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

合成复杂有机分子的新方法的发展继续激励着化学、生物学和医学方面的发现。然而，尽管做了很多努力，但在生物活性天然产物和药物先导中经常发现的立体化学丰富的杂环仍然是有机合成的一个重大挑战。同样，用于选择性修饰或功能化这种复杂分子的可用反应也非常有限，这往往会阻碍或阻碍药物化学的努力。*为了解决这些问题，我们小组对杂环的合成和发现选择性地使这些分子官能化的新工具产生了长期的兴趣。在这里，我们建议探索一类不寻常的分子的化学，称为卤代醛，通常由于它们的不稳定性而被避免，但它们是合成杂环的理想关键。具体地说，我们将开发新的工艺来生成卤代醛并直接反应，从而绕过它们有问题的不稳定性。我们还将更广泛地探索这一策略在生成和反应其他不寻常的官能化醛方面的效用，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Salinosporamide C和Phormidolide，并将在改进的药物Eribuin(乳腺癌)的合成中展示这一新工艺的多功能性，该药物被认为是全合成中最复杂的药物。*为了配合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，我们将重点介绍一种廉价的催化剂(十钨酸盐)的使用，这种催化剂可以被可见光激活来从复杂的分子(包括天然产品和多肽)中去除氢原子。具体地说，我们将确定和开发可以与十钨酸盐结合使用的试剂，以用氮、氧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，移除一个氢原子，并用医学上相关的官能团(如氟、三氟甲硫基)取代它。在这里，我们将合成和研究用于杂环功能化的新型二苯磺酰胺类化合物，并开发一种药物先导化合物后期优化的平台技术。*总体而言，该计划将为杂环和天然产物的合成以及药物化学的试剂和反应提供使能工具。该计划还将鼓励与学术界和行业利益攸关方进行新的合作，并为总部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.*****