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，以最大限度地提高生产重要有机化合物的效率。这些范围包括天然产物，其具有重要药用意义的非天然衍生物，手性构建块和试剂以及手性聚合物。重点放在简洁的设计和环保（“绿色”）执行。这些目标是通过对目标的多代追求和对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进行工艺改进研究，例如阿片衍生镇痛药。

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.