Synthesis of nuphar thiophane dimers: developing pertinent chemical methods

描述（由申请人提供）：该提案描述了基于生物合成原理的nuphar二聚体的全合成计划，并受到构建喹哪嗪生物碱的新化学方法开发的推动。在关于这些化合物的有前途但不完整的生物学知识的推动下，该路线将侧重于实用性和可扩展性，以促进药理学研究。值得注意的是，起源的生物体，日本努哈（Nuphar japonicum DC）和短小努哈（Nuphar pumilum（TIMM.）DC在中国和日本的传统医学中已经开了几个世纪的处方，可以作为正常饮食的一部分食用，这表明它们有可能成为癌症缓解剂。化学方法也将开发的催化，不对称安装的萜烯立构中心;证明的原则将证明这些生物碱和萜烯gnididione。该计划的最终目标将是天然产物化学的整体方法，包括生物遗传学阐明，方法开发和扩展，全合成和类似物合成，以及最终的药理学发现。这项工作将自然地支持工业药物开发和药理学，并有望为工业上无法获得的药物的初步研究提供模型，例如系统良性但复杂的天然产品;或针对被忽视的热带疾病（NTD）的化合物。天然产品不断为新方法的开发和合成化学的广泛进步提供动力和灵感。然而，经验发现和化学普罗维登斯的必要性怎么强调都不过分，化学认识仍处于婴儿期这一不可避免的结论也不过分。探索复杂的化学系统提供了一条通往化学基础发现的途径，最终实现并加速新药的工业管道。天然产物的合成反过来又带来了越来越复杂和生物相关性的分子，为治疗科学提供了基础，并为人类病理学提供了视野。

DESCRIPTION (provided by applicant): This proposal describes a plan for the total syntheses of nuphar dimmers based on biosynthetic rationale, and spurred by the development of new chemical methods for the construction of quinolizidine alkaloids. Impelled by the promising, yet incomplete biological knowledge regarding these compounds, the route will focus on practicality and scalabilty to facilitate pharmacological studies. Notably, the organisms of origin, the dried rhizomes of Nuphar japonicum DC and Nuphar pumilum (TIMM.) DC, have been prescribed for centuries in traditional Chinese and Japanese medicine, and can be eaten as part of a normal diet, suggesting their potential as cancer prophylaxes. Chemical methods will also be developed for the catalytic, asymmetric installation of terpenyl stereocenters; proof of principle will be demonstrated on these alkaloids and the terpene gnididione. The ultimate objective of this program will be a holistic approach to natural products chemistry, encompassing biogenetic elucidation, methods development and extension, total synthesis and analogue synthesis, and eventually pharmacological discovery. This work will naturally bolster industrial drug development and pharmacology, and will hopefully provide a model for the preliminary investigation of industrially inaccessible drugs, such as systemically benign, but complex natural products; or compounds that target neglected tropical diseases (NTDs). PUBLIC HEALTH RELEVANCE Natural products continually provide impetus and inspiration for the development of new methods and broad advances in synthetic chemistry. However, the necessity of empirical discovery and chemical providence cannot be overstated, nor can the inescapable conclusion that chemical understanding remains in its infancy. Exploration of complex chemical systems provides a route to fundamental discoveries in chemistry that ultimately enable and hasten the industrial pipeline of new pharmaceuticals. Natural products synthesis in turn brings within reach molecules of increasing complexity and biological relevance, providing a foundation for the therapeutic sciences and a horizon to human pathology.