diethyl etherate and the respective acyl chloride 6, which was racemic in the case of 6r, to furnish the corresponding 5 BF 2 -adducts 7 in a moderate 20-40% yield under classical thermal but in 30-65% yield under microwave irradiation conditions. The BF 2 -chelates 7 were finally converted to melophlins P, Q or R, respectively, by boiling in methanol. The required chlorides 6q and 6r were prepared from 13-methyltetradecanoic acid (13-MTA) [14] and 12-methyltetradecanoic acid (12-MTA), respectively. To assess the influence of metal chelation on the bioactivity we also prepared a stable Ca(II) complex of Biological evaluationKinases and phosphatases play a pivotal role in the signal transduction of cancer cells. As 3-acyltetramates were frequently reported to inhibit these enzymes, we looked for antiproliferative effects of a representative, structurally diverse subset of melophlins (A-C, G, P-R) in human KB-3-1 cervix, human epithelial A-498 kidney carcinoma, and U-937 leukemia cells as well as L929 mouse fibroblasts (Table 1). In terms of stereochemistry, the compounds were prepared and tes...

show abstract

“…6 is an expeditious synthesis of melophlin B from (S)-N-methyl-alanine tert-butyl ester hydrochloride and immobilized ylide PS-Ph 3 PCCO (Schobert and Jagusch 2005a). The melophlins are a class of N-methyl-3-acyltetramic acids recently isolated from the marine sponge Melophlus sarassinorum (order Astrophorida, family Ancorinidae) and structurally differing only in the substituents at C5 (R 5 = H or Me), the chain length (C 12 to C 16 ), and the branching of the 3-acyl residue (Wang et al 2003;Aoki et al 2000).…”

Section: Domino Syntheses Of Tetronic and Tetramic Acidsmentioning

confidence: 99%

Domino syntheses of bioactive tetronic and tetramic acids

Schobert

2006

Naturwissenschaften

Self Cite

View full text Add to dashboard Cite

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".

show abstract

An expedient synthesis of 3-acyltetramic acids of the melophlin family from α-aminoesters and immobilized Ph3PCCO

Cited by 45 publications

References 37 publications

Metal complexes of natural melophlins and their cytotoxic and antibiotic activities

Metal complexes of natural melophlins and their cytotoxic and antibiotic activities

First Syntheses of Melophlins P, Q, and R, and Effects of Melophlins on the Growth of Microorganisms and Tumor Cells

Domino syntheses of bioactive tetronic and tetramic acids

Contact Info

Product

Resources

About