Alkyllithium Cyclizations in Organic Snythesis

描述（由申请人提供）：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 是识别新受体和治疗途径的第一步 慢性疾病。从双分子靶点到实现改进的路径 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。在本提案中，我们将开发一个潜在的 合成小氮和氧螺环的强大方法。新 像这样的合成方法是一种改进技术 人类健康。 腈的还原裂解是一种很少使用的生成方法 烷基锂试剂。在许多六元环中，该反应是完全的 立体选择性，所得烷基锂将与亲电子试剂偶联 保留配置。我们建议使用这种还原锂化 反应，结合与腈基团相邻的容易的烷基化， 开发螺环的通用和立体选择性合成。这个方法 将开发用于制备螺四氢吡喃环。这些还原性的 环化反应将用于一般合成 反热力学螺缩醛，复杂天然结构中常见的结构 产品。第三个发展领域是综合 螺哌啶，其中底物的修饰将允许 选择性制备螺哌啶的构型。 该提案的合成目标是天然产物和 天然产品本身。丙醛酸片段（海绵抑素）和 将使用逆热力学方法制备氮杂螺酸 螺缩醛。 Histrionicotoxin 和 pinnaic 酸将使用以下方法制备 螺哌啶法。这些化合物对于合成和 药物化学家，有刚性、多环和极性类型 在许多测定中发现结构显示出高生物活性。

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.