Alkyllithium Cyclizations in Organic Snythesis

描述(申请人提供)：合成化学是一项技术 现代药物开发的基础。人类基因组图谱的成功绘制 是确定新的受体和治疗途径的第一步 慢性病。从双分子靶标到实现改进的途径 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。在这项提案中，我们将开发一种潜在的 合成氮氧螺环的有效方法。新的 像这样的合成方法是一种使能改进的技术 人类健康。 丁腈的还原裂解是一种很少使用的方法 烷基锂试剂。在许多六元环中，这个反应完全是 立体选择性，生成的烷基锂将与亲电性偶联 具有配置保留功能。我们建议使用这种还原锂化法 与与丁腈基团相邻的易发生的烷基化反应相结合， 开发一种螺环的通用立体选择性合成方法。这种方法 将被开发用于制备螺环-四氢吡喃环。这些简约式 环合反应将用于一般的合成。 反热力学螺缩醛，在复杂的天然化合物中常见的结构 产品。第三个发展领域是综合 螺哌啶类药物，其中对底物的修饰将允许 选择性地制备螺哌啶的构型。 这项提议的合成目标是天然产品和 天然产品本身。腺苷三磷酸(海绵抑素)和 阿司匹酸将用反热力学的方法制备 螺缩醛。组织毒素和品甲酸将使用 螺哌啶法。这些化合物对合成和 药物化学家，有刚性、多环和极性类型 在许多检测中发现结构具有很高的生物活性。

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.