【作者】 顾焕；

【导师】 史真；

【作者基本信息】 西北大学 ， 化学， 2007， 博士

【摘要】 酶在生物体内的作用是十分重要的，它使生物体内的化学反应在温和的生理条件下具有高活性、高选择性、高专一性的功能，是我们体外一般化学反应无法比拟的。生物体内酶的功能和作用机理逐渐被人们认识清楚。因此，近几年来有关辅酶仿生化学的研究成为国际、国内兴起的一个活跃领域，是当前有机化学的研究热点。四氢叶酸辅酶（THF）在生物体中的功能和作用，以及它的仿生合成，是近年仿生化学研究的重要课题。四氢叶酸辅酶（THF）在生物体内的作用是转移不同氧化态的一碳单元，当一碳单元处于甲醛氧化态时，活性部分是具有五元环状结构的咪唑烷环。模拟四氢叶酸辅酶一碳单元转移反应的仿生有机合成就是借鉴辅酶中起主要作用的部分（活性中心），用与其结构相类似而又简单的化合物作为四氢叶酸辅酶的模型化合物，使之与各种亲核试剂作用，将不同氧化态的一碳单元转移给亲核试剂，合成具有生理活性的化合物，为有机化合物或具有生物活性的化合物提供新的合成方法。以较易制备的苯并咪唑烷化合物作为四氢叶酸辅酶（THF）的新模型，使它们与亲核试剂作用，将甲醛氧化态的一碳单元转移给亲核试剂，则可以实现模拟四氢叶酸辅酶（THF）转移一碳单元的仿生合成。Mannich碱是重要的有机化合物，Mannich碱及其衍生物的应用已深入到人类生活资料生产的各个领域，特别是在医药工业中具有广泛的应用价值。本文模拟四氢叶酸辅酶（THF）转移一碳单元的反应，利用本课题组首先提出的四氢叶酸辅酶（THF）新模型1，3-二甲基苯并咪唑烷，在酸性条件下，以碱性胺作为接受一碳转移的亲核试剂，完成了8种Mannich碱的新合成方法研究，且以旋光性的芳香胺作为接受一碳转移的亲核试剂，得到了旋光保持一致的Mannich碱新药中间体。这种仿生合成可以被看成为隐蔽的Mannich反应，为从羧酸制备Mannich碱提供了一条重要途径。在心血管用药中，某些四氢异喹啉类化合物及其衍生物对心律失常、心肌缺血、高血压和心力衰竭有显著的治疗作用，对四氢异喹啉类化合物及其衍生物进行结构改造，进而发展成为药品成为当今医药的研发重点。本文以1，3-二甲基苯并咪唑碘盐和2-取代的1，3-二甲基苯并咪唑碘盐为原料，采用了NaBH₄还原和Grignard试剂加成两种方法，制备了13种1，3-二甲基苯并咪唑烷和2-取代的1，3-二甲基苯并咪唑烷作为四氢叶酸辅酶（THF）一碳单元转移新模型，在酸性条件下，以2-（3，4-二甲氧基苯基）乙胺作为接收一碳转移的亲核试剂，完成了13种重要的四氢异喹啉类化合物的新合成方法研究。这种新的仿生合成方法为从羧酸和卤代物为起始原料制备四氢异喹啉类化合物提供了新的方法，为新药的制备提供了新的思路。由四氢-β-咔啉类化合物，可制得多种具有较好抗病毒、抗菌和抗肿瘤活性的β-咔啉类生物碱，因而四氢-β-咔啉类化合物的合成受到人们的广泛关注。本文以1，3-二甲基苯并咪唑碘盐和2-取代的1，3-二甲基苯并咪唑碘盐为原料，采用了NaBH₄还原和Grignard试剂加成两种方法，制备了9种1，3-二甲基苯并咪唑烷和2-取代的1，3-二甲基苯并咪唑烷作为四氢叶酸辅酶（THF）一碳单元转移新模型，在酸性条件下，以色胺作为接受一碳转移的亲核试剂，完成9种四氢-β-咔啉类化合物的新合成方法研究。这种新的仿生合成方法，以羧酸和卤代物为起始原料制备四氢-β-咔啉类化合物，可为工业生产β-咔啉类生物碱提供更为方便的条件。以苯并咪唑烷作为四氢叶酸辅酶（THF）一碳单元转移新模型，反应副产物N，N′-二甲基邻苯二胺，可回收再次生成苯并咪唑烷重新参与反应，这一模型具有其它模型无法代替的成本和环保优势，符合绿色有机化学的发展方向。更多还原

【Abstract】 Enzomye acts important role in body, it can make the chemical reaction finished in mild physiological condition with high activity, high selectivity and high singularity and has the incomparable function with the usual chemical reaction. People have gradually cognized the function and mechanism of enzomye. So, in recent years, it is the hotspot about the research of coenzomye in biochemistry, esspecially in organic chemistry field.The tetrahydrofolate coenzyme is involved in the biochemical transfer of a one-carbon fragment at different oxidation levels. When the one-carbon unit is at the formaldehyde oxidation level, the imidazolidine with a five-membered ring structure is the active site. If benzimidazoline is used as tetrahydrofolate coenzyme model to react with nucleophilic reagent, the one-carbon unit at the formaldehyde and oxidation level will be transferred to the nucleophilic reagent, and the biomimetic synthesis to initiate the one-carbon unit transfer reaction of tetrahydrofolate coenzyme will be accomplished.Mannich alkali are an important organic compounds and have wide utility in the live especially in medical industry, dyeing industry. In this work, a convenient synthetic method for the preparation of Mannich alkali from carboxylic acids is provided with benzimidazoline used as tetrahydrofolate coenzyme model at formadehyde oxidation level. Thus the biomimetic synthesis of Mannich alkali was successfully accomplished by using benzimidazoline with alkaline amine as nucleophile reagents under the condition of acid. The novel synthetical method of 8 kind of Mannich alkali was finished including preserved configuration of Mannich alkali, this new sythetic method can be regarded as a covert Mannich reaction, it provides a important route to prepare Mannich alkali from carboxlic acid.1,2,3,4-Tetrahydroisoquinoline derivatives have prominent effects on cure the diseases of cardiopathy. So, the modification for the structures of 1,2,3, 4-tetrahydroisoquinone derivatives to find new drugs has been the emphasis of recent drug research. In this paper, we provided biomimetic synthetic methods for tetrahydroisoquinoline by using the benzimidazoline as a new tetrahydrofolate coenzyme model with 2-（3, 4-dimethoxyphenyl）ethylamine as nucleophile reagents under the condition of acid. Simultaneously we prepared benzimidazolines with two methods by the of reduction benzimidazolium salts with NaBH₄ and Grignard addition with benzimidazolium salts. Thus we provided a new biomimic synthetic method for 13 kind of tetrahydroisoquinoline starting from carboxylic aicd and halid, gave a new idea of the synthesis for new drugs.It can make many kind ofβ-carboline alkaloids which have bioactivity to antibacterium, antivirus and antitumor to start from 1,2,3,4-tetrahydro -β-carboline. So, it gets many attention of chemists to develop the methods for this kind of compounds. We provided biomimetic synthetic methods for tetrahydro-β-carboline by using the benzimidazoline as a new tetrahydrofolate coenzyme model with tryptamine as nucleophile reagents under the condition of acid. Simultaneously we prepared benzimidazolines with two methods by the reducton of benzimidazolium salts with NaBH₄ and Grignard addition with benzimidazolium salts. Thus we provided a new biomimic synthetic method for 9 kind of tetrahydro-β-carboline starting from carboxylic aicd and halid. A convenient synthetic method for preparing tetrahydro-β-carboline was provided.Benzimidazoline as a new tetrahydrofolate coenzyme model to perpare alkali can bring a byproduct N, N’-dimethylaniline, this byproduct can be recycled to produce benzimidazoline as raw materials. So, the model of benzimidazoline has predominance compared with other model in cost and environmental protection, meets the requirement of green organic chemistry.更多还原