Regioselective Research Articles

ENDOR Spectroscopy Reveals the "Free" 5'-Deoxyadenosyl Radical in a Radical SAM Enzyme Active Site Actually is Chaperoned by Close Interaction with the Methionine-Bound [4Fe-4S]2+ Cluster.

1/2H and 13C hyperfine coupling constants to 5'-deoxyadenosyl (5'-dAdo•) radical trapped within the active site of the radical S-adenosyl-l-methionine (SAM) enzyme, pyruvate formate lyase-activating enzyme (PFL-AE), both in the absence of substrate and the presence of a reactive peptide-model of the PFL substrate, are completely characteristic of a classical organic free radical whose unpaired electron is localized in the 2pπ orbital of the sp2 C5'-carbon (J. Am. Chem. Soc. 2019, 141, 12139-12146). However, prior electron-nuclear double resonance (ENDOR) measurements had indicated that this 5'-dAdo• free radical is never truly "free": tight van der Waals contact with its target partners and active-site residues guide it in carrying out the exquisitely precise, regioselective reactions that are hallmarks of RS enzymes. Here, our understanding of how the active site chaperones 5'-dAdo• is extended through the finding that this apparently unexceptional organic free radical has an anomalous g-tensor and exhibits significant 57Fe, 13C, 15N, and 2H hyperfine couplings to the adjacent, isotopically labeled, methionine-bound [4Fe-4S]2+ cluster cogenerated with 5'-dAdo• during homolytic cleavage of cluster-bound SAM. The origin of the 57Fe couplings through nonbonded radical-cluster contact is illuminated by a formal exchange-coupling model and broken symmetry-density functional theory computations. Incorporation of ENDOR-derived distances from C5'(dAdo•) to labeled-methionine as structural constraints yields a model for active-site positioning of 5'-dAdo• with a short, nonbonded C5'-Fe distance (∼3 Å). This distance involves substantial motion of 5'-dAdo• toward the unique Fe of the [4Fe-4S]2+ cluster upon S-C(5') bond-cleavage, plausibly an initial step toward formation of the Fe-C5' bond of the organometallic complex, Ω, the central intermediate in catalysis by radical-SAM enzymes.

Regioselective Diels-Alder Reactions of Anthracenes with Olefins via Visible Light Photocatalysis in a Homogeneous Solution.

Diels-Alder cycloaddition of anthracene with olefin is achieved in a homogeneous solution via energy transfer under visible light. A series of substrates including electroneutral styrene derivatives can be successfully converted into the corresponding cycloadducts in a head-to-head orientation with high to excellent yields. The high ortho-regioselectivity, mild condition, and broad substrate scope enable promising advances in organic transformation.

Adventures in the Chemistry of Nitro Compounds

AbstractThe present article provides an overview of our work related to cyclization reactions of nitro-substituted electrophilic building blocks with various nucleophiles. As electrophiles, we used nitro-substituted benzoylacetones, 3-ethoxy-2-nitro-2-en-1-ones, 2-nitrobenzoyl chlorides, 4-chloro-3-nitrocoumarin, 2-nitromalonic aldehyde, 3-nitrochromone and 1-(2-chloro-5-nitrophenyl)prop-2-yn-1-ones. As nucleophiles, 1,3-dicarbonyl compounds, 1,3-bis(silyloxy)-1,3-butadienes, (heterocyclic) enamines, hydroxylamine, hydrazines, amines and amino esters were employed. The products include a variety of nitro-substituted carbo- and heterocycles that are not readily available by other methods. The electron-withdrawing nitro group can be easily transformed into an electron-donating amino group which is not only pharmacologically relevant, but can also act as a nucleophile in inter- and intramolecular reactions with electrophiles, such as aldehydes, and can be converted into other functional groups. The nitro group has the capacity to activate compounds for regioselective palladium-catalyzed CH-arylation reactions. Inter- and intramolecular CH arylations of nitro-substituted heterocyclic building blocks, such as 4-nitropyrazoles, 4-nitroimidazoles, 2-nitroindole and nitro-substituted purine analogues, allow for a convenient diversity-oriented approach to the corresponding arylated products. In addition, the nitro group can act as a leaving group in SNAr reactions. Various fused benzofuro[3,2-b]pyridines were prepared by intramolecular SNAr reactions of 2-(hydroxyphenyl)-3-nitropyridines.1 Introduction2 Cyclizations of 1,3-Bis(silyloxy)-1,3-butadienes3 Cyclizations of Heterocyclic Enamines4 Reactions of Simple Nitro-Substituted Heterocycles5 Hydroamination Reactions of Alkynes6 Miscellaneous7 Conclusions

Metal Influence on Cyaphide-Azide 1,3-Dipolar Cycloaddition Reactions: Aromaticity and Activation Strain.

The factors governing 1,3-dipolar cycloaddition reactions involving C≡P-containing compounds are computationally explored in detail using quantum chemical tools. To this end, the parent process involving tBuN3 and tBuCP is analyzed and compared to the analogous reaction involving organometallic cyaphide complexes (metal=Au, Pt, Ge, Mg), in order to understand the role of the metal fragment in such transformations. It is found that while the metal fragment does not significantly influence the aromaticity of the corresponding concerted transition states or the regioselectivity of the transformation, it may modify the reactivity of the cyaphide complexes (i. e. Ge and Mg cyaphide complexes are comparatively more reactive). The computed reactivity trends and the factors behind the regioselectivity of the cycloaddition reaction are quantitatively analyzed with the help of the activation strain model in combination with the energy decomposition analysis method.

Mechanochemical synthesis of organoselenium compounds

We disclose herein a strategy for the rapid synthesis of versatile organoselenium compounds under mild conditions. In this work, magnesium-based selenium nucleophiles are formed in situ from easily available organic halides, magnesium metal, and elemental selenium via mechanical stimulation. This process occurs under liquid-assisted grinding (LAG) conditions, requires no complicated pre-activation procedures, and operates broadly across a diverse range of aryl, heteroaryl, and alkyl substrates. In this work, symmetrical diselenides are efficiently obtained after work-up in the air, while one-pot nucleophilic addition reactions with various electrophiles allow the comprehensive synthesis of unsymmetrical monoselenides with high functional group tolerance. Notably, the method is applied to regioselective selenylation reactions of diiodoarenes and polyaromatic aryl halides that are difficult to operate via solution approaches. Besides selenium, elemental sulfur and tellurium are also competent in this process, which showcases the potential of the methodology for the facile synthesis of organochalcogen compounds.

Bay-Substitution of Perylene Bisimides with Bidentate Nucleophiles: The Case of Aryloxide Anions.

In this study, we delve into the regioselectivity of nucleophilic reactions involving brominated perylene bisimides (PBIs) and various bidentate aryloxide anions, previously associated with an SRN1 mechanism. We present herein a new perspective, suggesting that a single-electron-transfer aromatic nucleophilic substitution (SeT-SNAr) mechanism is a more plausible scenario. Our study reveals the favorable impact of photostimulation on reaction yields, making our method a convenient approach for accessing O-arylated PBIs.

Total Syntheses of β-Carboline Alkaloids Manzamine C, Orthoscuticelline C, and Quassidine S.

A regioselective olefin hydrofunctionalization reaction of pavettine (4) with various nucleophiles was developed and used as the key step in the total syntheses of β-carboline natural products manzamine C (3), orthoscuticelline C (5), and quassidine S (6). In the 6-step total synthesis of manzamine C (3), an efficient two-step procedure, comprising a Wittig olefination reaction and a Fukuyama-Mitsunobu reaction, was devised for the synthesis of the N-macrocycle with a Z-olefin.

Synthesis of 2‐(β‐Trifluoromethyl‐β‐arylethylthio)pyridine through DBU‐Mediated Regioselective Addition of Pyridine‐2(1H)‐thione Onto α‐(Trifluoromethyl)styrenes

AbstractAn efficient and practical method for the synthesis of (β‐trifluoromethyl‐β‐aryl)ethyl 2‐pyridyl thioethers via hydrothiolation of α‐(trifluoromethyl)styrenes with pyridine‐2(1H)‐thione was reported. The reaction proceeded smoothly and regioselectively in an anti‐Markovnikov manner with the assistance of DBU and afforded a variety of trifluoromethyl‐containing 2‐pyridyl thioethers in moderate to good yields.

New bis-hydantoin/thiohydantoin derivatives: Regioselective synthesis, antibacterial activity, molecular docking, and computational insights

Concerning the reported biological activities of bis-heterocycles, hydantoin, and thiohydantoin moieties, a series of some new bis-hydantoins/thiohydantoins have been prepared, characterized, and screened for their antimicrobial properties. The regioselectivity of the synthetic reactions was discussed and chemical structures of products were elucidated using spectroscopic techniques in addition to elemental analysis. DFT calculations with the IEF-PCM model, to mimic the implicit solvation, have been performed to study the mechanism of reaction as well as the molecular structures and the relative stabilities of the synthesized compounds. The antimicrobial results show that some bis-hydantoin compounds exhibited high antibacterial response against Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Pseudomonas aeruginosa. The inhibitory activity of synthesized compounds may be due to the hydrogen acceptor/donor (HAD) behavior of substituted function groups like thiocarbonyl, carbonyl, acetyl, NH, and OH. The synthetic potential and antimicrobial activities of all compounds under investigation were confirmed using molecular docking simulation into the active sites of different kinds of proteins.

Regioselectivity in the sulfonium-mediated arylation reactions of 2-substituted phenols with benzothienyl sulfoxide

Abstract The regioselectivity in the sulfonium-mediated arylation of phenols with aryl sulfoxide is significantly influenced by the substituents at the 2 position of phenols. While most substituents tend to promote the expected C–C bond formation at the 6 position, alkyl substituents induce the minor formation of rearranged biaryls, the 1,2,3-substituted isomers.

Rh‐Catalyzed Cycloaddition of C60 with Enynes: Unveiling the Mechanistic Pathway

AbstractIn this study we present a method for functionalizing C60 through a Rh‐catalyzed cyclization reaction with 1,6‐enynes, resulting in the formation of a fused bicyclic structure. Additionally, fullerene derivatives are further functionalized through regioselective photooxygenation reactions. Our DFT calculations reveal two distinct reaction pathways: one involving rhodium‐catalyzed cycloisomerization of the enyne followed by Diels‐Alder with C60, and the other featuring a rhodium‐catalyzed [2+2+2] cycloaddition of enyne and C60 followed by isomerization. Surprisingly, both pathways exhibit nearly identical energy barriers. However, experimental tests indicate that the predominant pathway varies depending on the substitution motifs of the substrates.

Switching the regioselectivity of acid-catalyzed reactions of arylnaphtho[2,1-b]furans via a [1,2]-aryl shift.

The [1,2]-aryl shift reaction was used to synthesize naphtho[2,1-b]furans as promising fluorescent scaffolds for organic electronics. The target compounds are furan analogues of phenanthrene formally accessed by isosteric replacement of the CHCH moiety with an oxygen atom. The straightforward and robust approach involving a [1,2]-aryl shift as a key step provides easy access to a wide range of naphtho[2,1-b]furans with the possibility of late-stage functionalization. Efficient switching of the regioselectivity of acid-catalyzed reactions of arylnaphtho[2,1-b]furans via a [1,2]-aryl shift has been demonstrated. A one-pot protocol involving sequential intramolecular condensation/[1,2]-aryl shift/intermolecular oxidative aromatic coupling to provide access to binaphtho[2,1-b]furan analogues of BINOL was developed. The advantage of these compounds lies in the strong variation in chemical properties and spectral performance depending on the nature and position of the aryl substituent, which facilitates the synthesis of compounds with desired spectral characteristics and opens up prospects for their further use in electronics, biotechnologies and organic synthesis.

Controlling the regioselectivity of the bromolactonization reaction in HFIP.

The halolactonization reaction provides rapid access to densely functionalized lactones from unsaturated carboxylic acids. The endo/exo regioselectivity of this cyclization reaction is primarily determined by the electronic stabilization of alkene substituents, thus making it inherently dependent on substrate structures. Therefore this method often affords one type of halolactone regioisomer only. Herein, we introduce a simple and efficient method for regioselectivity-switchable bromolactonization reactions mediated by HFIP solvent. Two sets of reaction conditions were developed, each forming endo-products or exo-products in excellent regioselectivity. A combination of computational and experimental mechanistic studies not only confirmed the crucial role of HFIP, but also revealed the formation of endo-products under kinetic control and exo-products under thermodynamic control. This study paves the way for future work on the use of perfluorinated solvents to dictate reaction outcomes in organic synthesis.

A new armchair carbon nanobelt synthesized by tuning the regioselectivity of the Scholl reaction of quinquephenyl.

A new armchair carbon nanobelt is successfully synthesized by tuning the regioselectivity of the Scholl reaction of 1,1':2',1'':4'',1''':2''',1''''-quinquephenyl. This nanobelt exhibits a preferential binding affinity towards C70 over C60 as found from photoluminescence titration experiments.

Tandem site-selective bromination and highly regioselective Heck reaction of N-allyl enaminones: chemodivergent synthesis of polysubstituted pyrroles and pyridines

Chemodivergent synthesis of polysubstituted pyrroles and pyridines from N-allyl enaminones via tandem site-selective bromination and the highly regioselective Heck reaction.

Facile synthesis of diiodoheteroindenes and understanding their Sonogashira cross-coupling selectivity for the construction of unsymmetrical enediynes.

Electrophile-promoted cyclizations of functionalized alkynes offer a useful tool for constructing halogen-substituted heterocycles primed for further derivatization. Preinstallation of an iodo-substituent at the alkyne prior to iodo-cyclization opens access to ortho di-iodinated heterocyclic precursors for the preparation of unsymmetrical heterocycle-fused enediynes. This general approach was used to prepare 2,3-diiodobenzothiophene, 2,3-diiodoindole, and 2,3-diiodobenzofuran, a useful family of substrates for systematic studies of the role of heteroatoms on the regioselectivity of cross-coupling reactions. Diiodobenzothiophene showed much higher regioselectivity for Sonogashira cross-coupling at C2 than diiodoindole and diiodobenzofuran. As a result, benzothiophene can be conveniently involved in a one-pot sequential coupling with two different alkynes, yielding unsymmetrical benzothiophene-fused enediynes. On the other hand, the Sonogashira reaction of diiodoindole and diiodobenzofuran formed considerable amounts of di-substituted enediynes in addition to the monoalkyne product by coupling at C2. Interestingly, no C3-monocoupling products were observed for all of the diiodides, suggesting that the incorporation of the 1st alkyne at C2 activates the C3 position for the 2nd coupling. Additional factors affecting regioselectivity were detected, discussed and connected, through computational analysis, to transmetalation being the rate-determining step for the Sonogashira reaction. Several enediynes synthesized showed cytotoxic activity, which is not associated with DNA strand breaks typical of natural enediyne antibiotics.

Computational insights into Diels-Alder reactions of paramagnetic endohedral metallofullerenes: M@C82 (M = Sc, Y, La) and La@C72.

In fullerene chemistry, Diels-Alder cycloaddition is an essential reaction for exohedral modification of carbon cages. M@C2v(9)-C82 (M = Sc, Y, and La), incorporating one metal atom within the fullerene cage, are key compounds for understanding the impact of both endohedral and exohedral modifications on their electronic structures. In this work, the Diels-Alder (DA) cycloaddition of cyclopentadiene (Cp) to M@C2v(9)-C82 (M = Sc, Y, and La) and La@C2(10612)-C72 was systematically studied using density functional theory. The most reactive bonds were initially chosen for detailed mechanistic exploration, considering both concerted and stepwise mechanisms. Our findings revealed that DA cycloadditions for the three metals (Sc, Y, and La) consistently exhibit the same regioselectivity, favoring the concerted attack on the [5,6] bond. This observation is in agreement with previous experimental and theoretical studies on the regioselectivity of the Diels-Alder reaction between La@C2v(9)-C82 and Cp. In the case of La@C2(10612)-C72, the most favored pathway is the concerted attack on the [6,6] bond both kinetically and thermodynamically. In toluene and ortho-dichlorobenzene, while the energy barriers and the reaction free energies increased to different extents for most pathways, the regioselectivity largely mirrored that observed in the gas phase.

Regio-MPNN: predicting regioselectivity for general metal-catalyzed cross-coupling reactions using a chemical knowledge informed message passing neural network

As a fundamental problem in organic chemistry, regioselectivity is crucial in designing energy and cost-efficient reaction pathways for target compounds.

The cyanide, cyanate, thiocyanate ambident anions: Structure, topological analysis of electron density, and homolytic oxidative coupling regioselectivity

At the B3LYP/6-311++G(3df,3pd) level of theory, the spatial and electronic structure of the cyanide, cyanate and thiocyanate ambident anions has been studied. By means of the natural bond orbital (NBO) analysis and the R. F. W. Bader?s quantum theory ?Atoms in Molecules? (QTAIM), the electron density delocalization and topological properties in the above anions have been investigated. The distribution of electron density (NBO, QTAIM) in the XCN- (X = O, S) anions is reflected by the scheme [X-?C=?N]-. The relative contribution of the hypothetical structure X=C=N- to the resonance hybrid -X?C?N ?X=C=N- is higher in the case of X = O. The degree of the C?N or C=?N bond triple character and bond strength changes in the following series of anions: CN- > SCN- > OCN-. The occupancy of the lone electron pair (LP) orbital of the nitrogen atom in the above anions is close to 2, and the LP orbital is sp-hybridized. Condensed K. Fukui functions for the electrophilic attack have been evaluated. Local hardness of the donor reaction centres: N > C (CN-), O > N (OCN-), N > S (SCN-). The regioselectivity of the homolytic oxidative coupling reactions of CN-, OCN-, SCN- has been substantiated.

Asymmetric bifunctionalization of allenes with aryl iodides and amino acids enabled by chiral aldehyde/palladium combined catalysis.

Even though catalytic asymmetric bifunctionalization of allenes has been extensively studied, almost all of the reported examples have been achieved in a two-component manner. In this study, we report a highly efficient asymmetric bifunctionalization of allenes with iodohydrocarbons and NH2-unprotected amino acid esters. The adopted chiral aldehyde/palladium combined catalytic system precisely governs the chemoselectivity, regioselectivity, and stereoselectivity of this three-component reaction. A wide range of substituted aryl iodides, allenes and amino acid esters can well participate in this reaction and deliver structurally diverse α,α-disubstituted α-amino acid esters with excellent experimental outcomes. One of the resulting products is utilized for the total synthesis of the molecule (S,R)-VPC01091.