Synthetic tools for new antibiotics

描述(由申请人提供)：复杂的天然产品仍然是开发新的治疗方法的灵感和创新的重要来源之一。然而，当产生生物测试所需的类似物或数量时，它们的复杂性带来了合成方面的挑战。一个产生特殊挑战的结构基元是含四元立体中心的碳环结构的对映选择性合成。在目前的提案中，描述了合成化学工具，它将允许高效、对映选择性地构建具有两个四元立体中心、邻近的四元-三元立体中心和相邻的四元-三元立体中心的碳环结构。这些合成工具将把最近开发的Birch-Cope序列扩展到一个有价值的新方向。此外，该项目还描述了一种将这些工具应用于对映体选择性合成具有抗菌性能的二萜天然产物三七烯D的策略。开发一种合成三七七烯D的方法和产生其他具有抗生素特性的复杂分子的工具，将有助于解决日益升级的抗生素耐药性危机。 与公共健康相关：复杂的天然产品仍然是开发新的治疗方法，特别是抗生素治疗的灵感和创新的重要来源之一。三七烯D是最近报道的一种二萜天然产物，具有独特的化学结构和抗菌活性，是天然产物化学中丰富的代表。拟议的项目将开发合成化学工具，以允许高效和特定地合成三角花青烯D，从而促进其作为一种新的抗生素治疗方法的开发。随着现代医学面临日益严重的抗生素耐药性危机，这里开发的工具有可能促进在寻求改进治疗方法方面取得重要进展。

DESCRIPTION (provided by applicant): Complex natural products remain one of the great sources of inspiration and innovation in the development of novel therapeutic treatments. However, their complexity presents synthetic challenges when generating analogs or quantities necessary for biological testing. One structural motif that creates a particular challenge is the enantioselective synthesis of carbocyclic structures containing quaternary stereocenters. In the current proposal, synthetic chemistry tools are described which will allow the efficient, enantioselective construction of carbocyclic structures with two quaternary stereocenters, vicinal quaternary- tertiary stereocenters and contiguous quaternary-tertiary-quaternary stereocenters. The synthetic tools will extend the recently developed Birch-Cope sequence in a valuable, new direction. Furthermore, the project describes a strategy to apply these tools to the enantioselective synthesis of trigonochinene D, a diterpene natural product with antimicrobial properties. The development of a synthesis of trigonochinene D and the tools to generate other complex molecules with antibiotic properties will assist in addressing the escalating crisis of antibiotic resistance. PUBLIC HEALTH RELEVANCE: Complex natural products remain one of the great sources of inspiration and innovation in the development of novel therapeutic treatments, especially antibiotic therapy. Trigonochinene D is a recently reported diterpene natural product which, with its unique chemical architecture and antibiotic activity, is representative of the riches found in natural product chemistry. The proposed project will develop synthetic chemistry tools to permit the efficient and specific synthesis of trigonochinene D, thereby facilitating its development as a new antibiotic treatment. With modern medicine facing a burgeoning crisis in antibiotic resistance, the tools developed here have the potential to facilitate important advances in the search for improved therapeutic treatments.