Total Synthesis of Unnatural Products

非天然产物的全合成

• 批准号: RGPIN-2016-04283
• 负责人: Wulff, Jeremy
• 金额: $ 3.35万
• 依托单位: University of Victoria
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=614961
• 关键词: Total; Synthesis; Unnatural; Products

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.

我们的研究项目集中在结构复杂分子的靶向合成，以及这些“内部刚性”分子结构所具有的独特构象控制的生物学利用。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设计的，非天然分子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点上工作，使我们的研究团队能够对合成方法学，全合成，分子动力学，化学生物学和药物化学做出重要而独特的贡献。 在本申请中，我们靶向三种新的分子结构：氧杂甾体、非天然的didemnaketals和衍生自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，我们将扩展我们现有的低聚乙烯基醚（例如Org.Lett.2011，5552）的迭代合成和级联环化的专业知识，以快速组装在多环框架的关键点含有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-配体亲和力，导致相对于母体类固醇激素雌酮、雌二醇、睾酮和孕酮的生物学性质的显著改变。 在我们的第二个目标中，我们将利用我们最近发表的didemnakatals核心的第一个不对称合成（Tetrahedron 2015，2643），具有一系列活性的天然产物，这些活性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didemnaketals家族，其中两个悬垂侧链是相同的。通过研究这些分子，我们将更深入地了解didemnaketals本身的生物学作用。 在我们的第三个目标中，我们将建立在我们的能力上，以工程化约束支架来产生酶抑制剂（例如Org.Lett.2012，5876）。扩展我们对Thiele酯衍生物的化学研究（J.Org.Chem.2015，8979;专题文章），我们将创造一种新的刚性支架，用于产生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不断了解的能力，在构象偏好的细微变化，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目标，这将确保HQP训练环境的强大性。