- Ag/P-Stereogenic Phosphine-Catalyzed Enantioselective 1,3-Dipolar Cycloadditions: A Method to Optically Active Pyrrolidines
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A Ag/P-stereogenic phosphine-complex-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with electron-deficient olefins is reported. In this reaction, highly functionalized pyrrolines with a spiro-quaternary stereogenic center were obtained in good yields (up to 99%) with excellent levels of diastereo-(up to >20:1 dr) and enantioselectivities (up to >99% ee). The chirality of adducts was controlled predominantly by the P-stereogenic phosphines.
- Zhi, Mengna,Gan, Zhenjie,Ma, Rong,Cui, Hao,Li, Er-Qing,Duan, Zheng,Mathey, Fran?ois
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supporting information
(2019/05/07)
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- Chiral Cyclohexyl-Fused Spirobiindanes: Practical Synthesis, Ligand Development, and Asymmetric Catalysis
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1,1′-Spirobiindane has been one type of privileged skeleton for chiral ligand design, and 1,1′-spirobiindane-based chiral ligands have demonstrated outstanding performance in various asymmetric catalysis. However, the access to enantiopure spirobiindane is quite tedious, which obstructs its practical application. In the present article, a facile enantioselective synthesis of cyclohexyl-fused chiral spirobiindanes has been accomplished, in high yields and excellent stereoselectivities (up to >99% ee), via a sequence of Ir-catalyzed asymmetric hydrogenation of α,α′-bis(arylidene)ketones and TiCl4 promoted asymmetric spiroannulation of the hydrogenated chiral ketones. The protocol can be performed in one pot and is readily scalable, and has been utilized in a 25 g scale asymmetric synthesis of cyclohexyl-fused spirobiindanediol (1S,2S,2′S)-5, in >99% ee and 67% overall yield for four steps without chromatographic purification. Facile derivations of (1S,2S,2′S)-5 provided straightforward access to chiral monodentate phosphoramidites 6a-c and a tridentate phosphorus-amidopyridine 11, which were evaluated as chiral ligands in several benchmark enantioselective reactions (hydrogenation, hydroacylation, and [2 + 2] reaction) catalyzed by transition metal (Rh, Au, or Ir). Preliminary results from comparative studies showcased the excellent catalytic performances of these ligands, with a competency essentially equal to the corresponding well-established privileged ligands bearing a regular spirobiindane backbone. X-ray crystallography revealed a close resemblance between the structures of the precatalysts 20 and 21 and their analogues, which ultimately help to rationalize the almost identical stereochemical outcomes of reactions catalyzed by metal complexes of spirobiindane-derived ligands with or without a fused cyclohexyl ring on the backbone. This work is expected to stimulate further applications of this type of readily accessible skeletons in development of chiral ligands and functional molecules.
- Zheng, Zhiyao,Cao, Yuxi,Chong, Qinglei,Han, Zhaobin,Ding, Jiaming,Luo, Chenguang,Wang, Zheng,Zhu, Dongsheng,Zhou, Qi-Lin,Ding, Kuiling
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supporting information
p. 10374 - 10381
(2018/08/03)
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- Inhibitor of CBP histone acetyltransferase downregulates p53 activation and facilitates methylation at lysine 27 on histone H3
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Tumor suppressor p53-directed apoptosis triggers loss of normal cells, which contributes to the side-effects from anticancer therapies. Thus, small molecules with potential to downregulate the activation of p53 could minimize pathology emerging from anticancer therapies. Acetylation of p53 by the histone acetyltransferase (HAT) domain is the hallmark of coactivator CREB-binding protein (CBP) epigenetic function. During genotoxic stress, CBP HAT-mediated acetylation is essential for the activation of p53 to transcriptionally govern target genes, which control cellular responses. Here, we present a small molecule, NiCur, which blocks CBP HAT activity and downregulates p53 activation upon genotoxic stress. Computational modeling reveals that NiCur docks into the active site of CBP HAT. On CDKN1A promoter, the recruitment of p53 as well as RNA Polymerase II and levels of acetylation on histone H3 were diminished by NiCur. Specifically, NiCur reduces the levels of acetylation at lysine 27 on histone H3, which concomitantly increases the levels of trimethylation at lysine 27. Finally, NiCur attenuates p53-directed apoptosis by inhibiting the Caspase 3 activity and cleavage of Poly (ADP-ribose) polymerase (PARP) in normal gastrointestinal epithelial cells. Collectively, NiCur demonstrates the potential to reprogram the chromatin landscape and modulate biological outcomes of CBP-mediated acetylation under normal and disease conditions.
- Vincek, Adam S.,Patel, Jigneshkumar,Jaganathan, Anbalagan,Green, Antonia,Pierre-Louis, Valerie,Arora, Vimal,Rehmann, Jill,Mezei, Mihaly,Zhou, Ming-Ming,Ohlmeyer, Michael,Mujtaba, Shiraz
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