| This dissertation is divided into six chapters. We synthesized various 1,3,5-triazines with electron-withdrawing groups such as esters, thioesters and amides; developed a new IDA reaction for synthesis of 3-aza-α-carboline with 2-aminoindole and 1,3,5-triazines, and explored total synthesis of Grossularine-1 on the basis of it; found a way of applying 3-aminoindoles and 1,3,5-triazines with Lewis Acid catalysis to synthesize fused pyrimidine compounds, and finished total synthesis of 4-aza-eudistomin Y1 based on this.In Chaper One, the Inverse electron-demand Diels-Alder (IDA) rections of indoles and 1,3,5-triazine were reviewed respectly, and the content and . purpose of the dissertation appeared.As electron-rich dienophile, indoles could react smoothly with strong electron-deficient dienes, for example 1,2,4,5-triazines, but it reacted hard with less reactive dienes such as 1,2,4-triazines or pyridazine, which existed higher temperature, bad regioselectivity or side reactions followed. 1,3,5-Triazine was a highly reactive diene, and could react with lots of electron-rich dienophile, such as enamine, ynamine, amidine and 5-member aromatic heterocycles including 5-aminopyrazoles, 5-aminoimidazoles, 2-aminopyrroles. however no report exists for 1,3,5-triazine IDA reactions with indoles. So exploring the IDA reaction of 1,3,5-triazine with indoles, it would expand the scope of 1,3,5-triazine IDA reaction and provide an entry to construct aza-carboline or fused pyrimidine.In Chapter Two, most literatures of studying 1,3,5-triazines IDA reactions always investigated of the scope of dienophiles but only a limited number of 1,3,5-triazines have been studied to date and focused on 1,3,5-triazines with electron-rich groups. Therefore, we planned to synthesize various 1,3,5-triazines with electron-withdrawing groups. Finally, we found a way of synthesizing 1,3,5-triazines with universal applicability, and finished synthesis of various 1,3,5-triazines with electron-withdrawing groups such as esters, thioesters and amides using the acyl chloride coupling. The solubility of 1,3,5-triazines was compared and S,S,S-triethyl 1,3,5-triazine-2,4,6-tris(carbothioate) exhibited excellent solubility in all three organic solvents tested. Subsquently, the LUMO energies of parts of 1,3,5-triazines was calculated and 1,3,5-triazine-2,4,6-tricarbonitrile gave the least calculated LUMO energy. These provided a practical and theoretical basis on IDA reactions of 1,3,5-triazines.In Chapter Three,α-carbolines are an interesting class of heterocycles with intriguing bilolgical activities. The synthetic mothods existed lower yields, rare materials, harsh conditions, or expensive Pd catalyst used. 2-aminoindoles were introduced as productive dienophiles in IDA reactions with various 1,3,5-triazines, which produced highly substituted 3-aza-α-carbolines in excellent yields. This methodology represents a new entry to 3-aza-α-carboline synthesis and should complement existing methods to readily access the 3-aza-α-carboline scaffold. Meanwhile, regiochemistry of the IDA product was predicted and it should proceed as a cascade reaction in a similar manner as the previously reported 2-aminopyrrole IDA reactions, and an X-ray structure of compound confirmed the predicted regiochemistry. Furthermore, the two ester groups of the IDA product were differentially reduced with 95% selectivity toward the C4-ester group, and it could lead to further applications of the product.To exploring the total synthesis of Grossularine-1, tetracyclic structure core was built by IDA reaction of 3-aza-α-carboline in Chapter Four. Grossularines belong to the class ofα-carboline natural products and exhibit potent antitumor activities. The synthetic mothods existed longer steps, rare metal catalyst used, or inconveniently synthesizing its analogs. In chapter Two, the reaction of 2-aminoindole with 2,4,6-tris(ethoxycarobonyl) -1,3,5-triazine gave the desired 9H-pyrimido[4,5-b]indole in excellent yield, So we envisioned that a second IDA reaction could allow us to install the final key piece of the grossularine heterocyclic nucleus, and it was proved workable in theory and practice. But it was disappointed that 3-aza-α-carboline and 5-aminoimidazoles was attempted, but no reaction was taken place. According to IDA reaction, ruducing the electronic density of diene, it could promote the reaction. So we changed two COOEt groups of 3-aza-α-carboline into two CN groups and substituted a NO2 group on benzene ring of indole, but no reaction was taken place yet. At last, we uesd 2-aminoindole as dienophile, and the same result was obtained. One possible explanation was that the electronic factor prohibited the reaction. Subsequently, we tried another way to form tetracyclic structure core that 2-aza-diene, which was formed between 2-aminoindole and glyoxalic acid, reacted with 5-aminoimidazoles. but it did not succeed yet. NO other route was tried, and the synthetic work came to a temporary conclusion.In Chapter Five, pyrimido[5,4-b]indoles has intriguing bilolgical activities which could be prepared by 3-aminoindole IDA reaction. Because of unstability of N1-H 3-aminoindole, we found 2,4,6-tris(ethoxycarbonyl)-1,3,5-triazine could react with 1H-N-Boc-3-aminoindole to give 1-aza-β-carboline in 95% yield under BF3.Et2O catalysis, and the regioselectivity was determind by comparing 1H-NMR with 2-aminoindole IDA product. Subsquently, these can come to conclusions from experiments that it could obtained more IDA products when the ratio of 3-aminoindole and triazine was 1 to 2, and that BF3.Et2O was essential and the quantity should be enough, and that 3-aminoindole was more reactive than 2-aminoindole under the same conditions. The application of various IDA reactions to synthesis of diverse pyrimidine-fused heterocycles will be expanded in the future. Based on the results in Chapter five, the total synthesis of 4-aza eudistomin Y1 was explored.Eudistomin Y1 was isolated from natural source recently and it exhibited antibacterial activity against Gram-positive bacteria. Because Eudistomin Y1 showed no cytotoxicity in the MTT assay at the concentration of 100μM, it could serve as lead compound for development of new antibiotics targeting some pathogenic strains of Gram-positive bacteria. On the results in Chapters three and five, N1-Bn 3-aminoindole hydrochloride and 2,4,6-tris(ethoxycarbonyl)-1,3,5-triazine were chosen as starting materials. After above IDA reactions, followed by selective reduction ester (Its selectivity was determined by comparing the 1H-NMR data), decarboxylation, oxidation of alcohol, condensation of aldehyde, reoxidation of alcohol, the precursor compound N,O-dibenzyl 4-aza eudistomin Y1 was obtained. Some conditions were tried, but no object was obtained.So the synthetic route was modified, and 1H-N-Boc-3-aminoindole and 2,4,6-tris(ethoxycarbonyl)-1,3,5-triazine were chosen as starting materials. After IDA reaction, two ester groups of IDA product were differentially reduced. But some decarboxylation conditions were tried on reductive compound, and it did not succeed. The synthetic route was modified again, and the reductive compound was oxidated to form carboxylic acid, then it was turn into acyl chloride. But Friedel-Craft reaction between acyl chloride and phenol did not take place, and only ester was obtain. So anisol which was chosen reacted with above acyl chloride, and it succeeded. At last, 4-aza eudistominY1 was obtained, which took place decarboxylation and demethyl using concentrated HCl in one-pot reaction。The accomplishment of 4-aza eudistominY1 laid the foundation of exploring its biological activities. |
PDF Full Text Request