Total Synthesis of Waltherione Alkaloids: A Strategic Molecular Diversity Approach

We report the first total synthesis of <i>rac</i>-8-deoxoantidesmone and <i>rac</i>-waltherione M, key intermediates in the unexplored 5,6,7,8-tetrahydro-1H-quinolin-4-one waltherione (THQW) alkaloid family. These compounds have been synthesized in three steps via a diversity-oriented approach utilizing a versatile intermediate 8-bromo-5-fluoro-3-methoxy-2-methyl-1H-quinolin-4-one, which was obtained through a one-step synthesis between 2-bromo-5-fluoro-aniline and ethyl 2-methoxy-3-oxo-butanoate. This intermediate underwent a MgCl₂-mediated S_NAr reaction using alkyl Grignard reagents to provide 8-bromo-3-methoxy-2-methyl-5-alkyl-1H-quinolin-4-one. Furthermore, leveraging these common intermediates, we achieved the first total syntheses of waltherione R, 8-demethoxywaltherione F, 8-demethoxywaltherione R, walindicaone C, and walindicaone D, as well as developing a concise three-step synthesis of waltherione F.