SYNTHESIS OF ANTITUMOR AGENTS

本建议的主要目标是调查范围， 过渡金属卡宾几种反应的适用性 有机合成中的络合物，并将其应用于 合成两个抗肿瘤剂家族的成员。 一 串联Diel-Alder/环己二烯酮成环序列， 建议制定一项综合办法， 去甲二萜二内酯，当归内酯A，当归内酯F， 龙葵内酯D和podolide。 这将是第一位 这类化合物的合成方法应该是 足够灵活，以允许准备具有 功能的多样性。 合成路线， 拟quaianolides提出，涉及作为关键步骤， 卡宾配合物的环丙烷化反应及其合成 这类化合物中的靶是抗肿瘤剂helenalin。 其他一些目标包括发展一个 将通过以下方式说明的木兰素的合成路线 PGE 2的合成，包括环丙烷化反应 碳烯配合物。 前列腺素家族具有显著的 广泛的生理效应和特殊的利益， 一直专注于炎症、生殖和过敏 应答 使这种方法成为可能的化学物质是 针对抗肿瘤化合物的合成的工作的结果是， 海伦娜林探员。 对合成海伦娜灵的研究也取得了一定的进展， 导致一种新的方法来合成吡哆醇， 吡哆醛磷酸盐，其活性形式，作为辅因子， 绝大多数酶催化α- 个氨基酸 最后，新的方法，不对称羟醛，第尔斯- 过渡金属卡宾介导的桤木和Claisen反应 将对复合物进行研究。 后者将是一个一般性的研究 这是由这些反应的重要地位保证的， 在传统有机合成方法学中。

The chief objective this proposal is to investigate the scope and applicability of several reactions of transition metal carbene complexes in organic synthesis and to employ them in the synthesis of members of two families of antitumor agents. A tandem Diel-Alder/cyclohexadienone annulation sequence is proposed for development of a synthetic approach to the norditerpene dilactones wentilactone A, nagilactone F, nagilactone D, and podolide. This would be the first general synthetic approach to this family of compounds and should be flexible enough to allow for the preparation of members with a diversity of functionality. A synthetic route to the pseudoquaianolides is proposed that involve as the key step a cyclopropanation reaction of carbene complexes and the synthetic target in this class of compounds is the antitumor agent helenalin. Among some of the other objectives are the development of a synthetic route to the prostaglandins which will be illustrated by the synthesis of PGE2 and involves the cyclopropanation reactions of carbene complexes. The prostaglandin family has a remarkably broad range of physiological effects and special interests have been focused on inflammation, reproduction, and allergic responses. The chemistry that makes this approach possible was an outcome of the work directed to the synthesis of the antitumor agent helenalin. The efforts on the synthesis of helenalin also has lead to a new approach to the synthesis of pyridoxine which in pyridoxal phosphate, its active form, serves as cofactor for the great majority of enzymes catalyzing chemical changes in alpha- amino acids. Finally, new approaches to asymmetric aldol, Diels- Alder and Claisen reactions mediated by transition metal carbene complexes will be investigated. The latter will be a general study that is warranted by the important position that these reactions hold in traditional synthetic organic methodology.