Synthesis And Function Of Hydroxamic Derivatives And Chiral β-aminoAlcohol Ligands

Chiral pool synthesis serves as a classic and facile synthetic strategy of chiral substances from chiral natural products. With highly development of asymmetric synthesis, this strategy is still widely applied in chiral drug industry due to cheap enantiopure raw materials on large scale. Amino acids, the most significant category in natural chiral pool, have become pivotal building blocks in the synthesis of varied chiral compounds. In this dissertation, a review of pertinent background information for the topics of amino acids in chiral pool synthesis, natural sources, synthetic methods and applications of hydroxamic acids is provided in the introductory chapter. With amino acids as raw materials, the research work combines systematic experimental study of synthesis and bioactivity evaluation of hydroxamic acid derivates with synthesis and asymmetric catalysis of chiralβ-amino alcohols, aiming to explore new organic functional molecules and delve into wider applications of natural amino acid derivatives.The experiment part mainly consisted of the following four sections:1. Design and synthesis of analogues of NeoengleromycinNeoengleromycin, isolated from the fruiting bodies of the medicinal fungus Engleromyces goetzii, contains hydroxamic acid moiety which possess a wide spectrum of biological activities due to their inhibitory effect on various metalloenzymes. In order to develop new antitumor active compounds, analogues of the hydroxamic acid fraction of Neoengleromycin were synthesized, and their antitumor bioactivities were investigated as well in this section.80 hydroxamic acid derivates, including 18 hydroxamic acids and 62 hydroxamic esters, were synthes;zed from L-aspartic acid by selective esterification,N-acylation, condensation, deprotection and other steps.2. In vitro antitumor activities of hydroxamic acid derivativesWith utilization of the improved MTT method,28 hydroxamic acid derivatives were evaluated for their cytotoxic potential in vitro against seven human cancer cell lines (Raji, HO-8910, AGZY, HepG2, HL-60, Hep2, Hela). The initial structure-activity analysis was discussed based on the activity results. The results indicated that hydroxamic acid derivates exhibited potent cytotoxic activities against most cancer cell lines except Hela; the cytotoxic activities of hydroxamic esters were better than that of hydroxamic acids; the cytotoxic activities of hydroxamic acid derivatives depended on the type of substituent; cytotoxicity against lower concentration of Raji cell lines was much more effective than those with increasing concentration; 4 compounds (212c,212e,212i,212j) were found to have potent inhibitory activity against cancer cell lines close to or even better than DDP.3. Synthesis of novel chiralβ-amino alcoholsChiralβ-amino alcohols, as a vital class of small molecules, have been extensively employed as building blocks for the synthesis of Pharmaceuticals. Because of the chelating heteroatoms inβ-amino alcohols, they have also been used as chiral ligand or catalysts in a wide range of asymmetric reactions. In order to investigate the relationship between the structure of the chiral ligands and the enantioselectivity of reaction, as well as to prepare key synthon of bioactive oxazolidine derivatives, series of chiralβ-amino alcohols were synthesized from natural amino acids.In this section,29 new chiralβ-amino alcohols were synthesized from 10 natural amino acids (L-Ananine, L-Tryptophane, L-Phenylananine, L-Tryptophane, L-Leucine, L-Isoleucine, L-Proline, L-Valine, L-Methionine, L-Serine) via a four-step process: esterification,N-actylation, Grignard addition and LAH reduction, meanwhile, the synthetic procedure was optimized.4. Asymmetric addition of diethylzinc to benzaldehyde catalysed by chiralβ-amino alcoholsChiral amino alcohols have been employed to catalyse asymmetric addition of diethylzinc to benzaldehyde, and the enantiomeric excess (ee) of optically active secondary alcohols was determined by chiral HPLC. On the basis of this study, the following conclusions are drawn:(1) The enantioselectivity of N-dialkyl substitutions was distinctly higher than that of the monoalkyl ones. (2) Bulkier N-substituents can induce higher enantioselectivity. (3) The influence of C-substituents' carbon chain length on the enantioselectivity of catalysis corresponds with the "odd-even" carbon effect.All synthesized compounds mentioned in this dissertation were confirmed by1H NMR,13C NMR and MS spectral analysis.