NEW CYCLIZATION METHODS AND MULTICOMPONENT COUPLINGS

拟议研究的主要意义是潜在地-- 强大的新合成方法将被开发出来。具体目标 包括开发几种新的镍催化程序 包括环化反应和多组分偶合反应。相当可观 将致力于发展不对称和固体- 阶段性程序。在反应发现方面的努力旨在 开发快速构建复杂有机下层结构的流程 从简单、容易获得的前体到可预测和高效的 举止。这项研究将专门集中在开发 催化过程应该能够在 环保时尚。 将寻求一种合成α-氨基酸的新方法，即 独一无二的是，氨基酸侧链最多来自四个 组件在一个简单的三步操作中。快速而灵活的 在固相氨基酸的制备中应提供强大的 小分子药物发现与多肽的组合工具 使用非蛋白生成氨基酸的合成。一种普通合成材料 将开发别鞭毛霉毒素生物碱的方法，并 一种具有代表性的成员--别孔雀毒素的正式全合成 339B，将被追查。丹参的药理活性 褐藻毒素与钙易化机制的关系 流入肌纤维和/或促进钙释放 来自肌浆网。拟议的合成路线到 别孔雀毒素应允许快速建设中央 具有完全立体控制的双环骨架。一种通用的方法来 将开发海人藻类氨基酸，并对映体选择性总 最简单的成员(-)-海藻酸的合成将继续进行。 它们强大的神经兴奋活动使海藻类动物能够 作为治疗神经元疾病的有效模型，如癫痫和 亨廷顿舞蹈症和老年痴呆症的神经细胞丢失。这个 拟议的合成海藻类物质的路线将使引入 不同的C-4侧链，这是所有红藻氨酸 在结构上不同。建议的路线既简洁又灵活 别鞭毒素生物碱和海人藻类氨基酸的合成 允许方便地制备天然药物的制备量 用于进一步药理的产品和新的衍生品 调查。

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.