Multicomponent Coupling--Steroids /Etoposide Derivatices

这项建议的主要目的是探索一系列新的合成反应，最终形成具有重要药用价值的芳香族和杂芳族化合物的新合成路线，包括合成类固醇、依托泊苷抗癌药物和2-芳基呋喃天然产物。研究中的反应涉及高共轭乙炔衍生物与Fischer卡宾配合物的偶联，分为两部分：卡宾配合物与酶-羰基化合物的偶联，以及与共轭二炔类化合物的偶联。主要的焦点包括探索Fischer卡宾络合物与烯炔-羰基化合物的偶联，这在一步中提供了具有生物重要性的呋喃环系。将反应延伸到芳香族体系将导致不稳定的异苯并呋喃环系，它可以与缺电子的烯烃进行高产率的可预见的反应。利用这一反应一步合成甾体环系统，提供了一种非凡的通用方法来制备用于生物测试的各种类固醇衍生物。类似的反应过程可以为抗癌药物依托泊苷的结构类似物提供快速合成路线。另一个要研究的领域是共轭二炔类化合物与Fischer卡宾络合物的偶联。这一反应过程提供了芳香族双自由基中间体，并将努力了解和控制自由基中间体的反应途径。这些反应过程的一个主要特征是将官能团选择性地引入到未官能化的烷基链中。还将研究利用该反应合成2-芳基呋喃天然产物。合成有机化学领域对人类健康产生了深远的影响。对药学上重要分子的合成的研究可以提供类似物，这对于最大化所需的药理作用和更好地了解作用方式是有用的。

The major objective of this proposal is to explore a series of novel synthetic reactions which culminate in new synthetic routes to pharmaceutically-important aromatic and heteroaromatic compounds, including synthetic steroids, etoposide anti-cancer drugs, and 2-arylfuran natural products. The reaction under investigation involves the coupling of highly conjugated acetylene derivatives with Fischer carbene complexes, and is divided into two sections: coupling of carbene complexes with enzyme-carbonyl compounds, and coupling complexes with conjugated enediynes. The major focus involves exploration of the coupling of Fischer carbene complexes with enyne-carbonyl compounds, which provides the biologically-important furan ring system in a single step. Extension of the reaction to aromatic systems will lead to the unstable isobenzofuran ring system, which can undergo high-yielding a predictable reactions with electron-deficient alkenes. Exploitation of this reaction for the single step synthesis of the steroid ring system provides a remarkable versatile method to prepare a diverse array of steroid derivatives for biological testing. A similar reaction process can provide rapid synthetic routs to the structural analogs of the anti-cancer drug etoposide. The other area to be investigated is the coupling of conjugated enediynes with Fischer carbene complexes. This reaction process affords aromatic diradical intermediates, and a major effort will be made to understand and control the reaction pathways of the free radical intermediates. A major feature of these reaction processes is the selective introduction of functional groups into unfunctionalized alkyl chains. Use of this reaction for the synthesis of 2-arylfuran natural products will also be investigated. The field of synthetic organic chemistry has had a profound impact on human health. Investigation of the synthesis of pharmaceutically- important molecules can provide analogs, which are useful for maximizing the desired pharmacological effects and for a better understanding of the mode of action.