Asymmetric Synthesis of Biological Active Amino Derivatives and Multi-target Drug

描述（由申请人提供）：我们的长期总体目标是开发新型有机合成方法，用于制备潜在的非外消旋氨基药物，这些药物可以影响不同的胆碱能途径并具有神经保护特性，这对于治疗神经退行性疾病将是有价值的。非外消旋化合物，特别是非天然氨基酸和杂环氨基化合物是重要的生物活性小分子，作为药物本身，或作为合成各种药物的手性结构单元。非天然氨基醇和氨基酸是药物发现的重要工具，当它们被用于治疗性肽模拟物作为化学探针以了解生物系统的机制时。因此，迫切需要新的合适的和简便的不对称方法来合成这些氨基化合物。本研究的主要目的是设计一种新型的手性硼化合物的合成方法，利用简便、环境友好的手性硼化合物，以高的立体选择性合成对映体纯的关键氨基化合物。本论文的主要工作是：1）设计新的不对称合成新的氨基醇、非天然氨基酸和具有药用潜力的多功能胺的方法。2)开发新的多功能尼古丁和苯并氮杂卓类似物，用于治疗阿尔茨海默病等神经退行性疾病。这些过程的合成方面，包括影响反应性和立体化学结果的结构因素，将通过计算方法进行研究。 因此，将建立新的大规模不对称方法，特别是用于合成神经学感兴趣的非天然氨基醇、氨基酸和杂环氨基衍生物，这将为制备重要的对映体纯的非天然肽和其他生物活性中间体开辟新的途径。同样，该项目将对教育产生积极影响， 来自波多黎各的大量弱势本科生，为他们提供合成有机化学和药物化学方面的先进知识和经验。PHS 398/2590（Rev.06/09）

DESCRIPTION (provided by applicant): Our long term general goal is to develop novel organic synthetic methodologies for the preparation of potential nonracemic amino drugs that can affect different cholinergic pathways and have neuroprotective properties, which will be valuable for the treatment of neurodegenerative diseases. Nonracemic compounds, particularly non natural amino acids and heterocyclic amino compounds are important biologically active small molecules as drugs themselves, or as chiral building blocks for the synthesis of a variety of drugs. Non-natural amino alcohols and amino acids are important tools in drug discovery and when they are used in therapeutic peptidomimetics as chemical probes to understand the mechanism of biological systems. Thus, new suitable and facile asymmetric methods for the synthesis of these amino compounds are strongly needed. The main objective in this proposal is to design novel synthetic transformations using facile and environmentally friendly chiral boron compounds with high stereo-selectivity for the preparation of enantiopure key amino compounds. The previous expertise obtained in the enantioselective borane-mediated reductions catalyzed by novel aminoborate esters will be directed to: 1) To design new protocols for the asymmetric synthesis of novel amino alcohols, and non-natural amino acid and multi-functional amines with pharmaceutical potential. 2) To develop new multifunctional nicotine and benzazepine analogues for the treatment of neurodegenerative diseases such as Alzheimer's Disease. The synthetic aspects of these processes, including the structural factors affecting the reactivity and stereo chemical outcome, will be studied by computational methods. Thus, new large scale asymmetric methodologies will be established, particularly, for the synthesis of non-natural amino alcohols, amino acids and heterocyclic amino derivatives of neurological interest that will open new avenues to prepare important enantiopure non-natural peptides and other bioactive intermediaries. Likewise, this project will provide a positive impact on the education of a significant number of disadvantage undergraduate students from Puerto Rico offering them advanced knowledge and experience in synthetic organic and medicinal chemistry. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page