Synthesis and Functionalization of Isomeric Sesquihomodiamantenes.

anti- and syn-sesquihomodiamantenes (SDs) were prepared and structurally characterized. anti-SD and parent sesquihomoadamantene were CH-bond functionalized by utilizing a phase-transfer protocol. The density functional theory-computed ionization potentials of unsaturated diamondoid dimers correlate well with the experimental oxidation potentials obtained from cyclic voltammetry. Similar geometries ensue for both the reduced and ionized SD states, whose persistence is supported by the ß-hydrogen's spatial sheltering. This makes SDs promising building blocks for the construction of diamond materials with high stability and carrier mobility.

Catalytic undirected borylation of tertiary C-H bonds in bicyclo[1.1.1]pentanes and bicyclo[2.1.1]hexanes.

Catalytic borylations of sp3 C-H bonds occur with high selectivities for primary C-H bonds or secondary C-H bonds that are activated by nearby electron-withdrawing substituents. Catalytic borylation at tertiary C-H bonds has not been observed. Here we describe a broadly applicable method for the synthesis of boron-substituted bicyclo[1.1.1]pentanes and (hetero)bicyclo[2.1.1]hexanes by an iridium-catalysed borylation of the bridgehead tertiary C-H bond. This reaction is highly selective for the formation of bridgehead boronic esters and is compatible with a broad range of functional groups (>35 examples). The method is applicable to the late-stage modification of pharmaceuticals containing this substructure and the synthesis of novel bicyclic building blocks. Kinetic and computational studies suggest that C-H bond cleavage occurs with a modest barrier and that the turnover-limiting step of this reaction is an isomerization that occurs prior to reductive elimination that forms the C-B bond.

In Vitro Evaluation of In Silico Screening Approaches in Search for Selective ACE2 Binding Chemical Probes.

New models for ACE2 receptor binding, based on QSAR and docking algorithms were developed, using XRD structural data and ChEMBL 26 database hits as training sets. The selectivity of the potential ACE2-binding ligands towards Neprilysin (NEP) and ACE was evaluated. The Enamine screening collection (3.2 million compounds) was virtually screened according to the above models, in order to find possible ACE2-chemical probes, useful for the study of SARS-CoV2-induced neurological disorders. An enzymology inhibition assay for ACE2 was optimized, and the combined diversified set of predicted selective ACE2-binding molecules from QSAR modeling, docking, and ultrafast docking was screened in vitro. The in vitro hits included two novel chemotypes suitable for further optimization.

Synthetic Doping of Diamondoids through Skeletal Editing.

We present a strategy for the skeletal editing of diamondoid structures to selectively displace methylene for heteroatom moieties in the carbon framework. This constitutes a synthetic approach to doping diamond-like structures with electron donor dopants (O, N, and S). The key steps involve two subsequent retro-Barbier fragmentations followed by cage reconstruction in the presence of a dopant. Remarkably, the incorporation of n-dopants reduces the strain of the diamondoid cage as shown through homodesmotic equations.

Virtual Screening in Search for a Chemical Probe for Angiotensin-Converting Enzyme 2 (ACE2).

We elaborate new models for ACE and ACE2 receptors with an excellent prediction power compared to previous models. We propose promising workflows for working with huge compound collections, thereby enabling us to discover optimized protocols for virtual screening management. The efficacy of elaborated roadmaps is demonstrated through the cost-effective molecular docking of 1.4 billion compounds. Savings of up to 10-fold in CPU time are demonstrated. These developments allowed us to evaluate ACE2/ACE selectivity in silico, which is a crucial checkpoint for developing chemical probes for ACE2.

Selective α-Methylation of Ketones.

The convenient and scalable preparative approach for the two-step α-methylation of ketones is described. The optimized protocols for regioselective preparation of enaminones with further diastereoselective and functional groups tolerant hydrogenation to α-methylketones are developed. The scope and limitations of the proposed methodology are discussed. The advantages compared to known procedures are demonstrated. The unexpected role of acetone in the hydrogenation is suggested. The evaluation of the method for both early building block synthesis and late-stage CH-functionalization is shown. The elaborate procedures' preparability and scalability are demonstrated by the synthesis of several α-methyl ketones up to 100 g amount.

Intramolecular London Dispersion Interaction Effects on Gas-Phase and Solid-State Structures of Diamondoid Dimers.

The covalent diamantyl (C28H38) and oxadiamantyl (C26H34O2) dimers are stabilized by London dispersion attractions between the dimer moieties. Their solid-state and gas-phase structures were studied using a multitechnique approach, including single-crystal X-ray diffraction (XRD), gas-phase electron diffraction (GED), a combined GED/microwave (MW) spectroscopy study, and quantum chemical calculations. The inclusion of medium-range electron correlation as well as the London dispersion energy in density functional theory is essential to reproduce the experimental geometries. The conformational dynamics computed for C26H34O2 agree well with solution NMR data and help in the assignment of the gas-phase MW data to individual diastereomers. Both in the solid state and the gas phase the central C-C bond is of similar length for the diamantyl [XRD, 1.642(2) Å; GED, 1.630(5) Å] and the oxadiamantyl dimers [XRD, 1.643(1) Å; GED, 1.632(9) Å; GED+MW, 1.632(5) Å], despite the presence of two oxygen atoms. Out of a larger series of quantum chemical computations, the best match with the experimental reference data is achieved with the PBEh-3c, PBE0-D3, PBE0, B3PW91-D3, and M06-2X approaches. This is the first gas-phase confirmation that the markedly elongated C-C bond is an intrinsic feature of the molecule and that crystal packing effects have only a minor influence.

Toward an Understanding of Diamond sp(2)-Defects with Unsaturated Diamondoid Oligomer Models.

Nanometer-sized doubly bonded diamondoid dimers and trimers, which may be viewed as models of diamond with surface sp(2)-defects, were prepared from corresponding ketones via a McMurry coupling and were characterized by spectroscopic and crystallographic methods. The neutral hydrocarbons and their radical cations were studied utilizing density functional theory (DFT) and ab initio (MP2) methods, which reproduce the experimental geometries and ionization potentials well. The van der Waals complexes of the oligomers with their radical cations that are models for the self-assembly of diamondoids, form highly delocalized and symmetric electron-deficient structures. This implies a rather high degree of σ-delocalization within the hydrocarbons, not too dissimilar to delocalized π-systems. As a consequence, sp(2)-defects are thus also expected to be nonlocal, thereby leading to the observed high surface charge mobilities of diamond-like materials. In order to be able to use the diamondoid oligomers for subsequent surface attachment and modification, their C-H-bond functionalizations were studied, and these provided halogen and hydroxy derivatives with conservation of unsaturation.

Functionalization of homodiamantane: oxygen insertion reactions without rearrangement with dimethyldioxirane.

Homodiamantane bromination and nitroxylation are accompanied by contraction of the seven-membered ring to give the corresponding substituted 1-diamantylmethyl derivatives. In contrast, CH-bond hydroxylations with dimethyldioxirane retain the cage and give both apically and medially substituted homodiamantanes. The product ratios are in accord with the barriers for the oxygen insertion computed with density functional theory methods only if solvation is included through a polarizable continuum model. B3LYP-D3 and M06-2X computations with a 6-31G(d,p) basis set on the oligomeric van der Waals complexes predict the potential of homodiamantane derivatives for surface modifications with conformationally slightly flexible diamondoid homologues.

Design, synthesis and biological evaluation of 2-aminopyrimidinones and their 6-aza-analogs as a new class of CK2 inhibitors.

In order to find the new potent CK2 inhibitors the 60 derivatives of 2-aminopyrimidinone and their 6-aza-substituted analogs were synthesized and tested in vitro. Among them, the most efficient inhibitor 2-hydroxy-5-[4-(4-methoxyphehyl)-6-oxo-1,6-dihydropyrimidin-2-ylamino] benzoic acid was identified (IC50 = 1.1 µM). The structure--activity relationship study of newly synthesized derivatives was carried out and their binding mode with adenosine triphosphate-acceptor site of CK2 was proposed.

Oxygen-doped nanodiamonds: synthesis and functionalizations.

Oxadiamondoids representing a new class of carbon nanoparticles were prepared from the respective diamondoid ketones via an effective two-step procedure involving addition of methyl magnesium iodide and oxidation with trifluoroperacetic acid in trifluoroacetic acid. The reactivities of the oxacages are determined by the position of the dopant and are in good agreement with computational predictions.