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发化学，生物学和医学的发现。然而，尽管做了大量的努力，富含立体化学的杂环化合物，通常存在于具有生物活性的天然产物和药物先导物中，仍然对有机合成提出了重大挑战。同样地，用于选择性修饰或官能化此类复杂分子的可用反应是显著有限的，这常常阻止或阻碍药物化学中的努力。** 为了解决这些问题，我们的团队对杂环化合物的合成和发现选择性官能化这些分子的新工具产生了长期的兴趣。在这里，我们建议探索化学的一类不寻常的分子称为卤醛，往往避免由于其不稳定性，但代表理想的关键杂环合成。具体来说，我们将开发新的工艺来产生卤醛和直接反应，从而规避他们的问题不稳定性。我们还将更广泛地探索这种策略的效用，用于生成和反应其他不寻常的官能化醛，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-chloroaldehyde在合成的抗癌海洋天然产物salinosporamide C和phormidtine，并将证明这一新的过程中的多功能性，在一个改进的合成药物艾日布林（乳腺癌），这被认为是最复杂的药物由全合成。* 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（十聚钨酸盐），它可以被可见光激活，以从复杂分子（包括天然产物和肽）中去除氢原子。具体来说，我们将识别和开发可以与十聚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。我们还鉴定了一类独特的分子（二苯磺酰胺），其能够选择性地活化杂环，除去氢原子并用医学相关的官能团（例如，氟、三氟甲硫基）。在这里，我们将合成和研究用于杂环功能化的新的二苯磺酰胺，并开发用于药物先导物后期优化的平台技术。 * 总的来说，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有利的工具。该计划还将激发与学术和行业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.*****