LIGNAN ANTITUMOR PROTOTYPES VIA DIANION INTERMEDIATES

这项提案的具体目标是综合一系列 越来越具有挑战性的木脂素天然产品，最终达到 高效制备两种抗肿瘤原型药物：甜叶酸和甜叶酸 鬼臼毒素。这种序列的开发应该特别证明 对于探索类似物之间的结构-活性关系很有用 这些前途无量的特工。 双阴离子中间体表现出非凡的反应性 亲电者。初步研究表明，羧酸 二阴离子可以是二聚化的，也可以简单地通过改变 加碘的化学计量比。在这个简单的转变的基础上， 大量对称和不对称的丁二酸 衍生物(包括酸酐、内酯和酰胺)很容易 可用。 合成甜菊酸和甜叶酸的关键合成步骤 鬼臼毒素包括酰胺二阴离子与2-碘羧酸盐反应， 选择性地还原生成的酸酰胺产品，以及 N-碘酰胺分子内光化学驱动的碘化反应 先驱物。

The specific goal of this proposal is the synthesis of a series of increasingly challenging lignan natural products culminating in the efficient preparation of two antitumor prototypes: steganacin and podophyllotoxin. Development of such sequences should prove especially useful for exploration of structure-activity relationships among analogs to these promising agents. Dianion intermediates exhibit extraordinary reactivity towards electrophiles. Preliminary studies have demonstrated that carboxylic acid dianions can be either dimerized or iodinated simply by varying the stoichiometry of added I2. Building upon this simple transformation, numerous symmetrically- and unsymmetrically-submitted succinic acid derivatives (including anhydrides, lactones, and amides) become readily available. Key synthetic steps to be explored in the generation of both steganacin and podophyllotoxin include reaction of amide dianions with 2-iodocarboxylates, selective reduction of the resulting acid-amide products, and intramolecular photochemically-driven iodination using N-iodoamide precursors.