Program in chemoenzymatic synthesis: Morphine and Amaryllidaceae alkaloids, chiral building blocks, and design of new asymmetric protocols and reagents

化学酶合成项目：吗啡和石蒜科生物碱、手性结构单元以及新的不对称方案和试剂的设计

• 批准号: 262022-2013
• 负责人: Hudlicky, Tomas
• 金额: $ 5.03万
• 依托单位: Brock University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=632773
• 关键词: Program; chemoenzymatic; synthesis; Morphine; Amaryllidaceae

The central theme of our program involves a combination of chemical and biological methods to maximize efficiency in the manufacturing of important organic compounds. These range from natural products, their medicinally important unnatural derivatives, chiral building blocks and reagents, and chiral polymers. Emphasis is placed on brevity of design and environmentally benign ("green") execution. These goals are accomplished by multi-generational pursuit of the targets and continuous improvement in synthetic protocols. In addition, and through collaborations with industry, process improvement research is being conducted for compounds of commercial significance, for example, opiate-derived analgesics. During the next funding period, our well-integrated program expands in a number of new directions and is focused on the following areas: (1) Biotransformations of aromatics and provision of chiral building blocks for target-oriented synthesis. (2) Total synthesis of unnatural derivatives of Amaryllidaceae alkaloids with anti-cancer activities. (3) New generation designs for morphine (pain control) and Aspidosperma alkaloids (anti-cancer). (4) Catalytic and enzymatic methods for improved N-demethylation of opiates (pain control). (5) New [5+2] and [5+2+1] annulation protocols. (6) Synthesis of new derivatives of Tamiflu with anti-viral and anti-cancer activities. (7) Design of an enzyme mimic reagent for dihydroxylation of aromatics. Overall, the proposed research addresses focused investigations in asymmetric synthesis driven by the use of biological methods for a greater "green" component. The need for more efficient manufacturing processes is essential in order to save diminishing resources and protect the environment. Our research addresses future solutions to manufacturing of important compounds and materials. Highly qualified personnel at undergraduate, graduate, and postdoctoral levels will be trained in biocatalysis, synthesis, catalyst design, and process-development for the Canadian pharmaceutical sector and/or academic appointments. We expect to prepare marketable medicinal agents for commercialization.

我们计划的中心主题涉及化学和生物方法的结合，以最大限度地提高重要有机化合物的制造效率。这些范围包括天然产物、其药用重要的非天然衍生物、手性结构单元和试剂以及手性聚合物。重点放在设计的简洁性和环境友好（“绿色”）执行上。这些目标是通过多代人对目标的追求和合成方案的不断改进来实现的。此外，通过与工业界合作，正在对具有商业意义的化合物（例如阿片类镇痛药）进行工艺改进研究。在下一个资助期间，我们的综合项目将在许多新方向上扩展，并重点关注以下领域：（1）芳香族化合物的生物转化和为靶向合成提供手性结构单元。 (2)具有抗癌活性的石蒜科生物碱非天然衍生物的全合成。 (3)吗啡（止痛）和蜘蛛生物碱（抗癌）的新一代设计。 (4) 改进阿片类药物 N-去甲基化的催化和酶促方法（疼痛控制）。 (5) 新的[5+2]和[5+2+1]成环协议。 (6)具有抗病毒、抗癌活性的达菲新衍生物的合成。 (7)芳烃二羟基化酶模拟试剂的设计。总体而言，拟议的研究重点研究了通过使用生物方法驱动的不对称合成以获得更大的“绿色”成分。为了节省日益减少的资源并保护环境，需要更高效的制造工艺。我们的研究致力于解决重要化合物和材料制造的未来解决方案。本科生、研究生和博士后水平的高素质人员将接受加拿大制药行业和/或学术任命的生物催化、合成、催化剂设计和工艺开发方面的培训。我们期望制备适销对路的药物以进行商业化。