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。****在目前的应用中，我们针对三种新的分子结构：氧化小行星，非天然双金属和来自Thiele酸的新分子支架。我们提出的所有工作都建立在我们实验室以前的成功基础上，但同时也将推动我们进入新的研究领域，并将实现令人兴奋的新合作。下面总结的三个目标最终寻求解决我们所有研究中普遍存在的同一个问题：分子形状如何控制生物功能？***在我们的第一个目标中，我们将扩展我们在低聚乙烯基醚的迭代合成和级联环化方面的现有专业知识(例如Org.Lett。2011, 5552)快速组装非天然类固醇分子，这些分子在多环框架的关键点上含有氧原子。这将微妙地调整不同受体同种异构体之间的受体配体亲和力，导致相对于母体类固醇激素雌酮、雌二醇、睾酮和黄体酮的生物学特性发生实质性改变。***在我们的第二个目标中，我们将利用我们最近发表的第一个不对称合成didemnakatals核心（Tetrahedron 2015, 2643），具有一系列活性的天然产物，似乎源于它们解离蛋白质同源二聚体的能力。我们将创建一个非自然的双金属家族，其中两个侧链是相同的。通过研究这些分子，我们将对双金属本身的生物学作用有更深的了解。***在我们的第三个目标中，我们将以我们的能力为基础，为酶抑制剂的产生设计约束支架(例如Org.Lett。2012年,5876年)。在Thiele的酯衍生物上扩展我们的化学。2015年,8979年;我们将创造一种新的刚性支架来生成碳水化合物加工酶的抑制剂。***总之，这三个概念上相关的目标将有助于我们越来越多地了解构象偏好的细微变化能够引起相关蛋白质的生物反应的巨大差异。同样重要的是，每个Aim都为复杂分子合成提供了全新的靶标，这将确保一个强大的HQP训练环境

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 receptorligand 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.**