Discovery and Development of Enabling Tools for the Synthesis and Late-Stage Modification of Natural Products and Pharmaceuticals

合成复杂有机分子新方法的发展不断激发化学、生物学和医学领域的新发现。然而，尽管付出了巨大的努力，在具有生物活性的天然产物和药物先导物中发现的富含立体化学的杂环仍然是有机合成的一个重大挑战。同样，选择性修饰或功能化这些复杂分子的可用反应也非常有限，这常常阻碍或阻碍药物化学的努力。******为了解决这些问题，我们的团队对杂环的合成和发现新工具来选择性地功能化这些分子产生了长期的兴趣。在这里，我们建议探索一类不寻常的分子的化学性质，称为-卤代醛，由于其不稳定性而经常被避免，但代表了杂环合成的理想关键。具体来说，我们将开发新的工艺来生成-卤代醛并直接反应它们，从而绕过它们的不稳定性问题。我们还将更广泛地探索这种策略在生成和反应其他异常功能化醛方面的效用，并探索它们在合成结构复杂的天然产物中的应用。例如，我们将利用-氯醛合成抗癌海洋天然产物盐孢酰胺C和佛米多内酯，并将在改进的药物艾曲布林（乳腺癌）的合成中展示这一新工艺的多功能性，艾曲布林被认为是全合成最复杂的药物。******为了补充我们在杂环合成方面的努力，我们还将开发新的工具，使药物化学家能够选择性地修饰和改善这些分子的性质。在这里，我们将专注于使用一种廉价的催化剂（十钨酸盐），它可以被可见光光激活，从复杂分子（包括天然产物和肽）中去除氢原子。具体来说，我们将确定和开发可以与十钨酸盐结合使用的试剂，用氮基、氧基或碳基官能团取代这些氢原子。我们还确定了一类独特的分子（二苯磺酰胺），它们能够选择性地激活杂环，去除氢原子并用与医学相关的官能团（例如氟、三氟甲基硫）取代它。在此，我们将合成和研究用于杂环功能化的新型二苯磺酰胺，并为药物先导物的后期优化开发平台技术。******总体而言，该计划将为杂环化合物和天然产物的合成以及药物化学的试剂和反应提供有利的工具。该计划还将激发与学术界和工业界利益相关者的新合作，并为HQP.*****提供丰富的多学科培训环境

The development of new methods to synthesize complex organic molecules continues to inspire discoveries in chemistry, biology and medicine. However, despite much effort, stereochemically rich heterocycles that are often found in biologically active natural products and drug leads still present a significant challenge for organic synthesis. Likewise, the available reactions for selectively modifying or functionalizing such complex molecules are significantly limited, which often prevents or obstructs efforts in medicinal chemistry. ******To address these issues, our group has developed a longstanding interest in the synthesis of heterocycles and the discovery of new tools to selectively functionalize these molecules. Here, we propose to explore the chemistry of an unusual class of molecules known as -haloaldehydes that are often avoided due to their instabilities but represent ideal linchpins for heterocycle synthesis. Specifically, we will develop new processes to generate -haloaldehydes and directly react them, thus circumventing their problematic instabilities. We will also more broadly explore the utility of this strategy for generating and reacting other unusual -functionalized aldehydes and explore their application in the synthesis of structurally complex natural products. For example, we will exploit -chloroaldehydes in the synthesis of the anticancer marine natural products salinosporamide C and phormidolide, and will demonstrate the versatility of this new process in an improved synthesis of the drug eribulin (breast cancer), which is considered the most complex drug to be made by total synthesis. ******To compliment our efforts in heterocycle synthesis, we will also develop new tools that will allow medicinal chemists to selectively modify and improve the properties of these molecules. Here, we will focus on the use of an inexpensive catalyst (decatungstate) that can be photo-activated by visible light to remove hydrogen atoms from complex molecules (including natural products and peptides). Specifically, we will identify and exploit reagents that can operate in combination with decatungstate to replace these hydrogen atoms with nitrogen-, oxygen- or carbon-based functional groups. We have also identified a unique class of molecules (dibenzensulfonamides) that are capable of selectively activating heterocycles, removing a hydrogen atom and replacing it with medicinally relevant functional groups (e.g., fluorine, trifluoromethylthio). Here, we will synthesize and investigate new dibenzensulfonamides for heterocycle functionalization and develop a platform technology for late-stage optimization of drug leads. ******Overall, this Program will provide enabling tools for the synthesis of heterocycles and natural products, and reagents and reactions for medicinal chemistry. This Program will also inspire new collaborations with academic and industry stakeholders and sustain a rich, multidisciplinary training environment for HQP.*****