Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025, USA.
J Am Chem Soc. 2010 Apr 7;132(13):4894-906. doi: 10.1021/ja100178u.
Development of efficient sequences for the total syntheses of (+/-)-actinophyllic acid (rac-1) and (-)-actinophyllic acid (1) are described. The central step in these syntheses is the aza-Cope/Mannich reaction, which constructs the previously unknown hexacyclic ring system of actinophyllic acid in one step from much simpler tetracyclic precursors. The tetracyclic hexahydro-1,5-methano-1H-azocino[4,3-b]indole ketone rac-37 is assembled from o-nitrophenylacetic acid in four steps, with oxidative cyclization of a dienolate derivative of tricyclic precursor rac-35 being the central step. In the first-generation synthesis, this intermediate is transformed in two steps to homoallyl amine rac-43, whose formaldiminium derivative undergoes efficient aza-Cope/Mannich reaction to give pentacyclic ketone rac-44. In four additional steps, this intermediate is advanced to (+/-)-actinophyllic acid. The synthesis is streamlined by elaborating ketone rac-37 to beta-hydroxyester intermediate rac-53, which is directly transformed to (+/-)-actinophyllic acid upon exposure to HCl and paraformaldehyde. This concise second-generation total synthesis of (+/-)-actinophyllic acid is realized in 22% overall yield from commercially available di-tert-butyl malonate and o-nitrophenylacetic acid by a sequence that proceeds by way of only six isolated intermediates. The first enantioselective total synthesis of (-)-actinophyllic acid (1) is accomplished by this direct sequence from tricyclic keto malonate (S)-35. Catalytic enantioselective reduction of alpha,beta-unsaturated ketone 66 is the key step in the preparation of intermediate (S)-35 from the commercially available Boc-amino acid 65. Discussed also is the possibility that the aza-Cope/Mannich reaction might be involved in the biosynthesis of (-)-actinophyllic acid.
描述了高效序列的开发，用于（±）-actinophyllic 酸（rac-1）和（-）-actinophyllic 酸（1）的全合成。这些合成中的关键步骤是氮杂-Cope/Mannich 反应，它从更简单的四环前体一步构建了 actinophyllic 酸以前未知的六环体系。四环六氢-1,5-亚甲基-1H-氮杂环[4,3-b]吲哚酮 rac-37 由邻硝基苯乙酸经四步合成，三环前体 rac-35 的二烯醇化物衍生物的氧化环化为中心步骤。在第一代合成中，该中间体分两步转化为偕丙胺 rac-43，其甲亚胺衍生物经历有效的氮杂-Cope/Mannich 反应，得到五环酮 rac-44。再经过四个步骤，该中间体就可以得到（±）-actinophyllic 酸。通过将酮 rac-37 精制为β-羟基酯中间体 rac-53，使合成得到简化，该中间体在暴露于 HCl 和多聚甲醛时直接转化为（±）-actinophyllic 酸。该简洁的第二代（±）-actinophyllic 酸全合成以 22%的总产率从商业上可获得的二-tert-丁基丙二酸和邻硝基苯乙酸实现，该序列仅通过六个分离的中间体进行。（-）-actinophyllic 酸（1）的首次对映选择性全合成通过该三循环酮丙二酸（S）-35的直接序列完成。α，β-不饱和酮 66 的催化对映选择性还原是从商业上可获得的 Boc-氨基酸 65 制备中间（S）-35的关键步骤。还讨论了氮杂-Cope/Mannich 反应可能参与（-）-actinophyllic 酸生物合成的可能性。
