Lewis Acid–Base Interaction‐Controlled ortho‐Selective C−H Borylation of Aryl Sulfides

An iridium/bipyridine‐catalyzed ortho ‐selective C−H borylation of aryl sulfides was developed. High ortho ‐selectivity was achieved by a Lewis acid–base interaction between a boryl group of the ligand and a sulfur atom of the substrate. This is the first example of a catalytic and regioselective C−H transformation controlled by a Lewis acid–base interaction between a ligand and a substrate. The C−H borylation reaction could be conducted on a gram scale, and with a bioactive molecule as a substrate, demonstrating its applicability to late‐stage regioselective C−H borylation. A bioactive molecule was synthesized from an ortho ‐borylated product by converting the boryl and methylthio groups of the product.     

Polyethylene Glycol Backfilling Mitigates the Negative Impact of the Protein Corona on Nanoparticle Cell Targeting

In protein‐rich environments such as the blood, the formation of a protein corona on receptor‐targeting nanoparticles prevents target recognition. As a result, the ability of targeted nanoparticles to selectively bind to diseased cells is drastically inhibited. Backfilling the surface of a targeted nanoparticle with polyethylene glycol (PEG) molecules is demonstrated to reduce the formation of the protein corona and re‐establishes specific binding. The length of the backfilled PEG molecules must be less than the length of the ligand linker; otherwise, PEG interferes with the binding of the targeting ligand to its corresponding cellular receptor.     

Enantioselective Synthesis of Biaryl Atropisomers by Pd‐Catalyzed C−H Olefination using Chiral Spiro Phosphoric Acid Ligands

The discovery of proper ligands to simultaneously modulate the reactivity and effectively control the stereoselectivity is a central topic in the field of enantioselective C?H activation. Herein, we reported the synthesis of axially chiral biaryls by Pd‐catalyzed atroposelective C?H olefination. A novel chiral spiro phosphoric acid, STRIP, was identified as a superior ligand for this transformation. A broad range of axially chiral quinoline derivatives were synthesized in good yields with excellent enantioselectivities (up to 98 % ee). Density functional theory was used to gain a theoretical understanding of the enantioselectivities in this reaction.     

Fluorine Pseudocontact Shifts Used for Characterizing the Protein–Ligand Interaction Mode in the Limit of NMR Intermediate Exchange

The characterization of protein–ligand interaction modes becomes recalcitrant in the NMR intermediate exchange regime as the interface resonances are broadened beyond detection. Here, we determined the ¹⁹F low‐populated bound‐state pseudocontact shifts (PCSs) of mono‐ and di‐fluorinated inhibitors of the BRM bromodomain using a highly skewed protein/ligand ratio. The bound‐state ¹⁹F PCSs were retrieved from ¹⁹F chemical exchange saturation transfer (CEST) in the presence of the lanthanide‐labeled protein, which was termed the ¹⁹F PCS‐CEST approach. These PCSs enriched in spatial information enabled the identification of best‐fitting poses, which agree well with the crystal structure of a more soluble analog in complex with the BRM bromodomain. This approach fills the gap of the NMR structural characterization of lead‐like inhibitors with moderate affinities to target proteins, which are essential for structure‐guided hit‐to‐lead evolution.     

Regioselective C?F Bond Activation of Hexafluoropropylene on Palladium(0): Formation of a Cationic η2‐Perfluoroallylpalladium Complex

A chemoselective C(sp²) F or C(sp³) F bond activation of hexafluoropropylene (HFP) was achieved by adopting the proper combination of a Lewis acid co‐additive with a ligand which coordinates Pd⁰. The treatment of [(η²‐HFP)Pd(PCy₃)₂] with B(C₆F₅)₃ allowed a chemoselective C(sp³) F bond cleavage of HFP to give a unique cationic perfluoroallypalladium complex. In this complex, the coordination mode of the perfluoroallyl ligand was considered to be of the unique η²‐fashion.     

An N‐Heterocyclic Boryloxy Ligand Isoelectronic with N‐Heterocyclic Imines: Access to an Acyclic Dioxysilylene and its Heavier Congeners

Introduced here is a new type of strongly donating N‐heterocyclic boryloxy (NHBO) ligand, [(HCDippN)₂BO]^? (Dipp=2,6‐diisopropylphenyl), which is isoelectronic with the well‐known N‐heterocyclic iminato (NHI) donor class. This 1,3,2‐diazaborole functionalized oxy ligand has been used to stabilize the first acyclic two‐coordinate dioxysilylene and its Ge, Sn, and Pb congeners, thereby presenting the first complete series of heavier group 14 dioxycarbene analogues. All four compounds have been characterized by X‐ray crystallography and density‐functional theory, enabling analysis of periodic trends: the potential for the [(HCDippN)₂BO]^? ligand to subtly vary its electronic‐donor capabilities is revealed by snapshots showing the gradual evolution of arene π coordination on going from Si to Pb.     

An Epitope‐Imprinted Biointerface with Dynamic Bioactivity for Modulating Cell–Biomaterial Interactions

In this study, an epitope‐imprinting strategy was employed for the dynamic display of bioactive ligands on a material interface. An imprinted surface was initially designed to exhibit specific affinity towards a short peptide (i.e., the epitope). This surface was subsequently used to anchor an epitope‐tagged cell‐adhesive peptide ligand (RGD: Arg‐Gly‐Asp). Owing to reversible epitope‐binding affinity, ligand presentation and thereby cell adhesion could be controlled. As compared to current strategies for the fabrication of dynamic biointerfaces, for example, through reversible covalent or host–guest interactions, such a molecularly tunable dynamic system based on a surface‐imprinting process may unlock new applications in in situ cell biology, diagnostics, and regenerative medicine.     

Development of Chemo‐ and Enantioselective Palladium‐Catalyzed Decarboxylative Asymmetric Allylic Alkylation of α‐Nitroesters

We describe the development of a Pd‐catalyzed decarboxylative asymmetric allylic alkylation of α‐nitro allyl esters to afford acyclic tetrasubstituted nitroalkanes. Optimization of the reaction parameters revealed unique ligand and solvent combinations crucial for achieving chemo‐ and enantioselective C‐alkylation of electronically challenging benzylic nitronates and sterically encumbered 2‐allyl esters. Substrates were efficiently accessed in a combinatorial fashion by a cross‐Claisen/ α‐arylation sequence. The method provides functional group orthogonality that complements nucleophilic imine allylation strategies for α‐tertiary amine synthesis.     

Real‐Time Control of the Enantioselectivity of a Supramolecular Catalyst Allows Selecting the Configuration of Consecutively Formed Stereogenic Centers

The enantiomeric state of a supramolecular copper catalyst can be switched in situ in ca. five seconds. The dynamic property of the catalyst is provided by the non‐covalent nature of the helical assemblies supporting the copper centers. These assemblies are formed by mixing an achiral benzene‐1,3,5‐tricarboxamide (BTA) phosphine ligand (for copper coordination) and both enantiomers of a chiral phosphine‐free BTA co‐monomer (for chirality amplification). The enantioselectivity of the hydrosilylation reaction is fixed by the BTA enantiomer in excess, which can be altered by simple BTA addition. As a result of the complete and fast stereochemical switch, any combination of the enantiomers was obtained during the conversion of a mixture of two substrates.     

Disclosing Interfaces of ZnO Nanocrystals Using Dynamic Nuclear Polarization: Sol‐Gel versus Organometallic Approach

The unambiguous characterization of the coordination chemistry of nanocrystal surfaces produced by wet‐chemical synthesis presently remains highly challenging. Here, zinc oxide nanocrystals (ZnO NCs) coated by monoanionic diphenyl phosphate (DPP) ligands were derived by a sol‐gel process and a one‐pot self‐supporting organometallic (OSSOM) procedure. Atomic‐scale characterization through dynamic nuclear polarization (DNP‐)enhanced solid‐state NMR (ssNMR) spectroscopy has notably enabled resolving their vastly different surface‐ligand interfaces. For the OSSOM‐derived NCs, DPP moieties form stable and strongly‐anchored μ₂‐ and μ₃‐bridging‐ligand pairs that are resistant to competitive ligand exchange. The sol‐gel‐derived NCs contain a wide variety of coordination modes of DPP ligands and a ligand exchange process takes place between DPP and glycerol molecules. This highlights the power of DNP‐enhanced ssNMR for detailed NC surface analysis and of the OSSOM approach for the preparation of ZnO NCs.     

Discovery of Inhibitors of Shiga Toxin Type 2 by On‐Plate Generation and Screening of a Focused Compound Library

A new microtiter‐plate‐based method for the rapid generation and evaluation of focused compound libraries was developed and applied to screening ligand analogues for the E. coli Shiga‐like toxin Stx2a. The method is general, it mitigates the masking of intrinsic affinity gains by multivalency and enables the discovery of potential hits when starting from ligands that exhibit extremely low affinity with proteins that depend on multivalency for their function.     

Ligand‐Controlled Palladium(II)‐Catalyzed Regiodivergent Carbonylation of Alkynes: Syntheses of Indolo[3,2‐c]coumarins and Benzofuro[3,2‐c]quinolinones

Regiodivergent syntheses of indolo[3,2‐c]coumarins and benzofuro[3,2‐c]quinolinones through a controllable palladium(II)‐catalyzed carbonylative cyclization are established. The chemo‐ and regioselectivity are exclusively tuned by the ligand on the palladium catalyst. The rigid framework of the electron‐deficient ligand promotes the O‐attack/N‐carbonylation cyclization leading to benzofuro[3,2‐c]quinolinones, while a sterically bulky and electron‐rich ligand facilitates N‐attack/O‐carbonylation cyclization to generate indolo[3,2‐c]coumarins. Furthermore, various other nucleophiles are applicable for delivering a variety of indoloquinolinones, pyranoquinolones, and chromeno[3,4‐c]quinolinones in one step, and serves as a method for creating compound libraries for drug discovery.     

Redox and Anion Exchange Chemistry of a Stibine–Nickel Complex: Writing the L,X, Z Ligand Alphabet with a Single Element

According to the covalent bond classification (CBC) method, two‐electron donors are defined as L‐type ligands, one‐electron donors as X‐type ligands, and two‐electron acceptors as Z‐type ligands. These three ligand functions are usually associated to the nature of the ligating atom, with phosphine, alkyl, and borane groups being prototypical examples of L‐, X‐ and Z‐ligands, respectively. A new SbNi platform is reported in which the ligating Sb atom can assume all three CBC ligand functions. Using both experimental and computational data, it is shown that PhICl₂ oxidation of (o‐(Ph₂P)C₆H₄)₃SbNi(PPh₃) ( 1 ) into [(o‐(Ph₂P)C₆H₄)₃ClSb]NiCl ( 2 ) is accompanied by a conversion of the stibine L‐type ligand of 1 into a stiboranyl X‐type ligand in 2 . Furthermore, the reaction of 2 with the catecholate dianion in the presence of cyclohexyl isocyanide results in the formation of [(o‐(Ph₂P)C₆H₄)₃(o‐O₂C₆H₄Sb)]Ni(CNCy) ( 4 ), a complex featuring a nickel atom coordinated by a Lewis acidic, Z‐type, stiborane ligand.     

Fast NMR‐Based Determination of the 3D Structure of the Binding Site of Protein–Ligand Complexes with Weak Affinity Binders

In early drug discovery approaches, screening hits are often weak affinity binders that are difficult to characterize in structural detail, particularly towards obtaining the 3D structure of protein–ligand complexes at atomic resolution. NMR is the outstanding technique to tackle such problems, yet suffers from a tedious structure calculation process. N MR² was recently developed to alleviate the laborious element of routine NMR structure calculation procedures and provides the structural information at protein–ligand interaction sites orders of magnitude faster than standard procedures. The N MR² method was extended to weak binders and applied to the oncoproteins HDM2 and MDMX. The structure of the MDMX‐SJ212 complex is reported with a K _d of approximately 0.7 μm ; the complex structure of HDM2 with the mm affinity ligand #845 exhibits a new scaffold.     

Cooperative Effects between Chiral Cpx–Iridium(III) Catalysts and Chiral Carboxylic Acids in Enantioselective C−H Amidations of Phosphine Oxides

An enantioselective C−H amidation of phosphine oxides by using an iridium(III) catalyst bearing an atropchiral cyclopentadienyl (Cp^x) ligand is reported. A very strong cooperative effect between the chiral Cp^x ligand and a phthaloyl tert‐leucine enabled the transformation. Matched–mismatched cases of the different acid enantiomers are shown. The amidated P‐chiral arylphosphine oxides are formed in yields of up to 95 % and with excellent enantioselectivities of up to 99:1 er. Enantiospecific reduction provides access to valuable P‐chiral phosphorus(III) compounds.     

Reaction of Donor‐Acceptor Cyclobutanes with Indoles: A General Protocol for the Formal Total Synthesis of (±)‐Strychnine and the Total Synthesis of (±)‐Akuammicine

A ligand‐promoted catalytic [4+2] annulation reaction using indole derivatives and donor‐acceptor (D‐A) cyclobutanes is reported, thus providing an efficient and atom‐economical access to versatile cyclohexa‐fused indolines with excellent levels of diastereoselectivity and a broad substrate scope. In the presence of a chiral SaBOX ligand, excellent enantioselectivity was realized with up to 94 % ee. This novel synthetic method is applied as a general protocol for the total synthesis of (±)‐akuammicine and the formal total synthesis of (±)‐strychnine from the same common‐core scaffold.     

Synthesis of Optically Pure Helicene Metallocenes

Two types of ruthenocenes and a ferrocene coordinated by rac ‐9H ‐cyclopenta[1,2‐c :4,3‐c ′]diphenanthrenyl anion(s), a [7]helicene with a cyclopentadienyl moiety at the center of its skeleton, were successfully synthesized: mono‐helicene ruthenocene 1 and its iron analogue 1_Fe with one [7]helicene ligand bound to the central metal, and bis‐helicene ruthenocene 2 with two [7]helicenes. Starting from a racemic mixture of the ligand precursor, rac ‐ 2 and meso ‐ 2 were obtained in a 7:3 ratio. Since the [7]helicene has a high racemization barrier, enantiomers of the complexes were isolated in their pure forms; they showed large optical rotations and intense circular dichroism (CD) responses.     

Construction of Chiral Tetraorganosilicons by Tandem Desymmetrization of Silacyclobutanes/Intermolecular Dehydrogenative Silylation

We report a method to construct chiral tetraorganosilicons by tandem silacyclobutane (SCB) desymmetrization–dehydrogenative silylations. A wide array of dibenzosiloles with stereogenic quaternary silicon centers were obtained in good yields and enantioselectivities up to 93 % ee . Chiral TMS‐segphos was found to be a superior ligand in terms of reactivity and enantioselectivity.     

Regio‐ and Enantioselective Preparation of Chiral Allylic Sulfones Featuring Elusive Quaternary Stereocenters

We describe here the first general asymmetric synthesis of sterically encumbered α,α‐disubstituted allylic sulfones via Pd‐catalyzed allylic substitution. The design and application of a new and highly efficient phosphoramidite ligand ( L10 ) proved to be crucial, and a wide variety of challenging allylic sulfones featuring quaternary stereocenters could be obtained in good yields and with good to excellent levels of regio‐ and enantioselectivities under attractive process conditions. The developed methodology employs easily accessible chemical feedstock including racemic allylic precursors and sodium sulfinates. The utility of the method is further demonstrated by the synthesis of the sesquiterpene (?)‐Agelasidine A.