Development of Azomethine Ylide Cycloadditions and Synthesis of Daphniyunnine D

描述(由申请人提供)：复杂分子合成为开发和展示新的合成化学技术提供了一个无与伦比的机会。对新的反应或现有分子转化的扩展进行基础研究可以提高目标分子的合成效率。具体地说，这项提议的重点是开发快速有效地获得复杂的吡咯烷杂环。研究标准是排除剧毒试剂，这将允许直接应用于现代药物的制造，符合FDA当前的良好制造规范(CGMP)。瑞香素D是最近从云南瑞香茎和叶中分离得到的，占植物干重的0.0035%。该生物碱对两种肿瘤细胞株P-388和A-549有一定的抑制作用，其IC50值分别为3.0和0.6M。为了确保足够的剂量和充分确定瑞香碱D的治疗潜力，需要进行合成努力。这项建议的主要目标将是开发一类新的分子内甲亚胺叶立德环化反应，并在复杂的六环生物碱Daphniyunine D的全合成中展示这一反应。生成必需的甲亚胺叶立德的方法需要一个明智的选择。这一选择将随着这种III型分子内甲亚胺叶立德环化反应的发展而详细讨论。将讨论不同的反应条件，以获得必要的反应活性而不影响偶氮甲亚胺叶立德的稳定性。这一高复杂性的生成步骤将允许获得令人垂涎的吡咯烷杂环的复杂衍生物，并完成瑞香碱D的分子骨架。最后，瑞香云宁D的合成将探索一种合理的方法来控制Pauson-Khandd环化反应中的非对映选择性。

DESCRIPTION (provided by applicant): Complex molecule synthesis offers an unparalleled opportunity to develop and demonstrate new synthetic chemical technologies. Fundamental studies into a new reaction or expansion of an existing molecular transformation can increase the efficiency of the synthesis of a target molecule. Specifically, this proposal is focused on developing rapid and efficient access to complex pyrrolidine heterocycles. A research criterion is to exclude acutely toxic reagents, which will allow for straightforward application to the manufacturing of modern Pharmaceuticals in accord with the FDA's current Good Manufacturing Practices (cGMP). Daphniyunnine D was recently isolated from the stems and leaves of Daphniphyllum yunnanense and constitutes 0.0035% of the dry weight plant mass. This alkaloid shows activity against two tumor cell lines, P-388 and A-549, with IC50 values of 3.0 and 0.6 ?M, respectively. In order to secure sufficient quantities and fully determine the therapeutic potential of daphniyunnine D, a synthetic effort is required. A primary objective of this proposal will be the development of a new class of intramolecular azomethine ylide cyclizations and the demonstration of this reaction in the total synthesis of the complex hexacyclic alkaloid daphniyunnine D. The method for generating the requisite azomethine ylide requires a judicious choice. This choice will be discussed in detail along with the development of this Type III intramolecular azomethine ylide cyclization. Different reaction conditions designed to obtain the necessary reactivity without compromising the stability of the azomethine ylide will be discussed. This high complexity-generating step will allow access to complex derivatives of the coveted pyrrolidine heterocycle and complete the molecular skeleton of daphniyunnine D. Finally, this synthesis of daphniyunnine D will investigate a rational approach for controlling diastereoselectivity in the Pauson-Khand cyclization.