Sayam Sen Gupta

High-valent iron–oxo intermediates are well established as key oxidants in biological and synthetic oxidation chemistry, whereas their protonated counterparts, iron(IV)–hydroxo (FeIVOH) species, remain comparatively underexplored despite their central role in Cytochrome P450 catalysis. Herein, we report the synthesis, spectroscopic characterization, and reactivity of a room-temperature-stable FeIVOH complex supported by a biuret-modified tetraamido macrocyclic ligand (bTAML). One-electron oxidation of the crystallographically characterized precursor [Et4N]2[(Ph,Me-bTAML)FeIIIOH] using tris(4-bromophenyl)ammoniumyl hexachloroantimonate (Magic Blue) affords the one-electron-oxidized species [(Ph,Me-bTAML)Fe(OH)]− under ambient conditions. Comprehensive characterization by UV–vis, HRMS, EPR, Mössbauer spectroscopy, and X-ray absorption spectroscopy (XANES/EXAFS) conclusively identifies this species as a mononuclear FeIVOH complex. This species represents the first TAML-supported Compound II analogue and a rare non-heme model of the biologically relevant FeIVOH intermediate. Reactivity studies reveal efficient hydroxyl radical rebound chemistry, achieving hydroxylation of the trityl radical derived from Gomberg’s dimer in 60% yield. Thermodynamic analysis revealed an O–H bond dissociation free energy of 76.3 kcal mol–1, which is reflected in its selective reactivity toward O–H bond oxidation of substituted 2,6-di-tert-butylphenols. Kinetic and mechanistic studies support a concerted proton–electron transfer (CPET) pathway, providing new insights into the structure, thermodynamics, and reactivity of FeIVOH intermediates.

Sulfated glycosaminoglycans (GAGs) play important roles in a number of physiological and pathophysiological processes, including the coagulation cascade, tumor growth inhibition, viral transmission, and antioxidation. Heparin, a naturally occurring, highly sulfated GAG, remains widely used as a clinical anticoagulant. However, risks of contamination, variable pharmacological response, and its adverse side effects have motivated the development of synthetic alternatives. Earlier reports of heparin-mimicking polymers have focused on either incorporating sulfate groups via postpolymerization methods or polymerizing free sulfonic acid-containing monomers via RAFT and ROMP. Synthesis using more sensitive polymerization techniques such as ATRP, NMP, and NCA-ROP, which require polymerization of protected sulfate-containing monomers, remains challenging and largely unexplored. Herein, we report a novel synthetic methodology to prepare mannose-6-sulfate (M6S)-based glycopolypeptides as a structural mimic of heparin. Initially, the protected sulfate group was introduced, particularly at the 6-position of mannose, and an M6S-based N-carboxyanhydride (NCA) monomer was prepared. Further, the protected glycopolypeptides were synthesized via NCA-ROP techniques. The fully water-soluble sulfated M6S glycopolypeptides, subsequently obtained after deprotection steps, exhibited minimal cytotoxicity toward mammalian cells and negligible hemolytic activity, underscoring their potential suitability for biomedical applications. Furthermore, both aPTT and PT assays indicate that these synthetic materials can act as anticoagulants by significantly prolonging clotting times with performance comparable to that of heparin. The control mannose glycopolypeptides exhibited no activity, demonstrating the importance of sulfate groups in achieving anticoagulation. The mechanistic investigations elucidated the anticoagulation pathway to be dependent on factors IIa and Xa. This methodology of developing sulfated glycopolypeptides might bring in more valuable therapeutics for antiviral or anticancer materials.

High-valent iron–oxo complexes are among the most effective oxidants for C–H bond activation; however, the ability of non-oxo high-valent iron species to perform similar transformations remains an emerging area of research. Herein, we report a new generation of bTAML–Fe complexes featuring strategic ligand framework modifications that markedly enhance the redox potential of the iron center. Oxidation of the FeIIICl precursor generates a highly reactive FeIVCl species, which has been characterized by UV-vis, EPR and HRMS. Remarkably, this complex is the first FeIVCl species shown to abstract hydrogen atoms from O–H and weak C–H bonds. Kinetic and thermodynamic studies reveal that substrate oxidation proceeds through an oxidative asynchronous concerted proton-electron transfer (CPET) pathway.

High-valent iron-oxo complexes dominate C-H bond activation chemistry, whereas analogous reactivity of nonoxo iron oxidants remains largely unexplored. Here, we report two structurally characterized Fe^IV-cyanide complexes supported by a bTAML ligand: [Fe^IV(CN)(bTAML)]^- and [Fe^IV(CN)₂(bTAML)]^2-. Despite possessing a 150 mV more positive Fe^IV/III potential, the five-coordinated complex is ∼550-fold less reactive and incapable of C-H bond activation, whereas the six-coordinated analogue oxidizes both O-H and C-H bonds. Kinetic studies reveal no correlation with C-H bond dissociation energies but a strong dependence on substrate pK_a, indicating asynchronous (basicity-controlled) H atom abstraction. Large KIEs, Hammett analysis, and asynchronicity parameter of the HAA reactions support a proton-transfer-dominated asynchronous PCET mechanism, which is corroborated by quantum-chemical calculations that reproduce the reactivity trends and identify the electronic origin of the lower barrier in the dicyano complex, including revealing the Fe-C≡N → Fe-N≡C isomerization, which enables the PCET event. These results demonstrate that coordination-induced modulation of basicity and linkage isomerization can govern PCET asynchronicity in nonoxo iron complexes, establishing Fe-cyanide species as a distinct class of hydrogen-atom abstractors and providing a design principle for tuning C-H activation reactivity beyond conventional redox paradigms.

Three-dimensional (3D) scaffolds made of natural biopolymers that mimic the extracellular matrix provide a versatile platform for a wide range of biomedical applications.

Switching the solvent from acetonitrile to water, a non-heme Mn(V)-oxo complex shows ∼20 000-fold HAT rate enhancement for C–H substrates via stabilisation in the transition-state through enhanced electrostatics and hydrogen bonding interaction.

Mannose-6-phosphate (M6P) functionalised liposomal nanocarriers can achieve site-specific delivery of β-glucuronidase (β-GUS) to the targeted organelle lysosome of enzyme deficient cells in Mucopolysaccharidosis VII (MPS VII), a lysosomal storage disorder. Created with BioRender.com.

The development of the first chiral Fe-TAML catalyst, accessible in both ( R , R )- and ( S , S )-enantiomeric forms, that enables enantioselective oxidation of benzylic C–H bonds within spirocyclic oxindole substrates is reported.

Sulfated glycosaminoglycans play important roles in a number of physiological and patho-physiological processes, including the coagulation cascade, tumor growth inhibition, viral transmission, and antioxidation. The functional pentasaccharide unit of heparin, an important GAG and natural anticoagulant, has ubiquitous expression of O-sulfate and N-sulfate groups, which play an important role in the anticoagulation property, required to maintain a fine balance in hemostasis. Anticoagulants have been widely used for patients suffering from cardiovascular diseases and also during several surgeries. Earlier reports of heparin mimicking polymers have focused on either incorporating sulfate groups via post-polymerization methods or polymerizing free sulfonic acid-containing monomers via RAFT and ROMP. For synthesis using more sensitive polymerization techniques like ATRP, NMP, and NCA ROP, protected sulfate-containing monomers are desired. However, the development of necessary methodologies remains mostly unexplored. Herein, we report a novel synthetic methodology to prepare mannose-6-sulfate (M6S) based glycopolypeptides as a structural mimic of heparin. Initially, the protected sulfate group was introduced, particularly at the 6-position of mannose, and the M6S-based N-carboxyanhydride (NCA) monomer was prepared. Further, the glycopolypeptides were synthesized via NCA ROP techniques. The fully water-soluble sulphated M6S glycopolypeptides subsequently obtained after deprotection steps exhibited minimal cytotoxicity toward mammalian cells and negligible hemolytic activity, underscoring their potential suitability for biomedical applications. Furthermore, both aPTT and PT assays indicate that these synthetic materials can act as anticoagulants by significantly prolonging clotting times, with performance comparable to that of heparin. Detailed mechanistic investigations to elucidate the anticoagulation pathways of these glycopolypeptides are currently underway.