Total Synthesis of Unnatural Products

我们的研究计划专注于结构复杂分子的靶向合成，以及对这些“内部刚性”分子结构所具有的独特构象控制的生物利用。虽然我们从天然产品中获得了相当大的灵感，但我们的大多数目标都是设计的，非天然的分子是为实现特定范围的功能而创造的。在复杂分子结构和功能的交叉点上运作，使我们的研究团队在合成方法学、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。*在本应用中，我们针对三种新的分子结构：牛小行星、非天然双二异氰酸酯和从Thiele酸衍生的新分子支架。我们所有拟议的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，并将使令人兴奋的新合作成为可能。下面总结的三个目标最终寻求解决贯穿我们所有研究的同一个问题：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)，以快速组装在多环框架中的关键点包含氧原子的非天然类固醇分子。这将微妙地调节不同受体亚型之间的受体配基亲和力，导致与母体类固醇激素雌酮、雌二醇、睾酮和孕酮相关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didemnakatals核心的不对称合成(四面体2015,2643)，这些天然产物具有一系列活性，似乎源于它们解离蛋白质高二聚体的能力。我们将创建一个非自然的二元组，其中两个悬挂的侧链是相同的。通过对这些分子的研究，我们将对这些分子本身的生物学作用有一个更深入的了解。*在我们的第三个目标中，我们将建立我们的能力，设计用于产生酶抑制剂的受限支架(例如，Org.Lett.2012,5876)。扩展我们对Thiele的酯衍生物的化学(J.Org.Chem.2015,8979；专题文章)，我们将创建一种新的刚性支架，用于产生碳水化合物加工酶的抑制剂。*这三个概念上相关的目标将有助于我们越来越多地理解构象偏好的细微变化引起相关蛋白质生物反应的巨大差异的能力。同样重要的是，每个目标都为复杂分子合成提供了全新的目标，这将确保一个强大的HQP培训环境。**

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.**