Category Archives: Chemistry – A European Journal

Solid‐Phase Synthesis of PROTACs and SNIPERs on Backbone Amide Linked (BAL) Resin

Posted on 9 October 2023 by nLiam Thomas Hales, nPhilip Evan Thompsonn

Solid-phase approaches could offer many advantages over conventional PROTAC synthesis if the same chemistries and topographic diversity can be incorporated. We have examined solid-phase synthesis of both VHL-targeting PROTACS and IAP-targeting SNIPERS using backbone-amide linked (BAL resin) completing 8–11 step syntheses with products obtained with a single purification step.

Abstract

Developing straightforward but flexible approaches to PROTAC synthesis that can incorporate the structural elements of emerging designs can improve the quality and efficiency of PROTAC development. Solid-phase approaches could offer many advantages over conventional PROTAC synthesis if diverse chemistries and topographies can be incorporated. We have exploited the backbone-amide-linked (BAL) resin to employ an array of solid-phase organic reactions, providing access to VHL- and IAP-targeting degraders using the BRD4-targeting JQ1 conjugates as examples.

Highly Efficient Luminescence from a Red Thermally Activated Delayed Fluorescence Emitter with Flexible Conformation of Ancillary Groups

Posted on 9 October 2023 by

The freer it goes, the brighter it shines. Rigid structure usually shows a positive effect on the efficiency of TADF emitters. In this work, Ph-TPA with flexible conformation of ancillary groups exhibited higher efficiency than Mc-TPA with conformationally locked ancillary groups. The macrocycle in MC-TPA made a significant contribution to the reorganization energy, leading to a severe non-radiative decay.

Abstract

Robust scaffolds were typically applied in thermally activated delayed fluorescence (TADF) molecules to suppress the non-radiative decay, trigger the fast spin-flipping, and enhance the light out-coupling efficiency. Herein, we disclosed for the first time the positive effect of flexible conformation of ancillary groups on the photophysical properties of TADF emitter. The red TADF emitter Ph-TPA with flexible conformation demonstrated small excited-state structural distortion and low reorganization energy compared to the counterpart Mc-TPA with a rigid macrocycle. Consequently, Ph-TPA showed an excellent photoluminescent quantum yield (PLQY) of 92 % and a state-of-the-art external quantum efficiency (EQE) of 30.6 % at 630 nm. This work could deepen our understanding of structure-property relationships of organic luminophores and help us to rationalize the design of efficient TADF materials.

Revisiting sp2 Dilithio Methandiides: From Geometric Curiosity to Simple Bonding Description

Posted on 9 October 2023 by

The intriguing tetracoordinate geometry of a dilithio methandiide complex is probed from a coordination chemistry perspective, demonstrating the sp ² -hybridized nature of the methandiide carbon and the other (non-covalent) interactions responsible for its planarity.

Abstract

The reported tetracoordinate dilithio methandiide complex from Liddle and co-workers (1) is investigated from a coordination chemistry perspective, to probe the origin of its intriguing geometry. Through the application of a variety of computational techniques, non-covalent (steric, electrostatic) interactions are found to be dominant. Further, we arrive at a bonding description which emphasizes the tricoordinate sp ² -hybridized nature of the central methandiide carbon, differing somewhat from the original proposal. Thus, 1 is distinct from other dilithio methandiides since it contains only one C−Li σ-bond, and is found to be comparable to a simple aryllithium compound, phenyllithium.

Three Oxidative Addition Routes of Alkali Metal Aluminyls to Dihydridoaluminates and Reactivity with CO2

Posted on 9 October 2023 by

Three distinct methods have been studied to convert alkali metal aluminyls, AM[Al(NON^Dipp)] (AM=Li−Cs) to dihydridoaluminates AM[Al(NON^Dipp)(H)₂], which in turn reduce CO₂ to bis-formates AM[Al(NON^Dipp)(O₂CH)₂]. Diverting from its usual proton-hydride releasing behaviour, 1,4-cyclohexadiene undergoes a remarkable oxidative addition in a 1 : 1 stoichiometric reaction with Cs[Al(NON^Dipp)] yielding the inverse sandwich compound [{Cs(Et₂O)}₂{Al(NONDipp)(H)}₂(C₆H₆)] (pictured).

Abstract

Three distinct routes are reported to the soluble, dihydridoaluminate compounds, AM[Al(NON^Dipp)(H)₂] (AM=Li, Na, K, Rb, Cs; [NON^Dipp]²⁻=[O(SiMe₂NDipp)₂]²⁻; Dipp=2,6-iPr₂C₆H₃) starting from the alkali metal aluminyls, AM[Al(NON^Dipp)]. Direct H₂ hydrogenation of the heavier analogues (AM=Rb, Cs) produced the first examples of structurally characterized rubidium and caesium dihydridoaluminates, although harsh conditions were required for complete conversion. Using 1,4-cyclohexadiene (1,4-CHD) as an alternative hydrogen source in transfer hydrogenation reactions provided a lower energy pathway to the full series of products for AM=Li−Cs. A further moderation in conditions was noted for the thermal decomposition of the (silyl)(hydrido)aluminates, AM[Al(NON^Dipp)(H)(SiH₂Ph)]. Probing the reaction of Cs[Al(NON^Dipp)] with 1,4-CHD provided access to a novel inverse sandwich complex, [{Cs(Et₂O)}₂{Al(NON^Dipp)(H)}₂(C₆H₆)], containing the 1,4-dialuminated [C₆H₆]²⁻ dianion and representing the first time that an intermediate in the commonly utilized oxidation process of 1,4-CHD to benzene has been trapped. The synthetic utility of the newly installed Al−H bonds has been demonstrated by their ability to reduce CO₂ under mild conditions to form the bis-formate AM[Al(NON^Dipp)(O₂CH)₂] compounds, which exhibit a diverse series of eyecatching bimetallacyclic structures.

Photocatalyzed Hydroaminodifluoroalkylation of Alkenes

Posted on 9 October 2023 by nPierre Fossé, nEmmanuel Pfund, nThierry Lequeuxn

Undescribed aminosulfinates enabled the preparation of β-fluoroalkylamines in a photocatalyzed addition reaction of the corresponding aminodifluoroalkyl radicals to electron-deficient, electron-rich alkenes and vinylaryls or unactivated alkenes.

Abstract

The synthesis of undescribed β-aminodifluoroethylsulfinates and their uses in the hydroaminodifluoroalkylation of alkenes is reported. This reaction is performed in the presence of a photocatalyst (4CzIPN, Ru complexes) and enables the direct incorporation of a β-difluoroamine moiety into vinylic aryls, unactivated alkenes, and electron-rich, or -deficient alkenes. The mechanism was studied, and the formation of a gem-difluoromethyl radical was observed after the selective oxidation of the sulfinate function.

Rapid Unambiguous Structure Elucidation of Streptnatamide A, a New Cyclic Peptide Isolated from A Marine‐derived Streptomyces sp

Posted on 9 October 2023 by

An inspiring collaboration between pharmaceutical industry and academia enabled discovery, structure elucidation, and biosynthetic pathway analysis of streptnatamide A, a new cyclic peptide isolated from secondary metabolites of a marine invertebrate-associated Streptomyces sp. This study highlights the application of mass spectrometry tools that enables the rapid unambiguous structure elucidation of this complex molecule.

Abstract

Cyclic peptides have been excellent source of drug leads. With the advances in discovery platforms, the pharmaceutical industry has a growing interest in cyclic peptides and has pushed several into clinical trials. However, structural complexity of cyclic peptides brings extreme challenges for structure elucidation efforts. Isotopic fine structure analysis, Nuclear magnetic resonance (NMR), and detailed tandem mass spectrometry rapidly provided peptide sequence for streptnatamide A, a cyclic peptide isolated from a marine-derived Streptomyces sp. Marfey's analysis determined the stereochemistry of all amino acids, enabling the unambiguous structure determination of this compound. A non-ribosomal peptide synthetase biosynthetic gene cluster (stp) was tentatively identified and annotated for streptnatamide A based on the in silico analysis of whole genome sequencing data. These analytical tools will be powerful tools to overcome the challenges for cyclic peptide structure elucidation and accelerate the development of bioactive cyclic peptides.

Synthesis of Hierarchical CdS/NiS Photocatalysts Using Ni−MOF‐74 as Template for Efficient Ethanol Conversion and Hydrogen Production under Visible Light

Posted on 9 October 2023 by

Ni−MOF-74 was added to fabricate the hierarchical CdS/NiS−N composites with an elevated specific surface area during the hydrothermal synthesis of CdS microsphere, and the Ni−MOF-74 facilitate the self-assemble growth of CdS and provide a source of Ni for the formation of NiS. The prepared photocatalyst can efficiently convert ethanol while producing a large amount of hydrogen gas and exhibits excellent photocatalytic stability.

Abstract

The conversion of ethanol into high-valuable chemicals and H₂ by photocatalytic process provides a sustainable approach to produce carbon-chain-prolonged chemicals and hydrogen energy. In this article, Ni−MOF-74 was added to fabricate the hierarchical CdS/NiS−N composites with an elevated specific surface area during the hydrothermal synthesis of CdS microsphere, and the Ni−MOF-74 facilitate the self-assemble growth of CdS and provide a source of Ni for the formation of NiS. The as-prepared photocatalyst was subjected to photocatalytic ethanol conversion, and the hierarchical composite material CdS/NiS−N (100) formed by adding 100 mg of Ni−MOF-74 exhibits the highest photocatalytic activity and stability in an ethanol aqueous solution with a water content of 10 %. Under visible light irradiation, the conversion rate of ethanol reached 15.2 % at the photocatalytic reaction of 5 h. The selectivity of 2,3-butanediol(2,3-BDO) was 25 %, and the selectivity of acetaldehyde(AA) was 63 %. Through various characterizations, it has been proven that a large specific surface area and the coupling interface between CdS and NiS are key factors in improving photocatalytic performance. This work provides an effective strategy for constructing photocatalysts with coupled cocatalysts/semiconductors and large specific surface areas.

Induction and Stabilization of Columnar Mesophases in Fluorinated Polycyclic Aromatic Hydrocarbons by Arene‐Perfluoroarene Interactions

Posted on 9 October 2023 by

The efficient synthesis of fluorous polyaromatic hydrocarbons via the arene-fluorine nucleophilic substitution reaction offers a fast and clean synthetic route to highly π-conjugated systems of interest for organic electronics. The development of long-range noncovalent arene-fluoroarene interactions enables the formation of broader and thermally more stable mesophases than their hydrogenated counterparts, as well as supramolecular luminescent gels and films.

Abstract

The straightforward synthesis of several Fluorinated Polycyclic Aromatic Hydrocarbons by the efficient, transition-metal-free, arene fluorine nucleophilic substitution reaction is described, and the full investigation of their liquid crystalline and optical properties reported. The key precursors for this study, i. e. 2,2’-dilithio-4,4′,5,5′-tetraalkoxy-1,1’-biphenyl derivatives, were obtained in two steps from the highly selective Scholl oxidative homo-coupling of 3,4-dialkoxy-1-bromobenzene, followed by quantitative double-lithiation. In situ room temperature nucleophilic annulation with either perfluorobenzene or perfluoronaphthalene leads to 1,2,3,4-tetrafluoro-6,7,10,11-tetraalkxoytriphenylenes and 9,10,11,12,13,14-hexafluoro-2,3,6,7-tetraalkoxybenzo[f]tetraphenes, respectively, in good yields. Exploiting the same strategy, subsequent double annulations resulted in the formation of 9,18-difluoro-2,3,6,7,11,12,15,16-octa(alkoxy)tribenzo[f,k,m]tetraphenes and 9,10,19,20-tetrafluoro-2,3,6,7,12,13,16,17-octakis(hexyloxy)tetrabenzo[a,c,j,l]tetracenes, respectively. Despite the presence of only four alkoxy chains, the polar “Janus” mesogens display a columnar hexagonal mesophase over broad temperature ranges, with higher mesophase stability than the archetypical 2,3,6,7,10,11-hexa(alkoxy)triphenylenes and their hydrogenated counterparts. The improvement or induction of mesomorphism is attributed to efficient antiparallel face-to-face π-stacking driven by the establishment of non-covalent perfluoroarene-arene intermolecular interactions. The larger lipophilic discotic π-extended compounds also exhibit columnar mesomorphism, over similar temperature ranges and stability than their hydrogenated homologs. Finally, these fluorinated molecules form stringy gels in various solvents, and show interesting solvatochromic emission properties in solution as well as strong emission in thin films and gels.

The Cyanido‐Sulfate Anion [SO3CN]−

Posted on 9 October 2023 by nThomas Kasperowicz, nDavid van Gerven, nMathias S. Wickledern

The new cyanido-sulfate anion, [SO₃CN]⁻, is a complex of the Lewis base CN⁻ and the Lewis acid SO₃. The ion the a pseudo-halide analogon of the well-known fluorido- and chlorido-sulfates. Its formation is astonishing because the oxidation of the cyanide ion by SO₃ seems to be favorable. For the successful preparation it seems to be benefitial that the synthesis can be carried out at room temperature.

Abstract

The reaction of the pyridine adduct of SO₃ and tetra-n-butyl-ammonium cyanide, [N(ⁿBu)₄][CN] at room temperature leads to the unprecedented cyanido-sulfate anion [SO₃CN]⁻ stabilized in the salt [N(ⁿBu)₄][SO₃CN]. The anion is a pseudo-halogen congener of the well-known fluoro- and chloro-sulfates. The new anion has been studied by vibrational spectroscopy and theoretical calculations.

Inhibition of Amyloid β Aggregation and Cytotoxicity by Berbamine Hydrochloride

Posted on 9 October 2023 by nLi Dong, nHuan‐Zhang Xie, nLee Jia, nLiu Hong, nGao Lin

The inhibitory effects of berbamine hydrochloride (BBMH) on Aβ aggregation were comprehensively evaluated using several widely-used biophysical assays. Furthermore, the inhibitory mechanisms of BBMH were elucidated through SPR analysis and chemical kinetics analysis. These findings suggest that bisbenzylisoquinoline alkaloids hold great promise in the battle against Alzheimer's disease.

Abstract

Alzheimer's disease (AD) continues to be a major global health challenge, and the recent approval of Aduhelm and Leqembi has opened new avenues for its treatment. Small-molecule inhibitors targeting Aβ aggregation hold promise as an alternative to monoclonal antibodies. In this study, we evaluated the ability of berbamine hydrochloride (BBMH), a member of the bisbenzylisoquinoline alkaloids, to reduce Aβ aggregation and cytotoxicity. Thioflavin T kinetics, circular dichroism spectroscopy, and atomic force microscopy results indicated that BBMH effectively inhibited Aβ aggregation. Surface plasmon resonance and molecular docking results further revealed that BBMH could bind to Aβ fibrils, thereby hindering the aggregation process. This physical picture has been confirmed in a quantitative way by chemical kinetics analysis, which showed BBMH tends to bind with the fibril ends and thus prevents the transition from protofibrils to mature fibrils as well as the elongation process. Additionally, our MTT results showed that BBMH was able to reduce the cytotoxicity of Aβ40 on N2a cells. Our results demonstrate, for the first time, the potential of BBMH to inhibit Aβ aggregation and cytotoxicity, offering a promising direction for further research and drug development efforts in the fight against Alzheimer's disease.