Alkyllithium Cyclizations in Organic Snythesis

有机合成中的烷基锂环化

• 批准号: 6460197
• 负责人: SCOTT D. RYCHNOVSKY
• 金额: $ 22.58万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6460197
• 关键词: alkyl nitrile; alkylation; biological products; chemical cleavage; chemical structure function; chemical synthesis; chemical transfer reaction; cyclization; ketal; lithium; organic chemicals; piperidine; pyrans; spirane; stereochemistry; stereoisomer

DESCRIPTION (provided by applicant): Synthetic chemistry is the technology underlying modern drug development. The successful mapping of the human genome was the first step towards identifying new receptors and pathways to treat chronic diseases. The path from bimolecular targets to realizing improvements in human health usually requires the synthesis of small molecule agonists, antagonists, or inhibitors. In this proposal we will develop a potentially powerful method to synthesize small nitrogen and oxygen spiro rings. New synthetic methods such as this one are an enabling technology for improving human health. The reductive cleavage of nitrile is a rarely used method for generating alkyllithium reagents. In many six-membered rings this reaction is completely stereoselective, and the resulting alkyllithium will couple with electrophiles with retention of configuration. We propose to use this reductive lithiation reaction, in combination with facile alkylations adjacent to nitrile groups, to develop a general and stereoselective synthesis of spiro rings. This method will be developed to prepare the spiro-tetrahydropyran rings. These reductive cyclization reactions will be used in a general synthesis of contrathermodynamic spiroacetals, structures commonly found in complex natural products. The third area of development is in the synthesis of spiropiperidines, where modification of the substrate will allow either configuration of the spiropiperidine to be prepared selectively. The synthetic targets for this proposal are segments of natural products and natural products themselves. Segments of altohyrtin (spongistatin) and azaspiracid will be prepared using the approach to contrathermodynamic spiroacetals. Histrionicotoxin and pinnaic acid will be prepared using the spiropiperidine method. These compounds are of interest to synthetic and medicinal chemists, and have the types of rigid, polycyclic and polar structures found to show high bioactivity in many assays.

描述（申请人提供）：合成化学是技术 基本的现代药物开发。人类基因组的成功映射 是识别新受体和治疗途径的第一步 慢性疾病。从双分子目标到实现改进的路径 在人类健康中，通常需要合成小分子激动剂， 拮抗剂或抑制剂。在此提案中，我们将发展一个潜在的 合成小氮和氧气环的强大方法。新的 诸如此类的合成方法是一种改进的能力技术 人类健康。 硝酸的还原性切割是一种很少用于生成的方法 藻锂试剂。在许多六元环中，这个反应完全是 立体选择性，由此产生的树基锂将与电力物配对 保留配置。我们建议使用这种还原性静态 反应与氮基相邻的便捷烷基化结合到 发展螺旋环的一般和立体选择性合成。此方法 将开发以准备螺旋四氢吡喃环。这些还原性 环化反应将用于一般合成 对膜动力学的螺旋体，通常在复杂自然中发现的结构 产品。发展的第三个领域是合成 螺旋哌啶，底物的修饰将允许 螺旋哌啶的构型要有选择地制备。 该提案的合成目标是天然产品的细分市场 天然产品本身。 Altohyrtin（海绵蛋白）和 偶氮尿素将使用该方法进行对照动力学的方法 螺旋序。雌元毒素和甲虫酸将使用 螺内哌啶法。这些化合物对合成和 药物学家，具有刚性，多环和极性的类型 在许多测定中发现的结构表现出很高的生物活性。