Ruthenium-Catalyzed C–H Allylation of Alkenes with Allyl Alcohols via C–H Bond Activation in Aqueous Solution

A robust Ru­(II)-catalyzed C–H allylation of electron-deficient alkenes with allyl alcohols in aqueous solution is reported. This method provides a straightforward and efficient access to the synthetically useful 1,4-diene skeletons. With the assistance of the N-methoxycarbamoyl directing group, this allylation reaction features a broad substrate scope with good functional group tolerance, excellent regio- and stereoselectivity, absence of metal oxidants, water-tolerant solvents, and mild reaction conditions. The mechanistic studies indicate that the process of the reversible C–H bond ruthenation is assisted by acetate, and the rate-determining step is unlikely to be the step of C–H bond cleavage

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Characterization of Hydrophilic α‑Helical Hot Spots on the Protein–Protein Interaction Interfaces for the Design of α‑Helix Mimetics

The cooperativity index, Kc, was developed to examine the binding synergy between hot spots of the ligand–protein. For the first time, the convergence of the side-chain spatial arrangements of hydrophilic α-helical hot spots Thr, Tyr, Asp, Asn, Ser, Cys, and His in protein–protein interaction (PPI) complex structures was disclosed and quantified by developing novel clustering models. In-depth analyses revealed the driving force for the protein–protein binding conformation convergence of hydrophilic α-helical hot spots. This observation allows deriving pharmacophore models to design new mimetics for hydrophilic α-helical hot spots. A computational protocol was developed to search amino acid analogues and small-molecule mimetics for each hydrophilic α-helical hot spot. As a pilot study, diverse building blocks of commercially available nonstandard L-type α-amino acids and the phenyl ring-containing small-molecule fragments were obtained, which serve as a fragment collection to mimic hydrophilic α-helical hot spots for the improvement of binding affinity, selectivity, physicochemical properties, and synthesis accessibility of α-helix mimetics

Rhodium-Catalyzed [4 + 1] Cyclization via C–H Activation for the Synthesis of Divergent Heterocycles Bearing a Quaternary Carbon

The development of an efficient approach to construct fused polycyclic systems bearing a quaternary carbon center represents a great challenge to synthetic chemistry. Herein, we report a Rh­(III)-catalyzed [4 + 1] annulation of propargyl alcohols with various heterocyclic scaffolds under an air atmosphere. Diverse fused heterocycles containing a quaternary carbon center were obtained in moderate to good yields. Additionally, this method features a high atom-economy, metal oxidant free, simple operation, and compatibility with various functional groups

Characterization of Hydrophilic α‑Helical Hot Spots on the Protein–Protein Interaction Interfaces for the Design of α‑Helix Mimetics

The cooperativity index, Kc, was developed to examine the binding synergy between hot spots of the ligand–protein. For the first time, the convergence of the side-chain spatial arrangements of hydrophilic α-helical hot spots Thr, Tyr, Asp, Asn, Ser, Cys, and His in protein–protein interaction (PPI) complex structures was disclosed and quantified by developing novel clustering models. In-depth analyses revealed the driving force for the protein–protein binding conformation convergence of hydrophilic α-helical hot spots. This observation allows deriving pharmacophore models to design new mimetics for hydrophilic α-helical hot spots. A computational protocol was developed to search amino acid analogues and small-molecule mimetics for each hydrophilic α-helical hot spot. As a pilot study, diverse building blocks of commercially available nonstandard L-type α-amino acids and the phenyl ring-containing small-molecule fragments were obtained, which serve as a fragment collection to mimic hydrophilic α-helical hot spots for the improvement of binding affinity, selectivity, physicochemical properties, and synthesis accessibility of α-helix mimetics

Characterization of Hydrophilic α‑Helical Hot Spots on the Protein–Protein Interaction Interfaces for the Design of α‑Helix Mimetics

The cooperativity index, Kc, was developed to examine the binding synergy between hot spots of the ligand–protein. For the first time, the convergence of the side-chain spatial arrangements of hydrophilic α-helical hot spots Thr, Tyr, Asp, Asn, Ser, Cys, and His in protein–protein interaction (PPI) complex structures was disclosed and quantified by developing novel clustering models. In-depth analyses revealed the driving force for the protein–protein binding conformation convergence of hydrophilic α-helical hot spots. This observation allows deriving pharmacophore models to design new mimetics for hydrophilic α-helical hot spots. A computational protocol was developed to search amino acid analogues and small-molecule mimetics for each hydrophilic α-helical hot spot. As a pilot study, diverse building blocks of commercially available nonstandard L-type α-amino acids and the phenyl ring-containing small-molecule fragments were obtained, which serve as a fragment collection to mimic hydrophilic α-helical hot spots for the improvement of binding affinity, selectivity, physicochemical properties, and synthesis accessibility of α-helix mimetics

Ruthenium(II)-Catalyzed Regio- and Stereoselective C–H Allylation of Indoles with Allyl Alcohols

A ruthenium-catalyzed C–H allylation of indoles with allyl alcohols via β-hydroxide elimination is reported. Without external oxidants and expensive additives, this reaction features mild reaction conditions, compatibility with various functional groups, and good to excellent regioselectivity and stereoselectivity

Targeting the Side-Chain Convergence of Hydrophobic α‑Helical Hot Spots To Design Small-Molecule Mimetics: Key Binding Features for <i>i</i>, <i>i</i> + 3, and <i>i</i> + 7

The conformational convergence of hydrophobic α-helical hot spots was revealed by analyzing α-helix-mediated protein–protein interaction (PPI) complex structures. The pharmacophore models were derived for hydrophobic α-helical hot spots at positions i, i + 3, and i + 7. These provide the foundation for designing generalizable scaffolds that can directly mimic the binding mode of the side chains of α-helical hot spots, offering a new class of small-molecule α-helix mimetics. For the first time, the protocol was developed to identify the PPI targets that have similar binding pockets, allowing evaluation of inhibitor selectivities between α-helix-mediated PPIs. The mimicry efficiency of the previously designed scaffold 1 was disclosed. The close positioning of this small molecule to the additional α-helical hot spots suggests that the decoration of this series of generalizable scaffolds can conveniently reach the binding pockets of additional α-helical hot spots to produce potent small-molecule inhibitors for α-helix-mediated PPIs

Characterization of Hydrophilic α‑Helical Hot Spots on the Protein–Protein Interaction Interfaces for the Design of α‑Helix Mimetics

The cooperativity index, Kc, was developed to examine the binding synergy between hot spots of the ligand–protein. For the first time, the convergence of the side-chain spatial arrangements of hydrophilic α-helical hot spots Thr, Tyr, Asp, Asn, Ser, Cys, and His in protein–protein interaction (PPI) complex structures was disclosed and quantified by developing novel clustering models. In-depth analyses revealed the driving force for the protein–protein binding conformation convergence of hydrophilic α-helical hot spots. This observation allows deriving pharmacophore models to design new mimetics for hydrophilic α-helical hot spots. A computational protocol was developed to search amino acid analogues and small-molecule mimetics for each hydrophilic α-helical hot spot. As a pilot study, diverse building blocks of commercially available nonstandard L-type α-amino acids and the phenyl ring-containing small-molecule fragments were obtained, which serve as a fragment collection to mimic hydrophilic α-helical hot spots for the improvement of binding affinity, selectivity, physicochemical properties, and synthesis accessibility of α-helix mimetics

Targeting the Side-Chain Convergence of Hydrophobic α‑Helical Hot Spots To Design Small-Molecule Mimetics: Key Binding Features for <i>i</i>, <i>i</i> + 3, and <i>i</i> + 7

The conformational convergence of hydrophobic α-helical hot spots was revealed by analyzing α-helix-mediated protein–protein interaction (PPI) complex structures. The pharmacophore models were derived for hydrophobic α-helical hot spots at positions i, i + 3, and i + 7. These provide the foundation for designing generalizable scaffolds that can directly mimic the binding mode of the side chains of α-helical hot spots, offering a new class of small-molecule α-helix mimetics. For the first time, the protocol was developed to identify the PPI targets that have similar binding pockets, allowing evaluation of inhibitor selectivities between α-helix-mediated PPIs. The mimicry efficiency of the previously designed scaffold 1 was disclosed. The close positioning of this small molecule to the additional α-helical hot spots suggests that the decoration of this series of generalizable scaffolds can conveniently reach the binding pockets of additional α-helical hot spots to produce potent small-molecule inhibitors for α-helix-mediated PPIs