A hydrolytically stable complexant for minor An separation from Ln in process relevant diluents.

The evaluation of bis-1,2,4-triazine complexants containing eight-carbon, alkoxy-functionalized phenyl substituents at the 3,3'-positions for selective minor actinide extraction in simulated high level waste is reported. The complexant retained chemoselective extraction efficiency of actinides over lanthanides while breaking through the nonpolar diluent solubility and hydrolytic stability barriers that limit many BTP complexants. Thus, we report a BTP complexant that is readily soluble in both kerosene and isooctanol without forming precipitates, emulsions, or third phase after contact with nitric acid and extracts Am from Eu.

Synthesis of Fused [1,2,3]-Triazoloheteroarenes via Intramolecular Azo Annulation of -Tosylhydrazones Catalyzed by 1,8-Diaza-bicyclo[5.4.0]undec-7-ene.

The structural diversity of triazoloheteroarenes render this moiety an attractive synthon for drug discovery, C-H functionalization, and complexant design for minor actinide separations. While contemporary work has demonstrated the capacity to leverage downstream functional group interconversion of the triazolopyridine, a broadly applicable method tolerant of diverse heteroaryl constructs and pendant functionality to obtain triazoloheteroarenes remains under reported. In this work, the serendipitous discovery of a metal, azide, and oxidant free transformation of various heteroaryl -tosylhydrazones of carbaldehydes and ketones to the corresponding [1,2,3]-triazoloheteroarene via intramolecular azo annulation using a substoichiometric amount of 1,8-diaza-bicyclo[5.

Next-Generation 3,3'-AlkoxyBTPs as Complexants for Minor Actinide Separation from Lanthanides: A Comprehensive Separations, Spectroscopic, and DFT Study.

Progress toward the closure of the nuclear fuel cycle can be achieved if satisfactory separation strategies for the chemoselective speciation of the trivalent actinides from the lanthanides are realized in a nonproliferative manner. Since Kolarik's initial report on the utility of bis-1,2,4-triazinyl-2,6-pyridines (BTPs) in 1999, a perfect complexant-based, liquid-liquid separation system has yet to be realized. In this report, a comprehensive performance assessment for the separation of Am from Eu as a model system for spent nuclear fuel using hydrocarbon-actuated alkoxy-BTP complexants is described.

Synthetic Access to Unsymmetric, Tridentate, Pyridyl-1,3,4-oxadiazole Complexants via Intramolecular Oxidative Annulation of Arylhydrazides with Heteroaryl Carbaldehydes.

Over the last four decades, an ideal complexant for the chemoselective liquid-liquid separation of the minor actinides from the lanthanides contained within spent nuclear fuel has yet to be realized. As strategic performance objectives continue to evolve as a function of time, solubility in process-relevant diluents, fast complexation kinetics, as well as robustness to hydro- and radiolytic degradation remain at the forefront of this grand challenge. While the vast majority of soft-N-donors are symmetric in nature, this laboratory has focused on defining synthetic methods to afford unsymmetric complexants for further study to explore the impact subtle changes to the molecular topography of the complexant moiety have on performance, in addition to working toward the definition of structure-activity relationships.

Chemoselective, osmium-free, dihydroxylation/oxidative cleavage of heteroaryl isoprenes by a contemporary Malaprade reaction.

The methyl ketone is a central synthetic building block for the construction of advanced heteroaryl scaffolds and systems. Reactions, including oxidative cyclization strategies, are often predicated on efficient access to this ubiquitous moiety. In the context of arenes, standard approaches leveraging Markovnikov hydration/oxidation or oxidative cleavage of the C-C π bond often afford satisfactory performance.

Microwave-Assisted, Metal- and Azide-Free Synthesis of Functionalized Heteroaryl-1,2,3-triazoles via Oxidative Cyclization of N-Tosylhydrazones and Anilines.

As the search for competent soft-Lewis basic complexants for separations continues to evolve toward identification of a chemoselective moiety for speciation of the minor actinides from the electronically similar lanthanides, synthetic methods must congruently evolve. Synthetic options to convergently construct unsymmetric heteroaryl donor complexants incorporating a 1,2,3-triazole from accessible starting materials for evaluation in separation assays necessitated the development of the described methodology. In this report, metal- and azide-free synthesis of diversely functionalized pyridyl-1,2,3-triazole derivatives facilitated by microwave irradiation was leveraged to prepare a novel class of tridentate ligands.

Novel Small Molecule Fibroblast Growth Factor 23 Inhibitors Increase Serum Phosphate and Improve Skeletal Abnormalities in Mice.

Excess fibroblast growth factor (FGF) 23 causes hereditary hypophosphatemic rickets, such as X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO). A small molecule that specifically binds to FGF23 to prevent activation of the fibroblast growth factor receptor/-Klotho complex has potential advantages over the currently approved systemically administered FGF23 blocking antibody. Using structure-based drug design, we previously identified ZINC13407541 (N-[[2-(2-phenylethenyl)cyclopenten-1-yl]methylidene]hydroxylamine) as a small molecule antagonist for FGF23.

Prediction of An(III)/Ln(III) Separation by 1,2,4-Triazinylpyridine Derivatives.

The effect of frustrated Lewis donors on metal selectivity between actinides and lanthanides was studied using a series of novel organic ligands. Structures and thermodynamic energies were predicted in the gas phase, in water, and in butanol using 9-coordinate, explicitly solvated (HO) Eu, Gd, Am, and Cm in the +III oxidation state as reactants in the formation of complexes with 2-(6-[1,2,4]-triazin-3-yl-pyridin-2-yl)-1-indole (Core 1), 3-[6-(2-pyrazol-3-yl)pyridin-2-yl]-1,2,4-triazine (Core 2), and several derivatives. These complexations were studied using density functional theory (DFT) incorporating scalar relativistic effects on the actinides and lanthanides using a small core pseudopotential and corresponding basis set.

Design and development of FGF-23 antagonists: Definition of the pharmacophore and initial structure-activity relationships probed by synthetic analogues.

Hereditary hypophosphatemic disorders, TIO, and CKD conditions are believed to be influenced by an excess of Fibroblast Growth Factor-23 (FGF-23) which activates a binary renal FGFRs / α-Klotho complex to regulate homeostatic metabolism of phosphate and vitamin D. Adaptive FGF-23 responses from CKD patients with excess FGF-23 frequently lead to increased mortality from cardiovascular disease. A reversibly binding small molecule therapeutic has yet to emerge from research and development in this area.

Convergent access to bis-1,2,4-triazinyl-2,2'-bipyridines (BTBPs) and 2,2'-bipyridines a Pd-catalyzed Ullman-type reaction.

Multidentate, soft-Lewis basic, complexant scaffolds have displayed significant potential in the discrete speciation of the minor actinides from the neutron-absorbing lanthanides resident in spent nuclear fuel. Efforts to devise convergent synthetic strategies to targets of interest to improve liquid-liquid separation outcomes continue, but significant challenges to improve solubility in process-relevant diluents to effectively define meaningful structure-activity relationships remain. In the current work, a synthetic method to achieve the challenging 2,2'-bipyridine bond of the bis-1,2,4-triazinyl-2,2'-bipyridine (BTBP) complexant class leveraging a Pd-catalyzed Ullman-type coupling is reported.

Synthesis of Tridentate [1,2,4] Triazinyl-Pyridin-2-yl Indole Lewis Basic Complexants via Pd-Catalyzed Suzuki-Miyaura Cross-Coupling.

Full closure of the nuclear fuel cycle is predicated, in part, on defining efficient separations processes for the effective speciation of the neutron-absorbing lanthanides from the minor actinides post-PUREX. Pursuant to the aforementioned, a class of tridentate, Lewis basic procomplexants have been prepared leveraging a Pd-catalyzed Suzuki-Miyaura cross-coupling between 6-bromo-[1,2,4]-triazinylpyridine derivatives and various protected indole-boronic acids to afford functionalized 2-[6-(5,6-diphenyl-[1,2,4]triazin-3-yl)-pyridin-2-yl]-1-indoles. A highly active catalyst/ligand system with low loadings was employed rapidly affording 26 examples in yields as high as 85%.

Synthesis of 1-Pyrazol-5-yl-pyridin-2-yl-[1,2,4]triazinyl Soft-Lewis Basic Complexants via Metal and Oxidant Free [3 + 2] Dipolar Cycloaddition of Terminal Ethynyl Pyridines with Tosylhydrazides.

Soft-Lewis basic complexants that facilitate chemoselective separation of the minor actinides from the lanthanides are critical to the closure of the nuclear fuel cycle. Complexants that modulate covalent orbital interactions with relevant metals of interest can facilitate desired outcomes in liquid-liquid separation, allowing for further transmutative processes that decrease issues related with storage of spent nuclear fuel from energy and weapons production. Synthesis of previously unexplored scaffolds seeks to improve performance over benchmark complexants.

Synthetic Access to Functionalized Dipolarophiles of Lewis Basic Complexant Scaffolds through Sonogashira Cross-Coupling.

Soft Lewis basic complexants that facilitate selective removal of discrete ions resident in spent nuclear fuel can decrease repository volume and radiotoxicity and are of significant interest. Optimization of chelation efficacy is predicated on modular access to synthons to rapidly evaluate structure-activity relationships. The following work highlights efficient access to functionalized synthons for use as potential dipolarophiles in subsequent cycloaddition processes via Sonogashira coupling of 3-(6-bromo-pyridin-2-yl)-[1,2,4]triazine scaffolds.

A computationally identified compound antagonizes excess FGF-23 signaling in renal tubules and a mouse model of hypophosphatemia.

Fibroblast growth factor-23 (FGF-23) interacts with a binary receptor complex composed of α-Klotho (α-KL) and FGF receptors (FGFRs) to regulate phosphate and vitamin D metabolism in the kidney. Excess FGF-23 production, which causes hypophosphatemia, is genetically inherited or occurs with chronic kidney disease. Among other symptoms, hypophosphatemia causes vitamin D deficiency and the bone-softening disorder rickets.

Modular Approaches to Diversified Soft Lewis Basic Complexants through Suzuki-Miyaura Cross-Coupling of Bromoheteroarenes with Organotrifluoroborates.

Remediation or transmutation of spent nuclear fuel obtained as a function of energy production and legacy waste remains a significant environmental concern. Substantive efforts over the last three decades have focused on the potential of soft-Lewis basic complexants for the chemoselective separation of trivalent actinides from lanthanides in biphasic solvent systems. Recent efforts in this laboratory have focused on the concept of modularity to rapidly prepare complexants and complexant scaffolds not easily accessible via traditional linear methods in a convergent manner to better understand solubility and complexation structure/activity function in process-relevant solvents.

Pd-Catalyzed Diamination of 1,2,4-Triazinyl Complexant Scaffolds.

As part of ongoing efforts in this laboratory to design and synthesize multidentate soft-N-donors as effective complexants for chemoselective minor actinide extraction from used nuclear fuel, a series of aminated mono-1,2,4-triazinylpyridines were required. This study focuses on streamlining convergent access to a diverse array of functionalized N-donors using Pd-catalysis from a common synthon affording access to pyridinyl triazines as the 4,4'-amino derivatives which are commercially limited and unsuccessful in traditional condensation chemistry. A general Pd-catalyzed method for the double amination of functionalized pyridinyl-1,2,4-triazines with low catalyst/ligand loadings enabling the formation of 16 novel complexants is presented.

An efficient formal synthesis of (-)-clavosolide a featuring a "mismatched" stereoselective oxocarbenium reduction.

The enantioselective formal synthesis of the polyketide marine natural product (-)-clavosolide A is presented. The construction of the beta-C-glycoside subunit is highlighted by a one-pot oxocarbenium cation formation/reduction sequence. Yamaguchi dimerization afforded the diolide aglycon in 18 steps (longest linear sequence).