Application and Development of New Radical Synthetic Methods

自由基合成新方法的应用与发展

• 批准号: RGPIN-2015-05856
• 负责人: Sammis, Glenn
• 金额: $ 2.55万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=613788
• 关键词: Application; Development; New; Radical; Synthetic

This proposal focuses on the development of new technologies for the synthesis of molecules that are of interest to the pharmaceutical and agrochemical industries. A key goal is the development of new methods for fluorine incorporation into medicinal agents. While not common in natural organisms, fluorine is a valuable component of many bioactive molecules. Currently, over 20% of the top selling pharmaceutical agents contain fluorine. While fluorine is medicinally useful, it is often difficult to incorporate into molecules. The first and second portions of this proposal focus on new technologies for the synthesis of particularly challenging fluorinated motifs using organic free radicals. We will access the key radical intermediates using several different methods, including UV light. We will also investigate new technology using more environmentally-friendly and lower-energy visible light in combination with photoredox catalysis.       A second important application of fluorine is its medicinal use in positron emission tomography (PET). The 18F isotope is PET-active and is currently utilized in medicinal agents for a wide range of medicinal applications, including tumor imaging. There are a several technical challenges associated with using 18F: it has a short half-life (2 hours) and fluorine is challenging to incorporate into medicinal agents. New technology that can quickly add 18F to pharmaceuticals would, therefore, be of high impact to the medical community. We will utilize mechanistic insight recently obtained in my laboratory for the development of new 18F-incorporation technology exploiting both radical and ionic (fluoride) mechanisms.       The third portion of the research proposal focuses on new methods for the rapid synthesis of bioactive natural products. Natural products are of vital importance to the pharmaceutical industry as they often serve as the basis of new medicinal agents. To wit, nearly 50% of all anti-cancer compounds currently on the market either are natural products or are based upon them. Synthetically, one of the challenges in natural product synthesis is their rapid assembly to enable the synthesis of analogs. We plan to develop new radical and pericyclic methodologies for the synthesis of bioactive macrolides that will enable multiple bond forming processes in a single reaction.

该提案的重点是开发制药和农业化学工业感兴趣的分子合成新技术。一个关键的目标是开发新的方法将氟掺入药物制剂。虽然在自然生物中并不常见，但氟是许多生物活性分子的重要组成部分。目前，超过20%的最畅销的药剂含有氟。虽然氟在医学上是有用的，但它通常难以掺入分子中。该提案的第一和第二部分重点关注使用有机自由基合成特别具有挑战性的氟化基序的新技术。我们将使用几种不同的方法来获得关键的自由基中间体，包括紫外光。我们还将研究使用更环保和更低能量的可见光与光氧化还原催化相结合的新技术。 氟的第二个重要应用是其在正电子发射断层扫描（PET）中的医学用途。18F同位素具有PET活性，目前用于广泛的医学应用，包括肿瘤成像。使用18F有几个技术挑战：它的半衰期短（2小时），氟很难掺入药物中。因此，能够快速将18F添加到药物中的新技术将对医学界产生重大影响。我们将利用我的实验室最近获得的机械见解，开发新的18F掺入技术，利用自由基和离子（氟化物）机制。 研究计划的第三部分侧重于快速合成生物活性天然产物的新方法。天然产品对制药业至关重要，因为它们通常作为新药剂的基础。也就是说，目前市场上所有抗癌化合物中有近50%是天然产物或基于天然产物。在合成方面，天然产物合成中的挑战之一是它们的快速组装以能够合成类似物。我们计划开发新的自由基和周环的生物活性的大环内酯的合成方法，这将使多个键形成过程中的一个单一的反应。