Reactivity and Steric Parameters from 2D to 3D Bulky Pyridines: Increasing Steric Demand at Nitrogen with Chiral Azatriptycenes.

Sterically hindered pyridines embedded in a three-dimensional triptycene framework have been synthesized, and their resolution by chiral HPLC enabled access to unprecedented enantiopure pyridines exceeding the known steric limits. The design principles for new axially chiral pyridine derivatives are then described. To rationalize their associations with Lewis acids and transition metals, a comprehensive determination of the steric and electronic parameters for this new class of pyridines was performed. This led to the general parameterization of the steric parameters (percent buried volume %VBur, Tolman cone angle θ, and He8_steric descriptor) for a large set of two- and three-dimensional pyridine derivatives. These parameters are shown to describe quantitatively their interactions with carbon- and boron-centered Lewis acids and were used to predict the ΔG° of association with the prototypical B(C6F5)3 Lewis acid widely used in frustrated Lewis pair catalysis. This first parameterization of pyridine sterics is a fundamental basis for the future development of predictive reactivity models and for guiding new applications of bulky and chiral pyridines in organocatalysis, frustrated Lewis pairs, and transition-metal catalysis.

9-Phosphatriptycene Derivatives: From Their Weak Basicity to Their Application in Frustrated Lewis Pair Chemistry.

The accurate prediction of the basicity of tertiary phosphines in acetonitrile and water is reported by the linear correlation between computed ΔpKa's obtained by density functional theory (DFT) and experimental values extracted from the literature. This method is applied to the prediction of pKa values of 9-phosphatriptycene derivatives and showed that they are weaker Brønsted bases than their triphenylphosphine analogues. This lower reactivity is attributed to their high pyramidalization that increases their lone pair 3s character, stabilizing its energy level. Their potential application in frustrated Lewis pair chemistry is then considered by investigating the hydrogenation of 1,1-diphenylethylene by the tris(pentafluorophenyl)borane/1-chloro-9-phosphatriptycene frustrated Lewis pair.

Taming the Lewis Superacidity of Non-Planar Boranes: C-H Bond Activation and Non-Classical Binding Modes at Boron.

The rational design of a geometrically constrained boron Lewis superacid featuring exceptional structure and reactivity is disclosed. It enabled the formation of non-classical electron deficient B-H-B type of bonding, which was supported by spectroscopic and structural parameters as well as computational studies. Taming the pyramidal Lewis acid electrophilicity through weak coordinating anion dissociation enabled a series of highly challenging chemical transformations, such as Csp2 -H and Csp3 -H activation under a frustrated Lewis pair regime and the cleavage of Csp3 -Si bonds. The demonstration of such rich chemical behaviour and flexibility on a single molecular compound makes it a unique mediator of chemical transformations generally restricted to transition metals.

Rational Development of a Metal-Free Bifunctional System for the C-H Activation of Methane: A Density Functional Theory Investigation.

The activation or heterolytic splitting of methane, a challenging substrate usually restricted to transition metals, has so far proven elusive in experimental frustrated Lewis pair (FLP) chemistry. In this article, we demonstrate, using density functional theory (DFT), that 1-aza-9-boratriptycene is a conceptually simple intramolecular FLP for the activation of methane. Systematic comparison with other FLP systems allows to gain insight into their reactivity with methane. The thermodynamics and kinetics of methane activation are interpreted by referring to the analysis of the natural charges and by employing the distortion-interaction/activation strain (DIAS) model. These showed that the nature of the Lewis base influences the selectivity over the reaction pathway, with N Lewis bases favoring the deprotonation mechanism and P bases the hydride abstraction one. The lower barrier of activation for 1-aza-9-boratriptycene and the higher products stability are due to a better interaction energy than its counterparts, itself due to electrostatic interactions with the methane moiety, favorable orbital overlaps allowed by the side-attack, and space proximity between the B and N atoms.

Sterically hindered ortho-substituted phosphatriptycenes as configurationally stable P-chirogenic triarylphosphines.

ortho-Substituted and unsymmetrical 9-phospha-triptycenes were synthesized via two synthetic approaches involving densely functionalized ortho-halogenated triarylmethane or phosphine precursors. ortho-Substituents imposed a considerable steric shielding due to the tricyclic cage-shaped structure with the aryl rings p-systems orthogonal to the phosphorus electron pair. A series of Au(i) and Rh(i) complexes were analysed in the solid state to determine Tolman electronic parameters, cone angles and buried volumes of these unprecedented functionalized phosphines. Quantum chemical calculations of electronic and steric descriptors revealed that these cage-shaped phosphines are electron-poor and that single methyl substituent is enough to provide the largest effect on steric shielding reported so far in triarylphosphines. An unsymmetrically substituted 9-phosphatriptycene was resolved by chiral HPLC, opening the avenue towards stable P-chirogenic triarylphosphines with unlimited configurational stability for new catalyst development in asymmetric transition-metal catalysis.

Methylene Bridging Effect on the Structures, Lewis Acidities and Optical Properties of Semi-planar Triarylboranes.

Three synthetic methods towards semi-planar triarylboranes with two aryl rings connected by a methylene bridge have been developed. The fine-tuning of their stereoelectronic properties and Lewis acidities was achieved by introducing fluorine, methyl, methoxy, n-butyl and phenyl groups either at their exocyclic or bridged aryl rings. X-ray diffraction analysis and quantum-chemical calculations provided quantitative information on the structural distortion experienced by the near planar hydro-boraanthracene skeleton during the association with Lewis bases such as NH3 and F- . Though the methylene bridge between the ortho-positions of two aryl rings of triarylboranes decreased the Gibbs free energies of complexation with small Lewis bases by less than 5 kJ mol-1 relative to the classical Lewis acid BAr3 , the steric shielding of the CH2 bridge is sufficient to avoid the formation of Lewis adducts with larger Lewis bases such as triarylphosphines. A newly synthesized spirocyclic amino-borane with a long intramolecular B-N bond that could be dissociated under thermal process, UV-irradiation, or acidic conditions might be a potential candidate in Lewis pairs catalysis.

Controlled Generation of 9-Boratriptycene by Lewis Adduct Dissociation: Accessing a Non-Planar Triarylborane.

A highly bent triarylborane, 9-boratriptycene, was generated in solution by selective protodeboronation of the corresponding tetra-aryl boron ate complex with the strong Brønsted acid HNTf2 . The iptycene core confers enhanced Lewis acidity to 9-boratriptycene, making it unique in terms of structure and reactivity. We studied the stereoelectronic properties of 9-boratriptycene by quantifying its association with small N- and O-centered Lewis bases, as well as with sterically hindered phosphines. The resultant Lewis adducts exhibited unique structural, spectroscopic, and photophysical properties. Beyond the high pyramidalization of the 9-boratriptycene scaffold and its low reorganization energy upon Lewis base coordination, quantum chemical calculations revealed that the absence of π donation from the triptycene aryl rings to the boron vacant pz orbital is one of the main reasons for its high Lewis acidity.

[18F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging.

BACKGROUND: Poly (ADP-ribose) polymerase (PARP) inhibitors are extensively studied and used as anti-cancer drugs, as single agents or in combination with other therapies. Most radiotracers developed to date have been chosen on the basis of strong PARP1-3 affinity. Herein, we propose to study AZD2461, a PARP inhibitor with lower affinity towards PARP3, and to investigate its potential for PARP targeting in vivo. METHODS: Using the Cu-mediated 18F-fluorodeboronation of a carefully designed radiolabelling precursor, we accessed the 18F-labelled isotopologue of the PARP inhibitor AZD2461. Cell uptake of [18F]AZD2461 in vitro was assessed in a range of pancreatic cell lines (PSN-1, PANC-1, CFPAC-1 and AsPC-1) to assess PARP expression and in vivo in xenograft-bearing mice. Blocking experiments were performed with both olaparib and AZD2461. RESULTS: [18F]AZD2461 was efficiently radiolabelled via both manual and automated procedures (9 % ± 3 % and 3 % ± 1 % activity yields non-decay corrected). [18F]AZD2461 was taken up in vivo in PARP1-expressing tumours, and the highest uptake was observed for PSN-1 cells (7.34 ± 1.16 %ID/g). In vitro blocking experiments showed a lesser ability of olaparib to reduce [18F]AZD2461 binding, indicating a difference in selectivity between olaparib and AZD2461. CONCLUSION: Taken together, we show the importance of screening the PARP selectivity profile of radiolabelled PARP inhibitors for use as PET imaging agents.

Manual and automated Cu-mediated radiosynthesis of the PARP inhibitor [18F]olaparib.

Positron emission tomography (PET) is a diagnostic nuclear imaging modality that relies on automated protocols to prepare agents labeled with a positron-emitting radionuclide (e.g., 18F). In recent years, new reactions have appeared for the 18F-labeling of agents that are difficult to access by applying traditional radiochemistry, for example those requiring 18F incorporation into unactivated (hetero)arenes. However, automation of these new methods for translation to the clinic has progressed slowly because extensive modification of manual protocols is typically required when implementing novel 18F-labeling methodologies within automated modules. Here, we describe the workflow that led to the automated radiosynthesis of the poly(ADP-ribose) polymerase (PARP) inhibitor [18F]olaparib. First, we established a robust manual protocol to prepare [18F]olaparib from the protected N-[2-(trimethylsilyl)ethoxy]methyl (SEM) arylboronate ester precursor in a 17% ± 5% (n = 15; synthesis time, 135 min) non-decay-corrected (NDC) activity yield, with molar activity (Am) up to 34.6 GBq/µmol. Automation of the process, consisting of copper-mediated 18F-fluorodeboronation followed by deprotection, was achieved on an Eckert & Ziegler Modular-Lab radiosynthesis platform, affording [18F]olaparib in a 6% ± 5% (n = 3; synthesis time, 120 min) NDC activity yield with Am up to 319 GBq/µmol.

Complementary Synthetic Approaches toward 9-Phosphatriptycene and Structure-Reactivity Investigations of Its Association with Sterically Hindered Lewis Acids.

Two practical and high-yielding syntheses of 9-phosphatriptycene are reported. In both approaches, the key step is based on the cyclization of a (tris)lithio-triphenylmethane or a (tris)lithio-triphenylphosphine intermediate on a phosphorus or a carbon electrophile, respectively. The association of 9-phosphatriptycene with representative boron- and carbon-centered Lewis acids was investigated by IR, NMR, and UV-vis titration experiments and by computational methods, shedding light on its steric hindrance, σ-donating ability, and Brønsted and Lewis basicities.