【作者】 陈永飞；

【导师】 许鹏飞；

【作者基本信息】 兰州大学 ， 有机化学， 2010， 博士

【摘要】 第一：在对Bcr-Abl激酶抑制剂进行综述的基础上,通过计算机辅助设计并结合已有的抑制剂建立了药效团模型；在对该模型分析的基础上,找到了这些抑制剂的共同特征,设计合成了三类Bcr-Abl激酶抑制剂(苯并咪唑、苯并噻吩和噻二唑类),并对这些抑制剂进行了活性测试,结果表明,苯并噻吩类化合物具有较好的活性。第二：在对金属催化呋喃环及其衍生物合成方法综述的基础上,研究了K’OBu和Cu(OTf)2/PPh3体系催化2-炔丙基-1.3-二羰基化合物的分子内环化反应。使用易得的原料2-炔丙基-1.3-二羰基化合物、无机碱(KO’Bu),廉价催化剂(Cu2+)和配体(PPh3)在甲醇-二氯甲烷中高产率合成了2-亚甲基二氢呋喃,并将2-亚甲基二氢呋喃在CF3COOH-甲醇体系中转化为呋喃衍生物。该方法具有直接高效易于操作的特点。第三：在对Nikkomycin B的N-端氨基酸片断合成综述的基础上,对Nikkomycin B的N-端氨基酸片断的不对称合成进行了探索。采用手性氧化腈和烯丙醇进行1,3-偶极环加成反应合成手性异噁唑啉为关键步骤；随后经多步官能团转化得到Nikkomycin B的N-端氨基酸内酯片段。但遗憾的是内酯的相对构型与天然产物构型不符。第四：在对石蒜科生物碱Lycorane合成方法综述的基础上,对α-Lycorane的不对称合成进行了探索。通过手性奎宁硫脲催化硝基烯和不饱和酯的双迈克尔加成高效构筑了α-Lycorane的三个手性中心；随后经多步官能团转化得到重要前体101,为进行α-Lycorane不对称合成奠定了基础。更多还原

【Abstract】 The thesis aims at the studies on four parts as following:Part I The design, synthesis and activity assay of Bcr-Abl kinase inhibitorsBased on the review of Bcr-Abl kinase inhibitors, we were interested in building a pharmacophore model. A series of compounds (including benzo[d]imidazole, benzo[b]thiophene and thiadiazol) as potential inhibitors were designed and synthesized. For the inhibitor assay, some compounds were observed to have inhibitory activities, and the result indicated benzo[b]thiophene derivatives showed good inhibitory activities.PartⅡCu(Ⅱ)-catalyzed cyclization reactionBased on the review of synthetic method for furan derivatives, the intramolecular cyclization reaction of 2-propynyl-1,3-dicarbonyl compounds was explored. The reaction was performed using readily available materials (2-propynyl-1,3-dicarbonyl compounds), an inexpensive catalyst (Cu2+ salt) and ligand (PPh3) under very mild basic conditions in good to excellent yields. Then,5-methylene-4,5-dihydrofurans were easily converted into the corresponding furans under acidic conditions. The reaction provides a new approach to dihydrofurans in a direct, efficient and facile manner.Part III Asymmetric synthesis of N-terminal amino acid component of Nikkomycin BBased on the review of synthetic method for N-terminal amino acid component of Nikkomycin B, the asymmetric synthesis of N-terminal amino acid component of Nikkomycin B was explored.1,3-Dipolar cycloaddition reaction involving (E)-p-methoxycinnamyl alcohol and chiral nitrile oxide to construct the chiral isoxazoline was used as the key step. N-terminal amino acid component of Nikkomycin B was synthesized by subsequent functional group transformation. To our regret, the configuration is not consistent with the natural N-terminal amino acid component of Nikkomycin B.Part IV Asymmetric total synthesis of a-Lycorane Based on the review of synthetic method for Lycorane, the asymmetric synthesis of a-Lycorane was explored. Three stereogenic centers of a-Lycorane were effectively constructed with high diastereoselectivity and enantioselectivity via chiral thiourea catalyzing tandem Michael addition involving nitrostyrene and unsaturated ester. The key compound 101 was synthesized by subsequent functional group transformation, which established foundation for further asymmetric synthesis of a-Lycorane.更多还原