Browsing by Author "Hendea, Daniela"

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    Diastereoselective alkylation of bi- and tricyclic lactimethers as a pathway to biologically relevant diketopiperazines
    (2007) Hendea, Daniela; Laschat, Sabine (Prof. Dr.)
    Bi- and tricyclic diketopiperazines prove to be useful templates for diastereoselective alkylation. This synthetic route should allow a novel access to diketopiperazine alkaloids, such as tryprostatins and quinocarcins. Tryprostatins are secondary metabolites of an Aspergillus fumigatus marine strain and are inhibitors of the mammalian cell cycle. Quinocarcin has moderate activity against Gram(+)-bacteria and its citrate salt has shown potent antitumor activity against several tumor cell lines. Retrosynthetically, tryprostatin B 20b could be obtained from indole-derived bicyclic diketopiperazine 65, by regioselective prenylation. Breaking the diketopiperazine 65 further down, it derives from two building blocks, the proline-derived lactim ether 63 and bromomethyl indole 66 that could be assembled by stereoselective alkylation at C-3 of diketopiperazine molecule 73. The direct approach to the total synthesis of tryprostatin B 20b was preceded by the investigation of the stereoselective alkylation on a model system, the lactimether derived from the diketopiperazine 73, with different electrophiles, leading to the alkylated lactim ethers 75. In order to confirm the preliminary stereochemical assignment of the lactim ethers 75 and the corresponding diketopiperazines 76 based on NMR and NOE experiments, the diketopiperazines cis-76a,d,e,h were prepared from methyl L-alaninate (77a), L-leucinate (77b), L-valinate (77c) and L-phenylalaninate (77d). L-proline derivative 69 was condensed with the amino acid esters 77 in the presence of EDC and HOBT to give intermediate dipeptides which were immediately cyclized to the diketopiperazines cis-76. The cis-diketopiperazines resulted by cyclization were compared by 1H, 13C-NMR, optical rotation and X-ray crystal structures with the corresponding diketopiperazines obtained by alkylation, leading to the correct assignment of the diastereomers 76. Based on these alkylation experiments, the alkylation reaction of the lactim ether 63 with the bromoindole derivative 66 was carried out under similar reaction conditions. The second major part consists in the synthetic approach to the quinocarcin system. Retrosynthetically, the quinocarcin system 83 can be obtained via allylsilane addition to an iminium ion, in the allyl-alkylated molecule 124. Breaking the molecule 126 down, it derives from two building blocks, the trycliclic diketopiperazine 134 and (E)-4-bromo-2-butenyl-trimethylsilane 128 that could be assembled by stereoselective alkylation at C-3 of diketopiperazine molecule 134.