Synthesis of nuphar thiophane dimers: developing pertinent chemical methods

描述(由申请人提供)：本提案描述了一项基于生物合成原理的nuphar二聚体的全合成计划，该计划是在开发用于构建喹诺利定生物碱的新化学方法的基础上提出的。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，起源的生物是Nuphar Japan onicum DC和Nuphar Pumilum(Timm.)DC，在中国和日本的传统医学中已经被开了几个世纪的处方，可以作为正常饮食的一部分食用，这表明它们有预防癌症的潜力。还将开发催化不对称安装萜基立体中心的化学方法；将在这些生物碱和萜类格地二酮上证明原理。该计划的最终目标将是天然产品化学的整体方法，包括生物遗传学解释、方法开发和推广、全合成和类似物合成，以及最终的药理发现。这项工作自然将支持工业药物开发和药理学，并有望为工业上难以获得的药物的初步调查提供一个模式，例如系统无害但复杂的天然产品；或针对被忽视的热带病(NTDS)的化合物。与公众健康相关的天然产品不断为合成化学的新方法和广泛进步的发展提供动力和灵感。然而，经验发现和化学宿命的必要性怎么强调都不为过，化学认识仍处于初级阶段这一不可避免的结论也不为过。对复杂化学体系的探索提供了一条通往化学基础发现的途径，这些发现最终能够实现并加速新制药的工业管道。天然产物的合成反过来又带来了日益复杂和生物相关性的分子，为治疗科学提供了基础，也为人类病理学提供了一个视野。

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.