Development of CPA-Catalyzed b-Selective Reductive Amination of Cardenolides for the Synthesis of Hydrolytically Stable Analogs

This article describes the development of novel, hydrolysis-resistant cardiotonic steroid analogs featuring a 3b-aniline moiety instead of the commonly found 3b-carbohydrates such as oleandrose. To establish the desired 3b-amine configuration stereoselectively, a new method based on chiral phosphoric acid-controlled diastereoselective reductive amination with Hantzsch esters was developed. This method utilizes readily available unsubstituted (S)-BINOL-based hydrogen phosphate as the catalyst, enabling the synthesis of 13 distinct 5b-androsterone and digitoxigenin analogs with up to 36:1 b:a diastereoselectivity. Additionally, this strategy was applied to generate a novel oleandrigenin analog 15 in three steps from the readily available gitoxigenin. The synthetic analogs were screened against the NCI-60 human tumor cell lines, revealing several digitoxigenin derivatives with potent tumor cell growth inhibitory activity and cytotoxicity in the submicromolar range.