Tomer Rosen

The coordination chemistry and the activities in the ring‐opening polymerization catalysis of racemic lactide (LA) of magnesium complexes of a series of {ONNN}‐type sequential monoanionic ligands are described. All ligands include pyridyl and substituted‐phenolate as peripheral groups. The ligands bearing either chiral or meso‐bipyrrolidine cores led to single diastereomeric complexes, whereas the ligands bearing a diaminoethane core led to diastereomer mixtures. All {ONNN}Mg‐X complexes [X=Cl, HMDS (hexamethyldisilazide)] led to highly active and isoselective catalysts. The complexes bearing the chiral bipyrrolidine core exhibited the highest activities (full consumption of 5000 equiv. of rac‐LA at RT within 5 min) and highest isoselectivities (P_m=0.91), as well as a living character. The complexes of the meso‐bipyrrolidine based ligands were almost as active and slightly less stereoselective, while those of the diaminoethane based ligands exhibited reduced activities and isoselectivities.

Human calprotectin (CP, S100A8/S100A9 oligomer) is an abundant innate immune protein that sequesters transition metal ions in the extracellular space to limit nutrient availability and the growth of invading microbial pathogens. Our current understanding of the metal-sequestering ability of CP is based on biochemical and functional studies performed at neutral or near-neutral pH. Nevertheless, CP can be present throughout the human body and is highly expressed at infection and inflammation sites that tend to be acidic. Here, we evaluate the metal-binding and antimicrobial properties of CP in the pH 5.0–7.0 range. We show that Ca(II)-induced tetramerization, an important process for the extracellular functions of CP, is perturbed by acidic conditions. Moreover, low pH impairs the antimicrobial activity of CP against some bacterial pathogens, including Staphylococcus aureus and Salmonella enterica serovar Typhimurium. At mildly acidic pH, CP loses the ability to deplete Mn from microbial growth medium, indicating that Mn(II) sequestration is attenuated under acidic conditions. Evaluation of the Mn(II)-binding properties of CP at pH 5.0–7.0 indicate that mildly acidic conditions lower the Mn(II)-binding affinity of the His6 site. Lastly, CP is less effective at preventing capture of Mn(II) by the bacterial solute-binding proteins MntC and PsaA at low pH. These results indicate that acidic conditions compromise the ability CP to sequester Mn(II) and thereby starve microbial pathogens of this nutrient. Broadly, this work highlights the importance of considering the chemical complexity of biological sites when describing the interplay between CP and microbes in host-pathogen interactions.

Salophan ligands featuring the octahydrophenanthroline core are described for the first time. Two ligand precursors featuring either di‐tert‐butylphenolate or dichlorophenolate were prepared by 1,10‐phenanthroline hydrogenation followed by reaction with bromomethyl‐substituted phenols. The ligand precursors react with AlMe₃ to give the [{ONNO}Al‐Me]‐type complexes as single stereoisomers of averaged C_s‐symmetry on the NMR timescale. The reactivity of the methylaluminum complexes depends strongly on the phenolate substituents: The complex of the bulky ligand is inert towards alcohols and inactive in the ring‐opening polymerization of rac‐LA, whereas the complex of the non‐bulky ligand reacts readily with benzyl alcohol to yield the corresponding [{ONNO}Al‐OBn] complex, which polymerizes rac‐LA to give isotactically inclined PLA.

A magnesium complex of the type {ONNN}Mg‐HMDS wherein {ONNN} is a sequential tetradentate monoanionic ligand is introduced. In the presence of an alcohol initiator this complex catalyzes the living and immortal homopolymerization of the lactide enantiomers and ϵ‐caprolactone at room‐temperature with exceptionally high activities, as well as the precise block copolymerization of these monomers in a one‐pot synthesis by sequential monomer addition. Copolymers of unprecedented microstructures such as the PCL‐b‐PLLA‐b‐PDLA and PDLA‐b‐PLLA‐b‐PCL‐b‐PLLA‐b‐PDLA block–stereoblock microstructures that feature unique thermal properties are readily accessed.

A magnesium complex of the type {ONNN}Mg‐HMDS wherein {ONNN} is a sequential tetradentate monoanionic ligand is introduced. In the presence of an alcohol initiator this complex catalyzes the living and immortal homopolymerization of the lactide enantiomers and ϵ‐caprolactone at room‐temperature with exceptionally high activities, as well as the precise block copolymerization of these monomers in a one‐pot synthesis by sequential monomer addition. Copolymers of unprecedented microstructures such as the PCL‐b‐PLLA‐b‐PDLA and PDLA‐b‐PLLA‐b‐PCL‐b‐PLLA‐b‐PDLA block–stereoblock microstructures that feature unique thermal properties are readily accessed.

The ring-opening transesterification polymerization (ROTEP) of rac-lactide (rac-LA) using L^XZn catalysts (L^X = ligand having phenolate, amine, and pyridine donors with variable para substituents X on the bound phenolate donor; X = NO₂, Br, t-Bu, OMe) was evaluated through kinetics experiments and density functional theory, with the aim of determining how electronic modulation of the ligand framework influences polymerization rate, selectivity, and control. After determination that zinc-ethyl precatalysts required 24 h of reaction with benzyl alcohol to convert to active alkoxide complexes, the subsequently formed species proved to be active and fairly selective, polymerizing up to 300 equiv of rac-LA in 6–10 min while yielding isotactic (P_m = 0.72–0.78) polylactide (PLA) with low dispersities: Đ = 1.06–1.17. In contrast to previous work with aluminum catalysts for which electronic effects of ligand substituents were significant (Hammett ρ = +1.2–1.4), the L^XZn systems exhibited much less of an effect (ρ = +0.3). Density functional calculations revealed details of the initiation and propagation steps, enabling insights into the high isotacticity and the insensitivity of the rate on the identity of X.

A new, potentially dinucleating xanthene-bridged bis(iminophenolate) ligand L (L = 6,6′-((1E,1′E)-((2,7-di-tert-butyl-9,9-dimethyl-9H-xanthene-4,5-diyl)bis(azanylylidene))bis(methanylylidene))bis(2,4-di-tert-butylphenol)) has been synthesized and its coordination chemistry with zinc precursors featuring alkoxide, chloride, and ethyl leaving groups has been investigated. The reaction of a zinc precursor bearing two bulky alkoxides, Zn(Cl)(μ²-OR)₂Li(THF) (OR = di-tert-butyl-phenylmethoxide), formed a mononuclear complex Zn(L) that was isolated as an H-bond adduct with HOR, Zn(L)·HOR. In contrast, the reaction of L (or its lithium salt) with diethylzinc (or zinc chloride) led to the formation of the corresponding dinuclear complexes Zn₂(L)(Et)₂ and Zn₂(L)(μ²-Cl)₄Li₂(OEt₂)₂. X-ray crystallography revealed syn-parallel geometry for Zn₂(L)(Et)₂ (Zn⋯Zn distance of 4.5 Å) and anti-parallel geometry for Zn₂(L)(μ²-Cl)₄Li₂(OEt₂)₂ (Zn⋯Zn distance of 6.7 Å). Zn₂(L)(Et)₂ was found to be somewhat unstable, demonstrating decomposition into Zn(L) and ZnEt₂; this decomposition can be reversed by the addition of excess ZnEt₂. Treatment of Zn₂(L)(Et)₂ with benzyl alcohol (BnOH) in deuterated benzene, toluene, or dichloromethane resulted in the formation of Zn₂(L)(OBn)₂, which was characterized by ¹H and ¹³C NMR spectroscopy. Zn₂(L)(OBn)₂ was found to be active in the ring-opening polymerization of rac-lactide to afford heterotactically inclined PLA.