Total Synthesis of Unnatural Products

我们的研究项目主要集中在结构复杂分子的靶向合成，以及这些“内部固化”分子结构所具有的独特构象控制的生物开发。虽然我们从天然产品中获得了相当多的灵感，但我们的大多数目标都是经过设计的、非自然的分子，它们是为了实现特定的功能而创造的。在复杂分子结构和功能之间的交叉操作使我们的研究团队在合成方法，全合成，分子动力学，化学生物学和药物化学方面做出了重要而独特的贡献。

Our research program focuses on the target-directed synthesis of architecturally complex molecules, and on the biological exploitation of the unique conformational control possessed by these “internally rigidified” molecular structures. While we take considerable inspiration from natural products, most of our targets are designed, unnatural molecules that are created to fulfil a specific range of functions. Operating at the intersection between complex-molecule structure and function allows our research team to make important and unique contributions to synthetic methodology, total synthesis, molecular dynamics, chemical biology and medicinal chemistry. In the present application, we target three novel molecular architectures: oxasteroids, unnatural didemnaketals, and new molecular scaffolds derived from Thiele’s acid. All of our proposed work builds upon previous successes from our lab, but at the same time will push us into new research areas and will enable exciting new collaborations. The three Aims summarized below ultimately seek to address the same question that pervades all of our research: how does molecular shape control biological function? In our first Aim, we will extend our existing expertise in the iterative synthesis and cascade cyclization of oligo-vinyl ethers (e.g. Org.Lett.2011, 5552) to rapidly assemble unnatural steroid molecules that contain oxygen atoms at key points in the polycyclic framework. This will subtly tune the receptor-ligand affinities across different receptor isoforms, resulting in substantially modified biological properties relative to the parent steroid hormones estrone, estradiol, testosterone and progesterone. In our second Aim, we will capitalize on our recent publication of the first asymmetric synthesis of the core of the didemnakatals (Tetrahedron 2015, 2643), natural products with a range of activities that appear to stem from their ability to dissociate protein homo-dimers. We will create a family of unnatural didemnaketals in which the two pendent sidechains are the same. By studying these molecules, we will gain a deeper understanding of the biological roles of the didemnaketals themselves. In our third Aim, we will build upon our capacity to engineer constrained scaffolds for the generation of enzyme inhibitors (e.g. Org.Lett.2012, 5876). Extending our chemistry on Thiele’s ester derivatives (J.Org.Chem.2015, 8979; Featured Article) we will create a new rigid scaffold for generating inhibitors of carbohydrate processing enzymes. Together, these three conceptually related Aims will contribute to our growing understanding about the ability of subtle changes in conformational preference to elicit large differences in the biological responses of related proteins. Of equal importance, each Aim presents completely novel targets for complex molecule synthesis, which will ensure a robust HQP training environment.