New Method for the Synthesis of Tetrahydrogenated

• Main Authors: Jiann-Jyh Huang, 黃建智
• Other Authors: Reuben Jih Ru Hwu
• Format: Others
• Language: en_US
• Published: 2002
• Online Access: http://ndltd.ncl.edu.tw/handle/08181523314712381613

博士 === 國立清華大學 === 化學系 === 91 === In this thesis, I developed a new method for the synthesis of tetrahydrogenated 1,4-benzodiazepinones and 1,5-benzodiazocinones, and performed mechanistic study on the DNA cleavage by a novel platinum complex PtCl(DMSO)[h2-C5H4SN(O)]. In the first part, I developed a new method by the use of haloanisoles to react with cyclic ureas under basic conditions. The corresponding heterocycles were obtained through ring expansion. In the second part, we measured the binding constants and studied photo-dissociation properties of PtCl(DMSO)[h2-C5H4SN(O)]. The information provides clues for the understanding of the mechanism for DNA cleavage by this organoplatinum complex. In the first part, methoxybenzynes were generated from the reaction of haloanisoles and NaN(SiMe3). These species were allowed to react with cyclic ureas DMEU or DMPU to give the corresponding benzodiazepines in 64—95% yields and benzodiazocines in 37—73% yields, respectively. The methoxy group in benzodiazepines and benzodiazocines were further O-demethylated by use of the same base at 185 °C to provide the corresponding hydroxyl analogues in almost quantitative yields (>98%). Furthermore, application of this new method afforded pyrrolo[2,1-c][1,4]benzodiazepines in 87—91% yields. We propose plausible mechanisms for the new transformation, which may involve cycloaddition between arynes and ureas followed by a ring opening of the strained intermediates. In the second part, the mechanism was investigated for DNA cleavage by a new organoplatium complex PtCl(DMSO)[h2-C5H4SN(O)]. I used NMR technique to detect the photo-dissociation property of the DMSO ligand in PtCl(DMSO)[h2-C5H4SN(O)]. Furthermore, application of ESI-MS technique to detect the reactive intermediate formed from the coordination of Pt center to DNA was accomplished. From the spectrum obtained, I conclude that the mechanism for DNA cleavage by PtCl(DMSO)[h2-C5H4SN(O)] was the binding of the platinum center to the amino group on C-6 in adenine residues and amino group on C-2 in guanine residues at the first stage. Upon photolysis of 350-nm UV light, the DMSO ligand attached to the platinum center in DNA would dissociate to generate adenine—platinum complexes accompanied with a breakage of the glycosidic C—N bond in adenine residues. For guanine residues in DNA, an intramolecular cyclization did not occur between the Pt and the N-7 nitrogen atoms of guanosine. Accordingly, breakage of the glycosidic C—N bond required assistance from piperidine under elevated temperatures.