Photoinduced [4 + 2]-cycloaddition reactions of vinyldiazo compounds for the construction of heterocyclic and bicyclic rings.

Highly selective formal [4 + 2]-cycloaddition of vinyldiazoacetates with azoalkenes from α-halohydrazones, as well as with cyclopentadiene and furan, occurs with light irradiation at room temperature, producing highly functionalized heterocyclic and bicyclic compounds in good yields and excellent diastereoseletivity. Under blue light these vinyldiazoacetate reagents selectively form unstable cyclopropenes that undergo intermolecular cycloaddition reactions at a faster rate than their competitive ene dimerization. [4 + 2]-cycloaddition of vinyldiazoacetates with in situ formed azoalkenes produces bicyclo[4.1.0]tetrahydropyridazine derivatives and, together with their cycloaddition using cyclopentadiene and furan that form tricyclic compounds, they occur with high chemoselectivity and diastereocontrol, good functional group tolerance, and excellent scalability. Subsequent transformations portray the synthetic versatility of these structures.

Denitrogenative dismantling of heteroaromatics by nucleophilic substitution reactions with diazomethyl compounds.

Nucleophiles from deprotonation of diazomethyl compounds having diverse electron withdrawing groups react with 4-carboxylato-1,2,3-triazines at the 6-position to extrude dinitrogen and produce diazovinylketoesters compounds with five or six linear contiguous sp2-hybridized carbons, whereas these same nucleophiles react with 4-carboxylato-1,2,3-triazine 1-oxides, also at the 6-position, to form pyrazolines with the expulsion of nitrous oxide and cyanocarboxylate. This disparity is due to the significant difference in reactivity of the nucleophilic addition products.

Square-planar imido complexes of cobalt: synthesis, reactivity and computational study.

Treatment of [Co(N2)(tBuPNP)] (tBuPNP = anion of 2,5-bis(di-tert-butylphosphinomethyl)pyrrole) with one equivalent of an aryl azide generates the four-coordinate imido complexes [Co(NAr)(tBuPNP)] (Ar = mesityl, phenyl, or 4-tBu-phenyl). X-ray crystallographic analysis of the compounds shows an unusual square-planar geometry about cobalt with nearly linear imido units. In the presence of the hydrogen atom donor, TEMPOH, [Co(NPh)(tBuPNP)] undergoes addition of the H atom to the imido nitrogen to generate the corresponding amido complex, [Co(NHPh)(tBuPNP)], whose structure and composition were verified by independent synthesis. Despite the observation of H atom transfer reactivity with TEMPOH, the imido complexes do not show catalytic activity for C-H amination or aziridination for several substrates examined. In the case of [Co(NPh)(tBuPNP)], addition of excess azide produced the tetrazido complex, [Co(N4Ph2)(tBuPNP)], whose bond metrics were most consistent with an anionic Ph2N4 ligand. Density Functional Theory (DFT) investigations of the imido and tetrazido species suggest that they adopt a ground state best described as possessing a low-spin cobalt(II) ion ferromagnetically coupled to an iminyl radical.

Linker Engineering toward Tunable Emission Behavior of Porous Interpenetrated Zr-Organic Frameworks.

Conjugated molecules with donor-acceptor-donor (D-A-D) moieties have garnered significant attention for their ability to form luminescent metal-organic frameworks (LMOFs). D-A-D molecules feature tunable bandgaps, which can be varied systematically to control the fluorescence wavelength of LMOFs. In this study, we prepared and characterized the fluorescence properties of two porous interpenetrated Zr-organic frameworks (PIZOFs) constructed using 4,4'-(benzo[c][1,2,5]selenadiazole-4,7-diylbis(ethyne-2,1-diyl))dibenzoic acid (L-Se) or 4,4'-(benzo[c][1,2,5]thiadiazole-4,7-diylbis(ethyne-2,1-diyl))dibenzoic acid (L-S) as linkers. The corresponding MOFs are denoted as PIZOF-Se and PIZOF-S, respectively. Through our investigation, we explored the correlation between the structure of the frameworks and their respective optical properties. Our findings revealed that there are distinct differences in the fluorescence properties of the two PIZOFs. Specifically, the fluorescence of PIZOF-S is red-shifted from that characteristic of the corresponding linker, L-S. By contrast, the fluorescence of PIZOF-Se is substantially blue-shifted from that of linker L-Se. The emission of mixed-linker MOFs is explored by combining L-S or L-Se with structurally analogous, but nonfluorescent linker, 4,4'-((perfluoro-1,4-phenylene)bis(ethyne-2,1-diyl))dibenzoic acid (L-F). Based on steady-state and time-resolved photoluminescence experiments, as well as confocal fluorescence microscopy combined with fluorescence lifetime imaging (FILM), we demonstrated that linker engineering is an effective method to tune the emission behavior of LMOFs.

Acridine photocatalysis enables tricomponent direct decarboxylative amine construction.

Amines are centrally important motifs in medicinal chemistry and biochemistry, and indispensable intermediates and linchpins in organic synthesis. Despite their cross-disciplinary prominence, synthetic access to amine continues to rely on two-electron approaches based on reductions and additions of organometallic reagents, limiting their accessible chemical space and necessitating stepwise preassembly of synthetic precursors. We report herein a homogeneous photocatalytic tricomponent decarboxylative radical-mediated amine construction that enables modular access to α-branched secondary amines directly from the broad and structurally diverse chemical space of carboxylic acids in a tricomponent reaction with aldehydes and aromatic amines. Our studies reveal the key role of acridine photocatalysis acting in concert with copper and Brønsted acid catalytic processes in facilitating the previously inaccessible homogeneous photocatalytic reaction and provide a streamlined segue to a wide range of amines and nonproteinogenic α-amino acids.

HNTf2-Catalyzed Formal [3 + 2] Cycloaddition of Vinyldiazoacetates to Indole-Substituted Diazo Compounds and Their Conversion to Carbazoles.

Triflimide catalysis of the [3 + 2]-cycloaddition of 3-indolymethanols with vinyldiazoacetates provides general access to ß-tetrahydrocyclopenta[b]indol-substituted α-diazoesters. Initiated by addition of the in situ generated vinylogous iminium electrophile from 3-indolymethanol to the vinylogous position of the vinyldiazo compound and completed by intramolecular cyclization from the vinyldiazonium ion intermediate, this transformation occurs in good yields and excellent diastereoselectivity with a broad substrate scope under mild conditions. The resulting α-diazoesters undergo Rh2(OAc)4-catalyzed substrate-dependent 1,2-migration to form multisubstituted carbazoles in high yields.

Multimodal Acridine Photocatalysis Enables Direct Access to Thiols from Carboxylic Acids and Elemental Sulfur.

Development of photocatalytic systems that facilitate mechanistically divergent steps in complex catalytic manifolds by distinct activation modes can enable previously inaccessible synthetic transformations. However, multimodal photocatalytic systems remain understudied, impeding their implementation in catalytic methodology. We report herein a photocatalytic access to thiols that directly merges the structural diversity of carboxylic acids with the ready availability of elemental sulfur without substrate preactivation. The photocatalytic transformation provides a direct radical-mediated segue to one of the most biologically important and synthetically versatile organosulfur functionalities, whose synthetic accessibility remains largely dominated by two-electron-mediated processes based on toxic and uneconomical reagents and precursors. The two-phase radical process is facilitated by a multimodal catalytic reactivity of acridine photocatalysis that enables both the singlet excited state PCET-mediated decarboxylative carbon-sulfur bond formation and the previously unknown radical reductive disulfur bond cleavage by a photoinduced HAT process in the silane-triplet acridine system. The study points to a significant potential of multimodal photocatalytic systems in providing unexplored directions to previously inaccessible transformations.

Peptide recognition by a synthetic receptor at subnanomolar concentrations.

This paper describes the discovery and characterization of a dipeptide sequence, Lys-Phe, that binds to the synthetic receptor cucurbit[8]uril (Q8) in neutral aqueous solution with subnanomolar affinity when located at the N-terminus. The thermodynamic and structural basis for the binding of Q8 to a series of four pentapeptides was characterized by isothermal titration calorimetry, NMR spectroscopy, and X-ray crystallography. Submicromolar binding affinity was observed for the peptides Phe-Lys-Gly-Gly-Tyr (FKGGY, 0.3 µM) and Tyr-Leu-Gly-Gly-Gly (YLGGG, 0.2 µM), whereas the corresponding sequence isomers Lys-Phe-Gly-Gly-Tyr (KFGGY, 0.3 nM) and Leu-Tyr-Gly-Gly-Gly (LYGGG, 1.2 nM) bound to Q8 with 1000-fold and 170-fold increases in affinity, respectively. To our knowledge, these are the highest affinities reported between a synthetic receptor and an unmodified peptide. The high-resolution crystal structures of the Q8·Tyr-Leu-Gly-Gly-Gly and Q8·Leu-Tyr-Gly-Gly-Gly complexes have enabled a detailed analysis of the structural determinants for molecular recognition. The high affinity, sequence-selectivity, minimal size of the target binding site, reversibility in the presence of a competitive guest, compatibility with aqueous media, and low toxicity of Q8 should aid in the development of applications involving low concentrations of target polypeptides.

The "cesium effect" magnified: exceptional chemoselectivity in cesium ion mediated nucleophilic reactions.

Chemodivergent construction of structurally distinct heterocycles from the same precursors by adjusting specific reaction parameters is an emergent area of organic synthesis; yet, understanding of the processes that underpin the reaction divergence is lacking, preventing the development of new synthetic methods by systematically harnessing key mechanistic effects. We describe herein cesium carbonate-promoted oxadiaza excision cross-coupling reactions of ß-ketoesters with 1,2,3-triazine 1-oxides that form pyridones in good to high yields, instead of the sole formation of pyridines when the same reaction is performed in the presence of other alkali metal carbonates or organic bases. The reaction can be further extended to the construction of synthetically challenging pyridylpyridones. A computational study comparing the effect of cesium and sodium ions in the oxadiaza excision cross-coupling reactions reveals that the cesium-coordinated species changes the reaction preference from attack at the ketone carbonyl to attack at the ester carbon due to metal ion-specific transition state conformational accommodation, revealing a previously unexplored role of cesium ions that may facilitate the development of chemodivergent approaches to other heterocyclic systems.

Asymmetric Synthesis of CIDD-0072424 via an Enantioselective Nitro-Mannich Reaction: A Central Nervous System Penetrant, Selective Small Molecule Inhibitor of Protein Kinase C Epsilon.

CIDD-0072424 is a novel small molecule developed in silico with remarkable activity for the inhibition of protein kinase C (PKC)-epsilon to treat alcohol use disorder. We developed a concise synthesis of (S)-2 that is highly enantioselective, scalable, and amenable for 3-point structure-activity relationship (SAR) studies for compound optimization. The highly enantioselective nitro-Mannich reaction was achieved through a dual-reagent catalysis system. The overall utility and the efficiency of the enantioselective route provided a scalable synthesis of both PKCε inhibitors 1 and 2.

Aqua-bis-(2,2'-bi-pyridine-κ2N,N')(isonicotinamide-κN)ruthenium(II) bis-(trifluoromethanesulfonate).

In the title complex, [Ru(C10H8N2)2(C6H6N2O)(H2O)](CF3SO3)2, the central RuII atom is sixfold coordinated by two bidentate 2,2'-bi-pyridine, an isonic-otinamide ligand, and a water mol-ecule in a distorted octa-hedral environment with tri-fluoro-methane-sulfonate ions completing the outer coordination sphere of the complex. Hydrogen bonding involving the water mol-ecule and weak π-π stacking inter-actions between the pyridyl rings in adjacent mol-ecules contribute to the alignment of the complexes in columns parallel to the c axis.

(2,2'-Bi-pyridine-κ2N,N')(4,4'-dimeth-oxy-2,2'-bipyridine-κ2N,N')palladium(II) bis-(tri-fluoro-meth-anesulfonate).

In the title complex salt, [Pd(C10H8N2)(C12H12N2O2)](CF3SO3)2, the palladium(II) atom is fourfold coordinated by two chelating ligands, 2,2'-bi-pyridine and 4,4'-dimeth-oxy-2,2'-bi-pyridine, in a distorted square-planar environment. In the crystal, weak π-π stacking inter-actions between the 2,2'-bi-pyridine rings [centroid-to-centroid distances = 3.8984 (19) Å] and between the 4,4'-dimeth-oxy-2,2'-bi-pyridine rings [centroid-to-centroid distances = 3.747 (18) Å] contribute to the alignment of the complex cations in columns parallel to the b-axis direction.

Di-chlorido-(4,7-dimeth-oxy-1,10-phenanthroline-κ2N,N')zinc(II).

In the title complex, [ZnCl2(C14H12N2O2)], the ZnII atom is located on a twofold rotation axis and is fourfold coordinated by two chlorido ligands and a bidentate 4,7-meth-oxy-1,10-phenanthroline ligand in a distorted tetra-hedral environment. Weak π-π stacking inter-actions between adjacent 4,7-dimeth-oxy-1,10-phenanthroline rings [centroid-to-centroid distances = 3.5969 (11) and 3.7738 (11) Å] contribute to the alignment of the complexes in layers parallel to (01).

Bis[2,6-bis-(benzimidazol-2-yl)pyridine-κ3N,N',N'']nickel(II) bis-(tri-fluoro-methane-sulfonate) diethyl ether monosolvate.

In the title complex, [Ni(C19H13N5)2](CF3SO3)2·(CH3CH2)2O, the central NiII atom is sixfold coordinated by three nitro-gen atoms of each 2,6-bis-(2-benzimidazol-yl)pyridine ligand in a distorted octa-hedral geometry with two tri-fluoro-methane-sulfonate ions and a mol-ecule of diethyl ether completing the outer coordination sphere of the complex. Hydrogen bonding contributes to the organization of the asymmetric units in columns along the a axis generating a porous supra-molecular structure. The structure was refined as a two-component twin with a refined BASF value of 0.4104 (13).

Kinetically-driven reactivity of sulfinylamines enables direct conversion of carboxylic acids to sulfinamides.

Sulfinamides are some of the most centrally important four-valent sulfur compounds that serve as critical entry points to an array of emergent medicinal functional groups, molecular tools for bioconjugation, and synthetic intermediates including sulfoximines, sulfonimidamides, and sulfonimidoyl halides, as well as a wide range of other S(iv) and S(vi) functionalities. Yet, the accessible chemical space of sulfinamides remains limited, and the approaches to sulfinamides are largely confined to two-electron nucleophilic substitution reactions. We report herein a direct radical-mediated decarboxylative sulfinamidation that for the first time enables access to sulfinamides from the broad and structurally diverse chemical space of carboxylic acids. Our studies show that the formation of sulfinamides prevails despite the inherent thermodynamic preference for the radical addition to the nitrogen atom, while a machine learning-derived model facilitates prediction of the reaction efficiency based on computationally generated descriptors of the underlying radical reactivity.

Synthesis of 6ß-hydroxy androgens from a 3,5-diene steroid precursor to test for cytochrome P450 3A4-catalyzed hydroxylation of androstenedione.

6ß-Hydroxytestosterone is a biomarker for the activity of human cytochrome P450 3A4 (P450 3A4), the major drug metabolizing cytochrome P450 enzyme. Despite its significance, efficient routes for the chemical synthesis of 6ß-hydroxytestosterone are rare. In this study, 6ß-hydroxytestosterone was synthesized through the oxidation of a 3,5-diene precursor under the Uemura-Doyle reaction conditions using a dirhodium catalyst in the presence of tert-butylhydroperoxide. Mechanistic studies showed that some oxygen is incorporated from molecular oxygen and CH abstraction is partially rate-limiting. This reaction was used to synthesize 6ß-hydroxyandrostenedione, which was used as a standard to test the hypothesis of whether P450 3A4 catalyzes the hydroxylation of androstenedione. Upon incubation of P450 3A4 with androstenedione, a hydroxylated product was formed, which matched the retention time of synthetic 6ß-hydroxyandrostenedione. This reaction can be exploited to study other biochemical processes involving compounds with a 6 ß -hydroxy-3-keto-Δ4 steroid backbone.

Effect of bromine substitution on blue phosphorescent trans-(N-heterocyclic carbene)Pt(II) acetylide complexes.

N-heterocyclic carbene complexes of the type trans-(NHC)2PtII(CC-Ar)2 (where Ar = phenyl or substituted phenyl) are of interest as violet and blue phosphors. These complexes emit efficient phosphorescence in solution and in the solid state, and they have been applied as phosphors in organic light emitting diodes. This study explores the effect of bromine substitution on the trans-(NHC)2PtII(CC-Ar)2 chromophore through photophysical studies of a pair of complexes in which the phenyl groups feature either 3,5-dibromo- or 4-monobromo-substituents (IPt-DB and IPt-MB, respectively). The Br atoms were introduced as heavy atom(s) with the aim to enhance spin-orbit coupling and increase the radiative and non-radiative decay rates of the phosphorescent triplet state. Both IPt-MB and IPt-DB exhibit sky-blue phosphorescence in solution and in PMMA matrix. Interestingly, the emission quantum yield and lifetime of IPt-MB are substantially lower compared to IPt-DB in solution. This effect is attributed to a substantially larger non-radiative decay rate in the mono-bromo complex. Analysis of the photophysical data, combined with DFT and TD-DFT calculations, suggest that the difference in photophysical properties of the two complexes is related to the position of the Br-substituents on the phenyl acetylide rings. In short, in IPt-MB, the Br-substituents are located para-to the Pt-CC-unit, and this gives rise to stronger electron-vibrational coupling in the excited state, enhancing the rate of non-radiative decay.

Inhibition of Cysteine Proteases via Thiol-Michael Addition Explains the Anti-SARS-CoV-2 and Bioactive Properties of Arteannuin B.

Artemisia annua is the plant that produces artemisinin, an endoperoxide-containing sesquiterpenoid used for the treatment of malaria. A. annua extracts, which contain other bioactive compounds, have been used to treat other diseases, including cancer and COVID-19, the disease caused by the virus SARS-CoV-2. In this study, a methyl ester derivative of arteannuin B was isolated when A. annua leaves were extracted with a 1:1 mixture of methanol and dichloromethane. This methyl ester was thought to be formed from the reaction between arteannuin B and the extracting solvent, which was supported by the fact that arteannuin B underwent 1,2-addition when it was dissolved in deuteromethanol. In contrast, in the presence of N-acetylcysteine methyl ester, a 1,4-addition (thiol-Michael reaction) occurred. Arteannuin B hindered the activity of the SARS CoV-2 main protease (nonstructural protein 5, NSP5), a cysteine protease, through time-dependent inhibition. The active site cysteine residue of NSP5 (cysteine-145) formed a covalent bond with arteannuin B as determined by mass spectrometry. In order to determine whether cysteine adduction by arteannuin B can inhibit the development of cancer cells, similar experiments were performed with caspase-8, the cysteine protease enzyme overexpressed in glioblastoma. Time-dependent inhibition and cysteine adduction assays suggested arteannuin B inhibits caspase-8 and adducts to the active site cysteine residue (cysteine-360), respectively. Overall, these results enhance our understanding of how A. annua possesses antiviral and cytotoxic activities.

Site Reversal in Nucleophilic Addition to 1,2,3-Triazine 1-Oxides.

One of the most important reactions of 1,2,3-triazines with a dienophile is inverse electron demand Diels-Alder (IEDDA) cycloaddition, which occurs through nucleophilic addition to the triazine followed by N2 loss and cyclization to generate a heterocycle. The site of addition is either at the 4- or 6-position of the symmetrically substituted triazine core. Although specific examples of the addition of nucleophiles to triazines are known, a comprehensive understanding has not been reported, and the preferred site for nucleophilic addition is unknown and unexplored. With access to unsymmetrical 1,2,3-triazine-1-oxides and their deoxygenated 1,2,3-triazine compounds, we report C-, N-, H-, O-, and S-nucleophilic additions on 1,2,3-triazine and 1,2,3-triazine-1-oxide frameworks where the 4- and 6-positions could be differentiated. In the IEDDA cycloadditions using C- and N-nucleophiles, the site of addition is at C-6 for both heterocyclic systems, but product formation with 1,2,3-triazine-1-oxides is faster. Other N-nucleophile reactions with triazine 1-oxides show addition at either the 4- or 6-position of the triazine 1-oxide ring, but nucleophilic attack only occurs at the 6-position on the triazine. Hydride from NaBH4 undergoes addition at the 6-position on the triazine and the triazine 1-oxide core. Alkoxides show a high nucleophilic selectivity for the 4-position of the triazine 1-oxide. Thiophenoxide, cysteine, and glutathione undergo nucleophilic addition on the triazine core at the 6-position, while addition occurs at the 4-position of the triazine 1-oxide. These nucleophilic additions proceed under mild reaction conditions and show high functional group tolerance. Computational studies clarified the roles of the nucleophilic addition and nitrogen extrusion steps and the influence of steric and electronic factors in determining the outcomes of the reactions with different nucleophiles.

Synthesis of hyocholic acid and its derivatization with sodium periodate to distinguish it from cholic acid by mass spectrometry.

Low concentrations of hyocholic acid in human serum has been linked to diabetes. Due to its important role in human health, we were interested in synthesizing hyocholic acid to explore potential biochemical properties of this bile acid. Here, a synthesis of hyocholic acid is reported from chenodeoxycholic acid. The key step was a Rubottom oxidation of a silyl enol ether intermediate to directly incorporate the oxygen at C6. Furthermore, the synthesized hyocholic acid product was treated with NaIO4 to cleave the C6-C7 bond to yield a hemiacetal at C6. This CC bond cleavage reaction using NaIO4 was used to develop an ultra-performance liquid chromatography mass spectrometry method to distinguish between a 1 to 1 mixture of hyocholic acid and cholic acid (a 12α-hydroxylated bile acid), two bile acid regioisomers with identical masses. Upon treatment of the mixture with NaIO4, hyocholic acid was selectively cleaved in the B ring (C6-C7 bond) to yield the hemiacetal that formed between the C3-hydroxy and the C6-aldehyde moiety with an m/z 405 while cholic acid remained intact with an m/z 407 in the negative electrospray ionization mode. Subsequently, a commercially available ox bile extract was treated with NaIO4 to detect bile acid derivatives by mass spectrometry. Two possible hyocholic acid derivatives conjugated to serine and gamma-glutamic semialdehyde were detected in electrospray ionization positive mode, which oxidatively cleaved with NaIO4 (m/z 496 and 522 to m/z 494 and 520, respectively).