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

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。这些产品包括天然产物、具有重要药用价值的非天然衍生物、手性构建块和试剂以及手性聚合物。强调设计的简洁性和对环境友好的(“绿色”)执行。这些目标是通过几代人对目标的追求和合成协议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进行工艺改进研究，例如阿片剂衍生的镇痛剂。在下一个资金阶段，我们整合良好的计划将在许多新的方向上扩展，并集中在以下领域：(1)芳烃的生物转化和为目标导向的合成提供手性构建块。(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)和阿司匹林生物碱(抗癌)的新一代设计。(4)改进阿片类药物N-脱甲基的催化和酶促方法(止痛)。(5)新的[5+2]和[5+2+1]环扎方案。(6)具有抗病毒和抗癌活性的新型达菲衍生物的合成。(7)芳香族二羟基化模拟酶试剂的设计。总体而言，拟议的研究针对不对称合成中的重点研究，这些不对称合成是由生物方法驱动的，目的是为了获得更大的“绿色”成分。为了节约日益减少的资源和保护环境，需要更有效的制造工艺是至关重要的。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。本科生、研究生和博士后级别的高素质人员将接受生物催化、合成、催化剂设计和工艺开发方面的培训，用于加拿大制药部门和/或学术任命。我们希望为商业化准备适销对路的药剂。

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.