Asymmetric Synthesis of Nitrogen Heterocycles

氮杂环的不对称合成

• 批准号: 7683917
• 负责人: Tomislav Rovis
• 金额: $ 28.99万
• 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/7683917
• 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，这是由于 它们的极化性、碱性、氢键能力和其它生理特性。这项建议 描述了一个计划，在合成有机方法，旨在发展快速，立体选择性合成的 使用容易获得的前体合成氮杂环。我们方法的关键是效率：我们 需要快速获得起始材料，随后在组件组装中具有高选择性 能够从容易获得的前体两步至三步合成目标分子。作为这一目标的一部分， 我们设想能够快速组装复杂的生物活性杂环如secu'amamine A， 一叶秋碱/去甲一叶秋碱生物碱家族相关的化合物，其显示抗肿瘤，抗疟疾， 抗菌，和中枢神经系统的活性，有效的免疫抑制FR 901483，重要的神经生理 工具hydrohistrionicotoxin和perhydrohistrionicotoxin，和halichlorine，显示出选择性抑制 诱导血管细胞粘附分子-1（VCAM-1）。本研究的具体目标如下：1） 发展催化对映选择性烯基异氰酸酯和炔[2+2+2]环加成反应; 2）扩大 烯烃伙伴的范围包括二-，三-和四-取代的伙伴;3）探索性质， 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]环加成反应的各种生物碱; 5）研究新的PI系统在 [2+2+2]环加成使用我们的烯基异氰酸酯/炔偶联作为平台。的长期影响 这门科学是为了使化学家能够快速高效地组装胶体结构。项目叙述 涉及小分子的健康相关研究的最重要障碍之一是快速组装 治疗剂。该提案寻求开发新的方法来合成手性框架， 易于获得的前体，具有高效率。