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Using methods of DFT, we investigated the effect of electron withdrawing and electron donating groups on the relative stability of tentative glycosyl donor reaction intermediates. The calculation shows that by changing the stereoelectronic properties of the protecting group, we can influence the stability of the dioxolenium type of intermediates by up to 10 kcal mol−1, and that by increasing nucleophillicity of the 4-O-Bz group, the dioxolenium intermediate becomes more stable than a triflate–donor pair. We exploited this mechanism to design galactosyl donors with custom protecting groups on O2 and O4, and investigated the outcome of the reaction with cyclohexanol. The reaction showed no change in the product distribution, which suggests that the neighboring group participation takes precedence over remote group participation due to kinetic barriers. 

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. 

New and readily available chiral SPIROL-based diphosphinite ligands (SPIRAPO) have been prepared and employed for iridium-catalyzed asymmetric hydrogenations of quinolines, quinoxalines and 2 H -1,4-bezoxazin-2-ones. While the structurally similar ( R , R , R )-SPIRAPO and ( R )-SPINOL-based phosphinites were not the best ligands for these transformations, the ( S , R , R )-diastereomer of SPIRAPO was found to be highly effective ligand for the reduction of 20 different heterocyclic systems with loadings as low as S/C = 10 000. This dearomatizative hydrogenation provided direct access to optically active tetrahydroquinolines in high enantioselectivities (up to 94% ee) and excellent yields (up to 99%), and was used to generate 1.75 g of natural alkaloid (−)-( R )-angustureine. This protocol was subsequently extended to achieve asymmetric hydrogenation of quinoxalines and 2 H -1,4-benzoxazin-2-ones in good to excellent enantioselectivities.