Asymmetric Synthesis of Nitrogen Heterocycles

描述(申请人提供)：在具有显著生物活性的化合物中，由于其极化、碱性、氢键能力和其他生理特性，含氮分子普遍存在。本提案描述了合成有机方法学中的一项计划，旨在利用现成的前体开发快速、立体选择性的复杂氮杂环的合成。我们方法的关键是效率：我们需要快速获得起始材料，然后在组件组装中具有高选择性，从而能够从现成的前体合成两到三步目标分子。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，一种与具有抗肿瘤、抗疟疾、抗细菌和中枢神经系统活性的一系列生物碱相关的化合物Secu’amamine A，强大的免疫抑制药物FR901483，重要的神经生理学工具氢组纹毒素和过氢组纹毒素，以及卤代氯，显示出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)开发催化对映选择性的烯基异氰酸酯和炔烃[2+2+2]环加成反应；2)扩大烯烃对映体的范围，包括二、三和四取代基对映体；3)探索导致非对映选择性反应的系绳上的性质和取代模式；4)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)以我们的烯基异氰酸酯/炔烃偶联为平台，研究新的聚异氰酸酯体系在[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高效地快速组装生物碱结构。项目描述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。这项建议寻求开发新的方法，利用易于获得的前体高效地合成生物碱骨架。

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.