Stereoselective synthesis of unnatural α-amino acid derivatives through photoredox catalysis

A protocol for stereoselective C-radical addition to a chiral glyoxylate-derived N-sulfinyl imine was developed through visible light-promoted photoredox catalysis, providing a convenient method for the synthesis of unnatural α-amino acids. The developed protocol allows the use of ubiquitous carboxylic acids as radical precursors without prior derivatization. The protocol utilizes near-stoichiometric amounts of the imine and the acid radical precursor in combination with a catalytic amount of an organic acridinium-based photocatalyst. Alternative mechanisms for the developed transformation are discussed and corroborated by experimental and computational studies.

A protocol for stereoselective C-radical addition to a chiral glyoxylate-derived N-sulfinyl imine was developed through visible light-promoted photoredox catalysis, providing a convenient method for the synthesis of unnatural α-amino acids.     

Reaction of Tertiary 2-Chloroketones with Cyanide Ions: Application to 3-Chloroquinolinediones

3-Chloroquinoline-2,4-diones react with cyanide ions in dimethyl formamide to give 3-cyanoquinoline-2,4-diones in small yields due to the strong hindrance of the substituent at the C-3 atom. Good yields can be achieved if the substituent at this position is the methyl group. In the methanol solution, the reaction proceeds by an addition mechanism to form 2-oxo-1a,2,3,7b-tetrahydrooxireno[2,3-c]quinoline-7b-carbonitriles, from which 4-hydroxy-3-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-4-carbonitriles are subsequently formed by opening of the epoxide ring with methanol. Some minor products of these reactions have also been isolated. The ¹H, ¹³C and ¹⁵N NMR spectra of the prepared compounds were measured, and all resonances were assigned using appropriate two-dimensional spectra.     

Mono- and Diamination of 4,6-Dichloropyrimidine, 2,6-Dichloropyrazine and 1,3-Dichloroisoquinoline with Adamantane-Containing Amines

N-heteroaryl substituted adamantane-containing amines are of substantial interest for their perspective antiviral and psychotherapeutic activities. Chlorine atom at alpha-position of N-heterocycles has been substituted by the amino group using convenient nucleophilic substitution reactions with a series of adamantylalkylamines. The prototropic equilibrium in these compounds was studied using NMR spectroscopy. The introduction of the second amino substituent in 4-amino-6-chloropyrimidine, 2-amino-chloropyrazine, and 1-amino-3-chloroisoquinoline was achieved using Pd(0) catalysis.     

Selective Cross-Coupling of Unsaturated Substrates on AlI

The Al^I compound NacNacAl ( 1 , NacNac = [ArNC(Me)CHC(Me)NAr]⁻, Ar = 2,6-iPr₂C₆H₃) serves as a template for the chemoselective coupling between carbonyls (benzophenone, fenchone, isophorone, p-tolyl benzoate, N,N-dimethylbenzamide, (1-phenylethylidene)aniline) and pyridine. With the CH-acidic ketone (1R)-(+) camphor, the reaction affords a hydrido alkoxide compound of Al, formed as the result of enolization, whereas an enolizable imine, (1-phenylethylidene)aniline, and the bulky ketone isophorone, still chemoselectively couple with pyridine. In contrast, reaction with the ester p-tolyl benzoate results in cleavage of the ester bond together with replacement of the alkoxy group by a hydrogen atom of the pyridine moiety. This study demonstrates that for carbonyl substrates featuring phenyl substituents, the reaction proceeds via intermediate formation of η²(C,X)-coordinated (X = O, N) carbonyl adducts, whereas the reaction of 1 with (R)-(−)-fenchone in the absence of pyridine leads to CH activation in the pendant isopropyl group of the Ar substituent of the NacNac ligand.     

Separation of 44Sc from 44Ti in the Context of A Generator System for Radiopharmaceutical Purposes with the Example of [44Sc]Sc-PSMA-617 and [44Sc]Sc-PSMA-I&T Synthesis

Today, ⁴⁴Sc is an attractive radionuclide for molecular imaging with PET. In this work, we evaluated a ⁴⁴Ti/⁴⁴Sc radionuclide generator based on TEVA resin as a source of ⁴⁴Sc. The generator prototype (5 MBq) exhibits high ⁴⁴Ti retention and stable yield of ⁴⁴Sc (91 ± 6 %) in 1 mL of eluate (20 bed volumes, eluent—0.1 M oxalic acid/0.2 M HCl) during one year of monitoring (more than 120 elutions). The breakthrough of ⁴⁴Ti did not exceed 1.5 × 10⁻⁵% (average value was 6.5 × 10⁻⁶%). Post-processing of the eluate for further use in radiopharmaceutical synthesis was proposed. The post-processing procedure using a combination of Presep^® PolyChelate and TK221 resins made it possible to obtain ⁴⁴Sc-radioconjugates with high labeling yield (≥95%) while using small precursor amounts (5 nmol). The proposed method takes no more than 15 min and provides ≥90% yield relative to the ⁴⁴Sc activity eluted from the generator. The labeling efficiency was demonstrated on the example of [⁴⁴Sc]Sc-PSMA-617 and [⁴⁴Sc]Sc-PSMA-I&T synthesis. Some superiority of PSMA-I&T over PSMA-617 in terms of ⁴⁴Sc labeling efficiency was demonstrated (likely due to presence of DOTAGA chelator in the precursor structure). It was also shown that microwave heating of the reaction mixture considerably shortened the reaction time and improved radiolabeling yield and reproducibility of [⁴⁴Sc]Sc-PSMA-617 and [⁴⁴Sc]Sc-PSMA-I&T synthesis.     

Complex Activity and Sensor Potential toward Metal Ions in Environmental Water Samples of N-Phthalimide Azo-Azomethine Dyes

Herein, the spectral and electrochemical characterizations of three different substituted N-phthalimide azo-azomethine (NAA) dyes (L) containing an o-hydroxy group and their NAA-M(II) chelates [M(II): Cu, Ni, Co, Pb] were reported by using UV–Vis and fluorescence spectroscopy and potentiometric and voltamperometric techniques. The pK value of the dyes as well as the stoichiometry and stability of the NAA-metal chelates were studied, and the stoichiometry was found to be mostly 1:2 (ML₂) with high complex stability constant values. The sensor activity of N-phthalimide azo-azomethine derivatives toward pH and metal ions has been also investigated and tested for indicator application in acid–base analysis and detection of Cu(II) ions in real samples of surface river water using voltamperometric detection. The results showed that one of the ligands possesses the highest electrochemical response upon binding to copper ions and could be successfully used in the analysis of copper in water at a concentration range of the analyte from 3.7 × 10⁻⁷ to 5.0 × 10⁻⁶ mol L⁻¹, with analytical characteristics of the method being Sr = 1.5%, LOD = 3.58 µg L⁻¹ and LOQ =11.9 µg L⁻¹     

4D-QSAR analysis of a series of antifungal p450 inhibitors and 3D-pharmacophore comparisons as a function of alignment

A training set of 55 antifungal p450 analogue inhibitors was used to construct receptor-independent four-dimensional quantitative structure-activity relationship (RI 4D-QSAR) models. Ten different alignments were used to build the models, and one alignment yields a significantly better model than the other alignments. Two different methodologies were used to measure the similarity of the best 4D-QSAR models of each alignment. One method compares the residual of fit between pairs of models using the cross-correlation coefficient of their residuals of fit as a similarity measure. The other method compares the spatial distributions of the IPE types (3D-pharmacophores) of pairs of 4D-QSAR models from different alignments. Optimum models from several different alignments have nearly the same correlation coefficients, r(2), and cross-validation correlation coefficients, xv-r(2), yet the 3D-pharmacophores of these models are very different from one another. The highest 3D-pharmacophore similarity correlation coefficient between any pair of 4D-QSAR models from the 10 alignments considered is only 0.216. However, the best 4D-QSAR models of each alignment do contain some proximate common pharmacorphore sites. A test set of 10 compounds was used to validate the predictivity of the best 4D-QSAR models of each alignment. The "best" model from the 10 alignments has the highest predictivity. The inferred active sites mapped out by the 4D-QSAR models suggest that hydrogen bond interactions are not prevalent when this class of P450 analogue inhibitors binds to the receptor active site. This feature of the 4D-QSAR models is in agreement with the crystal structure results that indicate no ligand-receptor hydrogen bonds are formed.     

Strain‐Induced Isomerization in One‐Dimensional Metal–Organic Chains

The ability to use mechanical strain to steer chemical reactions creates completely new opportunities for solution‐ and solid‐phase synthesis of functional molecules and materials. However, this strategy is not readily applied in the bottom‐up on‐surface synthesis of well‐defined nanostructures. We report an internal strain‐induced skeletal rearrangement of one‐dimensional (1D) metal–organic chains (MOCs) via a concurrent atom shift and bond cleavage on Cu(111) at room temperature. The process involves Cu‐catalyzed debromination of organic monomers to generate 1,5‐dimethylnaphthalene diradicals that coordinate to Cu adatoms, forming MOCs with both homochiral and heterochiral naphthalene backbone arrangements. Bond‐resolved non‐contact atomic force microscopy imaging combined with density functional theory calculations showed that the relief of substrate‐induced internal strain drives the skeletal rearrangement of MOCs via 1,3‐H shifts and shift of Cu adatoms that enable migration of the monomer backbone toward an energetically favorable registry with the Cu(111) substrate. Our findings on this strain‐induced structural rearrangement in 1D systems will enrich the toolbox for on‐surface synthesis of novel functional materials and quantum nanostructures.     

A modular approach toward functionalized three-dimensional macromolecules: from synthetic concepts to practical applications

A new strategy for the preparation of functional, multiarm star polymers via nitroxide-mediated "living" radical polymerization has been explored. The generality of this approach to the synthesis of three-dimensional macromolecular architectures allows for the construction of nanoscopically defined materials from a wide range of different homo, block, and random copolymers combining both apolar and polar vinylic repeat units. Functional groups can also be included along the backbone or as peripheral/chain end groups, thereby modulating the reactivity and polarity of defined portions of the stars. This modular approach to the synthesis of three-dimensional macromolecules permits the application of these tailored materials as multifunctional hosts for hydrogen bonding, nanoparticle formation, and as scaffolds for catalytic groups. Examples of applications of the functional stars in catalysis include their use in a Heck-type coupling as well as an enantioselective addition reaction.     

The involvement of metal-to-CO charge transfer and ligand-field excited states in the spectroscopy and photochemistry of mixed-ligand metal carbonyls. A theoretical and spectroscopic study of [W(CO)(4)(1,2-ethylenediamine)] and [W(CO)(4)(N,N'-bis-alkyl-1,4-diazabutadiene)

A new interpretation of the electronic spectroscopy, photochemistry, and photophysics of group 6 metal cis-tetracarbonyls [M(CO)(4)L(2)] is proposed, that is based on an interplay between M --> L and M --> CO MLCT excited states. TD-DFT and resonance Raman spectroscopy show that the lowest allowed electronic transition of [W(CO)(4)(en)] (en = 1,2-ethylenediamine) has a W(CO(eq))(2) --> CO(ax) charge-transfer character, whereby the electron density is transferred from the equatorial W(CO(eq))(2) moiety to pi orbitals of the axial CO ligands, with a net decrease of electron density on the W atom. The lowest, emissive excited state of [W(CO)(4)(en)] was identified as a spin-triplet W(CO(eq))(2) --> CO(ax) CT excited state both computationally and by picosecond time-resolved IR spectroscopy. This state undergoes 1.5 ps vibrational relaxation/solvation and decays to the ground state with a approximately 160 ps lifetime. The nu(CO) wavenumbers and IR intensity pattern calculated by DFT for the triplet W(CO(eq))(2) --> CO(ax) CT excited state match well the experimental time-resolved spectrum. For [W(CO)(4)(R-DAB)] (R-DAB = N,N'-bis-alkyl-1,4-diazabutadiene), the W(CO(eq))(2) --> CO(ax) CT transition follows in energy the W --> DAB MLCT transition, and the emissive W(CO(eq))(2) --> CO(ax) CT triplet state occurs just above the manifold of triplet W --> DAB MLCT states. No LF electronic transitions were calculated to occur in a relevant energetic range for either complex. Molecular orbitals of both complexes are highly delocalized. The 5d(W) character is distributed over many molecular orbitals, while neither of them contains a predominant metal-ligand sigma 5d(W) component, contrary to predictions of the traditional ligand-field approach. The important spectroscopic, photochemical, and photophysical roles of M(CO(eq))(2) --> CO(ax) CT excited states and the limited validity of ligand field arguments can be generalized to other mixed-ligand carbonyl complexes.