Multicomponent/Palladium-Catalyzed Cascade Entry to Benzopyrrolizidine Derivatives: Synthesis and Antioxidant Evaluation

A versatile and efficient
protocol for the synthesis of highly
substituted benzopyrrolizidines (tetrahydro-3H-pyrrolo­[2,1-a]­isoindol-3-ones) is reported. The strategy consisted of
an Ugi four-component reaction/elimination methodology to afford dehydroalanines
containing trans-cinnamic acid derivatives and different
substituted 2-bromobenzylamines, followed by a palladium-catalyzed
5-exo-trig/5-exo-trig cascade carbocyclization process. Gratifyingly,
benzopyrrolizidines were obtained in moderate to good yields (42–77%)
with a Z geometry due to the structural requirements
for syn-β-hydride elimination. The prepared
heterocyclic scaffolds are decorated with several substituents and
incorporate a benzopyrrolizidine-fused system, along with an embedded
cinnamic acid derivative, two privileged medicinal chemistry scaffolds.
Additionally, since some of the compounds are derived from the well-known
antioxidants ferulic and sinapinic acids, they were tested for their
in vitro antioxidant capacity. The data suggested that compounds having
a p-hydroxyl group showed moderate 2,2-diphenyl-1-picrylhydrazyl-radical-scavenging
activity and were effective antioxidants in preventing lipoperoxidation
in a thiobarbituric acid reactive substances assay.

本报告提出了一种合成高度取代的苯并吡咯里西定（四氢-3H-吡咯[2,1-a]异喹啉-3-酮）的通用且高效的方法。该策略包括一个Ugi四组分反应/消除方法，以提供含有反式肉桂酸衍生物和不同取代的2-溴苄胺的脱氢丙氨酸，随后通过钯催化的5-外环化/5-外环化级联碳环化过程。令人欣慰的是，由于结构对合成β-氢消除的几何要求，苯并吡咯里西定在中等至良好的产率（42-77%）下以Z几何形态获得。所制备的杂环骨架上装饰有多个取代基，并包含一个苯并吡咯里西定融合体系，以及嵌入的肉桂酸衍生物，以及两个具有重要药用化学骨架的化合物。此外，由于一些化合物源自已知的抗氧化剂阿魏酸和异阿魏酸，因此对这些化合物的体外抗氧化能力进行了测试。数据显示，具有邻羟基的化合物表现出适度的2,2-二苯基-1-苯基自由基清除活性，并在硫代巴比妥酸反应物测试中表现出有效的抗氧化活性，防止脂质过氧化。