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1. A Pd−H/Isothiourea Cooperative Catalysis Approach to anti ‐Aldol Motifs: Enantioselective α‐Alkylation of Esters with Oxyallenes**

   https://doi.org/10.1002/ange.202201753  

   Lin, Hua‐Chen ; Knox, Gary J. ; Pearson, Colin M. ; Yang, Chao ; Carta, Veronica ; Snaddon, Thomas N. ( April 2022 , Angewandte Chemie)

   The biological and therapeutic significance of natural products is a powerful impetus for the development of efficient methods to facilitate their construction. Accordingly, and reflecting the prevalence of β‐oxy‐carbonyl motifs, a sophisticated arsenal of aldol‐based strategies has evolved that is contingent on the generation of single enolate isomers. Since this has the potential to compromise efficiency in reagent‐based paradigms, direct catalysis‐based solutions would be enabling. To complement the array of substrate‐based strategies, and regulate enolate geometry at the catalyst level, a direct catalytic alkylation of esters with oxyallenes has been developed. Synergizing metal hydride reactivity with Lewis base catalysis has resulted in a broad reaction scope with useful levels of stereocontrol (up to >99 %ee). Facile derivatization of these ambiphilic linchpins is demonstrated, providing access to high‐valuevicinalstereocenter‐containing motifs, including 1,2‐amino alcohols.

    

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2. Platinum‐Catalyzed α,β‐Desaturation of Cyclic Ketones through Direct Metal–Enolate Formation

   https://doi.org/10.1002/anie.202013628  

   Chen, Ming ; Dong, Guangbin ( February 2021 , Angewandte Chemie International Edition)

   The development of a platinum‐catalyzed desaturation of cyclic ketones to their conjugated α,β‐unsaturated counterparts is reported in this full article. A unique diene‐platinum complex was identified to be an efficient catalyst, which enables direct metal‐enolate formation. The reaction operates under mild conditions without using strong bases or acids. Good to excellent yields can be achieved for diverse and complex scaffolds. A wide range of functional groups, including those sensitive to acids, bases/nucleophiles, or palladium species, are tolerated, which represents a distinct feature from other known desaturation methods. Mechanistically, this platinum catalysis exhibits a fast and reversible α‐deprotonation followed by a rate‐determining β‐hydrogen elimination process, which is different from the prior Pd‐catalyzed desaturation method. Promising preliminary enantioselective desaturation using a chiral‐diene‐platinum complex has also been obtained.

    

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3. Platinum‐Catalyzed α,β‐Desaturation of Cyclic Ketones through Direct Metal–Enolate Formation

   https://doi.org/10.1002/ange.202013628  

   Chen, Ming ; Dong, Guangbin ( February 2021 , Angewandte Chemie)

   The development of a platinum‐catalyzed desaturation of cyclic ketones to their conjugated α,β‐unsaturated counterparts is reported in this full article. A unique diene‐platinum complex was identified to be an efficient catalyst, which enables direct metal‐enolate formation. The reaction operates under mild conditions without using strong bases or acids. Good to excellent yields can be achieved for diverse and complex scaffolds. A wide range of functional groups, including those sensitive to acids, bases/nucleophiles, or palladium species, are tolerated, which represents a distinct feature from other known desaturation methods. Mechanistically, this platinum catalysis exhibits a fast and reversible α‐deprotonation followed by a rate‐determining β‐hydrogen elimination process, which is different from the prior Pd‐catalyzed desaturation method. Promising preliminary enantioselective desaturation using a chiral‐diene‐platinum complex has also been obtained.

    

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4. Functional characterization of the HMP‐P synthase of Legionella pneumophila (Lpg1565)

   https://doi.org/10.1111/mmi.14622  

   Paxhia, Michael D. ; Swanson, Michele S. ; Downs, Diana M. ( November 2020 , Molecular Microbiology)

   The production of the pyrimidine moiety in thiamine synthesis, 2‐methyl‐4‐amino‐5‐hydroxymethylpyrimidine phosphate (HMP‐P), has been described to proceed through the Thi5‐dependent pathway inSaccharomyces cerevisiaeand other yeast. Previous work found thatScThi5 functioned poorly in a heterologous context. Here we report a bacterial ortholog to the yeast HMP‐P synthase (Thi5) was necessary for HMP synthesis inLegionella pneumophila. UnlikeScThi5,LpThi5 functioned in vivo inSalmonella entericaunder multiple growth conditions. The proteinLpThi5 is a dimer that binds pyridoxal‐5′‐phosphate (PLP), apparently without a solvent‐exposed Schiff base. A small percentage ofLpThi5 protein co‐purifies with a bound molecule that can be converted to HMP. Analysis of variant proteins both in vivo and in vitro confirmed that residues in sequence motifs conserved across bacterial and eukaryotic orthologs modulate the function ofLpThi5.

   Thiamine is an essential vitamin for the vast majority of organisms. There are multiple strategies to synthesize and salvage this vitamin. The predominant pathway for synthesis of the pyrimidine moiety of thiamine involves the Fe‐S cluster protein ThiC. An alternative pathway utilizes Thi5, a novel enzyme that uses PLP as a substrate. The Thi5‐dependent pathway is poorly characterized in yeast and has not been characterized in Bacteria. Here we demonstrate that a Thi5‐dependent pathway is necessary for thiamine biosynthesis inLegionella pneumophilaand provide biochemical data to extend knowledge of the Thi5 enzyme, the corresponding biosynthetic pathway, and the role of metabolic network architecture in optimizing its function.

    

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5. Coupling of conformational dynamics and inhibitor binding in the phosphodiesterase‐5 family

   https://doi.org/10.1002/pro.4720  

   Tripathi, Shubhandra ; Cote, Rick H. ; Vashisth, Harish ( July 2023 , Protein Science)

   Phosphodiesterase‐5 (PDE5) is responsible for regulating the concentration of the second messenger molecule cGMP by hydrolyzing it into 5′‐GMP. PDE5 is implicated in erectile dysfunction and cardiovascular diseases. The substrate binding site in the catalytic domain of PDE5 is surrounded by several dynamic structural motifs (including the α14 helix, M‐loop, and H‐loop) that are known to switch between inactive and active conformational states via currently unresolved structural intermediates. We evaluated the conformational dynamics of these structural motifs in the apo state and upon binding of an allosteric inhibitor (evodiamine) oravanafil, a competitive inhibitor. We employed enhanced sampling‐based replica exchange solute scaling (REST2) method, principal component analysis (PCA), time‐lagged independent component analysis (tICA), molecular dynamics (MD) simulations, and well‐tempered metadynamics simulations to probe the conformational changes in these structural motifs. Our results support a regulatory mechanism for PDE5, where the α14 helix alternates between an inward (lower activity) conformation and an outward (higher activity) conformation that is accompanied by the folding/unfolding of the α8′ and α8″ helices of the H‐loop. When the allosteric inhibitor evodiamine is bound to PDE5, the inward (inactive) state of the α14 helix is preferred, thus preventing substrate access to the catalytic site. In contrast, competitive inhibitors of PDE5 block catalysis by occupying the active site accompanied by stabilization of the outward conformation of the α14 helix. Defining the conformational dynamics underlying regulation of PDE5 activation will be helpful in rational design of next‐generation small molecules modulators of PDE5 activity.

    

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