A detailed study of the total synthesis of valerenic acid, a well known GABAA receptor subtype modulator, is described. Both successful as well as unsuccessful attempts towards the synthesis of the title compound are presented, including four different strategies to synthesize one of the key intermediates. The first two strategies are based on epoxides provided from the chiral pool, whereas the last two approaches rest on stereocontrolled modifications of 2-cyclopentenone. The streamlined synthesis implements a new one-pot reaction, which combines the addition of a Grignard species with an acid-catalyzed isomerization of the intermediate allylic alcohol. Further highlights are a stereo- and regioselective hydroxy-directed Diels–Alder reaction, a hydroxy-directed hydrogenation, and a final Negishi coupling reaction. After optimization of our synthesis, the preparation of several easily available derivatives is also discussed. Amides obtained by functionalization of the carboxyl group are more than twice as active as valerenic acid.

中文翻译：

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从规划到优化：缬草酸和一些生物活性衍生物的全合成

描述了对众所周知的 GABAA 受体亚型调节剂缬草酸全合成的详细研究。介绍了合成标题化合物的成功和失败尝试，包括四种不同的合成关键中间体的策略。前两种策略基于手性池提供的环氧化物，而后两种方法基于 2-环戊烯酮的立体控制修饰。流线型合成采用新的一锅法反应，将格氏物质的添加与中间烯丙醇的酸催化异构化相结合。进一步的亮点是立体和区域选择性羟基定向的 Diels-Alder 反应、羟基定向的氢化和最终的 Negishi 偶联反应。在优化我们的合成之后，还讨论了几种容易获得的衍生物的制备。通过羧基官能化获得的酰胺的活性是戊酸的两倍以上。