NEW CYCLIZATION METHODS AND MULTICOMPONENT COUPLINGS

这项研究的主要意义是，潜在的- 将开发出强大的新合成方法。具体目标 包括开发几种新的镍催化程序 包括环化和多组分偶联。 相当大 注意力将集中在非对称和固体的发展上， 阶段程序。 反应发现的努力旨在 开发快速构建复杂有机亚结构的过程 从简单、易得的前体， 方式 该研究将专门侧重于开发 催化过程，应该是经得起规模放大， 环保时尚。 将寻求一种新的α-氨基酸合成方法， 独特的是，氨基酸侧链来自多达四个 在一个简单的三步操作的组件。 快速灵活 在固相中制备氨基酸应该提供强有力的 用于小分子药物发现和多肽的组合工具 使用非蛋白质氨基酸的合成。 的一般合成 将开发出一种研究别仆毒素生物碱的方法， 正式全合成的一个代表性成员，allopumiliotoxin 第339章我会追的 的药理活性 与钙促进机制有关的短小毒素 流入肌纤维和/或促进钙释放 从肌浆网中分离出来 本发明提出的合成路线， allopumiliotoxins应允许快速建设的中央 具有完全立体控制的双环骨架。 的一般方法 将开发类海人藻氨酸，并且对映选择性总 将进行最简单的（-）-红藻氨酸的合成。 它们强大的神经兴奋活性使得海因酸 作为神经元疾病如癫痫和 亨廷顿舞蹈病和老年痴呆症中神经元细胞丢失。 的 拟合成红藻氨酸的路线将允许容易地引入 各种C-4侧链，这是所有kainoids 结构上不同。 建议的简明灵活路线， 别朴毒素生物碱和海人素氨基酸合成 允许容易地制备制备量的天然 产品以及用于进一步药理学的新衍生物 调查事务所

The primary significance of the proposed research is that potentially- powerful new synthetic methods will be developed. The specific aims include the development of several new nickel-catalyzed procedures involving cyclizations and multicomponent couplings. Considerable attention will be devoted to the development of asymmetric and solid- phase procedures. The efforts in reaction discovery are designed to develop processes that rapidly construct complex organic substructures from simple, readily-available precursors in a predictable and efficient manner. The research will focus exclusively on the development of catalytic processes that should be amenable to scaleup in an environmentally-benign fashion. A new approach to alpha-amino acid synthesis will be pursued which is unique that the amino acid side chain is derived from up to four components in a simple three-step operation. The rapid and flexible preparation of amino acids in the solid phase should provide a powerful combinatorial tool for small molecule drug discovery and polypeptide synthesis employing nonproteinogenic amino acids. A general synthetic approach to the allopumiliotoxin alkaloids will be developed, and a formal total synthesis of a representative member, allopumiliotoxin 339B, will be pursued. The pharmacological activity of the pumiliotoxins in linked to mechanisms involving facilitation of calcium influx into the muscle fiber and/or a facilitation of calcium release from the sarcoplasmic reticulum. The proposed synthetic route to the allopumiliotoxins should allow rapid construction of the central bicyclic skeleton with complete stereocontrol. A general approach to the kainoid amino acids will be developed, and an enantioselective total synthesis of (-)-kainic acid, the simplest member, will be pursued. Their potent neuroexcitatory activity has allowed the kainoids to serve as effective models for neuronal diseases such as epilepsy and Huntington's chorea and for neuronal cell loss in senile dementia. The proposed synthetic route to the kainoids will allow facile introduction of various C-4 side chains, which is the position at which all kainoids differ structurally. The concise and flexible routes proposed for the synthesis of allopumiliotoxin alkaloids and kainoid amino acids should allow the facile preparation of preparative quantities of the natural products as well as new derivatives for further pharmacological investigations.