Journal of Organic Chemistry
Journal of Organic Chemistry
5 years ago

The Catalytically Lignan-Activation-Based Approach for the Synthesis of (epi)-Podophyllotoxin Derivatives

The Catalytically Lignan-Activation-Based Approach for the Synthesis of (epi)-Podophyllotoxin Derivatives
Yang Hu, Jian-Song Sun, Hui Liu, Zhong-Yi He, Jun-Hao Wan, Yuan-Hong Tu
Under the effect of a catalytic amount of Au(I) complex, 4-O-(2-cyclopropylethynyl)benzoyl-(epi)-podophyllotoxins, easily prepared via dehydrative condensation between (epi)-podophyllotoxin and ortho-cyclopropylethynylbenzoic acid, could efficiently couple with a variety of nucleophiles including alcohol, phenol, aniline, and carbon nucleophiles, all to provide (epi)-podophyllotoxin derivatives. Thus, the first catalytic and lignan-activation-based approach for (epi)-podophyllotoxin derivatization was established. Based on the new methodology, as well as the judicious choice of N3, AZMB, and Cbz protecting groups, an efficient approach forward was set. NK-611, an antitumoral agent at a phase II clinical trial was established, featuring an in situ anomerization of the hemiacetal OHs in the critical condensation step. Commencing from easily available starting material, the target molecule was obtained using the longest linear sequence of six steps and a 38% overall yield.

Publisher URL: http://dx.doi.org/10.1021/acs.joc.7b00485

DOI: 10.1021/acs.joc.7b00485

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