Oxide‐Bridged Heterobimetallic Aluminum/Zirconium Catalysts for Ethylene Polymerization

Abstract

Protein‐based pharmaceuticals typically display high selectivity and low toxicity, but are also characterized by low oral availability, mainly because of enzymatic degradation in the gastrointestinal tract and poor permeability across the intestinal wall. One way to increase the proteolytic stability of peptides and proteins is by intramolecular crosslinking, such as the introduction of disulfide bridges. However, disulfide bridges are at risk of thiol‐disulfide exchange or reduction during production, purification, and/or therapeutic use, whereas thioether bridges are expected to be stable under the same conditions. In this study, thioether crosslinking was investigated for a 46 aa albumin‐binding domain (ABD) derived from streptococcal protein G. ABD binds with high affinity to human serum albumin (HSA) and has been proposed as a fusion partner to increase the in vivo half‐lives of therapeutic proteins. In the study, five ABD variants with single or double intramolecular thioether bridges were designed and synthesized. The binding affinity, secondary structure, and thermal stability of each protein was investigated by SPR‐based biosensor analysis and CD spectroscopy. The proteolytic stability in the presence of the major intestinal proteases pepsin (found in the stomach) and trypsin in combination with chymotrypsin (found in pancreatin secreted to the duodenum by the pancreas) was also investigated. The most promising crosslinked variant, ABD_CL1, showed high thermal stability, retained high affinity in binding to HSA, and showed dramatically increased stability in the presence of pepsin and trypsin/chymotrypsin, compared to the ABD reference protein. This suggests that the intramolecular thioether crosslinking strategy can be used to increase the stability towards gastrointestinal enzymes.

Insight into Oxide‐Bridged Heterobimetallic Al/Zr Olefin Polymerization Catalysts

“…However, addition of i Bu 3 Al gave a polymerization‐active system with an activity of 1180 kg PE mol Zr −1 h −1 bar −1 (Table , entry 4). This activity is slightly lower than that for the previously reported dimer [(DIPH)Al−O−Zr(Me)Cp* 2 ] 2 in the presence of MAO (1595 kg PE mol Zr −1 h −1 bar −1 ) . Decreasing the Al/Zr ratio from 300 to 30 only gave a small decrease in activity (1070 kg PE mol Zr −1 h −1 bar −1 ; Table , entry 5), which shows the effectiveness of i Bu 3 Al as a cocatalyst.…”

“…The centrosymmetric dimer shows an Al 2 O 2 core in which the bond lengths range from 1.858(1)–1.878(1) Å (average 1.868(1) Å). These values are slightly longer than in [(DIPH)AlMe] 2 (1.838(1)–1.854(1) Å; average=1.846(1) Å), which is likely due to increased steric hindrance in both the biphenolate ligand and alkyl substituent . Despite the increased steric bulk of TBBP, formation of a dimeric product could not be prevented.…”

“…The methyl protons of the Cp* ligand produce a sharp singlet at δ =1.91 ppm, therefore it is likely that the product is not dimeric. The dimer [(DIPH)Al(THF)−O−Zr(Me)Cp* 2 ] 2 (Scheme ) features chiral Al centers, thus two singlets for the Cp* ligands are observed in the 1 H NMR spectrum …”

“…The monomeric structure of [(TBBP)Al(THF)−O−Zr(Me)Cp* 2 ] was confirmed by X‐ray analysis (Figure ). The complex has no crystallographic symmetry and its main structural parameters are comparable to those of dimeric [(DIPH)Al−O−Zr(Me)Cp* 2 ] 2 (Table ) …”

“…This may allow for activation without the MAO cocatalyst, and might provide insight into which of the previously discussed activation pathways (Scheme i–iii) is most likely. We recently reported an attempt to synthesize such complexes by substitution of the monoanionic DIPPnacnac ligand with a dianionic biphenolate ligand (Scheme ) . We used a biphenolate ligand (DIPH, see Scheme ) functionalized with −CH 2 C(Me)=CH 2 ortho substituents to stabilize the complex by weak intramolecular alkene⋅⋅⋅Al coordination.…”