Application and Development of New Radical Synthetic Methods

该提案的重点是制药和农化工业感兴趣的分子合成新技术的发展。一个关键目标是开发将氟掺入药物的新方法。虽然氟在天然生物体中并不常见，但它是许多生物活性分子的重要组成部分。目前，超过20%的畅销药剂含有氟。虽然氟在医学上是有用的，但通常很难将其纳入分子中。本提案的第一和第二部分侧重于利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取关键的自由基中间体，包括紫外线。我们还将研究利用更环保和低能耗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，目前广泛用于药物制剂，包括肿瘤成像。使用18F有几个技术上的挑战：它的半衰期很短（2小时），氟很难加入到药物中。因此，能够迅速将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制见解，开发新的18f掺入技术，同时利用自由基和离子（氟）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。天然产物对制药工业至关重要，因为它们经常作为新药的基础。也就是说，目前市场上近50%的抗癌化合物要么是天然产物，要么是基于天然产物。在合成方面，天然产物合成的挑战之一是它们的快速组装以合成类似物。我们计划开发新的自由基和周环方法来合成生物活性大环内酯，使多个键形成过程在一个单一的反应。

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.