Total Synthesis of Clavicipitic Acid and Aurantioclavine: Stereochemistry of Clavicipitic Acid Revisited

The stereocontrolled total synthesis of clavicipitic acid and aurantioclavine from a common azepino[5,4,3-cd]-indole intermediate is reported. This key azepinoindole nucleus was constructed via a one-pot Heck/Boc-deprotection/aminocyclization process from the 4-iodotryptophan derivative, which was assembled by a Pd-catalyzed indole synthesis procedure. After two or three additional deprotection steps from the azepinoindole intermediates, (−)-trans- and (−)-cis-clavicipitic acid were prepared. The syntheses of both (−)- and (+)-aurantioclavine were achieved with the same azepinoindole intermediates utilizing the Barton decarboxylation reaction as the key step to remove the stereohindered carboxylic acid. During the course of our synthesis, mis-assigned configurations of the synthesized clavicipitic acids and their derivatives in the literature were identified. Extensive studies including 2D-NMR study, X-ray diffraction analysis, titration experiment, and Rf value comparison unambiguously confirmed the new configuration assignment. The trans and cis configuration assignments of the synthesized clavicipitic acids and their derivatives in the past literature should be switched.

本文报道了以共用氮杂卓并[5,4,3-cd]吲哚（azepino[5,4,3-cd]-indole）中间体为原料，立体控制全合成棒麦角酸（clavicipitic acid）与橙麦角碱（aurantioclavine）的研究。该关键氮杂卓吲哚环系可由4-碘色氨酸衍生物经一锅法Heck反应/Boc脱保护（Boc-deprotection）/氨基环化过程构建，而4-碘色氨酸衍生物则通过钯催化吲哚合成工艺制备得到。从该氮杂卓吲哚中间体再经两步或三步脱保护步骤后，即可得到(-)-反式棒麦角酸与(-)-顺式棒麦角酸。以同一氮杂卓吲哚中间体为原料，以巴顿脱羧反应（Barton decarboxylation）为关键步骤移除位阻型羧酸，即可完成(-)-型与(+)-型橙麦角碱的全合成。在本研究的合成过程中，我们发现已有文献中对所合成棒麦角酸及其衍生物的构型存在误判。通过二维核磁共振谱（2D-NMR）、X射线衍射分析、滴定实验及比移值（Rf value）对比等一系列系统性研究，我们明确证实了修正后的构型归属方案。过往文献中所标注的合成棒麦角酸及其衍生物的反式与顺式构型应当互换。