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1. Ligand‐Controlled Regiodivergence in Nickel‐Catalyzed Hydroarylation and Hydroalkenylation of Alkenyl Carboxylic Acids**

   https://doi.org/10.1002/anie.202010840  

   Li, Zi‐Qi; Fu, Yue; Deng, Ruohan; Tran, Van T.; Gao, Yang; Liu, Peng; Engle, Keary M. (October 2020, Angewandte Chemie International Edition)

   Abstract A nickel‐catalyzed regiodivergent hydroarylation and hydroalkenylation of unactivated alkenyl carboxylic acids is reported, whereby the ligand environment around the metal center dictates the regiochemical outcome. Markovnikov hydrofunctionalization products are obtained under mild ligand‐free conditions, with up to 99 % yield and >20:1 selectivity. Alternatively, anti‐Markovnikov products can be accessed with a novel 4,4‐disubstituted Pyrox ligand in excellent yield and >20:1 selectivity. Both electronic and steric effects on the ligand contribute to the high yield and selectivity. Mechanistic studies suggest a change in the turnover‐limiting and selectivity‐determining step induced by the optimal ligand. DFT calculations reveal that in the anti‐Markovnikov pathway, repulsion between the ligand and the alkyl group is minimized (by virtue of it being 1° versus 2°) in the rate‐ and regioselectivity‐determining transmetalation transition state. 

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2. Photomechanochemical control over stereoselectivity in the [2 + 2] photodimerization of acenaphthylene

   https://doi.org/10.1039/D2FD00122E  

   Biswas, Sankarsan; Banerjee, Sayan; Shlain, Milan A.; Bardin, Andrey A.; Ulijn, Rein V.; Nannenga, Brent L.; Rappe, Andrew M.; Braunschweig, Adam B. (January 2023, Faraday Discussions)

   Tuning solubility and mechanical activation alters the stereoselectivity of the [2 + 2] photochemical cycloaddition of acenaphthylene. Photomechanochemical conditions produce the syn cyclobutane, whereas the solid-state reaction in the absence of mechanical activation provides the anti . When the photochemical dimerization occurs in a solubilizing organic solvent, there is no selectivity. Dimerization in H 2 O, in which acenaphthylene is insoluble, provides the anti product. DFT calculations reveal that insoluble and solid-state reactions proceed via a covalently bonded excimer, which drives anti selectivity. Alternatively, the noncovalently bound syn conformer is more mechanosusceptible than the anti , meaning it experiences greater destabilization, thereby producing the syn product under photomechanochemical conditions. Cyclobutanes are important components of biologically active natural products and organic materials, and we demonstrate stereoselective methods for obtaining syn or anti cyclobutanes under mild conditions and without organic solvents. With this work, we validate photomechanochemistry as a viable new direction for the preparation of complex organic scaffolds. 

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3. Highly stereoselective syntheses of ( E )-δ-boryl- anti -homoallylic alcohols via allylation with α-boryl-( E )-crotylboronate

   https://doi.org/10.1039/d1cc04058h  

   Liu, Jiaming; Chen, Ming (October 2021, Chemical Communications)

   A highly stereoselective synthesis of ( E )-δ-boryl- anti -homoallylic alcohols is developed. In the presence of a Lewis acid, aldehyde allylation with α-boryl-( E )-crotylboronate gave δ-boryl- anti -homoallylic alcohols in good yields with excellent E -selectivity. The E -vinylboronate group in the products provides a useful handle for cross-coupling reactions as illustrated in the fragment synthesis of chaxamycins. 

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4. Characterization of Subtype Selective Cannabinoid CB2 Receptor Agonists as Potential Anti-Inflammatory Agents

   https://doi.org/10.3390/ph14040378  

   Tang, Yaliang; Wolk, Barbara; Nolan, Ryan; Scott, Caitlin E.; Kendall, Debra A. (April 2021, Pharmaceuticals)

   null (Ed.)

   Activation of the CB2 receptor has been shown to have anti-inflammatory and antinociceptive effects without causing psychoactive effects. Previously, we reported that the compound ethyl 2(2-(N-(2,3-dimethylphenyl) phenylsulfonamido)acetamido)benzoate (ABK5) is a CB2 subtype selective agonist with anti-inflammatory and antinociceptive effects. In the present study, we tested four ABK5 derivatives, ABK5-1, ABK5-2, ABK5-5, and ABK5-6, to analyze the structure of ABK5 to obtain CB2-selective agonists with higher affinity and efficacy. Affinity, subtype selectivity, and G-protein coupling were determined by radioligand binding assays. Selected compounds were then subjected to evaluation of anti-inflammatory effects using two different cell lines, Jurkat (ABK5-1 and 5-2) and BV-2 cells (ABK5-1), which are models of T cells and microglia, respectively. ABK5-1, ABK5-2, and ABK5-6 had comparable CB2 binding affinity with ABK5 (and stimulated G-protein coupling), while only ABK5-1 and ABK5-2 maintained CB2-subtype selectivity. ABK5-5 did not bind CB2 in the detectable range. RT-PCR and ELISA analysis showed that the two compounds also inhibit IL-2 and TNF-α production, and they were more efficacious than ABK5 in inhibiting TNF-α production. CXCL-12 mediated chemotaxis was also evaluated by the transwell migration assay, and both ABK5-1 and ABK5-2 inhibited chemotaxis with a stronger effect observed in ABK5-1. In the microglia cell line BV-2, ABK5-1 inhibited IL-1β and IL-6 production, which suggests this compound has anti-inflammatory effects through targeting multiple immune cells, and may be a candidate for treatment of inflammation. 

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5. Diastereoconvergent synthesis of anti -1,2-amino alcohols with N-containing quaternary stereocenters via selenium-catalyzed intermolecular C–H amination

   https://doi.org/10.1039/d2sc02648a  

   Zheng, Tianyi; Berman, Janna L.; Michael, Forrest E. (August 2022, Chemical Science)

   We report a diastereoconvergent synthesis of anti -1,2-amino alcohols bearing N-containing quaternary stereocenters using an intermolecular direct C–H amination of homoallylic alcohol derivatives catalyzed by a phosphine selenide. Destruction of the allylic stereocenter during the selenium-catalyzed process allows selective formation of a single diastereomer of the product starting from any diastereomeric mixture of the starting homoallylic alcohol derivatives, eliminating the need for the often-challenging diastereoselective preparation of starting materials. Mechanistic studies show that the diastereoselectivity is controlled by a stereoelectronic effect (inside alkoxy effect) on the transition state of the final [2,3]-sigmatropic rearrangement, leading to the observed anti selectivity. The power of this protocol is further demonstrated on an extension to the synthesis of syn -1,4-amino alcohols from allylic alcohol derivatives, constituting a rare example of 1,4-stereoinduction. 

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