Scramble-Free Synthesis of Unhindered trans-A2B2-Mesoaryl Porphyrins via Bromophenyl Dipyrromethanes.

Trans-disubstituted porphyrins are highly valuable intermediates across diverse fields, but they pose a significant synthesis challenge in some cases due to scrambling and formation of complex mixtures. Conditions that minimize scrambling also lower yields, but steric hindrance around the meso-aryl substituent can effectively suppress scrambling altogether. Here we report a straightforward approach to valuable trans-A2B2 porphyrin intermediates that are otherwise very difficult to obtain, through use of removable blocking bromide substituents.

Luminescent Au(III)-M(I) (M = Cu, Ag) Aggregates Based on Dicyclometalated Bis(alkynyl) Gold Anions†.

The syntheses and structures of a series of complexes based on the C∧C-chelated Au(III) unit (C∧C = 4,4'-bis(t-butyl) 2,2'-biphenyl-1,1'-diyl) are reported, namely, [{(C∧C)Au(C≡CtBu)2}2M2], (C∧C)Au(C≡CR)(C≡NXyl), and [{(C∧C)Au(C≡CR)2}{M(C≡NXyl)}] (M = Ag, Cu; R = tBu, C6H4tBu-4, C6H4OMe-4; Xyl = 3,5-Me2C6H3). The X-ray structures reveal a broad range of dispositions determined by the different coordination modes of Ag(I) or Cu(I). The complexes are bright photoemitters in the solid state and in poly(methyl methacrylate) (PMMA) films. The photoluminescence is dominated by 3IL(C∧C) transitions, with indirect effects from the rest of the molecules, as supported by theoretical calculations. This work opens up the possibility of accessing Au(III) carbon-rich anions to construct photoluminescent aggregates.

An expedient copper-catalysed asymmetric synthesis of γ-lactones and γ-lactams. Application to the synthesis of lucidulactone A.

The parent Josiphos ligand gave excellent ee values (95-99%) and good yields (60-97%) in the copper-catalysed asymmetric conjugate reduction of ß-aryl α,ß-unsaturated lactones and lactams with PMHS. The substrates were obtained from stereospecific copper-catalysed addition of arylboronic acids to alkynoates followed by deprotection and cyclisation. The acyclic lactam precursors also underwent reduction with good ee values (83-85%) and yields (79-95%). Application of this asymmetric reduction methodology included the synthesis of natural product lucidulactone A.

The anticancer and EGFR-TK/CDK-9 dual inhibitory potentials of new synthetic pyranopyrazole and pyrazolone derivatives: X-ray crystallography, in vitro, and in silico mechanistic investigations.

Treatment options for the management of breast cancer are still inadequate. This inadequacy is attributed to the lack of effective targeted medications, often resulting in the recurrence of metastatic disorders. Cumulative evidence suggests that epidermal growth factor receptor (EGFR-TK) and cyclin-dependent kinases-9 (CDK-9) overexpression correlates with worse overall survival in breast cancer patients. Pyranopyrazole and pyrazolone are privileged options for the development of anticancer agents. Inspired by this proven scientific fact, we report here the synthesis of two new series of suggested anticancer molecules incorporating both heterocycles together with their characterization by IR, 1H NMR, 13C NMR, 13C NMR-DEPT, and X-ray diffraction methods. An attempt to get the pyranopyrazole-gold complexes was conducted but unexpectedly yielded benzylidene-2,4-dihydro-3H-pyrazol-3-one instead. This unexpected result was confirmed by X-ray crystallographic analysis. All newly synthesized compounds were assessed for their anti-proliferative activity against two different human breast cancer cells, and the obtained results were compared with the reference drug Staurosporine. The target compounds revealed variable cytotoxicity with IC50 at a low micromolar range with superior selectivity indices. Target enzyme EGFR-TK and CDK-9 assays showed that compounds 22 and 23 effectively inhibited both biological targets with IC50 values of 0.143 and 0.121 µM, respectively. Molecular docking experiments and molecular dynamics simulation were also conducted to further rationalize the in vitro obtained results.Communicated by Ramaswamy H. Sarma.

Tweaking the bridge in metallocene Zr(IV)/W(IV) bimetallic hydrides.

Zirconocene cations react with Cp2WH2 affording the bimetallic [Cp2Zr(µ-H)(µ-η1:η5-C5H4)WHCp]+ bridging hydride 1 (Cp = cyclopentadienyl anion, C5H5-) via σ-bond metathesis. Complex 1 features an atypical out of plane Zr(µ-H)W moiety, where no intermetallic interaction is involved, and a fluxional core. Coordination geometry and bond distances of the bridging hydride interaction can be modulated upon reaction with Lewis bases and unsaturated substrates. PMe3, P(p-tol)3, 3,5-dimethylpyridine and THF bind to 1 and shift the hydride bridge on the coordination plane of Zr. Insertion of olefins and alkynes into the Zr-C bond of 1 leads instead to alkyl and vinyl species where the Zr and W coordination planes are perpendicular to each other. Such alterations of the Zr(µ-H)W arrangement are reflected in the average 1H NMR chemical shift values of the hydride, which correlate linearly with computed Zr-H distances. Reactivity experiments with H2 showed that the bridging hydride interaction prevents bimetallic cooperativity and that σ-bond metathesis between Zr-C and H-H bonds is the preferred pathway for all the investigated complexes.

Synthesis, Mechanism Elucidation and Biological Insights of Tellurium(IV)-Containing Heterocycles.

Inspired by the synthetic and biological potential of organotellurium substances, a series of five- and six-membered ring organotelluranes containing a Te-O bond were synthesized and characterized. Theoretical calculations elucidated the mechanism for the oxidation-cyclization processes involved in the formation of the heterocycles, consistent with chlorine transfer to hydroxy telluride, followed by a cyclization step with simultaneous formation of the new Te-O bond and deprotonation of the OH group. Moreover, theoretical calculations also indicated anti-diastereoisomers to be major products for two chirality center-containing compounds. Antileishmanial assays against Leishmania amazonensis promastigotes disclosed 1,2λ4 -oxatellurane LQ50 (IC50 =4.1±1.0; SI=12), 1,2λ4 -oxatellurolane LQ04 (IC50 =7.0±1.3; SI=7) and 1,2λ4 -benzoxatellurole LQ56 (IC50 =5.7±0.3; SI=6) as more powerful and more selective compounds than the reference, being up to four times more active. A stability study supported by 125 Te NMR analyses showed that these heterocycles do not suffer structural modifications in aqueous-organic media or at temperatures up to 65 °C.

Coordination chemistry of [2 + 2] Schiff-base macrocycles derived from the dianilines [(2-NH2C6H4)2X] (X = CH2CH2, O): structural studies and ROP capability towards cyclic esters.

Reaction of the [2 + 2] Schiff-base macrocycles {[2-(OH)-5-(R)-C6H2-1,3-(CH)2][CH2CH2(2-C6H4N)2]}2 (R = Me, L1H2; tBu, L2H2) with FeBr2 afforded the complexes [FeBr(L1H2)]2[(FeBr3)2O]·2MeCN (1·2MeCN), [FeBr(L2H2)][X] (X = 0.5(FeBr3)2O, 2·0.5MeCN, X = Br, 3·5.5MeCN), respectively. Reaction of L2H2 with [KFe(OtBu)3(THF)] (formed in situ from FeBr2 and KOtBu), following work-up, led to the isolation of the complex [Fe(L2)(L2H)]·3MeCN (4·3MeCN), whilst with [CuBr2] afforded [CuBr(L2H2)][CuBr2]·2MeCN (5·2MeCN). Attempts to form mixed Co/Ti species by reaction of [CoBrL2][CoBr3(NCMe)] with TiCl4 resulted in [L2H4][CoBr4]·2MeCN (6·2MeCN). Use of the related oxy-bridged Schiff-base macrocycles {[2-(OH)-5-(R)-C6H2-1,3-(CH)2][O(2-C6H4N)2]}2 (R = Me, L3H2; tBu, L4H2) with CoBr2 led to the isolation of the complexes [(CoBr)2(L3)]·2C3H6O (7·2C3H6O), [Co(NCMe)2(L4H2)][CoBr4]·5MeCN (8·5MeCN), [Co(NCMe)6][CoBr3(MeCN)]2·2MeCN (9·2MeCN). For comparative structural/polymerisation studies, the complexes {CoBr(NCMe)L5}2·2MeCN (10·2MeCN) and [Co(NCMe)2L5]2[CoBr3(NCMe)]2 (11), [FeBr(NCMe)L5]2·2MeCN (12·2MeCN) where L5H = 2,6-(CHO)2-4-tBu-C6H2OH, as well as the chelate-free salt [Fe(NCMe)6][FeBr3OFeBr3] (13) have been isolated and structurally characterized. The ability of these complexes to act as catalysts for the ring opening polymerisation (ROP) of ε-caprolactone (ε-CL) and δ-valerolactone (δ-VL) was investigated, as well as co-polymerisation of ε-CL with rac-lactide (r-LA) and vice versa.

Stability in solution and chemoprotection by octadecavanadates(IV/V) in E. coli cultures.

Two mixed-valence octadecavanadates, (NH4)2(Me4N)5[VIV12VV6O42I]·Me4NI·5H2O (V18I) and [{K6(OH2)12VIV11VV7O41(PO4)·4H2O}n] (V18P), were synthesized and characterized by single-crystal X-ray diffraction analysis and FTIR, Raman, 51V NMR, EPR and UV/Vis/NIR spectroscopies. The chemoprotective activity of V18I and V18P towards the alkylating agent diethyl sulfate was assessed in E. coli cultures. The complex V18I was nontoxic in concentrations up to 5.0 mmol L-1, while V18P presented moderate toxicity in the concentration range 0.10 - 10 mmol L-1. Conversely, a ca. 35% enhancement in culture growth as compared to cells treated only with diethyl sulfate was observed upon addition of V18I (0.10 to 2.5 mmol L-1), while the combination of diethyl sulfate with V18P increased the cytotoxicity presented by diethyl sulfate alone. 51V NMR and EPR speciation studies showed that V18I is stable in solution, while V18P suffers partial breakage to give low nuclearity oxidometalates of vanadium(V) and (IV). According to the results, the chemoprotective effect depends strongly on the direct reactivity of the polyoxidovanadates (POV) towards the alkylating agent. The reaction of diethyl sulfate with V18I apparently produces a new, rearranged POV instead of poorly-reactive breakage products, while V18P shows the formation and subsequent consumption of low-nuclearity species. The correlation of this chemistry with that of other mixed-valence polyoxidovanadates, [H6VIV2VV12O38PO4]5- (V14) and [VIV8VV7O36Cl]6- (V15), suggests a relationship between stability in solution and chemoprotective performance.

Complementary Syntheses Giving Access to a Full Suite of Differentially Substituted Phthalocyanine-Porphyrin Hybrids.

Phthalocyanines and porphyrins are often the scaffolds of choice for use in widespread applications. Synthetic advances allow bespoke derivatives to be made, tailoring their properties. The selective synthesis of unsymmetrical systems, particularly phthalocyanines, has remained a significant unmet challenge. Porphyrin-phthalocyanine hybrids offer the potential to combine the favorable features of both parent structures, but again synthetic strategies are poorly developed. Here we demonstrate strategies that give straightforward, controlled access to differentially substituted meso-aryl-tetrabenzotriazaporphyrins by reaction between an aryl-aminoisoindolene (A) initiator and a complementary phthalonitrile (B). The choice of precursors and reaction conditions allows selective preparation of 1:3 Ar-ABBB and, uniquely, 2:2 Ar-ABBA functionalized hybrids.

Seven-Coordinate Tb3+ Complexes with 90% Quantum Yields: High-Performance Examples of Combined Singlet- and Triplet-to-Tb3+ Energy-Transfer Pathways.

Seven-coordinate, pentagonal-bipyramidal (PBP) complexes [Ln(bbpen)Cl] and [Ln(bbppn)Cl], in which Ln = Tb3+ (products I and II), Eu3+ (III and IV), and Gd3+ (V and VI), with bbpen2- = N,N'-bis(2-oxidobenzyl)-N,N'-bis(pyridin-2-ylmethyl)ethylenediamine and bbppn2- = N,N'-bis(2-oxidobenzyl)-N,N'-bis(pyridin-2-ylmethyl)-1,2-propanediamine, were synthesized and characterized by single-crystal X-ray diffraction analysis, alternating-current magnetic susceptibility measurements, and photoluminescence (steady-state and time-resolved) spectroscopy. Under a static magnetic field of 0.1 T, the Tb3+ complexes I and II revealed single-ion-magnet behavior. Also, upon excitation at 320 nm at 300 K, I and II presented very high absolute emission quantum yields (0.90 ± 0.09 and 0.92 ± 0.09, respectively), while the corresponding Eu3+ complexes III and IV showed no photoluminescence. Detailed theoretical calculations on the intramolecular energy-transfer rates for the Tb3+ products indicated that both singlet and triplet ligand excited states contribute efficiently to the overall emission performance. The expressive quantum yields, QLnL, measured for I and II in the solid state and a dichloromethane solution depend on the excitation wavelength, being higher at 320 nm. Such a dependence was rationalized by computing the intersystem crossing rates (WISC) and singlet fluorescence lifetimes (τS) related to the population dynamics of the S1 and T1 levels. Thin films of product II showed high air stability and photostability upon continuous UV illumination, which allowed their use as downshifting layers in a green light-emitting device (LED). The prototypes presented a luminous efficacy comparable with those found in commercial LED coatings, without requiring encapsulation or dispersion of II in host matrixes. The results indicate that the PBP environment determined by the ethylenediamine (en)-based ligands investigated in this work favors the outstanding optical properties in Tb3+ complexes. This work presents a comprehensive structural, chemical, and spectroscopic characterization of two Tb3+ complexes of mixed-donor, en-based ligands, focusing on their outstanding optical properties. They constitute good molecular examples in which both triplet and singlet excited states provide energy to the Tb3+ ion and lead to high values of QLnL.

Quest for a Cure: Potential Small-Molecule Treatments for COVID-19, Part 2.

During the first year of the outbreak of the COVID-19 pandemic, many drugs and drug candidates have been evaluated as treatment options. None yet has proved to be an effective cure, but progress in controlling the disease has been made. In June 2020 we published an article that described the mechanistic rationale behind the repurposing of seven licensed drugs in clinical trials for the treatment of COVID-19 and reviewed synthetic routes to these drugs. Several developments have occurred since then. Remdesivir (trade name Veklury) has been approved for use in the U.S. and Europe. Dexamethasone, a steroid drug first approved in 1959, has shown mortality reduction in severe COVID patients. Molnupiravir, a new and promising oral antiviral drug, is being studied in late-stage clinical trials. In this review, we update synthetic work that has been recently published on remdesivir, provide an overview of several routes to molnupiravir, and review classical routes to dexamethasone as well as some of those more recently developed.

First COVID-19 molecular docking with a chalcone-based compound: synthesis, single-crystal structure and Hirshfeld surface analysis study.

The first example of molecular docking of the SARS-CoV-2 main protease for COVID-19 [Mpro, Protein Data Bank (PDB) code 7BQY] by a chalcone-based ligand, namely, (E)-1-(2,4-dichlorophenyl)-3-[4-(morpholin-4-yl)phenyl]prop-2-en-1-one, C19H17Cl2NO2, I, is presented. Two-dimensional (2D) LIGPLOT representations calculated for the inhibitor N3, viz. N-{[(5-methylisoxazol-3-yl)carbonyl]alanyl}-L-valyl-N1-((1R,2Z)-4-(benzyloxy)-4-oxo-1-{[(3R)-2-oxopyrrolidin-3-yl]methyl}but-2-enyl)-L-leucinamide, and 7BQY are included for comparison with our chalcone-based complexes. The binding affinity of our chalcone ligand with 7BQY is -7.0 kcal mol-1, a high value which was attributed to the presence of a hydrogen bond, together with many hydrophobic interactions between the drug and the active amino acid residues of the receptor. Docking studies were also performed, employing rigid and flexible binding modes for the ligand. The superposition of N3 and the chalcone docked into the binding pocket of 7BQY is also presented. The synthesis, single-crystal structure, Hirshfeld surface analysis (HSA) and spectral characterization of heterocyclic chalcone-based compound I, are also presented. The molecules are stacked, with normal π-π interactions, in the crystal.

Planar chiral palladacycle precatalysts for asymmetric synthesis.

Chiral non-racemic palladacycles were employed as precatalysts for Pd(0) mediated asymmetric synthesis. Addition of HPAr2/base to a ferrocenyloxazoline planar chiral palladacycle resulted in ligand synthesis and palladium capture to give a bidentate Phosferrox/Pd(0) complex. A series of these complexes were generated in situ and applied successfully as catalysts for asymmetric allylic alkylation.

Straightforward and Controlled Synthesis of Porphyrin-Phthalocyanine-Porphyrin Heteroleptic Triple-Decker Assemblies.

A versatile and straightforward protocol is disclosed for controlled synthesis of complex lanthanide-bridged heteroleptic porphyrin-phthalocyanine triple-decker assemblies. Two porphyrins, linked by a flexible spacer chain of intermediate length, sequentially capture lanthanide ions and a phthalocyanine to efficiently form the triple-decker complex. The bridge directs assembly, but also controls the mobility of the central macrocycle and further imparts a fully eclipsed arrangement of all three rings.

An Oxalate-Bridged Copper(II) Complex Combining Monodentate Benzoate, 2,2'-bipyridine and Aqua Ligands: Synthesis, Crystal Structure and Investigation of Magnetic Properties.

A dinuclear copper(II) complex of formula [{Cu(bipy)(bzt)(OH2)}2(µ-ox)] (1) (where bipy = 2,2'-bipyridine, bzt = benzoate and ox = oxalate) was synthesised and characterised by diffractometric (powder and single-crystal XRD) and thermogravimetric (TG/DTG) analyses, spectroscopic techniques (IR, Raman, electron paramagnetic resonance spectroscopy (EPR) and electronic spectroscopy), magnetic measurements and density functional theory (DFT) calculations. The analysis of the crystal structure revealed that the oxalate ligand is in bis(bidentate) coordination mode between two copper(II) centres. The other four positions of the coordination environment of the copper(II) ion are occupied by one water molecule, a bidentate bipy and a monodentate bzt ligand. An inversion centre located on the ox ligand generates the other half of the dinuclear complex. Intermolecular hydrogen bonds and π-π interactions are responsible for the organisation of the molecules in the solid state. Molar magnetic susceptibility and field dependence magnetisation studies evidenced a weak intramolecular-ferromagnetic interaction (J = +2.9 cm-1) between the metal ions. The sign and magnitude of the calculated J value by density functional theory (DFT) are in agreement with the experimental data.

Allene-derived gold and platinum complexes: synthesis and first applications in catalysis.

We report here the synthesis, full characterisation and first application in catalysis of novel Au(i), Au(iii) and Pt(ii) carbene-type complexes formed from bis(pyridyl)allenes. The catalytic activity of the new Au(i)-complexes in the cyclisation of 1,6-enynes, a benchmark reaction for new Au and Pt complexes, was comparable to Au(i)-state-of-the-art catalysts used in these reactions. Reactions with the new Au(iii)- and Pt(ii)-complexes occurred under milder conditions than those reported with AuCl3 and PtCl2.

Stereoselective Synthesis of All Possible Phosferrox Ligand Diastereoisomers Displaying Three Elements of Chirality: Stereochemical Optimization for Asymmetric Catalysis.

All four possible diastereoisomers of phosphinoferrocenyloxazoline (Phosferrox type) ligands containing three elements of chirality were synthesized as single enantiomers. The Sc configured oxazoline moiety (R = Me, i-Pr) was used to control the generation of planar chirality by lithiation, with the alternative diastereoisomer formed by use of a deuterium blocking group. In each case subsequent addition of PhPCl2 followed by o-TolMgBr resulted in a single P-stereogenic diastereoisomer (Sc,Sp,Sphos and Sc,Rp,Rphos, respectively). The alternative diastereoisomers were formed selectively by addition of o-TolPCl2 followed by PhMgBr ((Sc,Sp,Rphos and Sc,Rp,Sphos, respectively). Preliminary application of these four ligand diastereoisomers, together with (Sc,Sp) and (Sc,Rp) Phosferrox (PPh2), to palladium catalyzed allylic alkylation of trans-1,3-diphenylallyl acetate revealed a stepwise increase/decrease in ee, with the configuration of the matched/matched diastereoisomer as Sc,Sp,Sphos (97% ee).

Hydride Transfer to Gold: Yes or No? Exploring the Unexpected Versatility of Au⋠⋠⋠H-M Bonding in Heterobimetallic Dihydrides.

The potential for coordination and H-transfer from Cp2 MH2 (M=Zr, W) to gold(I) and gold(III) complexes was explored in a combined experimental and computational study. [(L)Au]+ cations react with Cp2 WH2 giving [(L)Au(κ2 -H2 WCp2 )]+ (L=IPr (1), cyclic (alkyl)(amino)carbene (2), PPh3 (3) and Dalphos-Me (4) [IPr=1,3-bis(diisopropylphenyl)imidazolylidene; Dalphos-Me=di(1-adamantyl)-2-(dimethylamino)phenyl-phosphine], while [Au(DMAP)2 ]+ (DMAP=p-dimethylaminopyridine) affords the C2 -symmetric [Au(κ-H2 WCp2 )2 ]+ (5). The Dalphos complex 4 can be protonated to give the bicationic adduct 4 H, showing AuI ⋅⋅⋅H+ -N hydrogen bonding. The gold(III) Lewis acid [(C^N-CH)Au(C6 F5 )(OEt2 )]+ binds Cp2 WH2 to give an Au-H-W σ-complex. By contrast, the pincer species [(C^N^C)Au]+ adds Cp2 WH2 by a purely dative W→Au bond, without Au⋅⋅⋅H interaction. The biphenylyl-based chelate [(C^C)Au]+ forms [(C^C)Au(µ-H)2 WCp2 ]+ , with two 2-electron-3-centre W-H⋅⋅⋅Au interactions and practically no Au-W donor acceptor contribution. In all these complexes, strong but polarized W-H bonds are maintained, without H-transfer to gold. On the other hand, the reactions of Cp2 ZrH2 with gold complexes led in all cases to rapid H-transfer and formation of gold hydrides. Relativistic DFT calculations were used to rationalize the striking reactivity and bonding differences in these heterobimetallic hydride complexes along with an analysis of their characteristic NMR parameters and UV/Vis absorption properties.

H2 activation by zirconaziridinium ions: σ-bond metathesis versus frustrated Lewis pair reactivity.

Zirconaziridinium ions [Cp2Zr(η2-CH2NR2)]+ can potentially activate H2 by two routes: σ-bond metathesis or FLP reactivity. We show here that Zr-C hydrogenolysis by σ-bond metathesis precedes and enables subsequent heterolytic H2 cleavage through FLP pathways. DFT calculations show the involvement of transition states with approximately linear NHH and bent ZrHH arrangements without any direct Zr-amine interaction.

Do Gold(III) Complexes Form Hydrogen Bonds? An Exploration of AuIII Dicarboranyl Chemistry.

The reaction of 1,1'-Li2 [(2,2'-C2 B10 H10 )2 ] with the cyclometallated gold(III) complex (C^N)AuCl2 afforded the first examples of gold(III) dicarboranyl complexes. The reactivity of these complexes is subject to the trans-influence exerted by the dicarboranyl ligand, which is substantially weaker than that of non-carboranyl anionic C-ligands. In line with this, displacement of coordinated pyridine by chloride is only possible under forcing conditions. While treatment of (C^N)Au{(2,2'-C2 B10 H10 )2 } (2) with triflic acid leads to Au-C rather than Au-N bond protonolysis, aqueous HBr cleaves the Au-N bond to give the pyridinium bromo complex 7. The trans-influence of a series of ligands including dicarboranyl and bis(dicarboranyl) was assessed by means of DFT calculations. The analysis demonstrated that it was not sufficient to rely exclusively on geometric descriptors (calculated or experimental) when attempting to rank ligands for their trans influence. Complex (C^N)Au(C2 B10 H11 )2 containing two non-chelating dicarboranyl ligands was prepared similar to 2. Its reaction with trifluoroacetic acid also leads to Au-N cleavage to give trans-(Hpy^C)Au(OAcF )(C2 B10 H11 )2 (8). In crystals of 8 the pyridinium N-H bond points towards the metal centre, while in 7 it is bent away. The possible contribution of gold(III)⋅⋅⋅H-N hydrogen bonding in these complexes was investigated by DFT calculations. The results show that, unlike the situation for platinum(II), there is no evidence for an energetically significant contribution by hydrogen bonding in the case of gold(III).