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Abstract Nitrogen-containing compounds, such as amines, hydrazines, and heterocycles, play an indispensable role in medicine, agriculture, and materials. Alkylated derivatives of these compounds, especially in sterically congested environments, remain a challenge to prepare. Here we report a versatile method for the regioselective hydroamination of readily available unactivated olefins with diazirines. Over fifty examples are reported, including the protecting group-free amination of fourteen different natural products. A broad functional group tolerance includes alcohols, ketones, aldehydes, and epoxides. The proximate products of these reactions are diaziridines, which, under mild conditions, are converted to primary amines, hydrazines, and heterocycles. Five target- and diversity-oriented syntheses of pharmaceutical compounds are shown, along with the preparation of a bis-15N diazirine validated in the late-stage isotopic labeling of an RNA splicing modulator candidate. In this work, we report using diazirine (1) as an electrophilic nitrogen source in a regioselective hydroamination reaction, and the diversification of the resulting diaziridines.
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Development of CPA‐Catalyzed β‐Selective Reductive Amination of Cardenolides for the Synthesis and Biological Evaluation of Hydrolytically Stable Analogs
Abstract This article describes the development of novel, hydrolytically stable cardiotonic steroid analogs featuring a 3β‐amine moiety instead of the commonly found 3β‐carbohydrates such as oleandrose. To establish the desired 3β‐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 different 5β‐androsterone and digitoxigenin analogs with up to 36:1 β:α diastereoselectivity. Additionally, this strategy was applied to generate two novel oleandrigenin analogs15aand15gin 3 steps from readily available gitoxigenin. The synthetic analogs were subjected to the NCI‐60 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 derivatives13a,13g,15a, and15gdemonstrated that these four analogs reduced steady‐state ATP1A1 levels in T98G cells in the 12–96 nM range. Interestingly, only the oleandrin analog15glowered also steady‐state levels of the cellular prion protein (PrPC), the main therapeutic target for the treatment of prion diseases.
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- Award ID(s):
- 1955069
- PAR ID:
- 10642275
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Chemistry – A European Journal
- Volume:
- 31
- Issue:
- 41
- ISSN:
- 0947-6539
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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