Multicomponent Coupling--Steroids /Etoposide Derivatices

本提案的主要目的是探索一系列新的合成反应，最终形成新的合成途径，以合成具有重要药用价值的芳香族和杂芳香族化合物，包括合成类固醇，依托opo苷抗癌药物和2-芳基呋喃天然产物。所研究的反应涉及高共轭乙炔衍生物与Fischer卡宾配合物的偶联，并分为两个部分：卡宾配合物与酶-羰基化合物的偶联，以及与共轭烯二炔的偶联。主要的重点是探索Fischer羰基复合物与烯羰基化合物的偶联，从而在一个步骤中提供生物上重要的呋喃环系统。将反应延伸到芳烃体系将导致不稳定的异苯并呋喃环体系，该体系可以与缺电子烯烃发生高产率可预测的反应。利用该反应的单步合成类固醇环系统提供了一种显著的通用方法来制备各种类固醇衍生物的生物测试。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的合成路线。另一个有待研究的领域是共轭烯二炔与费雪卡宾配合物的偶联。这一反应过程提供了芳香族双自由基中间体，对自由基中间体的反应途径的理解和控制将是一个重要的努力。这些反应过程的一个主要特点是选择性地将官能团引入未官能团的烷基链。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。研究具有重要药理意义的分子的合成可以提供类似物，这有助于最大限度地发挥所需的药理作用，并有助于更好地了解作用方式。

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.