Asymmetric Synthesis of Nitrogen Heterocycles

氮杂环的不对称合成

• 批准号: 7380212
• 负责人: Tomislav Rovis
• 金额: $ 27.72万
• 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/7380212
• 关键词: 5-(4-hydroxy-3-methoxyphenyl)-5-phenylhydantoin; Alkaloids; Alkenes; Alkynes; Anti-Bacterial Agents; Antimalarials; Biological; Complex; Coupling; FR 901483; 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; securinine; small molecule; tool

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：项目概述含氮分子由于其极化、碱性、氢键能力和其他生理特性而普遍存在于具有显著生物活性的化合物中。该提案描述了一个有机合成方法学的计划，旨在开发快速，立体选择性合成复杂的氮杂环使用容易获得的前体。我们的方法的关键是效率：我们需要快速获得起始材料，然后在组件组装中具有高选择性，从而能够从现成的前体中通过两到三步合成目标分子。作为该目标的一部分，我们设想允许快速组装复杂的生物活性杂环，例如secu'amamine A，一种与一叶秋碱/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CNS活性，有效的免疫抑制FR 901483，重要的神经生理学工具hydrohistrionicotoxin和perhydrohistrionicotoxin，以及卤氯，显示选择性抑制血管细胞粘附分子-1（VCAM-1）的诱导。本研究的具体目标如下：1）发展催化的烯基异氰酸酯与炔[2+2+2]环加成反应，2）将烯烃配体的范围扩大到包括二、三和四取代的配体，3）探索导致非对映选择性反应的系链的性质和取代模式，4）研究非对映选择性反应的机理。4）探索利用异氰酸酯[2+2+2]环加成反应快速全合成多种生物碱; 5）利用我们的烯基异氰酸酯/炔偶联反应作为平台，研究新的π体系在[2+2+2]环加成反应中的应用。这门科学的长期影响是使化学家能够快速高效地组装胶体结构。涉及小分子的健康相关研究的最大障碍之一是治疗剂的快速组装。该提案旨在开发使用易于获得的前体高效合成生物碱框架的新方法。