Catalytic Asymmetric Synthesis of Piperidene Derivatives

描述（由申请人提供）：项目摘要：本提案的具体目标是：1）通过发现新的不对称催化反应，开发对映体富集的哌啶衍生物的新途径，2）建立制备生物活性生物碱产品中常见的各种手性哌啶基序的一般策略。哌啶结构基序是大量药用生物碱天然和非天然产物的共同特征。因此，认为哌啶衍生的分子具有显著的治疗潜力。迄今为止，这种结构特征经常通过亚胺离子的分子内曼尼希型环化来获得;然而，目前还没有能够以对映选择性方式促进该反应的催化剂。Jacobsen实验室最近的工作表明，手性硫脲催化剂可以活化N-烷基亚胺和N-酰基亚胺离子，使其发生许多不对称反应。这类催化剂可用于对映选择性的Mannich型环化反应.将制备各种已知的和新颖的硫脲催化剂，并筛选它们促进烯丙基硅烷和乙烯基硅烷衍生的N-酰基亚胺离子或N-烷基亚胺的对映选择性分子内曼尼希型反应的能力。硫脲催化剂的模块化性质将允许系统的催化剂优化。在确定这种转化的成功催化剂后，将进一步探索底物范围和机制。鉴于哌啶衍生的生物活性分子的丰富性，催化不对称分子内Mannich型环化的发展将对生物和化学界都具有重要意义。相关性：通过发现针对常见疾病的改进的、负担得起的疗法来改善公共健康的持续努力需要用于制备小分子药物的新的、创新的方法。本提案中描述的方法开发将为学术界和工业界提供一种有价值的工具，用于有效合成已知的生物活性分子，或者潜在地发现新的、以前未知的小分子药物。

DESCRIPTION (provided by applicant): Project Summary: The specific aims of this proposal are: 1) to develop novel routes to enatio-enriched piperidine derivatives through the discovery of new asymmetric catalytic reactions, and 2) to establish general strategies for the preparation of a variety of chiral piperidine motifs commonly found in biologically active alkaloid products. The piperidine structural motif is a common feature in a large number of medicinally relevant alkaloid natural and unnatural products. Consequently piperidine-derived molecules are believed to hold significant therapeutic potential. To date, this structural feature is frequently accessed via intramolecular Mannich-type cyclizations of iminium ions; however, there is currently no catalyst capable of promoting this reaction in an enantioselective fashion. Recent work in the Jacobsen laboratory has shown that chiral thiourea catalysts can activate N-alkylimines and N-acyliminium ions towards a number of asymmetric processes. It is proposed that such catalysts could be exploited for enantioselective Mannich- type cyclizations. A variety of known and novel thiourea catalysts will be prepared and screened for their ability to promote enantioselective intramolecular Mannich-type reactions of allylsilane- and vinylsilane- derived N-acyliminium ions or N-alkylimines. The modular nature of the thiourea catalysts will allow for systematic catalyst optimization. Upon identification of a successful catalyst for this transformation, the substrate scope and mechanism will be further explored. In light of the abundance of piperidine-derived biologically active molecules, the development of a catalytic asymmetric intramolecular Mannich-type cyclization would be of significance to both the biological and chemical communities. Relevance: The continuing effort to improve public health by the discovery of improved, affordable therapies for common diseases requires new, innovative methods for the preparation of small molecule drugs. The methods development described in this proposal would contribute a valuable tool to the academic and industrial communities for the efficient synthesis known biologically active molecules, or, potentially, for the discovery of new, previously unknown small molecule drugs.