Intramolecular Oxidative Coupling Research Articles

Unveiling Amaryllidaceae alkaloids: from biosynthesis to antiviral potential - a review.

Covering: 2017 to 2023 (now)Amaryllidaceae alkaloids (AAs) are a unique class of specialized metabolites containing heterocyclic nitrogen bridging that play a distinct role in higher plants. Irrespective of their diverse structures, most AAs are biosynthesized via intramolecular oxidative coupling. The complex organization of biosynthetic pathways is constantly enlightened by new insights owing to the advancement of natural product chemistry, synthetic organic chemistry, biochemistry, systems and synthetic biology tools and applications. These promote novel compound identification, trace-level metabolite quantification, synthesis, and characterization of enzymes engaged in AA catalysis, enabling the recognition of biosynthetic pathways. A complete understanding of the pathway benefits biotechnological applications in the long run. This review emphasizes the structural diversity of the AA specialized metabolites involved in biogenesis although the process is not entirely defined yet. Moreover, this work underscores the pivotal role of synthetic and enantioselective studies in justifying biosynthetic conclusions. Their prospective candidacy as lead constituents for antiviral drug discovery has also been established. However, a complete understanding of the pathway requires further interdisciplinary efforts in which antiviral studies address the structure-activity relationship. This review presents current knowledge on the topic.

Oxidative Coupling Approach to Sarpagine Alkaloids: Total Synthesis of (-)-Trinervine, Vellosimine, (+)-Normacusine B, and (-)-Alstomutinine C.

Sarpagine alkaloids are bioactive indole natural products that contain a highly rigid indole-fused 1-azabicyclo[2.2.2]octane, more than 100 members of which have been identified. Herein, a detailed examination of the intramolecular oxidative coupling between a ketone and a Weinreb amide for assembling the complex 1-azabicyclo[2.2.2]octane core structure of sarpagine family alkaloids is described. Precise late-stage manipulations of the ketone and Weinreb amide enable the divergent syntheses of (-)-trinervine, (+)-vellosimine, (+)-normacusine B, and (-)-alstomutinine C. Other notable transformations of the synthesis featured an aza-Achmatowicz/indole cyclization cascade to generate the azabicyclo[3.3.1]nonane structure, a regioselective elimination reaction to form the ethylidene motif embedded in the (+)-vellosimine and (+)-normacusine B structures, and a diastereoselective indole oxidative rearrangement to form the spirooxindole structure in (-)-alstomutinine C.

Oxidative Coupling Approach to Sarpagine Alkaloids: Total Synthesis of (−)‐Trinervine, Vellosimine, (+)‐Normacusine B, and (−)‐Alstomutinine C

AbstractSarpagine alkaloids are bioactive indole natural products that contain a highly rigid indole‐fused 1‐azabicyclo[2.2.2]octane, more than 100 members of which have been identified. Herein, a detailed examination of the intramolecular oxidative coupling between a ketone and a Weinreb amide for assembling the complex 1‐azabicyclo[2.2.2]octane core structure of sarpagine family alkaloids is described. Precise late‐stage manipulations of the ketone and Weinreb amide enable the divergent syntheses of (−)‐trinervine, (+)‐vellosimine, (+)‐normacusine B, and (−)‐alstomutinine C. Other notable transformations of the synthesis featured an aza‐Achmatowicz/indole cyclization cascade to generate the azabicyclo[3.3.1]nonane structure, a regioselective elimination reaction to form the ethylidene motif embedded in the (+)‐vellosimine and (+)‐normacusine B structures, and a diastereoselective indole oxidative rearrangement to form the spirooxindole structure in (−)‐alstomutinine C.

Covalent Template-Directed Synthesis of a Spoked 18-Porphyrin Nanoring.

Rings of porphyrins mimic natural light-harvesting chlorophyll arrays and offer insights into electronic delocalization, providing a motivation for creating larger nanorings with closely spaced porphyrin units. Here, we demonstrate the first synthesis of a macrocycle consisting entirely of 5,15-linked porphyrins. This porphyrin octadecamer was constructed using a covalent six-armed template, made by cobalt-catalyzed cyclotrimerization of an H-shaped tolan with porphyrin trimer ends. The porphyrins around the circumference of the nanoring were linked together by intramolecular oxidative meso-meso coupling and partial β-β fusion, to give a nanoring consisting of six edge-fused zinc(II) porphyrin dimer units and six un-fused nickel(II) porphyrins. STM imaging on a gold surface confirms the size and shape of the spoked 18-porphyrin nanoring (calculated diameter: 4.7 nm).

Guanidinium Hypoiodite-Catalyzed Intramolecular Oxidative Coupling Reaction of Oxindoles with β-Dicarbonyls.

Spiro[indoline-3,4'-piperidine] is a fundamental motif present in various biologically active compounds. Here, we report an intramolecular oxidative coupling reaction of oxindoles with β-dicarbonyls in the presence of a guanidinium hypoiodite catalyst, providing spiro-coupling products in moderate to excellent yields. Furthermore, a chiral hypoiodite catalyst derived from the chiral guanidinium organocatalyst is effective for the challenging asymmetric carbon-carbon bond-forming reaction, affording optically active spiro[indoline-3,4'-piperidines].

(±)-Polysiphenol and Other Analogues via Symmetrical Intermolecular Dimerizations: A Synthetic, Spectroscopic, Structural, and Computational Study.

We report an improved total synthesis of 4,5-dibromo-9,10-dihydrophenanthrene-2,3,6,7-tetraol, (±)-polysiphenol, via intermolecular McMurray dimerization of 5-bromovanillin and subsequent intramolecular oxidative coupling as the key steps. The synthetic route is applicable to 4,5-dichloro- and 4,5-difluoro-halologues (as well as a 4,5-dialkyl-analogue). Distinctive AA'BB' multiplets in their 1H NMR spectra for the dimethylene bridges of the dibromo and dichloro compounds reveal them to be room-temperature stable atropisomers, while for the difluoro compound they present as a singlet. X-ray crystal structure determinations of their tetramethylated synthetic precursors show atropisomeric twist angles of 48°, 46°, and 32°, respectively, with the former representing the largest yet observed in any 4,5-disubstituted-9,10-dihydrophenanthrene. DFT computational studies reveal an unprecedented two-stage atropisomeric interconversion process involving time-independent asynchronous rotations of the dimethylene bridge and the biaryl axis for halologues containing chlorine or bromine, but a more synchronous rotation for the difluoro analogue.

A Symmetrically π-Expanded Carbazole Incorporating Fluoranthene Moieties.

A novel doubly cyclopentannulated carbazole which is accessible through a successive π-expansion of di(1-naphthylamine) is disclosed. The carbazole moiety is generated in the final step through intramolecular oxidative coupling. The π-expansion of carbazole resulted in strongly altered optoelectronic and electrochemical properties. The solid-state structure features an interesting packing motif with alternating face-to-face π⋅⋅⋅π and edge-to-face C-H⋅⋅⋅π interactions. The experimental findings were corroborated by theoretical calculations.

Palladium-catalyzed Synthesis of Fused Carbo- and Heterocycles.

The use of palladium catalysts in fused ring synthesis has been increasingly noteworthy in recent years in organic synthesis. It has a lot of potential compared to other transition metal catalysts, because of its one-of-a-kind feature that makes them more widely applicable in a variety of disciplines application. Palladium is important in a variety of Heck processes, including intramolecular, intermolecular, and reductive Heck reactions, which produce diverse carbocycles and heterocycles of biological importance. Under optimal reaction conditions, carbocyclization or heterocyclization occurs, resulting in the production of numerous structural building blocks of naturally occurring compounds. Beside intramolecular Heck-type reactions, cycloaddition, cycloalkylation, oxidative coupling, C-H functionalization, cross-coupling reactions, and carboamidation reactions have also been employed extensively to access fused carbo- and heterocycles of immense biological importance. This review article provides a well-summarized discussion (since 2001) on fused carbo- and heterocycle ring synthesis using palladium catalysts, overviewing their applications, and mechanistic insights.

Electrosynthesis of 2-Substituted Benzoxazoles via Intramolecular Shono-Type Oxidative Coupling of Glycine Derivatives.

Herein, an atom-economical and eco-friendly electrochemical oxidation/cyclization of glycine derivatives through intramolecular Shono-type oxidative coupling is disclosed, leading to a variety of 2-substituted benzoxazoles in 51-85% yields. This oxidative cyclization proceeded in transition metal- and oxidant-free conditions and generated H2 as only a byproduct. Additionally, gram-scale reactions and a broad substrate scope demonstrated the synthetic usefulness of this protocol.

(Digital Presentation) Evaluation on the Efficiency of Redox Reaction By Oxidation Potential Gap (ΔE ox)

Oxidative biaryl coupling of aryls with different electronic features generally fails. However, this has not been systematically studied via theoretical analysis, and thus, the crucial factor governing coupling efficiency remains unclear. Herein, we propose that the “oxidation potential gap (ΔE ox)” is a key parameter in evaluating the efficiency of an intramolecular oxidative coupling reaction, with ΔE ox defined as a difference in the oxidation potentials of the relevant aromatic rings. Our experimental and computational analyses revealed that the efficiency of an aromatic intramolecular coupling reaction correlates with the activation energy (ΔE‡ ) of C–C bond formation of the radical cation intermediates. Furthermore, ΔE‡ correlates with ΔE ox. Therefore, we demonstrate the tuning of ΔE ox by attaching cleavable extra electron-donating/withdrawing groups, enabling the rational synthesis of a phenanthridone skeleton using aromatic rings with an electronic gap. Figure 1

Oxidation Potential Gap (ΔEox): The Hidden Parameter in Redox Chemistry

AbstractOxidative biaryl coupling of aryls with different electronic features generally fails. However, this has not been systematically studied via theoretical analysis, and thus, the crucial factor governing coupling efficiency remains unclear. Herein, we propose that the “oxidation potential gap (ΔEox)” is a key parameter in predicting the efficiency of an intramolecular oxidative coupling reaction, with ΔEox defined as a difference in the oxidation potentials of the relevant aromatic rings. Our experimental and computational analyses revealed that the efficiency of an aromatic intramolecular coupling reaction correlates with the activation energy (ΔE≠) of C−C bond formation of the radical cation intermediates. Furthermore, ΔE≠ correlates with ΔEox. Therefore, we demonstrate the tuning of ΔEox by attaching cleavable extra electron‐donating/‐withdrawing groups, enabling the rational synthesis of a phenanthridone skeleton using aromatic rings with an electronic gap.

Oxidation Potential Gap (ΔEox ): The Hidden Parameter in Redox Chemistry.

Oxidative biaryl coupling of aryls with different electronic features generally fails. However, this has not been systematically studied via theoretical analysis, and thus, the crucial factor governing coupling efficiency remains unclear. Herein, we propose that the "oxidation potential gap (ΔEox )" is a key parameter in predicting the efficiency of an intramolecular oxidative coupling reaction, with ΔEox defined as a difference in the oxidation potentials of the relevant aromatic rings. Our experimental and computational analyses revealed that the efficiency of an aromatic intramolecular coupling reaction correlates with the activation energy (ΔE≠ ) of C-C bond formation of the radical cation intermediates. Furthermore, ΔE≠ correlates with ΔEox . Therefore, we demonstrate the tuning of ΔEox by attaching cleavable extra electron-donating/-withdrawing groups, enabling the rational synthesis of a phenanthridone skeleton using aromatic rings with an electronic gap.

Xanthone Biosynthetic Pathway in Plants: A Review.

Xanthones are secondary metabolites rich in structural diversity and possess a broad array of pharmacological properties, such as antitumor, antidiabetic, and anti-microbes. These aromatic compounds are found in higher plants, such as Clusiaceae, Hypericaceae, and Gentianaceae, yet their biosynthetic pathways have not been comprehensively updated especially within the last decade (up to 2021). In this review, plant xanthone biosynthesis is detailed to illuminate their intricacies and differences between species. The pathway initially involves the shikimate pathway, either through L-phenylalanine-dependent or -independent pathway, that later forms an intermediate benzophenone, 2,3′,4,6-tetrahydoxybenzophenone. This is followed by a regioselective intramolecular mediated oxidative coupling to form xanthone ring compounds, 1,3,5-trihydroxyxanthone (1,3,5-THX) or 1,3,7-THX, the core precursors for xanthones in most plants. Recent evidence has shed some lights onto the enzymes and reactions involved in this xanthone pathway. In particular, several biosynthetic enzymes have been characterized at both biochemical and molecular levels from various organisms including Hypericum spp., Centaurium erythraea and Garcinia mangostana. Proposed pathways for a plethora of other downstream xanthone derivatives including swertianolin and gambogic acid (derived from 1,3,5-THX) as well as gentisin, hyperixanthone A, α-mangostin, and mangiferin (derived from 1,3,7-THX) have also been thoroughly covered. This review reports one of the most complete xanthone pathways in plants. In the future, the information collected here will be a valuable resource for a more directed molecular works in xanthone-producing plants as well as in synthetic biology application.

Forging C–C Bonds through Intramolecular Oxidative Coupling of Organoborates – An Overview

AbstractC–C bond formation has challenged the community of synthetic organic chemists for decades. Organoboron derivatives represent a mild and functional-group-tolerant class of reagents that can be handled without the need for inert conditions, making them suitable scaffolds for the development of methods that increase the sustainability of current processes for coupling reactions. This short review summarizes the different approaches that have been developed to enable C–C bond formation through intramolecular rearrangements of organoborate species.1 Introduction2 Oxidative Coupling with Chemical Oxidants3 Electrocoupling of Tetraorganoborates4 Photocoupling of Tetraorganoborates

Synthesis of 1,3-Dioxepine-Fused (Tricyclic) Bispyrazoles Involved with Pyrazolone Derivatives and Dichloromethane.

A simple and novel method for the synthesis of novel 1,3-dioxepine-fused (tricyclic) bispyrazoles is described. It involves a Cs2CO3-mediated O-alkylation of readily available pyrazolone derivatives with dichloromethane as the methylene source followed by PhI(OAc)2-mediated intramolecular oxidative biheteroaryl coupling under mild conditions. This scalable protocol was applied for the preparation of valuable and novel 1,3-dioxepine-fused (tricyclic) bispyrazoles that could find applications in medicinal or material chemistry.

Synthesis of Novel Heteronanographenes via Fold-in Approach

Abstract The design of the precursor for intramolecular oxidative coupling is a key to construct novel polycyclic compounds. Fold-in type oxidative fusion reactions of heteroaromatic necklace-like molecules have been proved to be a powerful method to afford heteroatom-embedded circulenes and helicenes. The scope and limitation of this unique transformation as well as the intriguing properties of the particular products have been summarized.

Microwave-Assisted Synthesis of 2-Methyl-1H-indole-3-carboxylate Derivatives via Pd-Catalyzed Heterocyclization

Indole moiety is well-known as a superlative framework in many natural products and synthetic pharmaceuticals. Herein, we report an efficient procedure to synthesize a series of functionalized 2-methyl-1H-indole-3-carboxylate derivatives from commercially available anilines properly functionalized by different electron-withdrawing and -donating groups through a palladium-catalyzed intramolecular oxidative coupling. The conversion of a variety of enamines into the relevant indole was optimized by exposing the neat mixture of reactants to microwave irradiation, obtaining the desired products in excellent yields and high regioselectivity. The synthesized compounds were confirmed by 1H and 13C spectroscopic means as well as by high-resolution mass spectrometry.

Chiral binaphthylamine based emitters with donor-acceptor structures: Facile synthesis and circularly polarized luminescence

Materials capable of circularly polarized luminescence (CPL) have generated intensive interest for their potential applications. However, constructing chiral molecules with tunable CPL signals remains a challenge. In this paper, two pairs of binaphthylamine based chiral donors R/S-2 and R/S-3 were synthesized by Pd-catalyzed C–N coupling and intramolecular oxidative coupling with good yields. Then three pairs of chiral D-A type molecules R/S-4∼6 can be synthesized by introducing two kinds of achiral acceptors. The extention of the chiral binaphthy skeleton endows these chiral compounds with CPL signals ranged from 417 nm to 544 nm in solutions and film states. The glum can be up to −2.9 × 10−3 for R-2 in solution. The introduction of terephthalonitrile as acceptor endow R/S-4 thermally activated delayed fluorescence (TADF). Furthermore, when benzophenone is chosen as achiral acceptor, the obtained chiral D-A molecules R/S-5 and R/S-6 can exhibit reversed CPL signals compared with their corresponding chiral donors. This work demonstrates the introduction of chiral D-A structure not only alters the wavelength of the CPL signals but also can reverse the CPL sign.

Bis(2-methoxyethyl)ether promoted intramolecular acceptorless dehydrogenative coupling to construct structurally diverse quinazolinones by molecular oxygen

A simple, efficient and clean intramolecular oxidative dehydrogenative coupling for the synthesis of dihydroisoquinolino[2,1-a]quinazolinones, 2-aryl quinazolinones, and analogues promoted by bis(2-methoxyethyl)ether/O2 has been achieved.

Intramolecular Oxidative Diaryl Coupling of Tetrasubstituted Diphenylamines for the Preparation of Bis(trifluoromethyl) Dimethyl Carbazoles

AbstractSynthetic preparation of carbazoles can be challenging, requiring ring-building strategies and/or precious metal catalysts. Presented herein is a method for the preparation of carbazoles with the use of inexpensive and reliable hypervalent iodine chemistry. An oxidative single-electron-transfer (SET) event initiates cyclization for the preparation of our trifluoromethyl carbazoles. This method has been shown to be useful for a variety of bis(trifluoromethyl)carbazole isomers that are of primary interest for use as battery materials.