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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 (PrP^C), the main therapeutic target for the treatment of prion diseases. 

Abstract This manuscript describes transfer hydrogenation of bicyclic nitrogen-containing heterocyclic compounds using the immobilized chiral phosphoric acid catalyst (R)-PS-AdTRIP in batch and continuous flow. A significant improvement in enantioselectivities is achieved in continuous flow with a fluidized bed reactor packed with (R)-PS-AdTRIP when the flow rate is increased from 0.2 mL/min to 2.0–2.5 mL/min. The optimized continuous flow conditions consistently provide 4–6% ee higher selectivity than transfer hydrogenation in batch with 2 mol% of (R)-PS-AdTRIP, and are used to generate multiple chiral products with the same fluidized bed reactor. 

This communication describes the synthesis of new bis-oxazoline chiral ligands (SPIROX) derived from the C2-symmetric spirocyclic scaffold (SPIROL). The readily available (R,R,R)-SPIROL (2) previously developed by our group was subjected to a three-step sequence that provided key diacid intermediate (R,R,R)-7 in 75% yield. This intermediate was subsequently coupled with (R)- and (S)-phenylglycinols to provide diastereomeric products, the cyclization of which led to two diastereomeric SPIROX ligands (R,R,R,R,R)-3a and (R,R,R,S,S)-3b in 85% and 79% yield, respectively. The complexation of (R,R,R,R,R)-3a and (R,R,R,S,S)-3b with CuCl and Cu(OTf)2 resulted in active catalysts that promoted the asymmetric reaction of α-diazopropionate and phenol. The resultant O–H insertion product was formed in 88% yield, and with excellent selectivity (97% ee) when ligand (R,R,R,R,R)-3a was used.