Synthesis And Antimicrobial Activity Of Spiro-indolyl Diketopiperazines

Spiro-indolyl diketopiperazine is one of the most important partsof indolyl diketopiperazines. The class of spirotryprostatins, firstlyisolated from Aspergillus fumigates fermentation broth by Chinese andJapanese researchers, was an important type of spiro-indolyldiketopiperazines. They also found spirotryprostatin B could inhibit theG2/M progression of mammalian tsFT210cells, and determined theinhabitation of the growth of human cheonic myelogenous leukemiaK562cells and human promyelocytic leukemia HL-60cells. What’smore, these compounds also have some other good activities such astremors induction in insects, antimicrobiology and analgesia.According to the activities above, the synthesis of thesecompounds were reported during recent years. In this work, methylL-Trp hydrochloride was obtained by esterification and acidificationstarting with L-Trp. After that,1-chiral mixtures of methyl1-substituted-1,2,3,4-tetrahydro-β-carboline-3-carboxylates wereobtained from12aldehydes (propanal, n-butanal, n-pentanal, i-pentanal,aubepine, p-hydroxy benzaldehyde, benzaldehyde, p-nitrobenzaldehyde,vanillin, o-nitrobenzaldehyde, cuminal, i-butanal) via Pictet-Spenglerisoquinoline synthesis, and then the compounds were taken to give thesingle configurations (intermidates) in toluene-nitromethane mixture bythe crystallization induction asymmetric transformation (CIAT). Theintermidates and Fmoc-L-ProCl were mixed to give the dipeptidestructures by the Schotten-Baumann reaction, then the spiro-structyrewas obtained by an NBS rearrangement. Finally, the protecting groupwas removed and the ring was closed catalysing by base (morphiline),obtained four target compounds7a~7d and four NBS rearrangementopen-ring compounds10e~10h, six of which were reported for the firsttime. All intermediates and final products were characterized by meltingpoints,1D NMR,2D NMR, elemental analysis, and the relativeconfigurations of intermediates and compounds7a~7d were analysizedvia~1H-~1H NOESY. As the configurations of the starting meterials (L-Trp,Fmoc-L-Pro) were known and had never been changed, the absoluteconfigurations of other chiral carbons were refered.In addition, the mechanisms of CIAT and NBS rearrangement wereconfered according to the analysis of experimental phenomenon andstructural characterization of relative compounds. The mechanism ofCIAT may be that the C-N bond was broken to be C-sp2hydridaisatedtransition-state intermediate first and then re-bonded and made theconfiguration exchange. The conjugative effect of double bond in theintermidate showed more effect to NBS rearrangement, when the effectwas weak, it could be reacted as pinacol rearrangement; when strong, itcould be reacted as a nucleophilic addition, leading to differentproducts.During the antimicrobial experienment, we chose4becteria,including2Gram negative bacteria (Eschera coli and Pseudomonasaeruginosa) and2Gram positive bacteria (Bacillus sublis andStaphylococcus aureus), and4plant pathogenic fungi (Valsa mali,Alternaria alternate, Colletotirchum gloeosporioides and Alternariabrassicae) to test the antimicrobial activities of end products, andcompared with other indolyl diketopiperazines seperated or synthesizedearlier in our group. The results suggested that, the fourspiro-compounds showed both better antibacteria activity and betterantifigual activity, while the four open-ring compounds showed onlybetter antibacteria activity. This work will contribute to further studieson bacterial metabolism and high selective antibacterial activities.