Asymmetric Synthesis of Nitrogen Heterocycles

氮杂环的不对称合成

• 批准号: 7806857
• 负责人: Tomislav Rovis
• 金额: $ 0.97万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-21 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806857
• 关键词: Alkaloids; Alkenes; Alkynes; Anti-Bacterial Agents; Antimalarials; Biological; Complex; Coupling; Family; Goals; Hydrogen Bonding; Immunosuppressive Agents; Isocyanates; Methodology; Methods; Nature; Nitrogen; Pattern; Physiological; Property; Reaction; Research; Science; Structure; System; Therapeutic Agents; Vascular Cell Adhesion Molecule-1; alkalinity; cycloaddition; halichlorine; neurophysiology; norsecurinine; perhydrohistrionicotoxin; programs; small molecule; tool

Project Summary Nitrogen containing molecules are ubiquitous among compounds possessing significant biological activity due to their polarization, basicity, hydrogen-bonding ability and other physiological properties. This proposal describes a program in synthetic organic methodology aimed at developing rapid, stereoselective syntheses of complex nitrogen heterocycles using readily available precursors. The key to our approach is efficiency: we require rapid access to the starting material followed by high selectivity in the assembly of the components enabling two to three step syntheses of target molecules from readily available precursors. As part of this goal, we envision allowing the rapid assembly of complex biologically active heterocycles such as secu'amamine A, a compound related to the securinine/norsecurinine family of alkaloids that display antitumor, antimalarial, antibacterial, and CNS activity, the potent immunosuppressive FR901483, the important neurophysiological tools hydrohistrionicotoxin and perhydrohistrionicotoxin, and halichlorine, shown to selectively inhibit the induction of vascular cell adhesion molecule-1 (VCAM-1). The specific goals of this research are as follows: 1) develop the catalytic enantioselective alkenyl isocyanate and alkyne [2+2+2] cycloaddition; 2) expand the scope of alkene partners to include di-, tri- and tetra-substituted partners;3) explore the nature and substitution patterns on the tether leading to diastereoselective reactions; 4) pursue the rapid total synthesis of a variety of alkaloids using isocyanate [2+2+2] cycloadditions; 5) investigate the use of new pi systems in [2+2+2] cycloadditions using our alkenyl isocyanate/alkyne coupling as a platform. The long-term impact of this science is to enable chemists to rapidly assemble alkaloidal structures with high efficiency. Project Narrative One of the most significant barriers to health-related research involving small molecules is the rapid assembly of therapeutic agents. This proposal seeks to develop new methods to synthesize alkaloidal frameworks using easily accessible precursors with high efficiency.

项目摘要 含氮分子在具有显著生物活性的化合物中普遍存在。 它们的极化、碱性、氢键能力等生理特性。这项建议 描述了一个合成有机方法学的项目，旨在开发快速、立体选择性的合成 使用容易获得的前体的复杂的氮杂环。我们方法的关键是效率：我们 需要快速获得起始材料，然后在组件的组装中具有高选择性 使得能够从容易获得的前体中合成目标分子的两到三步。作为这一目标的一部分， 我们设想允许复杂的生物活性杂环的快速组装，例如Secu‘amamine A， 一种与一叶珊瑚碱/降一叶珊瑚碱家族有关的化合物，具有抗肿瘤，抗疟疾， 抗菌，和中枢神经系统活性，强大的免疫抑制FR901483，重要的神经生理学 工具氢组氨酸毒素和过氢组氨酸毒素，以及卤代氯，被证明选择性地抑制 血管细胞黏附分子-1(VCAM-1)的诱导。本研究的具体目标如下：1) 开发催化的对映选择性烯基异氰酸酯和炔烃[2+2+2]环加成反应；2)扩展 烯烃伙伴的范围包括二、三和四取代伙伴；3)探索性质和 导致非对映选择性反应的系链上的取代模式；4)追求快速全合成 使用异氰酸酯[2+2+2]环加成反应合成各种生物碱；5)研究新的pi体系在 以我们的烯基异氰酸酯/炔烃偶联为平台进行的[2+2+2]环加成反应。的长期影响 这门科学是为了使化学家能够高效地快速组装生物碱结构。项目叙事 涉及小分子的健康相关研究的最大障碍之一是快速组装 治疗药剂。这项提议寻求开发新的方法来合成生物碱骨架 高效、易得的前驱体。