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      Stereodivergent assembly of tetrahydro-γ-carbolines via synergistic catalytic asymmetric cascade reaction

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          Abstract

          Enantiomerically enriched indole-containing heterocycles play a vital role in bioscience, medicine, and chemistry. As one of the most attractive subtypes of indole alkaloids, highly substituted tetrahydro-γ-carbolines are the basic structural unit in many natural products and pharmaceuticals. However, the syntheses of tetrahydro-γ-carbolines with high functionalities from readily available reagents are significant challenging. In particular, the stereodivergent syntheses of tetrahydro-γ-carbolines containing multi-stereogenic centers remain quite difficult. Herein, we report an expedient and stereodivergent assembly of tetrahydro-γ-carbolines with remarkably high levels of stereoselective control in an efficient cascade process from aldimine esters and indolyl allylic carbonates via a synergistic Cu/Ir catalyst system. Control experiments-guided optimization of synergistic catalysts and mechanistic investigations reveal that a stereodivergent allylation reaction and a subsequent highly stereoselective iso-Pictet-Spengler cyclization are the key elements to success.

          Abstract

          Tetrahydro-γ-carbolines are the basic structural unit in many natural products and pharmaceuticals. Here, the authors report a synergistic Cu/Ir system to assemble chiral tetrahydro-γ-carbolines via a stereodivergent allylation followed by a stereoselective iso-Pictet-Spengler cyclization.

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          Enantio- and diastereodivergent dual catalysis: α-allylation of branched aldehydes.

          An important challenge in asymmetric synthesis is the development of fully stereodivergent strategies to access the full complement of stereoisomers of products bearing multiple stereocenters. In the ideal case, where four products are possible, applying distinct catalysts to the same set of starting materials under identical conditions would in a single step afford any given stereoisomer. Herein, we describe the realization of this concept in a fully stereodivergent dual-catalytic synthesis of γ,δ-unsaturated aldehydes bearing vicinal quaternary/tertiary stereogenic centers. The reaction is enabled by chiral iridium and amine catalysts, which activate the allylic alcohol and aldehyde substrates, respectively. Each catalyst exerts high local stereocontrol irrespective of the other's inherent preference.
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            Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A.

            Structure-based drug design combined with homology modeling techniques were used to develop potent inhibitors of HDAC6 that display superior selectivity for the HDAC6 isozyme compared to other inhibitors. These inhibitors can be assembled in a few synthetic steps, and thus are readily scaled up for in vivo studies. An optimized compound from this series, designated Tubastatin A, was tested in primary cortical neuron cultures in which it was found to induce elevated levels of acetylated alpha-tubulin, but not histone, consistent with its HDAC6 selectivity. Tubastatin A also conferred dose-dependent protection in primary cortical neuron cultures against glutathione depletion-induced oxidative stress. Importantly, when given alone at all concentrations tested, this hydroxamate-containing HDAC6-selective compound displayed no neuronal toxicity, thus, forecasting the potential application of this agent and its analogues to neurodegenerative conditions.
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              Iridium-Catalyzed Asymmetric Allylic Substitution Reactions

              In this review, we summarize the origin and advancements of iridium-catalyzed asymmetric allylic substitution reactions during the past two decades. Since the first report in 1997, Ir-catalyzed asymmetric allylic substitution reactions have attracted intense attention due to their exceptionally high regio- and enantioselectivities. Ir-catalyzed asymmetric allylic substitution reactions have been significantly developed in recent years in many respects, including ligand development, mechanistic understanding, substrate scope, and application in the synthesis of complex functional molecules. In this review, an explicit outline of ligands, mechanism, scope of nucleophiles, and applications is presented.
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                Author and article information

                Contributors
                cjwang@whu.edu.cn
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                5 December 2019
                5 December 2019
                2019
                : 10
                : 5553
                Affiliations
                [1 ]ISNI 0000 0001 2331 6153, GRID grid.49470.3e, Engineering Research Center of Organosilicon Compounds & Materials, Ministry of Education, College of Chemistry and Molecular Sciences, , Wuhan University, ; Wuhan, 430072 China
                [2 ]ISNI 0000 0001 1015 4378, GRID grid.422150.0, State Key Laboratory of Organometallic Chemistry, , Shanghai Institute of Organic Chemistry, ; Shanghai, 230021 China
                Article
                13529
                10.1038/s41467-019-13529-z
                6895234
                31804483
                f77e9781-c250-4272-9f87-509cfd6903f2
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 30 August 2019
                : 13 November 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100011002, National Science Foundation of China | National Natural Science Foundation of China-Yunnan Joint Fund (NSFC-Yunnan Joint Fund);
                Award ID: 21525207
                Award ID: 21772147
                Award Recipient :
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                © The Author(s) 2019

                Uncategorized
                asymmetric catalysis,synthetic chemistry methodology
                Uncategorized
                asymmetric catalysis, synthetic chemistry methodology

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