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To establish the desired 3\u03b2\u2010configuration stereoselectively, a new method based on chiral phosphoric acid\u2010controlled diastereoselective reductive amination with Hantzsch esters was developed. This method utilizes readily available unsubstituted (S)\u2010BINOL\u2010based hydrogen phosphate as the catalyst, enabling the synthesis of 13 different 5\u03b2\u2010androsterone and digitoxigenin analogs with up to 36:1\u00a0\u03b2:\u03b1 diastereoselectivity. Additionally, this strategy was applied to generate two novel oleandrigenin analogs\n                    <jats:bold>15a<\/jats:bold>\n                    and\n                    <jats:bold>15<\/jats:bold>\n                    <jats:bold>g<\/jats:bold>\n                    in 3 steps from readily available gitoxigenin. The synthetic analogs were subjected to the NCI\u201060 human tumor cell lines screen, and several different digitoxigenin derivatives with tumor cell growth inhibitory power in submicromolar range were identified. The subsequent in vitro evaluation of digitoxigenin and oleandrin derivatives\n                    <jats:bold>13a<\/jats:bold>\n                    ,\n                    <jats:bold>13<\/jats:bold>\n                    <jats:bold>g<\/jats:bold>\n                    ,\n                    <jats:bold>15a<\/jats:bold>\n                    , and\n                    <jats:bold>15<\/jats:bold>\n                    <jats:bold>g<\/jats:bold>\n                    demonstrated that these four analogs reduced steady\u2010state ATP1A1 levels in T98G cells in the 12\u201396\u00a0nM range. Interestingly, only the oleandrin analog\n                    <jats:bold>15<\/jats:bold>\n                    <jats:bold>g<\/jats:bold>\n                    lowered also steady\u2010state levels of the cellular prion protein (PrP\n                    <jats:sup>C<\/jats:sup>\n                    ), the main therapeutic target for the treatment of prion diseases.\n                  <\/jats:p>","DOI":"10.1002\/chem.202501552","type":"journal-article","created":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T16:06:13Z","timestamp":1750262773000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Development of CPA\u2010Catalyzed \u03b2\u2010Selective Reductive Amination of Cardenolides for the Synthesis and Biological Evaluation of Hydrolytically Stable Analogs"],"prefix":"10.1002","volume":"31","author":[{"given":"Natasha","family":"Perry","sequence":"first","affiliation":[{"name":"Chemistry Department University of Michigan  930 N. 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