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生产效率。这些范围从天然产物，其医学上重要的非天然衍生物，手性构件和试剂，以及手性聚合物。重点放在简洁的设计和环境友好（“绿色”）执行。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，通过与工业界的合作，正在对具有商业意义的化合物，例如从鸦片中提取的止痛剂进行工艺改进研究。在下一个资助期内，我们整合良好的项目将向多个新方向扩展，并专注于以下领域：（1）芳烃的生物转化和为靶向合成提供手性结构单元。(2)石蒜科生物碱非天然抗癌衍生物的全合成。(3)新一代吗啡（止痛）和Aspidosperma生物碱（抗癌）的设计。(4)用于改进阿片类药物的N-去甲基化（疼痛控制）的催化和酶促方法。(5)新的[5+2]和[5+2+1]环化方案。(6)具有抗病毒和抗癌活性的达菲新衍生物的合成。(7)芳香族化合物双羟化模拟酶试剂的设计。总的来说，拟议的研究地址集中调查不对称合成驱动的生物方法的使用更大的“绿色”的组成部分。为了节约日益减少的资源和保护环境，对更高效的制造工艺的需求至关重要。我们的研究致力于重要化合物和材料制造的未来解决方案。本科，研究生和博士后水平的高素质人员将接受加拿大制药部门和/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。我们希望能够为商业化提供有市场的药物。